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ReviewStroke and Bleeding Risk Assessments in Patients with Atrial Fibrillation: Concepts and ControversiesWern Yew Ding1, MRCP Stephanie Harrison1, PhDDhiraj Gupta1, MDGregory Y. H. Lip1,2, MD*Deirdre A. Lane1,2, PhD*1Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom; 2Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark [*joint senior authors]Corresponding Author:Prof Gregory Y H Lip gregory.lip@liverpool.ac.uk Full mailing addressUniversity of LiverpoolWilliam Henry Duncan Building6 West Derby StreetLiverpool, L7 8TXTelephone number0151 794 9020Word count7,243Key wordsStroke; bleeding; risk factors; risk assessment; atrial fibrillationAbstractRisk assessments are an important element in the management of patients with atrial fibrillation (AF). In this review, we aim to discuss the concepts and controversies surrounding the various risk factors for stroke and bleeding in AF. Indeed, there are a variety of clinical, electrical, biological and genetic markers to guide stroke and bleeding risk assessments in AF. The more common factors have been used to formulate risk stratification scores. Some risk factors have shown promise, but others remain less well-defined. Our aim is to discuss concepts and controversies surrounding current evidence of risk factors for stroke and bleeding assessments in AF.IntroductionRisk assessments are an important element in clinical practice. Therefore, it is crucial to understand the evidence supporting the individual risk factors to help guide management of patients with complex conditions such as atrial fibrillation (AF). Atrial fibrillation is the most common sustained cardiac arrhythmia. In 2010, the estimated global prevalence of AF was 33.5 million with approximately 5 million new cases identified ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.113.005119","ISSN":"00097322","PMID":"24345399","abstract":"BACKGROUND- : The global burden of atrial fibrillation (AF) is unknown. METHODS AND RESULTS- : We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5-22.2 million] and 12.6 million women [95% UI, 12.0-13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8-19.3) in men and 18.9% (95% UI, 15.8-23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8-612.7) and 359.9 in women (95% UI, 334.7-392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2-78.5) and 43.8 in women (95% UI, 35.9-55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4-636.7) in men and 373.1 (95% UI, 347.9-402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2-95.4) in men and 59.5 (95% UI, 49.9-74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0-2.2) and 1.9-fold (95% UI, 1.8-2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. CONCLUSIONS- : These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies. ? 2013 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Chugh","given":"Sumeet S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Havmoeller","given":"Rasmus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Narayanan","given":"Kumar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singh","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rienstra","given":"Michiel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benjamin","given":"Emelia J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gillum","given":"Richard F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Young-Hoon Hoon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McAnulty","given":"John H. Jr","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zheng","given":"Zhi-Jie Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forouzanfar","given":"Mohammad H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Naghavi","given":"Mohsen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mensah","given":"George A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezzati","given":"Majid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"Christopher J.L. L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2014","2"]]},"language":"eng","page":"837-847","publisher-place":"United States","title":"Worldwide epidemiology of atrial fibrillation: A global burden of disease 2010 study","type":"article-journal","volume":"129"},"uris":[""]}],"mendeley":{"formattedCitation":"(1)","plainTextFormattedCitation":"(1)","previouslyFormattedCitation":"(1)"},"properties":{"noteIndex":0},"schema":""}(1). The condition is associated with a greater risk of stroke and heart failure, reduced quality of life, and a 2-fold increased mortality ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.113.005119","ISSN":"00097322","PMID":"24345399","abstract":"BACKGROUND- : The global burden of atrial fibrillation (AF) is unknown. METHODS AND RESULTS- : We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5-22.2 million] and 12.6 million women [95% UI, 12.0-13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8-19.3) in men and 18.9% (95% UI, 15.8-23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8-612.7) and 359.9 in women (95% UI, 334.7-392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2-78.5) and 43.8 in women (95% UI, 35.9-55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4-636.7) in men and 373.1 (95% UI, 347.9-402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2-95.4) in men and 59.5 (95% UI, 49.9-74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0-2.2) and 1.9-fold (95% UI, 1.8-2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. CONCLUSIONS- : These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies. ? 2013 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Chugh","given":"Sumeet S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Havmoeller","given":"Rasmus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Narayanan","given":"Kumar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singh","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rienstra","given":"Michiel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benjamin","given":"Emelia J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gillum","given":"Richard F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Young-Hoon Hoon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McAnulty","given":"John H. Jr","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zheng","given":"Zhi-Jie Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forouzanfar","given":"Mohammad H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Naghavi","given":"Mohsen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mensah","given":"George A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezzati","given":"Majid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"Christopher J.L. L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2014","2"]]},"language":"eng","page":"837-847","publisher-place":"United States","title":"Worldwide epidemiology of atrial fibrillation: A global burden of disease 2010 study","type":"article-journal","volume":"129"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1161/01.CIR.98.10.946","ISSN":"0009-7322 (Print)","PMID":"9737513","abstract":"BACKGROUND: Atrial fibrillation (AF) causes substantial morbidity. It is uncertain whether AF is associated with excess mortality independent of associated cardiac conditions and risk factors. METHODS AND RESULTS: We examined the mortality of subjects 55 to 94 years of age who developed AF during 40 years of follow-up of the original Framingham Heart Study cohort. Of the original 5209 subjects, 296 men and 325 women (mean ages, 74 and 76 years, respectively) developed AF and met eligibility criteria. By pooled logistic regression, after adjustment for age, hypertension, smoking, diabetes, left ventricular hypertrophy, myocardial infarction, congestive heart failure, valvular heart disease, and stroke or transient ischemic attack, AF was associated with an OR for death of 1.5 (95% CI, 1.2 to 1.8) in men and 1.9 (95% CI, 1.5 to 2.2) in women. The risk of mortality conferred by AF did not significantly vary by age. However, there was a significant AF-sex interaction: AF diminished the female advantage in survival. In secondary multivariate analyses, in subjects free of valvular heart disease and preexisting cardiovascular disease, AF remained significantly associated with excess mortality, with about a doubling of mortality in both sexes. CONCLUSIONS: In subjects from the original cohort of the Framingham Heart Study, AF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for the preexisting cardiovascular conditions with which AF was related. The decreased survival seen with AF was present in men and women and across a wide range of ages.","author":[{"dropping-particle":"","family":"Benjamin","given":"Emelia J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolf","given":"Philip A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Agostino","given":"Ralph B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silbershatz","given":"Halit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kannel","given":"William B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levy","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-2","issue":"10","issued":{"date-parts":[["1998","9"]]},"language":"eng","page":"946-952","publisher-place":"United States","title":"Impact of atrial fibrillation on the risk of death: The Framingham Heart Study","type":"article-journal","volume":"98"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/S0002-9343(02)01236-6","ISSN":"00029343","PMID":"12401529","abstract":"PURPOSE: To describe the effect of atrial fibrillation on long-term morbidity and mortality. SUBJECTS AND METHODS: The Renfrew/Paisley Study surveyed 7052 men and 8354 women aged 45-64 years between 1972 and 1976. All hospitalizations and deaths occurring during the subsequent 20 years were analyzed by the presence or absence of atrial fibrillation at baseline. Lone atrial fibrillation was defined in the absence of other cardiovascular signs or symptoms. Cox proportional hazards models were used to adjust for age and cardiovascular conditions. RESULTS: After 20 years, 42 (89%) of the 47 women with atrial fibrillation had a cardiovascular event (death or hospitalization), compared with 2276 (27%) of the 8307 women without this arrhythmia. Among men, 35 (66%) of 53 with atrial fibrillation had an event, compared with 3151 (45%) of 6999 without atrial fibrillation. In women, atrial fibrillation was an independent predictor of cardiovascular events (rate ratio [RR] = 3.0; 95% confidence interval [CI]: 2.1-4.2), fatal or nonfatal strokes (RR = 3.2; 95% CI: 1.0-5.0), and heart failure (RR = 3.4; 95% CI: 1.9-6.2). The rate ratios among men were 1.8 (95% CI: 1.3-2.5) for cardiovascular events, 2.5 (95% CI: 1.3-4.8) for strokes, and 3.4 (95% CI: 1.7-6.8) for heart failure. Atrial fibrillation was an independent predictor of all-cause mortality in women (RR = 2.2; 95% CI: 1.5-3.2) and men (RR = 1.5; 95% CI: 1.2-2.2). However, lone atrial fibrillation (which occurred in 15 subjects) was not associated with a statistically significant increase in either cardiovascular events (RR = 1.5; 95% CI: 0.6-3.6) or mortality (RR = 1.8; 95% CI: 0.9-3.8). CONCLUSION: Atrial fibrillation is associated with an increased long-term risk of stroke, heart failure, and all-cause mortality, especially in women. ? 2002 by Excerpta Medica, Inc.","author":[{"dropping-particle":"","family":"Stewart","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"Carole L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hole","given":"David J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"McMurray","given":"John J.V.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Medicine","id":"ITEM-3","issue":"5","issued":{"date-parts":[["2002","10"]]},"language":"eng","page":"359-364","publisher-place":"United States, United States","title":"A population-based study of the long-term risks associated with atrial fibrillation: 20-Year follow-up of the Renfrew/Paisley study","type":"article-journal","volume":"113"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1016/j.amjmed.2005.10.057","ISSN":"1555-7162 (Electronic)","PMID":"16651058","abstract":"The impact of atrial fibrillation (AF) on patients' quality of life (QoL) has yet to be fully elucidated in a systematic manner. This article examines QoL in \"general\" patients with AF as well as the effects that rate and/or rhythm-control interventions have on QoL. Patients with AF have significantly poorer QoL compared with healthy controls, the general population, and other patients with coronary heart disease. Studies examining rate or rhythm-control strategies alone demonstrate improved QoL after intervention. Three of the four large randomized control trials (STAF, PIAF, RACE) comparing rate versus rhythm control demonstrated a greater improvement in QoL in patients receiving rate control. However, the AFFIRM trial revealed a similar improvement in QoL for both rate and rhythm-control groups. The data, although frequently compromised by various methodologic weaknesses, suggest that patients with AF have impaired QoL, and that QoL can be significantly improved through rate or rhythm-control strategies.","author":[{"dropping-particle":"","family":"Thrall","given":"Graham","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carroll","given":"Douglas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American journal of medicine","id":"ITEM-4","issue":"5","issued":{"date-parts":[["2006","5"]]},"language":"eng","page":"448.e1-19","publisher-place":"United States, United States","title":"Quality of life in patients with atrial fibrillation: a systematic review.","type":"article-journal","volume":"119"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1016/j.jacc.2015.06.1314","ISSN":"15583597","PMID":"26314526","abstract":"Background Important improvements have been made in treatment of diseases associated with atrial fibrillation (AF), such as hypertension, myocardial infarction, and heart failure. Incidence rates and risk factors may have changed with the aging of the population and changing lifestyles. Currently, the risk for AF is only partially explained, possibly because of differences between older cohorts and contemporary populations. Objectives This study investigated the incidence of AF in a contemporary cohort in the Netherlands, together with comorbidities associated with AF and associations of AF with cardiovascular outcomes. Methods Incident AF was ascertained for hospital and study electrocardiograms in 8,265 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study in Groningen, the Netherlands. Results During 9.7 ± 2.3 years of follow-up, 265 participants developed AF, with a resulting overall AF incidence of 3.3 per 1,000 person-years. Advancing age, male sex, antihypertensive drug use, higher body mass index, previous myocardial infarction, and previous stroke were associated with AF. After multivariable adjustment, AF was associated with cardiovascular events (hazard ratio [HR]: 2.24; 95% confidence interval [CI]: 1.06 to 4.75; p = 0.035), heart failure with either reduced or preserved ejection fraction (HR: 4.52; 95% CI: 2.02 to 10.09; p < 0.001), and all-cause mortality (HR: 3.02; 95% CI: 1.73 to 5.27; p < 0.001). Conclusions The incidence of AF in the present cohort was comparable to that shown in data of older studies. Obesity has become a major risk factor for incident AF. Although overall cardiovascular event rates were lower in the present study, the present study confirms the association of incident AF with such events.","author":[{"dropping-particle":"","family":"Vermond","given":"Rob A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geelhoed","given":"Bastiaan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verweij","given":"Niek","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tieleman","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harst","given":"Pim","non-dropping-particle":"Van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hillege","given":"Hans L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilst","given":"Wiek H.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gelder","given":"Isabelle C.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rienstra","given":"Michiel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-5","issue":"9","issued":{"date-parts":[["2015","9"]]},"language":"eng","page":"1000-1007","publisher-place":"United States, United States","title":"Incidence of Atrial Fibrillation and Relationship With Cardiovascular Events, Heart Failure, and Mortality A Community-Based Study From the Netherlands","type":"article-journal","volume":"66"},"uris":[""]}],"mendeley":{"formattedCitation":"(1–5)","plainTextFormattedCitation":"(1–5)","previouslyFormattedCitation":"(1–5)"},"properties":{"noteIndex":0},"schema":""}(1–5). In addition, it poses a significant healthcare economic burden. Conservative estimates in the United Kingdom found that AF was associated with a direct annual cost of ?459 million, based on an estimated 0.5 million affected patients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/hrt.2002.008748","ISSN":"1468-201X (Electronic)","PMID":"14966048","abstract":"OBJECTIVE: To evaluate the cost of atrial fibrillation (AF) to health and social services in the UK in 1995 and, based on epidemiological trends, to project this estimate to 2000. DESIGN, SETTING, AND MAIN OUTCOME MEASURES: Contemporary estimates of health care activity related to AF were applied to the whole population of the UK on an age and sex specific basis for the year 1995. The activities considered (and costs calculated) were hospital admissions, outpatient consultations, general practice consultations, and drug treatment (including the cost of monitoring anticoagulant treatment). By adjusting for the progressive aging of the British population and related increases in hospital admissions, the cost of AF was also projected to the year 2000. RESULTS: There were 534 000 people with AF in the UK during 1995. The \"direct\" cost of health care for these patients was 244 million pounds sterling (approximately 350 million euros) or 0.62% of total National Health Service (NHS) expenditure. Hospitalisations and drug prescriptions accounted for 50% and 20% of this expenditure, respectively. Long term nursing home care after hospital admission cost an additional 46.4 million pounds sterling (approximately 66 million euros). The direct cost of AF rose to 459 million pounds sterling (approximately 655 million euros) in 2000, equivalent to 0.97% of total NHS expenditure based on 1995 figures. Nursing home costs rose to 111 million pounds sterling (approximately 160 million euros). CONCLUSIONS: AF is an extremely costly public health problem.","author":[{"dropping-particle":"","family":"Stewart","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murphy","given":"N. F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGuire","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"McMurray","given":"J. J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart (British Cardiac Society)","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2004","3"]]},"language":"eng","page":"286-292","publisher-place":"England, England","title":"Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK.","type":"article-journal","volume":"90"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"(6)"},"properties":{"noteIndex":0},"schema":""}(6). However, as AF has detrimental effects on many other comorbidities, the total cost of AF is expected to be significantly higher. A study in the United States on AF-related cost estimates this to be as high as $26 billion per year ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCOUTCOMES.110.958165","ISSN":"1941-7705 (Electronic)","PMID":"21540439","abstract":"BACKGROUND: Detailed information on the cost burden of atrial fibrillation (AF) is limited. To provide an up-to-date estimate of the national cost of AF, we conducted a retrospective, observational cohort study using administrative claims from the MarketScan Commercial and Medicare Supplemental research data bases, 2004 to 2006. METHODS AND RESULTS: Patients aged >/=20 years with >/=1 inpatient or >/=2 outpatient AF diagnoses in 2005 (first diagnosis=index) and >/=12 months' enrollment before and after index were selected. AF patients were propensity score-matched (1:1) with non-AF control subjects. Medical costs (2008 US$), including AF costs, other cardiovascular, and noncardiovascular costs, were examined over 1 year after index. National incremental costs of AF were based on age-/sex-specific AF prevalence projections for 2010. In total, 89 066 AF patients were matched to non-AF control subjects. Over 1 year, 37.5% of AF versus 17.5% of control subjects were hospitalized and 2.1% versus 0.1% died during hospitalization. For AF versus control subjects, mean annual inpatient costs per patient were $7841 versus $2622 (incremental cost, $5218), outpatient medical costs were $9225 versus $5629 ($3596), and outpatient pharmacy costs were $3605 versus $3714 (-$109) (all P<0.001). The total incremental cost of AF was $8705 per patient. The national incremental cost of AF was $26.0 billion (AF, $6.0 billion; other cardiovascular, $9.9 billion; noncardiovascular, $10.1 billion). Cardiovascular costs were based on claims with a primary disease diagnosis and may be underestimates. CONCLUSIONS: On the basis of current US age- and sex-specific prevalence data, the national incremental AF cost is estimated to range from $6.0 to $26.0 billion.","author":[{"dropping-particle":"","family":"Kim","given":"Michael H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnston","given":"Stephen S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chu","given":"Bong-Chul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dalal","given":"Mehul R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schulman","given":"Kathy L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation. Cardiovascular quality and outcomes","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2011","5"]]},"language":"eng","page":"313-320","publisher-place":"United States, United States","title":"Estimation of total incremental health care costs in patients with atrial fibrillation in the United States.","type":"article-journal","volume":"4"},"uris":[""]}],"mendeley":{"formattedCitation":"(7)","plainTextFormattedCitation":"(7)","previouslyFormattedCitation":"(7)"},"properties":{"noteIndex":0},"schema":""}(7). Perhaps most worryingly, the incidence and prevalence of AF is increasing worldwide ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/hrt.2006.110791","ISSN":"1468-201X (Electronic)","PMID":"17435064","author":[{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kakar","given":"Puneet","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watson","given":"Timothy","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart (British Cardiac Society)","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2007","5"]]},"language":"eng","page":"542-543","publisher-place":"England, England","title":"Atrial fibrillation - the growing epidemic.","type":"article","volume":"93"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.11909/j.issn.1671-5411.2017.03.011","ISSN":"1671-5411 (Print)","PMID":"28592963","abstract":"Atrial fibrillation (AF) is the most common arrhythmia diagnosed in clinical practice. The consequences of AF have been clearly established in multiple large observational cohort studies and include increased stroke and systemic embolism rates if no oral anticoagulation is prescribed, with increased morbidity and mortality. With the worldwide aging of the population characterized by a large influx of \"baby boomers\" with or without risk factors for developing AF, an epidemic is forecasted within the next 10 to 20 years. Although not all studies support this evidence, it is clear that AF is on the rise and a significant amount of health resources are invested in detecting and managing AF. This review focuses on the worldwide burden of AF and reviews global health strategies focused on improving detection, prevention and risk stratification of AF, recently recommended by the World Heart Federation.","author":[{"dropping-particle":"","family":"Morillo","given":"Carlos A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Banerjee","given":"Amitava","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perel","given":"Pablo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wood","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jouven","given":"Xavier","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of geriatric cardiology : JGC","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2017","3"]]},"language":"eng","page":"195-203","publisher-place":"China, China","title":"Atrial fibrillation: the current epidemic.","type":"article-journal","volume":"14"},"uris":[""]}],"mendeley":{"formattedCitation":"(8,9)","plainTextFormattedCitation":"(8,9)","previouslyFormattedCitation":"(8,9)"},"properties":{"noteIndex":0},"schema":""}(8,9). Between 5.6 to 15.9 million people in the United States are projected to have AF by 2050 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.105.595140","ISSN":"1524-4539 (Electronic)","PMID":"16818816","abstract":"BACKGROUND: Limited data exist on trends in incidence of atrial fibrillation (AF). We assessed the community-based trends in AF incidence for 1980 to 2000 and provided prevalence projections to 2050. METHODS AND RESULTS: The adult residents of Olmsted County, Minnesota, who had ECG-confirmed first AF in the period 1980 to 2000 (n=4618) were identified. Trends in age-adjusted incidence were determined and used to construct model-based prevalence estimates. The age- and sex-adjusted incidence of AF per 1000 person-years was 3.04 (95% CI, 2.78 to 3.31) in 1980 and 3.68 (95% CI, 3.42 to 3.95) in 2000. According to Poisson regression with adjustment for age and sex, incidence of AF increased significantly (P=0.014), with a relative increase of 12.6% (95% CI, 2.1 to 23.1) over 21 years. The increase in age-adjusted AF incidence did not differ between men and women (P=0.84). According to the US population projections by the US Census Bureau, the number of persons with AF is projected to be 12.1 million by 2050, assuming no further increase in age-adjusted incidence of AF, but 15.9 million if the increase in incidence continues. CONCLUSIONS: The age-adjusted incidence of AF increased significantly in Olmsted County during 1980 to 2000. Whether or not this rate of increase continues, the projected number of persons with AF for the United States will exceed 10 million by 2050, underscoring the urgent need for primary prevention strategies against AF development.","author":[{"dropping-particle":"","family":"Miyasaka","given":"Yoko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barnes","given":"Marion E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gersh","given":"Bernard J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cha","given":"Stephen S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bailey","given":"Kent R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abhayaratna","given":"Walter P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seward","given":"James B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsang","given":"Teresa S M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2006","7"]]},"language":"eng","page":"119-125","publisher-place":"United States, United States","title":"Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.","type":"article-journal","volume":"114"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1001/jama.285.18.2370","ISSN":"0098-7484 (Print)","PMID":"11343485","abstract":"CONTEXT: Atrial fibrillation is the most common arrhythmia in elderly persons and a potent risk factor for stroke. However, recent prevalence and projected future numbers of persons with atrial fibrillation are not well described. OBJECTIVE: To estimate prevalence of atrial fibrillation and US national projections of the numbers of persons with atrial fibrillation through the year 2050. DESIGN, SETTING, AND PATIENTS: Cross-sectional study of adults aged 20 years or older who were enrolled in a large health maintenance organization in California and who had atrial fibrillation diagnosed between July 1, 1996, and December 31, 1997. MAIN OUTCOME MEASURES: Prevalence of atrial fibrillation in the study population of 1.89 million; projected number of persons in the United States with atrial fibrillation between 1995-2050. RESULTS: A total of 17 974 adults with diagnosed atrial fibrillation were identified during the study period; 45% were aged 75 years or older. The prevalence of atrial fibrillation was 0.95% (95% confidence interval, 0.94%-0.96%). Atrial fibrillation was more common in men than in women (1.1% vs 0.8%; P<.001). Prevalence increased from 0.1% among adults younger than 55 years to 9.0% in persons aged 80 years or older. Among persons aged 50 years or older, prevalence of atrial fibrillation was higher in whites than in blacks (2.2% vs 1.5%; P<.001). We estimate approximately 2.3 million US adults currently have atrial fibrillation. We project that this will increase to more than 5.6 million (lower bound, 5.0; upper bound, 6.3) by the year 2050, with more than 50% of affected individuals aged 80 years or older. CONCLUSIONS: Our study confirms that atrial fibrillation is common among older adults and provides a contemporary basis for estimates of prevalence in the United States. The number of patients with atrial fibrillation is likely to increase 2.5-fold during the next 50 years, reflecting the growing proportion of elderly individuals. Coordinated efforts are needed to face the increasing challenge of optimal stroke prevention and rhythm management in patients with atrial fibrillation.","author":[{"dropping-particle":"","family":"Go","given":"A S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"E M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phillips","given":"K A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henault","given":"L E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Selby","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"D E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA","id":"ITEM-2","issue":"18","issued":{"date-parts":[["2001","5"]]},"language":"eng","page":"2370-2375","publisher-place":"United States, United States","title":"Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.","type":"article-journal","volume":"285"},"uris":[""]}],"mendeley":{"formattedCitation":"(10,11)","plainTextFormattedCitation":"(10,11)","previouslyFormattedCitation":"(10,11)"},"properties":{"noteIndex":0},"schema":""}(10,11) and 17.9 million people in Europe by 2060 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/eht280","ISSN":"1522-9645 (Electronic)","PMID":"23900699","abstract":"AIMS: Since atrial fibrillation (AF) is associated with increased risks of cardiovascular and cerebrovascular complications, estimations on the number of individuals with AF are relevant to healthcare planning. We aimed to project the number of individuals with AF in the Netherlands and in the European Union from 2000 to 2060. METHODS AND RESULTS: Age- and sex-specific AF prevalence estimates were obtained from the prospective community-based Rotterdam Study. Population projections for the Netherlands and the European Union were obtained from the European Union's statistics office. In the age stratum of 55-59 years, the prevalence of AF was 1.3% in men (95% CI: 0.4-3.6%) and 1.7% in women (95% CI: 0.7-4.0%). The prevalence of AF increased to 24.2% in men (95% CI: 18.5-30.7%), and 16.1% in women (95% CI: 13.1-19.4%), for those >85 years of age. This age- and sex-specific prevalence remained stable during the years of follow-up. Furthermore, we estimate that in the European Union, 8.8 million adults over 55 years had AF in 2010 (95% CI: 6.5-12.3 million). We project that this number will double by 2060 to 17.9 million (95% CI: 13.6-23.7 million) if the age- and sex-specific prevalence remains stable. CONCLUSION: We estimate that from 2010 to 2060, the number of adults 55 years and over with AF in the European Union will more than double. As AF is associated with significant morbidities and mortality, this increasing number of individuals with AF may have major public health implications.","author":[{"dropping-particle":"","family":"Krijthe","given":"Bouwe P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunst","given":"Anton","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benjamin","given":"Emelia J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franco","given":"Oscar H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hofman","given":"Albert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Witteman","given":"Jacqueline C M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stricker","given":"Bruno H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heeringa","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"35","issued":{"date-parts":[["2013","9"]]},"language":"eng","page":"2746-2751","publisher-place":"England, England","title":"Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060.","type":"article-journal","volume":"34"},"uris":[""]}],"mendeley":{"formattedCitation":"(12)","plainTextFormattedCitation":"(12)","previouslyFormattedCitation":"(12)"},"properties":{"noteIndex":0},"schema":""}(12).Given the higher stroke risk associated with AF, an integrated approach in the management of patients with AF must include accurate stroke risk stratification. Patients who are not identified as ‘low risk’ should then be offered anticoagulation therapy to reduce their risk of stroke. However, the use of anticoagulation carries an increased risk of bleeding. Most bleeding events are multifactorial in nature and some may have devastating clinical consequences. Therefore, it is important to consider and treat any modifiable bleeding risk factors prior to commencing anticoagulation. Overall, stroke and bleeding risk assessments in AF are complex with ever emerging evidence. Therefore, it can be challenging for clinicians to stay up to date with the most recent literature and appreciate the interplay of the various factors involved. This article is not an exhaustive systematic review of the vast literature on this topic. Our aim is to discuss concepts and controversies surrounding current evidence of risk factors for stroke and bleeding assessments in AF.Stroke risk assessmentIn general, AF is associated with a five-fold increased risk of stroke ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1212/wnl.28.10.973","ISSN":"0028-3878 (Print)","PMID":"570666","abstract":"Chronic atrial fibrillation (AF) as a precursor of stroke was assessed over 24 years of follow-up of the general population sample at Framingham, Massachusetts. Persons with chronic established AF, with or without rheumatic heart disease (RHD), are at greatly increased risk of stroke, and the stroke is probably due to embolism. Chronic AF in the absence of RHD is associated with more than a fivefold increase in stroke indicence, while AF with RHD has a 17-fold increase. Stroke occurrence increased as duration of AF increased, with no evidence of a particularly vulnerable period. Chronic idiopathic AF is an important precursor of cerebral embolism. Controlled trials of anticoagulants or antiarrhythmic agents in persons with chronic AF may demonstrate if strokes can be prevented in this highly susceptible group.","author":[{"dropping-particle":"","family":"Wolf","given":"P A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dawber","given":"T R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomas","given":"H E Jr","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kannel","given":"W B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neurology","id":"ITEM-1","issue":"10","issued":{"date-parts":[["1978","10"]]},"language":"eng","page":"973-977","publisher-place":"United States, United States","title":"Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study.","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"(13)","plainTextFormattedCitation":"(13)","previouslyFormattedCitation":"(13)"},"properties":{"noteIndex":0},"schema":""}(13). Furthermore, stroke outcomes are more severe in the presence of AF, as determined by clinical or radiological assessment ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.str.16.2.182","ISSN":"0039-2499 (Print)","PMID":"3975954","abstract":"The association between non-rheumatic atrial fibrillation (AF) and stroke has been studied in 402 patients consecutively admitted to a stroke unit. Brain infarction patients with sinus rhythm (n = 196) and non-rheumatic AF (n = 92) were further compared. Some findings supported an embolic origin of the stroke: half of the deceased AF patients (n = 24) at autopsy either had left atrial thrombosis or arterial embolism compared to none of the ten with sinus rhythm. Patients with AF also had a higher mortality and more severe brain lesions, findings compatible with a sudden occlusion of blood flow. However, these differences might also be explained by an atherothrombotic occlusion with impaired autoregulation in the ischaemic region in conjunction with heart failure, which was more common in the AF patients. Other findings supporting an atherothrombotic mechanism were: the prevalence of AF was higher (19-29%) in all kinds of stroke, including haemorrhage, than in age-matched controls (3-9%). Also patients with previous AF and no present embolic source resembled the whole AF group and differed from patients with sinus rhythm. Thus embolism is a plausible cause of stroke in many AF patients, whereas an atherothrombotic origin is more likely in others. Characteristics identifying the mechanism in an individual case were not found.","author":[{"dropping-particle":"","family":"Britton","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gustafsson","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1985"]]},"language":"eng","page":"182-188","publisher-place":"United States, United States","title":"Non-rheumatic atrial fibrillation as a risk factor for stroke.","type":"article-journal","volume":"16"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1161/01.str.27.10.1760","ISSN":"0039-2499 (Print)","PMID":"8841325","abstract":"BACKGROUND AND PURPOSE: Stroke occurring with atrial fibrillation (AF) is more likely to be fatal or more severe than non-AF stroke based on clinical series, but data from prospective epidemiological studies are sparse and inconsistent. METHODS: Over 40-year follow-up of the original 5070 Framingham cohort, 501 initial ischemic strokes, including 103 with AF, were analyzed. Stroke severity was rated as none, mild, moderate, severe, or fatal. Since 1981, functional status indicated by the Barthel index has been evaluated acutely and at 3, 6, and 12 months. Severity and functional status of AF strokes were compared with non-AF strokes using chi 2 test and Student's t test. Thirty-day mortality was assessed by logistic regression analyses. RESULTS: AF was associated with increased stroke severity (P = .048). Thirty-day mortality was greater in AF strokes than in non-AF strokes (25% versus 14%). The multivariate-adjusted odds ratio for 30-day mortality for AF subjects was 1.84 (95% confidence interval, 1.04 to 3.27). Since 1981, follow-up was available for 150 initial ischemic strokes, including 30 with AF. Compared with the non-AF group, the AF group had poorer survival and more recurrences during 1 year of follow-up. The AF subjects had lower mean Barthel index scores acutely (29.6 versus 58.6, P < .001) and at 3 months (P = .005), 6 months (P = .003), and 12 months (P = .130) after stroke among survivors. CONCLUSIONS: Ischemic stroke associated with AF was nearly twice as likely to be fatal as non-AF stroke. Recurrence was more frequent, and functional deficits were more likely to be severe among survivors. Since stroke is usually the initial manifestation of embolism in AF, prevention is critical to reducing disability and mortality.","author":[{"dropping-particle":"","family":"Lin","given":"H J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolf","given":"P A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kelly-Hayes","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beiser","given":"A S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kase","given":"C S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benjamin","given":"E J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Agostino","given":"R B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-2","issue":"10","issued":{"date-parts":[["1996","10"]]},"language":"eng","page":"1760-1764","publisher-place":"United States, United States","title":"Stroke severity in atrial fibrillation. The Framingham Study.","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(14,15)","plainTextFormattedCitation":"(14,15)","previouslyFormattedCitation":"(14,15)"},"properties":{"noteIndex":0},"schema":""}(14,15). Various factors based on clinical, electrical, biological and genetic markers have been shown to predict stroke risk in AF ( REF _Ref23961041 \r \h \* MERGEFORMAT Table 1 REF _Ref20484734 \r \h \* MERGEFORMAT Table 1). Using a culmination of different risk factors, predominantly clinical, various authors have developed a total of at least 15 risk scores to assist stroke risk stratification in AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmjopen-2017-017157","ISSN":"2044-6055 (Electronic)","PMID":"29273652","abstract":"OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, …","author":[{"dropping-particle":"","family":"Fox","given":"Keith A A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lucas","given":"Joseph E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pieper","given":"Karen S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bassand","given":"Jean-Pierre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Camm","given":"A John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fitzmaurice","given":"David A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldhaber","given":"Samuel Z","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goto","given":"Shinya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haas","given":"Sylvia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hacke","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kayani","given":"Gloria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oto","given":"Ali","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mantovani","given":"Lorenzo G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Misselwitz","given":"Frank","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Piccini","given":"Jonathan P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turpie","given":"Alexander G G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verheugt","given":"Freek W A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kakkar","given":"Ajay K","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMJ open","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2017","12"]]},"language":"eng","page":"e017157","publisher-place":"England, England","title":"Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.","type":"article-journal","volume":"7"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1161/CIRCULATIONAHA.112.107128","ISSN":"00097322","PMID":"23212720","abstract":"BACKGROUND - : We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS - : In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R2CHADS2) improved net reclassification index by 6.2% compared with CHA2DS2VASc (C statistic=0.578) and by 8.2% compared with CHADS2 (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R2CHADS2 in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS2. CONCLUSIONS - : In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. ? 2013 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Piccini","given":"Jonathan P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stevens","given":"Susanna R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lokhnygina","given":"Yuliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Manesh R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahaffey","given":"Kenneth W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"Jonathan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Breithardt","given":"Günter Gunter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hankey","given":"Graeme J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hacke","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Becker","given":"Richard C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nessel","given":"Christopher C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fox","given":"Keith A.A. 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Thus, many potential risk factors have not been included. METHODS: We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF. RESULTS: Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003). CONCLUSIONS: Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. 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fibrillation.","type":"article-journal","volume":"137"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1161/STROKEAHA.107.501825","ISSN":"00392499","PMID":"18420954","abstract":"BACKGROUND AND PURPOSE: More than a dozen schemes for stratifying stroke risk in patients with nonvalvular atrial fibrillation have been published. Differences among these schemes lead to inconsistent stroke risk estimates for many atrial fibrillation patients, resulting in confusion among clinicians and nonuniform use of anticoagulation. METHODS: Twelve published schemes stratifying stroke risk in patients with nonvalvular atrial fibrillation are analyzed, and observed stroke rates in independent test cohorts are compared with predicted risk status. RESULTS: Seven schemes were based directly on event-rate analyses, whereas 5 resulted from expert consensus. Four considered only clinical features, whereas 7 schemes included echocardiographic variables. The number of variables per scheme ranged from 4 to 8 (median, 6). The most frequently included features were previous stroke/TIA (100% of schemes), patient age (83%), hypertension (83%), and diabetes (83%), and 8 additional variables were included in ?‰?1 schemes. Based on published test cohorts, all 8 tested schemes stratified stroke risk, but the absolute stroke rates varied widely. Observed rates for those categorized as low risk ranged from 0% to 2.3% per year and those categorized as high risk ranged from 2.5% to 7.9% per year. When applied to the same cohorts, the fractions of patients categorized by the different schemes as low risk varied from 9% to 49% and those categorized by the different schemes as high-risk varied from 11% to 77%. CONCLUSIONS: There are substantial, clinically relevant differences among published schemes designed to stratify stroke risk in patients with atrial fibrillation. Additional research to identify an optimum scheme for primary prevention and subsequent standardization of recommendations may lead to more uniform selection of patients for anticoagulant prophylaxsis. ? 2008 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Hart","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stroke Risk in Atrial Fibrillation Working Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-4","issue":"6","issued":{"date-parts":[["2008","6"]]},"language":"eng","page":"1901-1910","publisher-place":"United States, United States","title":"Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation","type":"article-journal","volume":"39"},"uris":[""]}],"mendeley":{"formattedCitation":"(16–19)","plainTextFormattedCitation":"(16–19)","previouslyFormattedCitation":"(16–19)"},"properties":{"noteIndex":0},"schema":""}(16–19). At present, the majority of clinical guidelines recommend the use of CHA2DS2-VASc score to aid decision on anticoagulation therapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehw210","ISSN":"1522-9645 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We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. METHODS: Systematic literature reviews were conducted to identify relevant articles published from the last formal search perfomed for the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). The overall quality of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Graded recommendations and ungraded consensus-based statements were drafted, voted on, and revised until consensus was reached. RESULTS: For patients with AF without valvular heart disease, including those with paroxysmal AF, who are at low risk of stroke (eg, CHA2DS2-VASc [congestive heart failure, hypertension, age >/= 75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65-74 and sex category (female)] score of 0 in males or 1 in females), we suggest no antithrombotic therapy. The next step is to consider stroke prevention (ie, oral anticoagulation therapy) for patients with 1 or more non-sex CHA2DS2-VASc stroke risk factors. For patients with a single non-sex CHA2DS2-VASc stroke risk factor, we suggest oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel; and for those at high risk of stroke (eg, CHA2DS2-VASc >/= 2 in males or >/= 3 in females), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest using a non-vitamin K antagonist oral anticoagulant drug rather than adjusted-dose vitamin K antagonist therapy. With the latter, it is important to aim for good quality anticoagulation control with a time in therapeutic range > 70%. Attention to modifiable bleeding risk factors (eg, uncontrolled BP, labile international normalized ratios, concomitant use of aspirin or nonsteroidal antiinflammatory drugs in an anticoagulated patient, alcohol excess) should be made at each patient contact, and HAS-BLED (hypertension, abnormal renal/liver function [1 point each], stroke, bleeding histor…","author":[{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Banerjee","given":"Amitava","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boriani","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chiang","given":"Chern En","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fargo","given":"Ramiz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freedman","given":"Ben","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruff","given":"Christian T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turakhia","given":"Mintu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Werring","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Sheena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moores","given":"Lisa","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-4","issue":"5","issued":{"date-parts":[["2018","11"]]},"language":"eng","page":"1121-1201","publisher-place":"United States","title":"Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report.","type":"article-journal","volume":"154"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1016/j.joa.2017.05.004","ISSN":"1880-4276 (Print)","PMID":"28765771","abstract":"Atrial fibrillation (AF) is the most common sustained arrhythmia, causing a 2-fold increase in mortality and a 5-fold increase in stroke. The Asian population is rapidly aging, and in 2050, the estimated population with AF will reach 72 million, of whom 2.9 million may suffer from AF-associated stroke. Therefore, stroke prevention in AF is an urgent issue in Asia. Many innovative advances in the management of AF-associated stroke have emerged recently, including new scoring systems for predicting stroke and bleeding risks, the development of non-vitamin K antagonist oral anticoagulants (NOACs), knowledge of their special benefits in Asians, and new techniques. The Asia Pacific Heart Rhythm Society (APHRS) aimed to update the available information, and appointed the Practice Guideline sub-committee to write a consensus statement regarding stroke prevention in AF. The Practice Guidelines sub-committee members comprehensively reviewed updated information on stroke prevention in AF, emphasizing data on NOACs from the Asia Pacific region, and summarized them in this 2017 Consensus of the Asia Pacific Heart Rhythm Society on Stroke Prevention in AF. This consensus includes details of the updated recommendations, along with their background and rationale, focusing on data from the Asia Pacific region. We hope this consensus can be a practical tool for cardiologists, neurologists, geriatricians, and general practitioners in this region. We fully realize that there are gaps, unaddressed questions, and many areas of uncertainty and debate in the current knowledge of AF, and the physicians decision remains the most important factor in the management of AF.","author":[{"dropping-particle":"","family":"Chiang","given":"Chern-En","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okumura","given":"Ken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Shu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chao","given":"Tze-Fan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siu","given":"Chung-Wah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wei Lim","given":"Toon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saxena","given":"Anil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takahashi","given":"Yoshihide","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siong Teo","given":"Wee","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of arrhythmia","id":"ITEM-5","issue":"4","issued":{"date-parts":[["2017","8"]]},"language":"eng","page":"345-367","publisher-place":"Japan","title":"2017 consensus of the Asia Pacific Heart Rhythm Society on stroke prevention in atrial fibrillation.","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"(20–24)","plainTextFormattedCitation":"(20–24)","previouslyFormattedCitation":"(20–24)"},"properties":{"noteIndex":0},"schema":""}(20–24). This tool was refined from the original 2006 Birmingham/’National Institute for Health and Care Excellence’ stroke risk schema with a specific focus on optimal identification of low-risk individuals and subsequently validated in several large AF cohorts ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1378/chest.09-1584","ISSN":"19313543","PMID":"19762550","abstract":"BACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism (TE) in patients with atrial fibrillation (AF) are largely derived from risk factors identified from trial cohorts. Thus, many potential risk factors have not been included. METHODS: We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF. RESULTS: Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003). CONCLUSIONS: Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. This schema could improve our approach to stroke risk stratification in patients with AF.","author":[{"dropping-particle":"","family":"Lip","given":"Gregory Y.H. 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Ivanovich","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Makienko","given":"Nataliya Volodimirovna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Potpara","given":"Tatjana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Knezevic","given":"Sofija","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Randjelovic","given":"Miomir","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2010","2"]]},"language":"eng","page":"263-272","publisher":"The American College of Chest Physicians","publisher-place":"United States","title":"Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.","type":"article-journal","volume":"137"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1093/eurheartj/ehr488","ISSN":"1522-9645 (Electronic)","PMID":"22246443","abstract":"AIMS: The impact of some risk factors for stroke and bleeding, and the value of stroke and bleeding risk scores, in atrial fibrillation (AF), has been debated, as clinical trial cohorts have not adequately tested these. Our objective was to investigate risk factors for stroke and bleeding in AF, and application of the new CHA(2)DS(2)-VASc and HAS-BLED schemes for stroke and bleeding risk assessments, respectively. METHODS AND RESULTS: We used the Swedish Atrial Fibrillation cohort study, a nationwide cohort study of 182 678 subjects with a diagnosis of AF at any Swedish hospital between 1 July 2005 and 31 December 2008, who were prospectively followed for an average of 1.5 years (260 000 years at risk). With the use of the National Swedish Drug Registry, all patients who used an oral anticoagulant anytime during follow-up were identified. Most of the analyses were made on a subset of 90 490 patients who never used anticoagulants. Risk factors for stroke, the composite thromboembolism endpoint (stroke, TIA, or systemic embolism), and bleeding, and the performance of published stroke and bleeding risk stratification schemes were investigated. On multivariable analysis, significant associations were found between the following 'new' risk factors and thromboembolic events; peripheral artery disease [hazard ratio (HR) 1.22 (95% CI 1.12-1.32)], 'vascular disease' [HR 1.14 (1.06-1.23)], prior myocardial infarction [HR 1.09 (1.03-1.15)], and female gender [HR 1.17 (1.11-1.22)]. Previous embolic events, intracranial haemorrhage (ICH), hypertension, diabetes, and renal failure were other independent predictors of the composite thromboembolism endpoint, while thyroid disease (or hyperthyroidism) was not an independent stroke risk factor. C-statistics for the composite thromboembolic endpoint with the CHADS(2) and CHA(2)DS(2)-VASc schemes were 0.66 (0.65-0.66) and 0.67 (0.67-0.68), respectively. On multivariable analysis, age, prior ischaemic stroke or thromboembolism, prior major bleeding events, and hypertension were significant predictors of ICH and major bleeding. Heart failure, diabetes, renal failure, liver disease, anaemia or platelet/coagulation defect, alcohol abuse, and cancer were other significant predictors for major bleeding, but not ICH. The ability for predicting ICH and major bleeding with both bleeding risk schemes (HEMORR(2)HAGES, HAS-BLED) were similar, with c-statistics of ~0.6. CONCLUSION: Several independent risk factors (prior ICH, myocardia…","author":[{"dropping-particle":"","family":"Friberg","given":"Leif","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenqvist","given":"Marten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-2","issue":"12","issued":{"date-parts":[["2012","6"]]},"language":"eng","page":"1500-1510","publisher-place":"England","title":"Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study.","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"(18,25)","plainTextFormattedCitation":"(18,25)","previouslyFormattedCitation":"(18,25)"},"properties":{"noteIndex":0},"schema":""}(18,25). In general, higher scores are associated with an increased annual risk of ischaemic stroke. Males with a score of 0 and females with a score of 1 are considered at ‘low-risk’ of stroke, with event rates <1% per year. Current recommendations support consideration of anticoagulation therapy in all other patients where there is sufficient stroke risk to justify the hazards of anticoagulation.Older studies have suggested that so-called ‘lone AF’, contributes to an annual stroke risk of 1% ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0003-9926 (Print)","PMID":"8018000","abstract":"BACKGROUND AND METHODS: Atrial fibrillation is associated with an increased risk of ischemic stroke. Data on individual patients were pooled from five recently completed randomized trials comparing warfarin (all studies) or aspirin (the Atrial Fibrillation, Aspirin, Anticoagulation Study and the Stroke Prevention in Atrial Fibrillation Study) with control in patients with atrial fibrillation. The purpose of the analysis was to (1) identify patient features predictive of a high or low risk of stroke, (2) assess the efficacy of antithrombotic therapy in major patient subgroups (eg, women), and (3) obtain the most precise estimate of the efficacy and risks of antithrombotic therapy in atrial fibrillation. For the warfarin-control comparison there were 1889 patient-years receiving warfarin and 1802 in the control group. For the aspirin-placebo comparison there were 1132 patient-years receiving aspirin and 1133 receiving placebo. The daily dose of aspirin was 75 mg in the Atrial Fibrillation, Aspirin, Anticoagulation Study and 325 mg in the Stroke Prevention in Atrial Fibrillation Study. To monitor warfarin dosage, three studies used prothrombin time ratios and two used international normalized ratios. The lowest target intensity was a prothrombin time ratio of 1.2 to 1.5 and the highest target intensity was an international normalized ratio of 2.8 to 4.2. The primary end points were ischemic stroke and major hemorrhage, as assessed by each study. RESULTS: At the time of randomization the mean age was 69 years and the mean blood pressure was 142/82 mm Hg. Forty-six percent of the patients had a history of hypertension, 6% had a previous transient ischemic attack or stroke, and 14% had diabetes. Risk factors that predicted stroke on multivariate analyses in control patients were increasing age, history of hypertension, previous transient ischemic attack or stroke, and diabetes. Patients younger than 65 years who had none of the other predictive factors (15% of all patients) had an annual rate of stroke of 1.0%, 95% confidence interval (CI) 0.3% to 3.0%. The annual rate of stroke was 4.5% for the control group and 1.4% for the warfarin group (risk reduction, 68%; 95% CI, 50% to 79%). The efficacy of warfarin was consistent across all studies and subgroups of patients. In women, warfarin decreased the risk of stroke by 84% (95% CI, 55% to 95%) compared with 60% (95% CI, 35% to 76%) in men. The efficacy of aspirin was not as consistent. The risk reduction with …","container-title":"Archives of internal medicine","id":"ITEM-1","issue":"13","issued":{"date-parts":[["1994","7"]]},"language":"eng","page":"1449-1457","publisher-place":"United States, United States","title":"Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.","type":"article-journal","volume":"154"},"uris":[""]}],"mendeley":{"formattedCitation":"(26)","plainTextFormattedCitation":"(26)","previouslyFormattedCitation":"(26)"},"properties":{"noteIndex":0},"schema":""}(26). However, more contemporary studies have found that stroke rate in such low-risk patients is <1% per year, as defined by age <65 years and the absence of any established stroke risk factors ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2015.01.044","ISSN":"1558-3597 (Electronic)","PMID":"25770314","abstract":"BACKGROUND: Even a single additional stroke risk factor in patients with atrial fibrillation may confer a risk of stroke. However, there is no consensus on how best to treat these patients. OBJECTIVES: Our objective was to investigate the risk of stroke and bleeding and the impact of antithrombotic therapy among low-risk patients, i.e., with 0 or 1 CHA2DS2-VASc (congestive heart failure, hypertension, age >/=75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score risk factor. METHODS: The nationwide cohort for this study was established by linking data from the Danish Civil Registration System, the Danish National Patient Register, and the Danish National Prescription Registry. We studied 39,400 patients discharged with incident nonvalvular atrial fibrillation with 0 or 1 CHA2DS2-VASc risk factor; 23,572 were not treated, 5,353 were initiated on aspirin, and 10,475 were initiated on warfarin. RESULTS: Stroke event rates for untreated low-risk patients (CHA2DS2-VASc = 0 [male], 1 [female]) were 0.49 per 100 person-years at 1 year and 0.47 per 100 person-years at full follow-up (intention-to-treat). Bleeding event rates among untreated low-risk patients were 1.08 per 100 person-years at 1 year and 0.97 at full follow-up. The presence of 1 additional stroke risk factor (CHA2DS2-VASc = 1 [male], = 2 [female]) among untreated patients increased the stroke rate at 1 year to 1.55 per 100 person-years, representing a significant 3.01-fold increase. At the 1-year follow-up, bleeding increased 2.35-fold, and death increased 3.12-fold. CONCLUSIONS: Low-risk patients (CHA2DS2-VASc = 0 [male], 1 [female]) have a truly low risk for stroke and bleeding. With 1 additional stroke risk factor (CHA2DS2-VASc = 1 [male], = 2 [female]), there was a significant increase in event rates (particularly mortality) if nonanticoagulated.","author":[{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Skjoth","given":"Flemming","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rasmussen","given":"Lars Hvilsted","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Larsen","given":"Torben Bjerregaard","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"14","issued":{"date-parts":[["2015","4"]]},"language":"eng","page":"1385-1394","publisher-place":"United States, United States","title":"Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score.","type":"article-journal","volume":"65"},"uris":[""]}],"mendeley":{"formattedCitation":"(27)","plainTextFormattedCitation":"(27)","previouslyFormattedCitation":"(27)"},"properties":{"noteIndex":0},"schema":""}(27).Clinical markersAtrial fibrillation is a multi-systemic disorder that often occurs alongside other comorbidities. Many of these co-morbidities are risk factors for incident AF and may also increase the risk of subsequent complications. Pooled analysis from five randomised controlled trials (RCTs) demonstrated that a history of stroke or transient ischaemic attack (TIA), increasing age, hypertension, diabetes mellitus and congestive heart failure were individual risk factors for stroke in AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0003-9926 (Print)","PMID":"8018000","abstract":"BACKGROUND AND METHODS: Atrial fibrillation is associated with an increased risk of ischemic stroke. Data on individual patients were pooled from five recently completed randomized trials comparing warfarin (all studies) or aspirin (the Atrial Fibrillation, Aspirin, Anticoagulation Study and the Stroke Prevention in Atrial Fibrillation Study) with control in patients with atrial fibrillation. The purpose of the analysis was to (1) identify patient features predictive of a high or low risk of stroke, (2) assess the efficacy of antithrombotic therapy in major patient subgroups (eg, women), and (3) obtain the most precise estimate of the efficacy and risks of antithrombotic therapy in atrial fibrillation. For the warfarin-control comparison there were 1889 patient-years receiving warfarin and 1802 in the control group. For the aspirin-placebo comparison there were 1132 patient-years receiving aspirin and 1133 receiving placebo. The daily dose of aspirin was 75 mg in the Atrial Fibrillation, Aspirin, Anticoagulation Study and 325 mg in the Stroke Prevention in Atrial Fibrillation Study. To monitor warfarin dosage, three studies used prothrombin time ratios and two used international normalized ratios. The lowest target intensity was a prothrombin time ratio of 1.2 to 1.5 and the highest target intensity was an international normalized ratio of 2.8 to 4.2. The primary end points were ischemic stroke and major hemorrhage, as assessed by each study. RESULTS: At the time of randomization the mean age was 69 years and the mean blood pressure was 142/82 mm Hg. Forty-six percent of the patients had a history of hypertension, 6% had a previous transient ischemic attack or stroke, and 14% had diabetes. Risk factors that predicted stroke on multivariate analyses in control patients were increasing age, history of hypertension, previous transient ischemic attack or stroke, and diabetes. Patients younger than 65 years who had none of the other predictive factors (15% of all patients) had an annual rate of stroke of 1.0%, 95% confidence interval (CI) 0.3% to 3.0%. The annual rate of stroke was 4.5% for the control group and 1.4% for the warfarin group (risk reduction, 68%; 95% CI, 50% to 79%). The efficacy of warfarin was consistent across all studies and subgroups of patients. In women, warfarin decreased the risk of stroke by 84% (95% CI, 55% to 95%) compared with 60% (95% CI, 35% to 76%) in men. The efficacy of aspirin was not as consistent. The risk reduction with …","container-title":"Archives of internal medicine","id":"ITEM-1","issue":"13","issued":{"date-parts":[["1994","7"]]},"language":"eng","page":"1449-1457","publisher-place":"United States, United States","title":"Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.","type":"article-journal","volume":"154"},"uris":[""]}],"mendeley":{"formattedCitation":"(26)","plainTextFormattedCitation":"(26)","previouslyFormattedCitation":"(26)"},"properties":{"noteIndex":0},"schema":""}(26). A more recent systematic review of seven studies which included over 12,000 patients found similar results, although there was inconclusive evidence to support congestive heart failure and coronary artery disease as risk factors ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1212/01.wnl.0000267275.68538.8d","ISSN":"00283878","PMID":"17679673","abstract":"BACKGROUND: Absolute stroke rates vary widely among patients with nonvalvular atrial fibrillation. To balance the benefits and risks of chronic antithrombotic prophylaxis, it is important to estimate the absolute risk of stroke for individual patients. METHODS: Systematic review of studies using multivariate regression techniques to identify independent risk factors for stroke in patients with atrial fibrillation was conducted, and reports of absolute stroke rates in subgroups of patients with these risk factors collected. A summary estimate of the relative risk associated with each independent risk factor was calculated using maximum likelihood methods. RESULTS: Seven studies (including six entirely independent cohorts) were identified. Prior stroke/TIA (relative risk 2.5, 95% CI 1.8 to 3.5), increasing age (relative risk 1.5 per decade, 95% CI 1.3 to 1.7), a history of hypertension (relative risk 2.0, 95% CI 1.6 to 2.5), and diabetes mellitus (relative risk 1.7, 95% CI 1.4 to 2.0) were the strongest, most consistent independent risk factors. Observed absolute stroke rates for nonanticoagulated patients with single independent risk factors were in the range of 6 to 9% per year for prior stroke/TIA, 1.5 to 3% per year for history of hypertension, 1.5 to 3% per year for age >75, and 2.0 to 3.5% per year for diabetes. Female sex was inconsistently associated with stroke risk, whereas the evidence was inconclusive that either heart failure or coronary artery disease is independently predictive of stroke. CONCLUSIONS: Four clinical features (prior stroke/TIA, advancing age, hypertension, diabetes) are consistent independent risk factors for stroke in atrial fibrillation patients. Prior stroke/TIA is the most powerful risk factor and reliably confers a high stroke risk (>5% per year, averaging 10% per year). Absolute stroke rates associated with other individual risk factors are difficult to precisely estimate from available data. ?2007AAN Enterprises, Inc.","author":[{"dropping-particle":"","family":"Stroke Risk in Atrial Fibrillation Working Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neurology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2007","8"]]},"language":"eng","page":"546-554","publisher-place":"United States","title":"Independent predictors of stroke in patients with atrial fibrillation: A systematic review","type":"article-journal","volume":"69"},"uris":[""]}],"mendeley":{"formattedCitation":"(28)","plainTextFormattedCitation":"(28)","previouslyFormattedCitation":"(28)"},"properties":{"noteIndex":0},"schema":""}(28). Prior stroke or TIA was the most powerful predictor of further stroke events, contributing to an annual risk of >5%. Increasing age (per decade), hypertension and diabetes mellitus were each associated with a 1.5 to two-fold greater stroke risk. In a separate study, Olesen et al. demonstrated that the presence of heart failure, previous stroke and vascular disease were independent predictors of stroke or thromboembolism among AF patients aged under 65 years ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1378/chest.11-0862","ISSN":"1931-3543 (Electronic)","PMID":"21680645","abstract":"BACKGROUND: According to the latest European guidelines on the management of nonvalvular atrial fibrillation (NVAF), all patients aged >/= 65 years should be treated with oral anticoagulation (if not contraindicated). Therefore, stroke risk factors should be investigated exclusively in patients with NVAF aged < 65 years. METHODS: Patients diagnosed with NVAF in a four-hospital institution between 2000 and 2010 were identified. Event rates of stroke/thromboembolism were calculated according to age category (ie, age < 65, 65-74, and >/= 75 years). Independent risk factors of stroke and thromboembolism were investigated in univariate and multivariate Cox regression models including patients with NVAF aged < 65 years only. The effect of adding vascular disease to the CHADS(2) (congestive heart failure, hypertension, age >/= 75 years, diabetes, previous stroke) score was examined by net reclassification improvement (NRI) and integrated discrimination improvement (IDI) models. RESULTS: Among 6,438 patients with NVAF, 2,002 (31.1%) were aged < 65 years. In patients with no CHADS(2) risk factors who were not treated with anticoagulation (n = 1,035), the stroke/thromboembolic event rate per 100 person-years was 0.23 (95% CI, 0.08-0.72), 2.05 (95% CI, 1.07-3.93), and 3.99 (95% CI, 2.63-6.06) in those aged < 65, 65-74, and >/= 75 years, respectively. Heart failure, previous stroke, and vascular disease were significantly associated with increased risk of stroke/thromboembolism in both univariate and multivariate analyses, and vascular disease significantly improved the predictive ability of the CHADS(2) score (NRI, 0.40; IDI, 0.031). CONCLUSIONS: Patients with NVAF aged >/= 65 years have event rates that merit oral anticoagulation. In patients with NVAF aged < 65 years, the risk of stroke/thromboembolism is independently increased by the presence of heart failure, previous stroke, or vascular disease. As proposed in the new CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age >/= 75 years, diabetes, previous stroke, vascular disease, age 65-74 years, sex category [female]) score, stroke risk stratification by the CHADS(2) score can be improved by the addition of age 65 to 74 years and vascular disease.","author":[{"dropping-particle":"","family":"Olesen","given":"Jonas Bjerring","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fauchier","given":"Laurent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taillandier","given":"Sophie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2012","1"]]},"language":"eng","page":"147-153","publisher-place":"United States, United States","title":"Risk factors for stroke and thromboembolism in relation to age among patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project.","type":"article-journal","volume":"141"},"uris":[""]}],"mendeley":{"formattedCitation":"(29)","plainTextFormattedCitation":"(29)","previouslyFormattedCitation":"(29)"},"properties":{"noteIndex":0},"schema":""}(29). A Swedish cohort study found that peripheral artery disease, vascular disease, prior myocardial infarction, female sex, prior embolism, intra-cranial haemorrhage (ICH), hypertension and diabetes mellitus were associated with additional thromboembolic events ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehr488","ISSN":"1522-9645 (Electronic)","PMID":"22246443","abstract":"AIMS: The impact of some risk factors for stroke and bleeding, and the value of stroke and bleeding risk scores, in atrial fibrillation (AF), has been debated, as clinical trial cohorts have not adequately tested these. Our objective was to investigate risk factors for stroke and bleeding in AF, and application of the new CHA(2)DS(2)-VASc and HAS-BLED schemes for stroke and bleeding risk assessments, respectively. METHODS AND RESULTS: We used the Swedish Atrial Fibrillation cohort study, a nationwide cohort study of 182 678 subjects with a diagnosis of AF at any Swedish hospital between 1 July 2005 and 31 December 2008, who were prospectively followed for an average of 1.5 years (260 000 years at risk). With the use of the National Swedish Drug Registry, all patients who used an oral anticoagulant anytime during follow-up were identified. Most of the analyses were made on a subset of 90 490 patients who never used anticoagulants. Risk factors for stroke, the composite thromboembolism endpoint (stroke, TIA, or systemic embolism), and bleeding, and the performance of published stroke and bleeding risk stratification schemes were investigated. On multivariable analysis, significant associations were found between the following 'new' risk factors and thromboembolic events; peripheral artery disease [hazard ratio (HR) 1.22 (95% CI 1.12-1.32)], 'vascular disease' [HR 1.14 (1.06-1.23)], prior myocardial infarction [HR 1.09 (1.03-1.15)], and female gender [HR 1.17 (1.11-1.22)]. Previous embolic events, intracranial haemorrhage (ICH), hypertension, diabetes, and renal failure were other independent predictors of the composite thromboembolism endpoint, while thyroid disease (or hyperthyroidism) was not an independent stroke risk factor. C-statistics for the composite thromboembolic endpoint with the CHADS(2) and CHA(2)DS(2)-VASc schemes were 0.66 (0.65-0.66) and 0.67 (0.67-0.68), respectively. On multivariable analysis, age, prior ischaemic stroke or thromboembolism, prior major bleeding events, and hypertension were significant predictors of ICH and major bleeding. Heart failure, diabetes, renal failure, liver disease, anaemia or platelet/coagulation defect, alcohol abuse, and cancer were other significant predictors for major bleeding, but not ICH. The ability for predicting ICH and major bleeding with both bleeding risk schemes (HEMORR(2)HAGES, HAS-BLED) were similar, with c-statistics of ~0.6. CONCLUSION: Several independent risk factors (prior ICH, myocardia…","author":[{"dropping-particle":"","family":"Friberg","given":"Leif","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenqvist","given":"Marten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2012","6"]]},"language":"eng","page":"1500-1510","publisher-place":"England","title":"Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study.","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"(25)","plainTextFormattedCitation":"(25)","previouslyFormattedCitation":"(25)"},"properties":{"noteIndex":0},"schema":""}(25). The mechanism by which the conditions above influence stroke risk in AF is likely multifactorial and partly related to its influence on progression of the disease through atrial substrate remodelling. Furthermore, many of these conditions are pro-thrombotic by nature.Among non-anticoagulated patients in the ATRIA study, females had a 60% higher risk of thromboembolism compared to males ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.105.553438","ISSN":"1524-4539 (Electronic)","PMID":"16157766","abstract":"BACKGROUND: Previous studies provide conflicting results about whether women are at higher risk than men for thromboembolism in the setting of atrial fibrillation (AF). We examined data from a large contemporary cohort of AF patients to address this question. METHODS AND RESULTS: We prospectively studied 13,559 adults with AF and recorded data on patients' clinical characteristics and the occurrence of incident hospitalizations for ischemic stroke, peripheral embolism, and major hemorrhagic events through searching validated computerized databases and medical record review. We compared event rates by patient sex using multivariable log-linear regression, adjusting for clinical risk factors for stroke, and stratifying by warfarin use. We identified 394 ischemic stroke and peripheral embolic events during 15,494 person-years of follow-up off warfarin. After multivariable analysis, women had higher annual rates of thromboembolism off warfarin than did men (3.5% versus 1.8%; adjusted rate ratio [RR], 1.6; 95% CI, 1.3 to 1.9). There was no significant difference by sex in 30-day mortality after thromboembolism (23% for both). Warfarin use was associated with significantly lower adjusted thromboembolism rates for both women and men (RR, 0.4; 95% CI, 0.3 to 0.5; and RR, 0.6; 95% CI, 0.5 to 0.8, respectively), with similar annual rates of major hemorrhage (1.0% and 1.1%, respectively). CONCLUSIONS: Women are at higher risk than men for AF-related thromboembolism off warfarin. Warfarin therapy appears be as effective in women, if not more so, than in men, with similar rates of major hemorrhage. Female sex is an independent risk factor for thromboembolism and should influence the decision to use anticoagulant therapy in persons with AF.","author":[{"dropping-particle":"","family":"Fang","given":"Margaret C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henault","given":"Lori E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jensvold","given":"Nancy G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Go","given":"Alan S","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2005","9"]]},"language":"eng","page":"1687-1691","publisher-place":"United States, United States","title":"Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study.","type":"article-journal","volume":"112"},"uris":[""]}],"mendeley":{"formattedCitation":"(30)","plainTextFormattedCitation":"(30)","previouslyFormattedCitation":"(30)"},"properties":{"noteIndex":0},"schema":""}(30). Similar findings were shown in a cohort of anticoagulated patients where females had a two-fold higher risk of ischaemic stroke ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0340-6245 (Print)","PMID":"19404548","abstract":"The efficacy of adjusted-dose oral anticoagulant treatment (OAT) in the prevention of stroke in atrial fibrillation (AF) is well documented. Available data show that AF patients are widely heterogeneous in terms of ischaemic stroke risk. The role of female gender as a predictor of stroke risk is inconsistent, in particular it is unclear if warfarin treatment is able to prevent stroke equally in both sexes. We performed a prospective study on 780 AF patients on OAT, followed by an Anticoagulation Clinic, to evaluate if female gender is a risk factor for stroke among patients on OAT and if the quality of anticoagulation is different between genders. No difference was found in relation to the quality of anticoagulation between genders (p=0.5). During follow-up 33 patients had major bleedings (rate 1.37 x 100 pt/yrs) but no difference was found between genders in bleeding risk. Forty patients had ischaemic events [rate 1.66 x 100 pt/yrs; males rate 1.2 x 100 pt/yrs; females rate 2.43 x 100 pt/yrs; p=0.042; relative risk (RR) of females vs. males 2.0 (95% confidence interval [CI] 1.3-3.1); p= 0.004]. The higher rate of ischaemic events in females with respect to males was confirmed at Cox regression analysis after correction for age (p=0.009). In addition, strokes occurring in females were more disabling, and RR for severe and fatal stroke, defined according to Modified Rankin scale, of females vs. males was 3.1 (95% CI 1.3-6.5; p=0.001). In conclusion, our data show a higher risk of stroke in anticoagulated AF females with respect to males, despite a similar quality of anticoagulation.","author":[{"dropping-particle":"","family":"Poli","given":"Daniela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Antonucci","given":"Emilia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grifoni","given":"Elisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abbate","given":"Rosanna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gensini","given":"Gian Franco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prisco","given":"Domenico","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2009","5"]]},"language":"eng","page":"938-942","publisher-place":"Germany, Germany","title":"Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment.","type":"article-journal","volume":"101"},"uris":[""]}],"mendeley":{"formattedCitation":"(31)","plainTextFormattedCitation":"(31)","previouslyFormattedCitation":"(31)"},"properties":{"noteIndex":0},"schema":""}(31). However, a subsequent population-based cohort study of 147,622 patients with AF failed to reproduce these results ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehw613","ISSN":"1522-9645 (Electronic)","PMID":"28073863","abstract":"Aims: In patients with non-valvular atrial fibrillation (NVAF), it is uncertain whether the higher risk of ischaemic stroke in women reported in some studies is due to residual confounding. We assessed this association using standard time-fixed and more accurate time-dependent adjustment for confounders. Methods and results: Using the computerized databases of the Regie de l'assurance maladie du Quebec (RAMQ), we identified a cohort of patients with NVAF during 2000-2009 and RAMQ medication coverage. Cox proportional hazards models were used to estimate the hazard ratio (HR) of ischaemic stroke, death, and bleeding, associated with sex, adjusting for time-fixed covariates at cohort entry. This was compared with adjustment for time-dependent covariates using an age and time-matched nested case-control analysis. The cohort included 147 622 patients. During a mean follow-up of 2.9 years 11 326 patients had a stroke (incidence rate 2.6 per 100 per year). Using time-fixed adjustment for confounders, women had a moderately higher risk of ischaemic stroke than men (HR 1.16 (Confidence interval (CI) 95% 1.11-1.21). Matching on age and using time-dependent adjustment for confounders, women were not at higher risk of stroke than men (Rate Ratio 1.01; 95% CI 0.97-1.05). Mortality and bleeding rates were lower in women compared with men in both analyses. Conclusion: In NVAF, women were not at higher risk of thromboembolic events than men in our study. The small increased risk reported in previous studies may be related to residual confounding, in particular from insufficient control for age.","author":[{"dropping-particle":"","family":"Renoux","given":"Christel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coulombe","given":"Janie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suissa","given":"Samy","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"19","issued":{"date-parts":[["2017","5"]]},"language":"eng","page":"1473-1479","publisher-place":"England, England","title":"Revisiting sex differences in outcomes in non-valvular atrial fibrillation: a population-based cohort study.","type":"article-journal","volume":"38"},"uris":[""]}],"mendeley":{"formattedCitation":"(32)","plainTextFormattedCitation":"(32)","previouslyFormattedCitation":"(32)"},"properties":{"noteIndex":0},"schema":""}(32). A study by Nielsen et al. demonstrated similar rates of thromboembolism for both sexes among AF patients deemed at lowest risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"1524-4539 (Electronic)","PMID":"29459469","abstract":"BACKGROUND: Stroke risk in atrial fibrillation is assessed by using the CHA2DS2-VASc score. Sex category (Sc, ie, female sex) confers 1 point on CHA2DS2-VASc. We hypothesized that female sex is a stroke risk modifier, rather than an overall risk factor, when added to a CHA2DS2-VA (sex-independent thromboembolism risk) score scale. METHODS: Using 3 nationwide registries, we identified patients with incident nonvalvular atrial fibrillation from January 1, 1997, through December 31, 2015. Patients receiving oral anticoagulant treatment at baseline were excluded, and person-time was censored at the time of treatment initiation (if any). CHA2DS2-VA scores were calculated for men and women, and were followed for up to 1 year in the Danish National Patient Registry. The primary outcome was a primary hospital code for ischemic stroke or systemic embolism (thromboembolism). We calculated crude event rates for risk strata as events per 100 person-years. For quantifying absolute risk of stroke, we calculated risks based on the pseudovalue method. Female sex as a prognostic factor was investigated by inclusion as an interaction term on the CHA2DS2-VA score to calculate the thromboembolic risk ratio for different score points. RESULTS: A total of 239 671 patients with atrial fibrillation (48.7% women) contributed to the analyses. The mean ages for women and men were 76.6 years and 70.3 years, respectively; the mean CHA2DS2-VA scores were 2.7 for women and 2.3 for men. The overall 1-year thromboembolic rate per 100 person-years for women was 7.3 and 5.7 for men. The 1-year absolute risk of thromboembolism was 0.5% among men and women with a CHA2DS2-VA score of 0 and increased up to >7% among very comorbid patients (score >5). The risk ratio (male as reference) across points >1 indicated that women exhibit a higher stroke risk. The interaction was statistically significant (P<0.001). CONCLUSIONS: Female sex is a risk modifier for stroke in patients with atrial fibrillation. Initial decisions on oral anticoagulant treatment could be guided by a CHA2DS2-VA score (ie, excluding the sex category criterion), but the Sc risk component modifies and accentuates stroke risk in women who would have been eligible for oral anticoagulant treatment on the basis of >/=2 additional stroke risk factors.","author":[{"dropping-particle":"","family":"Nielsen","given":"Peter Bronnum","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Skjoth","given":"Flemming","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Overvad","given":"Thure Filskov","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Larsen","given":"Torben Bjerregaard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2018","2"]]},"language":"eng","page":"832-840","publisher-place":"United States","title":"Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation: Should We Use a CHA2DS2-VA Score Rather Than CHA2DS2-VASc?","type":"article-journal","volume":"137"},"uris":[""]}],"mendeley":{"formattedCitation":"(33)","plainTextFormattedCitation":"(33)","previouslyFormattedCitation":"(33)"},"properties":{"noteIndex":0},"schema":""}(33). Excess risk in females were only evident for those with two or more non-sex-related stroke risk factors. Therefore, although female sex should remain an important component for stroke risk assessment in AF, it should be considered in the context of other risk factors (‘risk modifier’).Electrical markersSeveral electrical markers relating to AF have been described to predict stroke risk ( REF _Ref25707176 \r \h \* MERGEFORMAT Table 2). The impact of AF type (paroxysmal or sustained) on stroke risk remains controversial with earlier studies reporting a similar risk of stroke and systemic thromboembolism in paroxysmal AF compared to sustained or permanent AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehn599","ISSN":"1522-9645 (Electronic)","PMID":"19176537","abstract":"AIMS: Knowledge about stroke risk in paroxysmal atrial fibrillation (PxAF) is limited. Although current guideline recommendations advocate the same treatment as in permanent atrial fibrillation (PermAF), most patients with PxAF do not receive prophylactic anticoagulation. The aim of this study is to investigate whether there are differences in stroke risk between PxAF and PermAF. METHODS AND RESULTS: All patients with PxAF (n = 855) and PermAF (n = 1126) treated for atrial fibrillation (AF) during 2002 at one of Scandinavia's largest hospitals were followed-up for 3.6 years regarding incidence of stroke. Information about type of AF, comorbidity, medication, and clinical events during follow-up was acquired from medical records and the National Register of Hospital Discharges. The incidence of ischaemic stroke was similar in PxAF and PermAF (26 vs. 29 events/1000 patient years). The multivariable-adjusted hazard ratio (HR) for ischaemic stroke in PxAF compared with PermAF was 1.07 (95% CI 0.71-1.61) in subjects without prior stroke. The corresponding HR for any stroke, ischaemic or haemorrhagic, was 0.89 (95% CI 0.61-1.30). Compared with the general population, ischaemic stroke was twice as common as expected in PxAF after standardization for age and sex (standardized incidence ratio 2.12, 95% CI 1.52-2.71). PxAF patients who took warfarin had approximately half as many ischaemic strokes as those who did not take warfarin (HR 0.44, 95% CI 0.30-0.65). CONCLUSION: Ischaemic stroke is about as common in PxAF as in PermAF, and about twice as common as in the general population. Yet, PxAF patients do not receive protective anticoagulant treatment as often as patients with PermAF do. It is therefore important to increase the use of anticoagulants among PxAF patients in accordance with current guideline recommendations.","author":[{"dropping-particle":"","family":"Friberg","given":"Leif","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hammar","given":"Niklas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenqvist","given":"Marten","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2010","4"]]},"language":"eng","page":"967-975","publisher-place":"England, England","title":"Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation.","type":"article-journal","volume":"31"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/S0735-1097(99)00489-1","ISSN":"07351097","PMID":"10636278","abstract":"OBJECTIVE: This study was performed to characterize the risk of stroke in elderly patients with recurrent intermittent atrial fibrillation (AF). BACKGROUND: Although intermittent AF is common, relatively little is known about the attendant risk of stroke. METHODS: A longitudinal cohort study was performed comparing 460 participants with intermittent AF with 1,552 with sustained AF treated with aspirin in the Stroke Prevention in Atrial Fibrillation studies and followed for a mean of two years. Independent risk factors for ischemic stroke were identified by multivariate analysis. RESULTS: Patients with intermittent AF were, on average, younger (66 vs. 70 years, p < 0.001), were more often women (37% vs. 26% p < 0.001) and less often had heart failure (11% vs. 21%, p < 0.001) than those with sustained AF. The annualized rate of ischemic stroke was similar for those with intermittent (3.2%) and sustained AF (3.3%). In patients with intermittent AF, independent predictors of ischemic stroke were advancing age (relative risk [RR] = 2.1 per decade, p < 0.001), hypertension (RR = 3.4, p = 0.003) and prior stroke (RR = 4.1, p = 0.01). Of those with intermittent AF predicted to be high risk (24%), the observed stroke rate was 7.8% per year (95% confidence interval 4.5 to 14). CONCLUSIONS: In this large cohort of AF patients given aspirin, those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors. Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation. High-risk patients with intermittent AF can be identified using the same clinical criteria that apply to patients with sustained AF.","author":[{"dropping-particle":"","family":"Hart","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"Lesly A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rothbart","given":"Robert M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McAnulty","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asinger","given":"Richard W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"Jonathan L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2000","1"]]},"language":"eng","page":"183-187","publisher-place":"United States, United States","title":"Stroke with intermittent atrial fibrillation: Incidence and predictors during aspirin therapy","type":"article-journal","volume":"35"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.jacc.2007.07.076","ISSN":"07351097","PMID":"18036454","abstract":"Objectives: Our goal was to determine the risk of stroke or non-cerebral embolism associated with paroxysmal compared with sustained atrial fibrillation (AF). Background: The risk of stroke and non-cerebral embolism and the efficacy of oral anticoagulation (OAC) in paroxysmal AF as compared with sustained AF are not precisely known. Methods: The ACTIVE W (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) was a trial comparing OAC to combined antiplatelet therapy with aspirin and clopidogrel for prevention of vascular events in 6,706 AF patients. The incidence of thromboembolic events and major bleeds were compared in patients with paroxysmal AF (n = 1,202) and persistent or permanent AF (n = 5,495). Results: Patients with paroxysmal AF were younger, had a shorter AF history, more hypertension, and less valvular disease, heart failure, and diabetes mellitus than patients with sustained AF. At baseline, patients with paroxysmal AF had a CHADS2 (cardiac failure, hypertension, age, diabetes, stroke [doubled]) risk score of 1.79 ± 1.03 compared with 2.04 ± 1.12 in patients with sustained AF (p < 0.00001). The annualized risk of stroke or non-central nervous system (CNS) systemic embolism was 2.0 in paroxysmal AF compared with 2.2 in sustained AF (relative risk 0.87, 95% confidence interval [CI] 0.59 to 1.30, p = 0.496). After adjusting for confounding baseline variables, the relative risk was 0.94 (95% CI 0.63 to 1.40, p = 0.755). The incidence of stroke and non-CNS embolism was lower for patients treated with OAC irrespective of type of AF. There were more bleedings of any type in patients receiving clopidogrel plus aspirin, irrespective of the type of AF. Conclusions: Patients with paroxysmal AF treated with aspirin plus clopidogrel or OAC have a similar risk for thromboembolic events than patients with sustained AF. This risk can be significantly lowered with OAC. (The ACTIVE W trial; ; NCT00243178). ? 2007 American College of Cardiology Foundation.","author":[{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pajitnev","given":"Dimitri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pogue","given":"Janice","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Healey","given":"Jeff S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pfeffer","given":"Marc A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-3","issue":"22","issued":{"date-parts":[["2007","11"]]},"language":"eng","page":"2156-2161","publisher-place":"United States, United States","title":"Incidence of Stroke in Paroxysmal Versus Sustained Atrial Fibrillation in Patients Taking Oral Anticoagulation or Combined Antiplatelet Therapy. An ACTIVE W Substudy","type":"article-journal","volume":"50"},"uris":[""]}],"mendeley":{"formattedCitation":"(34–36)","plainTextFormattedCitation":"(34–36)","previouslyFormattedCitation":"(34–36)"},"properties":{"noteIndex":0},"schema":""}(34–36). These results were supported by two independent systematic reviews which included a total of nine relevant studies ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1212/01.wnl.0000267275.68538.8d","ISSN":"00283878","PMID":"17679673","abstract":"BACKGROUND: Absolute stroke rates vary widely among patients with nonvalvular atrial fibrillation. To balance the benefits and risks of chronic antithrombotic prophylaxis, it is important to estimate the absolute risk of stroke for individual patients. METHODS: Systematic review of studies using multivariate regression techniques to identify independent risk factors for stroke in patients with atrial fibrillation was conducted, and reports of absolute stroke rates in subgroups of patients with these risk factors collected. A summary estimate of the relative risk associated with each independent risk factor was calculated using maximum likelihood methods. RESULTS: Seven studies (including six entirely independent cohorts) were identified. Prior stroke/TIA (relative risk 2.5, 95% CI 1.8 to 3.5), increasing age (relative risk 1.5 per decade, 95% CI 1.3 to 1.7), a history of hypertension (relative risk 2.0, 95% CI 1.6 to 2.5), and diabetes mellitus (relative risk 1.7, 95% CI 1.4 to 2.0) were the strongest, most consistent independent risk factors. Observed absolute stroke rates for nonanticoagulated patients with single independent risk factors were in the range of 6 to 9% per year for prior stroke/TIA, 1.5 to 3% per year for history of hypertension, 1.5 to 3% per year for age >75, and 2.0 to 3.5% per year for diabetes. Female sex was inconsistently associated with stroke risk, whereas the evidence was inconclusive that either heart failure or coronary artery disease is independently predictive of stroke. CONCLUSIONS: Four clinical features (prior stroke/TIA, advancing age, hypertension, diabetes) are consistent independent risk factors for stroke in atrial fibrillation patients. Prior stroke/TIA is the most powerful risk factor and reliably confers a high stroke risk (>5% per year, averaging 10% per year). Absolute stroke rates associated with other individual risk factors are difficult to precisely estimate from available data. ?2007AAN Enterprises, Inc.","author":[{"dropping-particle":"","family":"Stroke Risk in Atrial Fibrillation Working Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neurology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2007","8"]]},"language":"eng","page":"546-554","publisher-place":"United States","title":"Independent predictors of stroke in patients with atrial fibrillation: A systematic review","type":"article-journal","volume":"69"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1160/TH07-08-0508","ISSN":"0340-6245 (Print)","PMID":"18278178","abstract":"The risk of stroke in atrial fibrillation (AF) needs to be assessed in each patient to determine the clinical and cost-effectiveness of thromboprophylaxis, with the aim of appropriate use of antithrombotic therapy. To achieve this, stroke risk factors in AF populations need to be identified and stroke risk stratification models have been devised on the basis of these risk factors. In this article, we firstly provide a systematic review of studies examining the attributable stroke risk of various clinical, demographic and echocardiographic patient characteristics in AF populations. Secondly, we performed a systematic review of published stroke risk stratification models, in terms of the results of the review of stroke risk factors and their ability to accurately discriminate between different levels of stroke risk. Thirdly, we review the health economic evidence relating to the cost-effectiveness of anticoagulation and antiplatelet therapy as thromboprophylaxis in AF patients. The studies included in the systematic review of stroke risk factors identified history of stroke or TIA, increasing age, hypertension and structural heart disease (left-ventricular dysfunction or hypertrophy) to be good predictors of stroke risk in AF patients. The evidence regarding diabetes mellitus, gender and other patient characteristics was less consistent. Three stroke risk stratification models were identified that were able to discriminate between different categories of stroke risk to at least 95% accuracy. Few models had addressed the cumulative nature of risk factors where a combination of risk factors would confer a greater risk than either factor alone. In patients at high risk of stroke, anticoagulation is cost effective, but not for those with a low risk of stroke. With the evidence available for stroke risk factors and the various alternative stroke risk stratification models, a review of these models in terms of the evidence on which they are devised and their performance in representative AF populations is important. The appropriate administration of thromboprophylaxis in AF patients would need to balance the risks and benefits of antithrombotic therapy with its cost-effectiveness.","author":[{"dropping-particle":"","family":"Hughes","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2008","2"]]},"language":"eng","page":"295-304","publisher-place":"Germany, Germany","title":"Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data.","type":"article-journal","volume":"99"},"uris":[""]}],"mendeley":{"formattedCitation":"(28,37)","plainTextFormattedCitation":"(28,37)","previouslyFormattedCitation":"(28,37)"},"properties":{"noteIndex":0},"schema":""}(28,37). However, a third systematic review of 12 studies which included just under 100,000 patients demonstrated that non-paroxysmal AF was associated with a hazard ratio of 1.38 (95% confidence interval (CI), 1.17 - 1.57) for thromboembolism compared to paroxysmal AF, after multivariable adjustment ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehw007","ISSN":"1522-9645 (Electronic)","PMID":"26888184","abstract":"AIMS: Thromboembolic risk stratification schemes and clinical guidelines for atrial fibrillation (AF) regard risk as independent of classification into paroxysmal (PAF) and non-paroxysmal atrial fibrillation (NPAF). The aim of the current study was to conduct a systematic review evaluating the impact of AF type on thromboembolism, bleeding, and mortality. METHODS AND RESULTS: PubMed was searched through 27 November 2014 for randomized controlled trials, cohort studies, and case series reporting prospectively collected clinical outcomes stratified by AF type. The incidence of thromboembolism, mortality, and bleeding was extracted. Atrial fibrillation clinical outcome data were extracted from 12 studies containing 99 996 patients. The unadjusted risk ratio (RR) for thromboembolism in NPAF vs. PAF was 1.355 (95% CI: 1.169-1.571, P < 0.001). In the study subset off oral anticoagulation, unadjusted RR was 1.689 (95% CI: 1.151-2.480, P = 0.007). The overall multivariable adjusted hazard ratio (HR) for thromboembolism was 1.384 (95% CI: 1.191-1.608, P < 0.001). The overall unadjusted RR for all-cause mortality was 1.462 (95% CI: 1.255-1.703, P < 0.001). Multivariable adjusted HR for all-cause mortality was 1.217 (95% CI: 1.085-1.365, P < 0.001). Rates of bleeding were similar, with unadjusted RR 1.00 (95% CI: 0.919-1.087, P = 0.994) and adjusted HR 1.025 (95% CI: 0.898-1.170, P = 0.715). CONCLUSION: Non-paroxysmal atrial fibrillation is associated with a highly significant increase in thromboembolism and death. These data suggest the need for new therapies to prevent AF progression and further studies to explore the integration of AF type into models of thromboembolic risk.","author":[{"dropping-particle":"","family":"Ganesan","given":"Anand N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chew","given":"Derek P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartshorne","given":"Trent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Selvanayagam","given":"Joseph B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aylward","given":"Philip E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sanders","given":"Prashanthan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGavigan","given":"Andrew D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"20","issued":{"date-parts":[["2016","5"]]},"language":"eng","page":"1591-1602","publisher-place":"England, England","title":"The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: a systematic review and meta-analysis.","type":"article-journal","volume":"37"},"uris":[""]}],"mendeley":{"formattedCitation":"(38)","plainTextFormattedCitation":"(38)","previouslyFormattedCitation":"(38)"},"properties":{"noteIndex":0},"schema":""}(38). The finding was reinforced by results from the ENGAGE AF-TIMI 48 trial which showed fewer thromboembolic events among patients with paroxysmal AF compared to those with sustained AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCEP.116.004267","ISSN":"19413084","PMID":"28077507","abstract":"Background - Whether the pattern of atrial fibrillation (AF) modifies the risk/benefit of anticoagulation is controversial. In ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48), the factor Xa inhibitor edoxaban was noninferior to warfarin in preventing stroke or systemic embolic events and significantly reduced bleeding and cardiovascular mortality. However, detailed analyses by AF pattern have not been reported. Methods and Results - The 21 105 patients were categorized as having paroxysmal (<7 days duration), persistent (≥7 days but <1 year), or permanent (≥1 year or failed cardioversion) AF patterns at randomization. Efficacy and safety outcomes were evaluated during the 2.8 years median follow-up and compared by AF pattern. The primary end point of stroke/systemic embolic event was lower in those patients with paroxysmal AF (1.49%/year), compared with persistent (1.83%/year; P-adj =0.015) and permanent AF (1.95%/year; P-adj =0.004). Overall, all-cause mortality also was lower with paroxysmal (3.0%/year) compared with persistent (4.4%/year; P-adj <0.001) and permanent AF (4.4%/year; P-adj <0.001). Annualized major bleeding rates were similar across AF patterns (2.86% versus 2.65% versus 2.73%). There was no effect modification by treatment assignment. Conclusions - In ENGAGE AF-TIMI 48 trial, patients with paroxysmal AF suffered fewer thromboembolic events and deaths compared with those with persistent and permanent AF. The efficacy and safety profile of edoxaban as compared with warfarin was consistent across the 3 patterns of AF.","author":[{"dropping-particle":"","family":"Link","given":"Mark S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giugliano","given":"Robert P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruff","given":"Christian T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scirica","given":"Benjamin M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huikuri","given":"Heikke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oto","given":"Ali","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crompton","given":"Andrea E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murphy","given":"Sabina A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lanz","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mercuri","given":"Michele F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Antman","given":"Elliott M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Braunwald","given":"Eugene","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation: Arrhythmia and Electrophysiology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017","1"]]},"language":"eng","page":"1-7","publisher-place":"United States, United States","title":"Stroke and Mortality Risk in Patients with Various Patterns of Atrial Fibrillation: Results from the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48)","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(39)","plainTextFormattedCitation":"(39)","previouslyFormattedCitation":"(39)"},"properties":{"noteIndex":0},"schema":""}(39). There was no difference in thromboembolic risk between patients with persistent and permanent AF in the study. Given the current evidence, it would appear that sustained AF is likely to be associated with a higher stroke risk overall. However, it remains unclear whether the increased risk is due to shared underlying mechanisms of the disease or if the burden of AF itself is directly implicated. The method(s) by which AF is identified has evolved significantly over the past decade. While AF was previously detected predominantly using standard 12-lead electrocardiogram (ECG), the increased use of implantable devices has contributed to a rise in ‘device-detected AF’. The rise of device-detected AF has also led to new terms such as ‘atrial high-rate episodes’ (AHRE) and ‘subclinical atrial tachyarrhythmias’ - both of which are sometimes used interchangeably with AF. These changes have sparked important questions such as “what duration of AF is required for diagnosis?”, “what is the threshold of AF burden where it becomes clinically important?” and “what is the threshold of AF burden at which anticoagulation will provide a net benefit?”. While many of these questions remain unanswered, there are some evidence to shed light on the matter. Several studies have investigated the threshold of AF burden associated with a negative clinical outcome. The MOST study found that patients with at least one AHRE (defined as an atrial rate >220 bpm) lasting ≥5 minutes had a two-fold risk of stroke or mortality, and six-fold risk of developing AF compared to patients without AHRE ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.CIR.0000057981.70380.45","ISSN":"00097322","PMID":"12668495","abstract":"Background - Some current pacing systems can automatically detect and record atrial tachyarrhythmias that may be asymptomatic. We prospectively studied a 312-patient (pt) subgroup of MOST (MOde Selection Trial), a 2010-patient, 6-year randomized trial of DDDR versus VVIR pacing in sinus node dysfunction (SND). The purpose of the study was to correlate atrial high rate events (AHREs) detected by pacemaker diagnostics with clinical outcomes. Methods and Results - Pacemakers were programmed to log an AHRE when the atrial rate was >220 bpm for 10 consecutive beats. Analysis was confined to patients with at least 1 AHRE duration exceeding 5 minutes. The 312 patients were median age 74 years, 55% female, and 60% had a history of SVT. 160 of 312 (51.3%) patients enrolled had at least 1 AHRE > 5 minutes duration over median follow-up of 27 months. Cox proportional hazards analysis assessed the relationship of AHREs with clinical events, adjusting for prognostic variables and baseline covariates. The presence of any AHRE was an independent predictor of the following: total mortality (hazard ratio AHRE versus no AHRE and 95% confidence intervals=2.48 [1.25, 4.91], P = 0.0092); death or nonfatal stroke (2.79 [1.51, 5.15], P = 0.0011); and atrial fibrillation (5.93 [2.88, 12.2], P = 0.0001). There was no significant effect of pacing mode on the presence or absence of AHREs. Conclusions - AHRE detected by pacemakers in patients with SND identify patients that are more than twice as likely to die or have a stroke, and 6 times as likely to develop atrial fibrillation as similar patients without AHRE.","author":[{"dropping-particle":"V.","family":"Glotzer","given":"Taya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hellkamp","given":"Anne S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zimmerman","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sweeney","given":"Michael O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yee","given":"Raymond","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marinchak","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cook","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paraschos","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Love","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Radoslovich","given":"Glauco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Kerry L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamas","given":"Gervasio A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2003","4"]]},"language":"eng","page":"1614-1619","publisher-place":"United States","title":"Atrial high rate episodes detected by pacemaker diagnostics predict death and stroke: Report of the atrial diagnostics ancillary study of the MOde Selection Trial (MOST)","type":"article-journal","volume":"107"},"uris":[""]}],"mendeley":{"formattedCitation":"(40)","plainTextFormattedCitation":"(40)","previouslyFormattedCitation":"(40)"},"properties":{"noteIndex":0},"schema":""}(40). The ASSERT study similarly found that subclinical atrial tachyarrhythmias (defined as an atrial rate >190 bpm) lasting >6 minutes was associated with an increased risk of incident AF, and ischaemic stroke or systemic embolism ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa1105575","ISSN":"15334406","PMID":"22475610","abstract":"Background: One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation. Methods: We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing. Results: By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P = 0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P = 0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation. Conclusions: Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. (Funded by St. Jude Medical; ASSERT number, NCT00256152.) Copyright ? 2012 Massachusetts Medical Society. All rights reserved.","author":[{"dropping-particle":"","family":"Healey","given":"Jeff S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gold","given":"Michael R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Israel","given":"Carsten W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gelder","given":"Isabelle C.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Capucci","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lau","given":"C. P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fain","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Sean","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bailleul","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morillo","given":"Carlos A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carlson","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Themeles","given":"Ellison","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"Elizabeth S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012","1"]]},"language":"eng","page":"120-129","publisher-place":"United States","title":"Subclinical atrial fibrillation and the risk of stroke","type":"article-journal","volume":"366"},"uris":[""]}],"mendeley":{"formattedCitation":"(41)","plainTextFormattedCitation":"(41)","previouslyFormattedCitation":"(41)"},"properties":{"noteIndex":0},"schema":""}(41). In contrast, Capucci et al. performed a study using pre-specified AF durations in which the authors demonstrated that AF duration of >5 minutes was not associated with thromboembolic events unlike episodes >24 hours which were independently associated with thromboembolic events ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2005.07.044","ISSN":"1558-3597 (Electronic)","PMID":"16286180","abstract":"OBJECTIVES: The aim of our study was to evaluate arterial embolism (AE) occurrence rates and predictors in patients suffering from bradycardia and wearing a pacemaker with antitachycardia pacing therapies. BACKGROUND: Atrial fibrillation (AF) is associated with a high incidence of AE. METHODS: A total of 725 patients (360 men, age 71 +/- 11 years) were implanted with a DDDRP pacemaker (Medtronic AT500, Medtronic Inc., Minneapolis, Minnesota). At baseline 225 (31.0%) patients received antiplatelet therapy and 264 (36.4%) patients received anticoagulation agents. RESULTS: Over a median 22-month follow-up (25th to 75th interquartile range 16 to 30 months), AE occurred in 14 (1.9%) patients: 7 patients suffered a nonfatal ischemic stroke (0.6% per year), 4 patients had transient ischemic attack (0.34% per year), and 3 patients had embolic complications. Among baseline patients' characteristics, multivariate logistic analysis showed that embolic events are independently associated to ischemic heart disease (7.0 odds ratio [OR], 95% confidence interval [CI] 2.3 to 21.3, p = 0.001), prior embolic event (7.3 OR, 95% CI 1.2 to 43.9, p = 0.029), diabetes (5.0 OR, 95% CI 1.2 to 15.7, p = 0.032), and hypertension (4.1 OR, 95% CI 1.1 to 15.6, p = 0.036). The risk of embolism, adjusted for known risk factors, was 3.1 times increased (95% CI 1.1 to 10.5, p = 0.044) in patients with device-detected atrial fibrillation episodes longer than one day during follow-up. CONCLUSIONS: In a cohort of patients with bradycardia and AF, arterial embolism was common in patients with ischemic cardiopathy, hypertension, diabetes mellitus, and in patients with known stroke risk factors. Atrial fibrillation occurrences longer than one day were independently associated with embolic events.","author":[{"dropping-particle":"","family":"Capucci","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santini","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Padeletti","given":"Luigi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gulizia","given":"Michele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Botto","given":"GianLuca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boriani","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ricci","given":"Renato","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Favale","given":"Stefano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zolezzi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Belardino","given":"Natale","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Molon","given":"Giulio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drago","given":"Fabrizio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Villani","given":"Giovanni Q","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mazzini","given":"Elena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vimercati","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grammatico","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2005","11"]]},"language":"eng","page":"1913-1920","publisher-place":"United States","title":"Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers.","type":"article-journal","volume":"46"},"uris":[""]}],"mendeley":{"formattedCitation":"(42)","plainTextFormattedCitation":"(42)","previouslyFormattedCitation":"(42)"},"properties":{"noteIndex":0},"schema":""}(42). A potential explanation for the differences observed in this study may be related to the fact that a significant proportion of patients had short episodes of AF (about 80%). Pooled analysis of five prospective studies that included 10,016 patients with implantable devices found that AF burden was an independent predictor of ischaemic stroke ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/eht491","ISSN":"1522-9645 (Electronic)","PMID":"24334432","abstract":"OBJECTIVE: The aim of this study was to assess the association between maximum daily atrial fibrillation (AF) burden and risk of ischaemic stroke. BACKGROUND: Cardiac implanted electronic devices (CIEDs) enhance detection of AF, providing a comprehensive measure of AF burden. DESIGN, SETTING, AND PATIENTS: A pooled analysis of individual patient data from five prospective studies was performed. Patients without permanent AF, previously implanted with CIEDs, were included if they had at least 3 months of follow-up. A total of 10 016 patients (median age 70 years) met these criteria. The risk of ischaemic stroke associated with pre-specified cut-off points of AF burden (5 min, 1, 6, 12, and 23 h, respectively) was assessed. RESULTS: During a median follow-up of 24 months, 43% of 10 016 patients experienced at least 1 day with at least 5 min of AF burden and for them the median time to the maximum AF burden was 6 months (inter-quartile range: 1.3-14). A Cox regression analysis adjusted for the CHADS2 score and anticoagulants at baseline demonstrated that AF burden was an independent predictor of ischaemic stroke. Among the thresholds of AF burden that we evaluated, 1 h was associated with the highest hazard ratio (HR) for ischaemic stroke, i.e. 2.11 (95% CI: 1.22-3.64, P = 0.008). CONCLUSIONS: Device-detected AF burden is associated with an increased risk of ischaemic stroke in a relatively unselected population of CIEDs patients. This finding may add to the basis for timely and clinically appropriate decision-making on anticoagulation treatment.","author":[{"dropping-particle":"","family":"Boriani","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Glotzer","given":"Taya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santini","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"West","given":"Teena M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Melis","given":"Mirko","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sepsi","given":"Milan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gasparini","given":"Maurizio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewalter","given":"Thorsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Camm","given":"John A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2014","2"]]},"language":"eng","page":"508-516","publisher-place":"England, England","title":"Device-detected atrial fibrillation and risk for stroke: an analysis of >10,000 patients from the SOS AF project (Stroke preventiOn Strategies based on Atrial Fibrillation information from implanted devices).","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"(43)","plainTextFormattedCitation":"(43)","previouslyFormattedCitation":"(43)"},"properties":{"noteIndex":0},"schema":""}(43). In this study, patients with one hour of AF per day were found to be at highest risk. Among patients with paroxysmal AF, authors of the KP-RHYTHM study reported a three-fold increased risk of thromboembolism in those with the highest tertile of AF burden (≥11.4%) compared to the lower two tertiles, after adjusting for either ATRIA or CHA2DS2-VASc score ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1001/jamacardio.2018.1176","ISSN":"2380-6591 (Electronic)","PMID":"29799942","abstract":"Importance: Atrial fibrillation is a potent risk factor for stroke, but whether the burden of atrial fibrillation in patients with paroxysmal atrial fibrillation independently influences the risk of thromboembolism remains controversial. Objective: To determine if the burden of atrial fibrillation characterized using noninvasive, continuous ambulatory monitoring is associated with the risk of ischemic stroke or arterial thromboembolism in adults with paroxysmal atrial fibrillation. Design, Setting, and Participants: This retrospective cohort study conducted from October 2011 and October 2016 at 2 large integrated health care delivery systems used an extended continuous cardiac monitoring system to identify adults who were found to have paroxysmal atrial fibrillation on 14-day continuous ambulatory electrocardiographic monitoring. Exposures: The burden of atrial fibrillation was defined as the percentage of analyzable wear time in atrial fibrillation or flutter during the up to 14-day monitoring period. Main Outcomes and Measures: Ischemic stroke and other arterial thromboembolic events occurring while patients were not taking anticoagulation were identified through November 2016 using electronic medical records and were validated by manual review. We evaluated the association of the burden of atrial fibrillation with thromboembolism while not taking anticoagulation after adjusting for the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) or CHA2DS2-VASc stroke risk scores. Results: Among 1965 adults with paroxysmal atrial fibrillation, the mean (SD) age was 69 (11.8) years, 880 (45%) were women, 496 (25%) were persons of color, the median ATRIA stroke risk score was 4 (interquartile range [IQR], 2-7), and the median CHA2DS2-VASc score was 3 (IQR, 1-4). The median burden of atrial fibrillation was 4.4% (IQR ,1.1%-17.23%). Patients with a higher burden of atrial fibrillation were less likely to be women or of Hispanic ethnicity, but had more prior cardioversion attempts compared with those who had a lower burden. After adjusting for either ATRIA or CHA2DS2-VASc stroke risk scores, the highest tertile of atrial fibrillation burden (>/=11.4%) was associated with a more than 3-fold higher adjusted rate of thromboembolism while not taking anticoagulants (adjusted hazard ratios, 3.13 [95% CI, 1.50-6.56] and 3.16 [95% CI, 1.51-6.62], respectively) compared with the combined lower 2 tertiles of atrial fibrillation burden. Results were consistent ac…","author":[{"dropping-particle":"","family":"Go","given":"Alan S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reynolds","given":"Kristi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Jingrong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gupta","given":"Nigel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lenane","given":"Judith","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sung","given":"Sue Hee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harrison","given":"Teresa N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Taylor I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Solomon","given":"Matthew D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA cardiology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2018","7"]]},"language":"eng","page":"601-608","publisher-place":"United States, United States","title":"Association of Burden of Atrial Fibrillation With Risk of Ischemic Stroke in Adults With Paroxysmal Atrial Fibrillation: The KP-RHYTHM Study.","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"(44)","plainTextFormattedCitation":"(44)","previouslyFormattedCitation":"(44)"},"properties":{"noteIndex":0},"schema":""}(44). A further study in patients with dual-chamber pacemakers also confirmed that patients with thromboembolism had higher AF burden ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.hrtlng.2019.07.007","ISSN":"01479563","PMID":"31376922","abstract":"BACKGROUND: Atrial fibrillation (AF) burden might link to increased risk of systemic embolism. Current scoring systems for evaluating stroke risks such as CHA2DS2-VASc do not incorporate AF burden partly because of the difficulty to assess these data. Patients with dual-chamber pacemakers implanted have opportunities to acquire incidence and duration of AF. OBJECTIVES: We aimed to evaluate the AF burden and its association with thromboembolism in patients with dual-chamber pacemakers. METHODS: This retrospective cohort study enrolled patients who underwent dual-chamber pacemaker implantation at our center between October 2003 and May 2017. We excluded patients with prior thromboembolism or receiving anticoagulants. The incidence and duration of pacemaker-detected AF were compared between patients with and without thromboembolic outcomes. Propensity score matching (1:1) was conducted based on clinical characteristics. Multivariate regressions were performed to determine the predictors of thromboembolic outcomes. Survival free from stroke and thromboembolism was assessed using Kaplan-Meier analysis in groups with different AF burden. RESULTS: Among the 152 patients enrolled (43.4% women; age 73.2+/-13.3 years), ten experienced thromboembolic events within a median follow-up of 67 months. Patients with thromboembolisms had higher CHA2DS2-VASc scores but not higher AF burden. Higher CHA2DS2-VASc score was associated with increased risk for systemic thromboembolism [hazard ratio (HR), 1.87; 95% confidence interval (CI), 1.07-3.24; P=0.027). In the propensity score-matched cohort with comparable CHA2DS2-VASc score, patients with thromboembolism had higher AF burden. Pacemaker-detected AF was associated with increased risk for thromboembolism (propensity-adjusted HR, 9.33; 95% CI, 1.19-72.99; P=0.033). Experiencing AF episodes lasting >6 min was a predictor of significantly higher risk of future stroke or thromboembolism (propensity-adjusted HR, 6.75; 95% CI, 1.30-35.11; P=0.023). CONCLUSION: In patients with dual-chamber pacemakers and comparable CHA2DS2-VASc score, pacemaker-detected AF burden is associated with elevated risk for thromboembolism. Further research is needed to clarify how pacemaker-detected AF burden could incorporate with CHA2DS2-VASc score variables and help to guide anticoagulation.","author":[{"dropping-particle":"","family":"Chu","given":"Song-Yun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiang","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Yu-Ling","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheng","given":"Qin-Hui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhou","given":"Jing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ding","given":"Yan-Sheng","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart & Lung","id":"ITEM-1","issued":{"date-parts":[["2019","7"]]},"language":"eng","publisher":"Elsevier Inc.","publisher-place":"United States, United States","title":"Pacemaker-detected atrial fibrillation burden and risk of ischemic stroke or thromboembolic events—A cohort study","type":"article-journal","volume":"000"},"uris":[""]}],"mendeley":{"formattedCitation":"(45)","plainTextFormattedCitation":"(45)","previouslyFormattedCitation":"(45)"},"properties":{"noteIndex":0},"schema":""}(45). Overall, AF burden may reflect the proportion of time spent in mechanical dyssynchrony, thereby promoting thrombus formation. Though it is recognised to be an important predictor of stroke risk, the exact relationship remains to be defined and further research is warranted. Furthermore, determining the AF burden in patients without implantable cardiac devices can be challenging. There are also important considerations when treating patients with a high burden of AF. Although a strategy to reduce this burden may be appropriate for some patients, attempts to restore sinus rhythm is not without risk. The FibStroke study revealed that electrical and pharmacological cardioversions were related to occurrences of ischaemic stroke ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ijcard.2015.10.168","ISSN":"1874-1754 (Electronic)","PMID":"26519683","abstract":"BACKGROUND: Cardioversion of atrial fibrillation (AF) is associated with an increased risk for stroke. We identified all cardioversions during the 30 days preceding stroke or transient ischemic attack (TIA) in patients with a previously diagnosed AF, and sought to assess the characteristics of cardioversions leading to stroke or TIA. METHODS: FibStroke is a cross-sectional observational multicenter registry that included AF patients with an ischemic stroke or intracranial bleed identified from a discharge registry of four Finnish hospitals. In total 3677 consecutive AF patients suffered 3252 strokes and 956 TIA episodes during 2003-2012. This pre-specified analysis focused on the 1644 events that occurred to patients with paroxysmal or persistent AF at the time of stroke/TIA. RESULTS: A total of 78 strokes and 22 TIA episodes were preceded by a cardioversion. Post-cardioversion strokes accounted for 6.4% of strokes in patients with paroxysmal/persistent AF. Of the 100 cardioversions leading to an ischemic event, 77 were acute and 23 were elective, 63 events occurred in patients not using anticoagulation, and 5 patients had periprocedural INR < 2. Importantly, 21 patients were in low risk of stroke, i.e. CHA2DS2-VASc score < 2. The median delay from cardioversion to event was 2 days. All nine patients who after an unsuccessful cardioversion developed a stroke had a spontaneous cardioversion prior to stroke. CONCLUSIONS: Every sixteenth stroke of patients with paroxysmal/persistent AF is preceded by a cardioversion. Most post-cardioversion strokes occur in patients not using oral anticoagulation before cardioversion of acute AF.","author":[{"dropping-particle":"","family":"Palomaki","given":"Antti","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mustonen","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartikainen","given":"Juha E K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuotio","given":"Ilpo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kiviniemi","given":"Tuomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ylitalo","given":"Antti","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartikainen","given":"Paivi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehtola","given":"Heidi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luite","given":"Riho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Airaksinen","given":"K E Juhani","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International journal of cardiology","id":"ITEM-1","issued":{"date-parts":[["2016","1"]]},"language":"eng","page":"269-273","publisher-place":"Netherlands, Netherlands","title":"Strokes after cardioversion of atrial fibrillation--The FibStroke study.","type":"article-journal","volume":"203"},"uris":[""]}],"mendeley":{"formattedCitation":"(46)","plainTextFormattedCitation":"(46)","previouslyFormattedCitation":"(46)"},"properties":{"noteIndex":0},"schema":""}(46). As the majority of events occurred in patients who underwent electrical cardioversion, it could be postulated that the delivery of electrical energy may have dislodged pre-formed thrombi. However, many of the stroke events only occurred after a significant time delay (median of two days) following cardioversion. Therefore, there are likely to be other factors involved. Furthermore, there are even reports of acute thromboembolic complications following spontaneous cardioversion of AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.7326/0003-4819-126-8-199704150-00005","ISSN":"0003-4819 (Print)","PMID":"9103128","abstract":"BACKGROUND: It has been assumed that cardioversion in patients with atrial fibrillation lasting less than 48 hours is associated with a low risk for thromboembolism. However, no clinical data support this assumption. OBJECTIVE: To determine the incidence of cardioversion-related clinical thromboembolism among patients presenting with atrial fibrillation lasting less than 48 hours. DESIGN: Patients were prospectively identified on admission, and clinical data on the duration of atrial fibrillation were recorded. Data on cardioversion and thromboembolism were obtained retrospectively from hospital and outpatient records. SETTING: Academic medical center. PATIENTS: 1822 consecutive patients admitted to the hospital for atrial fibrillation were screened. Three hundred seventy-five adults (mean age +/- SD, 68 +/- 16 years) with atrial fibrillation that had lasted less than 48 hours were identified. One hundred eighty-one patients (48.3%) had a history of atrial fibrillation; 23 (6.1%) had a history of thromboembolism. RESULTS: 357 patients (95.2%) converted to sinus rhythm during the index admission; spontaneous conversion occurred in 250 patients (66.7%) and active pharmacologic or electrical conversion was done in 107 patients (28.5%). Three patients (0.8% [95% CI, 0.2% to 2.4%]), all of whom had converted spontaneously after ventricular rate control was begun, had a clinical thromboembolic event: One had a stroke, 1 had a transient ischemic attack, and 1 had a peripheral embolus. None of these 3 patients had a history of atrial fibrillation or thromboembolism, and all had normal left ventricular systolic function. CONCLUSION: Among patients presenting with atrial fibrillation that was clinically estimated to have lasted less than 48 hours, the likelihood of cardioversion-related clinical thromboembolism is low. These data support the current recommendation for early cardioversion in these patients.","author":[{"dropping-particle":"","family":"Weigner","given":"M J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caulfield","given":"T A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Danias","given":"P G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silverman","given":"D I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manning","given":"W J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of internal medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["1997","4"]]},"language":"eng","page":"615-620","publisher-place":"United States, United States","title":"Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours.","type":"article-journal","volume":"126"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/s0196-0644(99)70300-8","ISSN":"0196-0644 (Print)","PMID":"10092714","abstract":"STUDY OBJECTIVE: Patients presenting to the emergency department with acute atrial fibrillation are traditionally admitted to hospital. The objective of this study was to review the success and safety of ED cardioversion and discharge of patients with acute atrial fibrillation. METHODS: This health records survey included a cohort sample of consecutive patients presenting with acute atrial fibrillation to the ED of a university-affiliated tertiary hospital. Patients who were in unstable condition on presentation, who had a complicating cardiac diagnosis, or those with other medical or surgical conditions requiring admission were excluded from the study analysis. Patient visit information was entered into a database that included demographics and clinical presentation, investigations, ED therapy, complications, consultations, disposition, and follow up. Patient visits were then categorized into the following groups: no ED intervention, spontaneous resolution, heart rate control, attempted chemical cardioversion, or electrical cardioversion. The data were analyzed using descriptive methods. RESULTS: Of the 289 eligible patients seen during an 18-month period, 62% (180) underwent attempted chemical cardioversion with a 50% success rate and 28% (80) had attempted electrical cardioversion with a 89% success rate. Ninety-three percent of electrical cardioversions were performed by emergency physicians. There was an overall 6% (19) complication rate, 95% of which were regarded as minor. One patient had a complication caused by a rate control medication, which necessitated hospital admission. Ninety-seven percent (280) of the patients were discharged home directly from the ED. CONCLUSION: Cardioversion and immediate discharge of patients who present to the ED with acute atrial fibrillation appears to be both safe and effective. This management approach should be prospectively evaluated in multiple settings.","author":[{"dropping-particle":"","family":"Michael","given":"J A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stiell","given":"I G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Agarwal","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mandavia","given":"D P","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of emergency medicine","id":"ITEM-2","issue":"4","issued":{"date-parts":[["1999","4"]]},"language":"eng","page":"379-387","publisher-place":"United States, United States","title":"Cardioversion of paroxysmal atrial fibrillation in the emergency department.","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"(47,48)","plainTextFormattedCitation":"(47,48)","previouslyFormattedCitation":"(47,48)"},"properties":{"noteIndex":0},"schema":""}(47,48). A potential cause for this may be linked to atrial stunning that occurs regardless of the means of cardioversion ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/s0167-5273(03)00107-4","ISSN":"0167-5273 (Print)","PMID":"14659842","abstract":"Conversion of atrial fibrillation and flutter to sinus rhythm results in a transient mechanical dysfunction of atrium and atrial appendage, termed atrial stunning. Atrial stunning has been reported with all modes of conversion of atrial fibrillation and flutter to sinus rhythm including both transthoracic and low energy internal electrical, pharmacological, and spontaneous cardioversion, and conversion by overdrive pacing and by radiofrequency ablation. Atrial stunning is a function of the underlying arrhythmia becoming apparent at the restoration of sinus rhythm, not the function of the mode of conversion, and does not develop after the unsuccessful attempts of cardioversion or the delivery of electric current to the heart during rhythms other than atrial fibrillation or flutter. Tachycardia-induced atrial cardiomyopathy, cytosolic calcium accumulation, and atrial hibernation are the suggested mechanisms of atrial stunning. Atrial stunning is at maximum immediately after cardioversion and improves progressively with a complete resolution within a few minutes to 4-6 weeks depending on the duration of the preceding atrial fibrillation, atrial size, and structural heart disease. Atrial stunning causes postcardioversion thromboembolism despite restoration of sinus rhythm. Duration of anticoagulation therapy after successful cardioversion should depend on the duration of atrial stunning. Lack of improvement in cardiac output and functional recovery of patients immediately after cardioversion is attributed to the atrial stunning. Verapamil, acetylstrophenathidine, isoproterenol, and dofetilide have been reported to protect from atrial stunning in animal and small human studies. Right atrium stunning is less marked and improves earlier than that of left atrium, resulting in a differential atrial stunning explaining the rare occurrence of pulmonary edema after cardioversion.","author":[{"dropping-particle":"","family":"Khan","given":"Ijaz A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International journal of cardiology","id":"ITEM-1","issue":"2-3","issued":{"date-parts":[["2003","12"]]},"language":"eng","page":"113-128","publisher-place":"Netherlands, Netherlands","title":"Atrial stunning: basics and clinical considerations.","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"(49)","plainTextFormattedCitation":"(49)","previouslyFormattedCitation":"(49)"},"properties":{"noteIndex":0},"schema":""}(49). It was previously suggested that the morphology of AF as assessed on ECG may be useful for stroke risk assessment. In a study of 811 consecutive patients, Yilmaz et al. classified AF based on surface ECG as ‘coarse’ or ‘fine’ AF, and was able to demonstrate that patients with coarse AF had increased risk of stroke ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000095416","ISSN":"1421-9751 (Electronic)","PMID":"16943646","abstract":"BACKGROUND: Atrial fibrillation (AF) is a frequent arrhythmia, associated with morbidity and mortality. It is identified by two types on surface electrocardiogram as fine and coarse AF. We aimed to search the association of subtypes of AF with clinical parameters. METHODS: Eight hundred and eleven consecutive patients, who had AF attack which lasted longer than 24 h or more, were evaluated along with clinical and laboratory data. RESULTS: Coarse AF was noticed in 51.7% (n = 419), and fine AF in 48.3% (n = 392). Sex was associated with subtype of AF such that coarse AF was present in 46.5% of male patients, but in 56.1% of female patients (p = 0.009). Coarse AF was present in 85.3% of patients with mitral stenosis, whereas it was present in 35.3% of patients with normal heart valve (p < 0.001). ). Patients having fine AF were significantly older than those having coarse AF (64 +/- 12, 57 +/- 13 years, p < 0.001). 19.6% of those with coarse AF had history of cerebrovascular event (CVE), whereas 13.5% of those with fine AF had history of CVE (p = 0.021). After controlling for age in the multivariable logistic regression analysis, presence of coarse AF (B = 1.585, p = 0.031) was found to be independently associated with the history of CVE. CONCLUSION: AF is identified by two morphological forms on the surface electrocardiogram. These two forms were found to be associated with different clinical parameters, acting on vascular endpoints differently.","author":[{"dropping-particle":"","family":"Yilmaz","given":"Mehmet Birhan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guray","given":"Yesim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guray","given":"Umit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cay","given":"Serkan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caldir","given":"Vedat","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Biyikoglu","given":"Senay Funda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sasmaz","given":"Hatice","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Korkmaz","given":"Sule","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cardiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2007"]]},"language":"eng","page":"193-196","publisher-place":"Switzerland, Switzerland","title":"Fine vs. coarse atrial fibrillation: which one is more risky?","type":"article-journal","volume":"107"},"uris":[""]}],"mendeley":{"formattedCitation":"(50)","plainTextFormattedCitation":"(50)","previouslyFormattedCitation":"(50)"},"properties":{"noteIndex":0},"schema":""}(50). The authors defined ‘coarse’ AF as the presence of undulations moving ≥1 mm from the isoelectric baseline with different morphologies and ‘fine’ AF as the presence of minimal or no undulation from the isoelectric baseline. At present, there is insufficient evidence to draw any firm conclusions. Nevertheless, if deemed reliable, classification of AF according to the different morphologies on ECG may provide a readily assessible tool to support clinical decisions.Given the increased risk of stroke in AF, it would seem plausible that a temporal relationship might exists between these two conditions. If true, it may provide us a method of identifying patients at the point of highest stroke risk in order to instigate additional protective measures to avoid this complication. However, an initial study by ASSERT investigators revealed that only 8% of patients had subclinical AF detected within 30 days before their stroke or systemic embolism ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.113.007825","ISSN":"15244539","PMID":"24633881","abstract":"Background - Among patients with implantable pacemakers and defibrillators, subclinical atrial fibrillation (SCAF) is associated with an increased risk of stroke; however, there is limited understanding of their temporal relationship. Methods and Results - The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) enrolled 2580 pacemaker and defibrillator patients aged ≥65 years with a history of hypertension but without a history of atrial fibrillation. Pacemakers and implantable cardioverter-defibrillators precisely logged the time and duration of all episodes of SCAF and recorded electrograms that were adjudicated by experts. We examined the temporal relationship between SCAF >6 minutes in duration and stroke or systemic embolism. Of 51 patients who experienced stroke or systemic embolism during follow-up, 26 (51%) had SCAF. In 18 patients (35%), SCAF was detected before stroke or systemic embolism. However, only 4 patients (8%) had SCAF detected within 30 days before stroke or systemic embolism, and only 1 of these 4 patients was experiencing SCAF at the time of the stroke. In the 14 patients with SCAF detected >30 days before stroke or systemic embolism, the most recent episode occurred at a median interval of 339 days (25th to 75th percentile, 211-619) earlier. Eight patients (16%) had SCAF detected only after their stroke, despite continuous monitoring for a median duration of 228 days (25th to 75th percentile, 202-719) before their event. Conclusions - Although SCAF is associated with an increased risk of stroke and embolism, very few patients had SCAF in the month before their event. ? 2014 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Brambatti","given":"Michela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gold","given":"Michael R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morillo","given":"Carlos A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Capucci","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muto","given":"Carmine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lau","given":"Chu P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gelder","given":"Isabelle C.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carlson","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fain","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakamya","given":"Juliet","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mairesse","given":"Georges H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halytska","given":"Marta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deng","given":"Wei Q.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Israel","given":"Carsten W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Healey","given":"Jeff S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"21","issued":{"date-parts":[["2014","5"]]},"language":"eng","page":"2094-2099","publisher-place":"United States, United States","title":"Temporal relationship between subclinical atrial fibrillation and embolic events","type":"article-journal","volume":"129"},"uris":[""]}],"mendeley":{"formattedCitation":"(51)","plainTextFormattedCitation":"(51)","previouslyFormattedCitation":"(51)"},"properties":{"noteIndex":0},"schema":""}(51). Thus far, there is no strong evidence to support a temporal relationship between the episodes of AF and stroke events.Biological markers (‘biomarkers’)Many biomarkers involving blood, urine and structural parameters have been studied in AF and been shown to improve the accuracy of stroke risk stratification. Despite this, their clinical applicability remains limited. Possible reasons include inter- and intra-patient and assay variability; diurnal variation of the results obtained; costs involved; strong influences of associated comorbidities and treatments in AF on these parameters; and lack of specificity. As such, these biomarkers are mainly reserved for research purposes. Blood-based biomarkersIn general, blood-based biomarkers may be divided into those that relate to cardiac function (troponins and natriuretic peptides), haemostatic processes (D-dimer, von Willebrand factor (vWF), soluble E-selectin and P-selectin), inflammation (interleukin-6 (IL-6) and C-reactive protein (CRP)) or ‘others’ (renal function) ( REF _Ref25707324 \r \h \* MERGEFORMAT Table 3). Cardiac functionTroponins and natriuretic peptides are among the most frequently used cardiac biomarkers. Their value in a variety of cardiovascular diseases such as myocardial infarction and heart failure have previously been established ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehv320","ISSN":"1522-9645 (Electronic)","PMID":"26320110","author":[{"dropping-particle":"","family":"Roffi","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patrono","given":"Carlo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Collet","given":"Jean-Philippe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mueller","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valgimigli","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andreotti","given":"Felicita","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bax","given":"Jeroen J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borger","given":"Michael 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of","type":"article-journal","volume":"37"},"uris":[""]}],"mendeley":{"formattedCitation":"(52,53)","plainTextFormattedCitation":"(52,53)","previouslyFormattedCitation":"(52,53)"},"properties":{"noteIndex":0},"schema":""}(52,53). Further studies have also consistently demonstrated that levels of these biomarkers may be used to improve predictions of stroke risk in AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00380-010-0084-2","ISSN":"1615-2573 (Electronic)","PMID":"21188387","abstract":"The aim of the present study was to assess whether elevated B-type natriuretic peptide (BNP) levels, as an objective marker of heart failure, is a predictor of subsequent thromboembolic events in patients with atrial fibrillation (AF) during oral anticoagulant therapy. This was a post hoc analysis of a single-center, prospective, observational study. Consecutive patients with AF (261 patients, 74 +/- 9 years old, 153 paroxysmal AF) treated with warfarin were included for the analysis. BNP level at baseline examination was measured to assess the relationship of this parameter with subsequent thromboembolic events. BNP levels at the time of entry were 161 +/- 188 (5-1,500, median 105) pg/ml. During an average follow-up time of 762 +/- 220 (median 742) days, nine (1.8%/year) thromboembolic events occurred. Receiver operating characteristic curve showed that an optimal cut-off value for BNP to predict thromboembolic events was 218 pg/ml. There were six thromboembolic events observed among patients with a baseline BNP levels >/=200 pg/ml (n = 73) as compared to three such events in those with baseline BNP levels <200 pg/ml (n = 188). Kaplan-Meier curves for BNP level showed that elevated BNP level (>/=200 pg/ml) was significantly associated with thromboembolic events (p < 0.01). Cox-proportional hazard analysis also revealed that a high BNP level (>/=200 pg/ml) was a significant predictor of subsequent thromboembolic events (hazard ratio 5.32, p = 0.018). Elevated BNP levels (>/=200 pg/ml) could be a useful marker of subsequent thromboembolic events in patients with AF during oral anticoagulant therapy. However, the number of patients and events in this study was small and drawing a definite conclusion was not possible with this small sample size. Therefore, further larger-scale, multicenter studies are needed to confirm these findings.","author":[{"dropping-particle":"","family":"Sadanaga","given":"Tsuneaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kohsaka","given":"Shun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mitamura","given":"Hideo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogawa","given":"Satoshi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart and vessels","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2011","9"]]},"language":"eng","page":"530-535","publisher-place":"Japan, Japan","title":"Elevated B-type natriuretic peptide level as a marker of subsequent thromboembolic events in patients with atrial fibrillation.","type":"article-journal","volume":"26"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1111/j.1538-7836.2012.04812.x","ISSN":"1538-7836 (Electronic)","PMID":"22681487","abstract":"UNLABELLED: There are limited data on the prognostic role of biomarkers in anticoagulated patients with atrial fibrillation (AF). We evaluated the prognostic value of high sensitivity TnT (hsTnT) and high-sensitivity interleukin-6 (hsIL6) in a large cohort of AF patients taking oral anticoagulant therapy (OAC) as both biomarkers have been associated with adverse cardiovascular events. METHODS: We studied 930 patients (51% male; median age 76) with permanent/ paroxysmal AF who were stabilized (for at least 6 months) on OAC (INRs 2.0-3.0). Plasma hsTnT and hsIL6 levels were quantified by electrochemiluminescense immunoassay at baseline. Patients were followed-up for up to 2 years, and adverse events (thrombotic and vascular events, mortality and major bleeding) were recorded. RESULTS: At follow-up, 96 patients (3.97%/year) died whilst 107 had an adverse cardiovascular event (3.14%/year). On multivariate analysis, high hsTnT and high hsIL6 remained significantly associated with prognosis even after adjusting for CHADS2 score: HR 2.21 (1.46-3.35, P<0.001) for high hsTnT and 1.97 (1.29-3.02, P=0.002) for high hsIL6, for adverse cardiovascular events. For all-cause mortality, the HRs were 1.79 (1.13-2.83, P=0.013) and 2.48 (1.60-3.85, P<0.001), respectively. The integrated discrimination index (IDI) values of clinical scores (CHADS2 and CHA2 DS2-VASc) were improved by the addition of hsTnT and/or hsIL6 (all P<0.05). CONCLUSION: In a large 'real world' cohort of anticoagulated AF patients, both hsTnT and hsIL6 levels provided prognostic information that was complementary to clinical risk scores for prediction of long-term cardiovascular events and death, suggesting that these biomarkers may potentially be used to refine clinical risk stratification in AF.","author":[{"dropping-particle":"","family":"Roldan","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diaz","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallego","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jover","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Romera","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manzano-Fernandez","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casas","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"G Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of thrombosis and haemostasis : JTH","id":"ITEM-2","issue":"8","issued":{"date-parts":[["2012","8"]]},"language":"eng","page":"1500-1507","publisher-place":"England, England","title":"High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation.","type":"article-journal","volume":"10"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1161/CIRCULATIONAHA.111.038729","ISSN":"1524-4539 (Electronic)","PMID":"22374183","abstract":"BACKGROUND: Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. METHODS AND RESULTS: Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS(2) and CHA(2)DS(2)-VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 mug/L, n=2663; 0.010 to 0.019 mug/L, n=2006; 0.020 to 0.039 mug/L, n=1023; >/=0.040 mug/L, n=497; and on NT-proBNP concentration quartiles: <387; 387 to 800; 801 to 1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17-3.39]; P=0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41-4.07]; P=0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05-6.29]; P<0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95-11.49]; P<0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P<0.0001, for a composite of thromboembolic events. CONCLUSIONS: Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables.","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reilly","given":"Paul A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinereanu","given":"Dragos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-3","issue":"13","issued":{"date-parts":[["2012","4"]]},"language":"eng","page":"1605-1616","publisher-place":"United States, United States","title":"Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy.","type":"article-journal","volume":"125"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1016/j.jacc.2012.11.082","ISSN":"1558-3597 (Electronic)","PMID":"23563134","abstract":"OBJECTIVES: This study sought to assess the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and the treatment effect of apixaban according to NT-proBNP levels. BACKGROUND: Natriuretic peptides are associated with mortality and cardiovascular events in several cardiac diseases. METHODS: In the ARISTOTLE trial, 18,201 patients with AF were randomized to apixaban or warfarin. Plasma samples at randomization were available from 14,892 patients. The association between NT-proBNP concentrations and clinical outcomes was evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors. RESULTS: Quartiles of NT-proBNP were: Q1, </=363 ng/l; Q2, 364 to 713 ng/l; Q3, 714 to 1,250 ng/l; and Q4, >1,250 ng/l. During 1.9 years, the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile, an adjusted hazard ratio of 2.35 (95% confidence interval [CI]: 1.62 to 3.40; p < 0.0001). Annual rates of cardiac death ranged from 0.86% in Q1 to 4.14% in Q4, with an adjusted hazard ratio of 2.50 (95% CI: 1.81 to 3.45; p < 0.0001). Adding NT-proBNP levels to the CHA2DS2VASc score improved C-statistics from 0.62 to 0.65 (p = 0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p < 0.0001). Apixaban reduced stroke, mortality, and bleeding regardless of the NT-proBNP level. CONCLUSIONS: NT-proBNP levels are often elevated in AF and independently associated with an increased risk of stroke and mortality. NT-proBNP improves risk stratification beyond the CHA2DS2VASc score and might be a novel tool for improved stroke prediction in AF. The efficacy of apixaban compared with warfarin is independent of the NT-proBNP level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984).","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christersson","given":"Christina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Justin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gersh","given":"Bernard J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanna","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horowitz","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huber","given":"Kurt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"Renato D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"McMurray","given":"John J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-4","issue":"22","issued":{"date-parts":[["2013","6"]]},"language":"eng","page":"2274-2284","publisher-place":"United States, United States","title":"N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation).","type":"article-journal","volume":"61"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1161/STROKEAHA.113.003338","ISSN":"1524-4628 (Electronic)","PMID":"24519407","abstract":"BACKGROUND AND PURPOSE: Oral anticoagulation is highly effective in reducing stroke and mortality in atrial fibrillation (AF). Several risk stratification schemes have been developed using clinical characteristics. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) are important markers of increased mortality and morbidity in congestive heart failure and general community population. The aim of our study was to assess the predictive value of NT-proBNP levels in an unselected real-world cohort of anticoagulated patients with AF. METHODS: We studied 1172 patients (49% male; median age, 76 years) with permanent AF who were well stabilized on oral anticoagulation (international normalized ratio, 2.0-3.0). Plasma NT-proBNP levels were quantified at baseline. We recorded thrombotic and vascular events, mortality, and major bleeding. The best cutoff points were assessed by receiver-operating characteristic curves. RESULTS: Median levels (interquartile range) of NT-proBNP were 610 (318-1037) pg/mL. Median follow-up was 1007 (806-1279) days. On multivariate analysis, high NT-proBNP was significantly associated with the risk of stroke (hazards ratio, 2.71; P=0.001) and composite vascular events (acute coronary syndrome or acute heart failure; hazards ratio, 1.85; P=0.016), as well as a significant association with mortality (adjusted hazards ratio, 1.66; P=0.006). No association with bleeding was found (P=0.637). The integrated discrimination improvement (IDI) analysis demonstrated that NT-proBNP improved the Congestive heart failure, Hypertension, Age>/=75 (doubled), Diabetes mellitus, Stroke (doubled)-Vascular disease and Sex category (female); CHA2DS2-VASc score for predicting embolic events (relative IDI, 2.8%; P=0.001) and all-cause death (relative IDI, 1.8%; P=0.001). CONCLUSIONS: In real-world cohort of anticoagulated patients with AF, NT-proBNP provided complementary prognostic information to an established clinical risk score (CHA2DS2-VASc) for the prediction of stroke/systemic embolism. NT-proBNP was also predictive of all-cause mortality, suggesting that this biomarker may potentially be used to refine clinical risk stratification in anticoagulated patients with AF.","author":[{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vilchez","given":"Juan Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manzano-Fernandez","given":"Sergio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jover","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galvez","given":"Josefa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Puche","given":"Carmen M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-5","issue":"3","issued":{"date-parts":[["2014","3"]]},"language":"eng","page":"696-701","publisher-place":"United States, United States","title":"Usefulness of N-terminal pro-B-type natriuretic Peptide levels for stroke risk prediction in anticoagulated patients with atrial fibrillation.","type":"article-journal","volume":"45"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"10.1253/circj.CJ-17-1085","ISSN":"1347-4820 (Electronic)","PMID":"29491320","abstract":"BACKGROUND: B-type natriuretic peptide (BNP) may be a predictor of stroke risk in patients with nonvalvular atrial fibrillation (NVAF); because heart failure is associated with the incidence of stroke in AF patients. However, limited data exist regarding the association between BNP at baseline and risks of thromboembolic events (TE) and death in NVAF patients. Methods and Results: We prospectively studied 1,013 NVAF patients (725 men, 72.8+/-9.7 years old) from the Hokuriku-plus AF Registry to determine the relationship between BNP at baseline and prognosis among Japanese NVAF patients. During the follow-up period (median, 751 days); 31 patients experienced TE and there were 81 cases of TE/all-cause death. For each endpoint we constructed receiver-operating characteristic curves that gave cutoff points of BNP for TE (170 pg/mL) and TE/all-cause death (147 pg/mL). Multivariate analysis with the Cox-proportional hazards model indicated that high BNP was significantly associated with risks of TE (hazard ratio [HR] 3.86; 95% confidence interval [CI] 1.83-8.67; P=0.0003) and TE/all-cause death (HR 2.27; 95% CI 1.45-3.56; P=0.0003). Based on the C-index and net reclassification improvement, the addition of BNP to CHA2DS2-VASc statistically improved the prediction of TE. CONCLUSIONS: In a real-world cohort of Japanese NVAF patients, high BNP was significantly associated with TE and death. Plasma BNP might be a useful biomarker for these adverse clinical events.","author":[{"dropping-particle":"","family":"Hayashi","given":"Kenshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsuda","given":"Toyonobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nomura","given":"Akihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fujino","given":"Noboru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nohara","given":"Atsushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sakata","given":"Kenji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Konno","given":"Tetsuo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakanishi","given":"Chiaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tada","given":"Hayato","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagata","given":"Yoji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teramoto","given":"Ryota","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanaka","given":"Yoshihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawashiri","given":"Masa-Aki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamagishi","given":"Masakazu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation journal : official journal of the Japanese Circulation Society","id":"ITEM-6","issue":"5","issued":{"date-parts":[["2018","4"]]},"language":"eng","page":"1271-1278","publisher-place":"Japan, Japan","title":"Impact of B-Type Natriuretic Peptide Level on Risk Stratification of Thromboembolism and Death in Patients With Nonvalvular Atrial Fibrillation- The Hokuriku-Plus AF Registry.","type":"article-journal","volume":"82"},"uris":[""]}],"mendeley":{"formattedCitation":"(54–59)","plainTextFormattedCitation":"(54–59)","previouslyFormattedCitation":"(54–59)"},"properties":{"noteIndex":0},"schema":""}(54–59). A RE-LY sub-study found that elevations in troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were common among AF patients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.111.038729","ISSN":"1524-4539 (Electronic)","PMID":"22374183","abstract":"BACKGROUND: Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. METHODS AND RESULTS: Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS(2) and CHA(2)DS(2)-VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 mug/L, n=2663; 0.010 to 0.019 mug/L, n=2006; 0.020 to 0.039 mug/L, n=1023; >/=0.040 mug/L, n=497; and on NT-proBNP concentration quartiles: <387; 387 to 800; 801 to 1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17-3.39]; P=0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41-4.07]; P=0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05-6.29]; P<0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95-11.49]; P<0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P<0.0001, for a composite of thromboembolic events. CONCLUSIONS: Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables.","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reilly","given":"Paul A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinereanu","given":"Dragos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"13","issued":{"date-parts":[["2012","4"]]},"language":"eng","page":"1605-1616","publisher-place":"United States, United States","title":"Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy.","type":"article-journal","volume":"125"},"uris":[""]}],"mendeley":{"formattedCitation":"(56)","plainTextFormattedCitation":"(56)","previouslyFormattedCitation":"(56)"},"properties":{"noteIndex":0},"schema":""}(56). Both were independently related to an increased risk of stroke and there was a graded relationship such that patients with higher levels of these cardiac biomarkers were at greater risk compared to those with lower levels. The highest quartile of NT-proBNP was associated with 2.4-fold greater risk of stroke compared to the lowest quartile while the higher tertile of troponin I was associated with a 2.0-fold greater risk of stroke compared to the lowest tertile. There are several proposed mechanisms for the prognostic value of these cardiac biomarkers. In AF, unlike heart failure, B-type natriuretic peptides (BNPs) may originate from the atria ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehl109","ISSN":"0195-668X (Print)","PMID":"16785247","abstract":"In the normal heart, the endocrine capacity resides in the atria. Atrial myocytes express and secrete natriuretic hormones that regulate fluid homeostasis and blood pressure. But in ventricular disease, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression is also activated in ventricular myocytes. Plasma concentrations of natriuretic peptides and their biosynthetic precursors are accordingly increased in patients with marked ventricular dysfunction. In contrast, atrial peptide secretion in ventricular disease has received less attention, and our present understanding of the endocrine atria during ventricular dysfunction is still scarce. Although ventricular disease and increased circulating concentrations are associated, it does not entail that the ventricle is the sole or even the main source in all types of heart disease. Clearly, the endocrine atria are also active in heart failure. Plasma measurement of cardiac natriuretic peptides and their molecular precursors can perhaps help us to discriminate when, where and how.","author":[{"dropping-particle":"","family":"Goetze","given":"Jens Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friis-Hansen","given":"Lennart","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rehfeld","given":"Jens F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nilsson","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svendsen","given":"Jesper Hastrup","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"14","issued":{"date-parts":[["2006","7"]]},"language":"eng","page":"1648-1650","publisher-place":"England, England","title":"Atrial secretion of B-type natriuretic peptide.","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(60)","plainTextFormattedCitation":"(60)","previouslyFormattedCitation":"(60)"},"properties":{"noteIndex":0},"schema":""}(60). This is supported by the fact that restoration of sinus rhythm is associated with a rapid fall in the level of natriuretic peptides ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjcard.2005.12.071","ISSN":"00029149","abstract":"It has been reported that plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels are elevated in patients with atrial fibrillation (AF). The aim of this study was to investigate the change in these patients after pulmonary vein isolation (PVI). In 66 patients with paroxysmal AF (PAF) and without any structural heart disease, plasma ANP and BNP levels were measured before and 3 months after successful PVI. At baseline, in 14 patients, ANP and BNP levels were elevated, and in 52 patients, only BNP levels were elevated. There were no significant relations between the attack frequency or the duration of PAF episodes and ANP or BNP levels. Neither ANP nor BNP level at baseline was a valid predictor of AF recurrence. Even in 31 patients (47%) with recurrent PAF, attacks of PAF were significantly reduced. In 66 patients with elevated ANP and/or BNP levels at baseline, levels were significantly reduced after PVI independent of PAF recurrence (ANP: 69.0 ± 23.0 vs 25.0 ± 7.7 pg/ml, p <0.0001; BNP: 58.4 ± 50.7 vs 22.5 ± 27.1 pg/ml, p <0.0001). In 42 patients without AF recurrences, ANP and BNP levels were reduced to within the normal range. In conclusion, in patients with PAF without any structural heart disease, ANP and/or BNP levels were elevated. In those patients, relief of the AF burden by successful PVI significantly reduced elevated plasma ANP and BNP levels. ? 2006 Elsevier Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Yamada","given":"Takumi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murakami","given":"Yoshimasa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okada","given":"Taro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamoto","given":"Mitsuhiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimizu","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toyama","given":"Junji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoshida","given":"Yukihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsuboi","given":"Naoya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ito","given":"Teruo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muto","given":"Masahiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kondo","given":"Takahisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inden","given":"Yasuya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirai","given":"Makoto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murohara","given":"Toyoaki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Cardiology","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2006","6","15"]]},"page":"1741-1744","title":"Plasma Atrial Natriuretic Peptide and Brain Natriuretic Peptide Levels After Radiofrequency Catheter Ablation of Atrial Fibrillation","type":"article-journal","volume":"97"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.amjcard.2004.03.013","ISSN":"00029149","abstract":"Plasma brain natriuretic peptide (BNP) was evaluated before and after sinus rhythm restoration in patients with paroxysmal and persistent atrial fibrillation (AF) who had underlying hypertension or coronary heart disease and normal left ventricle function. Twenty-four hours after successful cardioversion, plasma BNP decreased significantly to levels that had been measured in controlled subjects: from 95 to 28 pg/ml in 24 patients in the paroxysmal AF group and from 75 to 41 pg/ml in 36 patients in the persistent AF group. This indicates that AF affects BNP secretion in patients with AF and that some BNP may be atrially delivered. ? 2004 by Excerpta Medica, Inc.","author":[{"dropping-particle":"","family":"Wozakowska-Kap?on","given":"Beata","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Cardiology","id":"ITEM-2","issue":"12","issued":{"date-parts":[["2004","6","15"]]},"page":"1555-1558","title":"Effect of sinus rhythm restoration on plasma brain natriuretic peptide in patients with atrial fibrillation","type":"article-journal","volume":"93"},"uris":[""]}],"mendeley":{"formattedCitation":"(61,62)","plainTextFormattedCitation":"(61,62)","previouslyFormattedCitation":"(61,62)"},"properties":{"noteIndex":0},"schema":""}(61,62). The elevated levels of natriuretic peptides may reflect the degree of atrial stretch ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/endo.133.3.8365376","ISSN":"0013-7227 (Print)","PMID":"8365376","abstract":"Pressure and volume overload in vivo is characterized by induction of the expression of two cardiac hormones, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), but whether stretch directly or other pathophysiological factors associated with cardiac overload cause the activation of these genes is not known. In the present study we examined the effect of short-term (from 30 min to 2 h) direct myocardial stretch on atrial ANP and BNP synthesis and release in modified perfused rat heart preparation that enabled the stepwise distension of the right atrium by pressures approximating those found in vivo. The increase in right atrial pressure by 3.6 mm Hg for 2 h resulted in a 3.3- (p < 0.001) and 1.7-fold (p < 0.02) increase in the rate of IR-ANP and IR-BNP release, respectively, into the perfusate. The maximal increase in both ANP and BNP release was seen after 20 min distension. Thereafter the perfusate IR-ANP and IR-BNP concentration gradually decreased, reaching control values within 2 hours. Chromatographic analysis showed that the hearts primarily release the active, processed 28- and 45-amino acid ANP- and BNP-like peptides, respectively, both before and during atrial stretch. Atrial stretch induced rapid stimulation of BNP gene expression: 1.9- (p < 0.001) and 4.5-fold (p < 0.001) increase in right auricular BNP mRNA levels after 1.0 and 2.0 hours' stretching, respectively, was found on Northern blot analysis, while no change was seen after 30 min distension. In contrast, stretching for up to 2 h did not change auricular ANP mRNA, IR-ANP or IR-BNP levels. Our results show for the first time that atrial stretch induces rapid stimulation of both synthesis and secretion of BNP. The induction of BNP gene expression in the very early stages of cardiac overload mimics the induction of protooncogenes and occurred without involvement of humoral or neural factors. The lack of response of atrial ANP mRNA levels demonstrates that the regulation of BNP gene expression differs from that of ANP.","author":[{"dropping-particle":"","family":"Mantymaa","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vuolteenaho","given":"O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marttila","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruskoaho","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["1993","9"]]},"language":"eng","page":"1470-1473","publisher-place":"United States, United States","title":"Atrial stretch induces rapid increase in brain natriuretic peptide but not in atrial natriuretic peptide gene expression in vitro.","type":"article-journal","volume":"133"},"uris":[""]}],"mendeley":{"formattedCitation":"(63)","plainTextFormattedCitation":"(63)","previouslyFormattedCitation":"(63)"},"properties":{"noteIndex":0},"schema":""}(63). This in turn indicates atrial dysfunction which is linked to thrombus formation ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.7326/0003-4819-128-8-199804150-00005","ISSN":"0003-4819 (Print)","PMID":"9537937","abstract":"BACKGROUND: Transesophageal echocardiography (TEE) visualizes potential sources of embolism in patients with atrial fibrillation, but the clinical significance of TEE findings has not been prospectively established. OBJECTIVE: To define TEE predictors of stroke in patients with atrial fibrillation and to examine response to antithrombotic therapy. DESIGN: Prospective correlation of TEE findings at study entry with subsequent ischemic stroke during 1.1-year mean follow-up of participants in a randomized trial. SETTING: 18 echocardiography laboratories. PATIENTS: 382 patients with atrial fibrillation at high risk for thromboembolism. INTERVENTION: Adjusted-dose warfarin (international normalized ratio, 2 to 3) or low-intensity warfarin (international normalized ratio, 1.2 to 1.5) plus aspirin (325 mg/d). MEASUREMENTS: Size of left atrium and left atrial appendage, flow velocity, spontaneous echocardiographic contrast, thrombus, and plaque on the aortic arch. RESULTS: 23 ischemic strokes occurred. In patients with dense spontaneous echocardiographic contrast (20%), the rate of stroke was 18.2% per year with combination therapy (2.9 times the rate in patients without this finding; P = 0.06) and 4.5% per year with adjusted-dose warfarin (P = 0.09 for rate reduction). Appendage thrombus, detected in 10% of patients, was associated with dense spontaneous echocardiographic contrast (P < 0.001), was seen more frequently after 2 weeks of combination therapy (15%) than after 2 weeks of adjusted-dose warfarin (4%) (P = 0.004), and tripled the overall rate of stroke (P = 0.04). Patients with complex aortic plaque (35%) had a fourfold increased rate of stroke compared with plaque-free patients (P = 0.005); adjusted-dose warfarin decreased risk by 75% (P = 0.02). Dense spontaneous echocardiographic contrast and complex aortic plaque were independent of each other as predictors of thromboembolism. CONCLUSIONS: In high-risk patients with atrial fibrillation, subsequent rates of thromboembolism are correlated with dense spontaneous echocardiographic contrast, thrombus of the atrial appendage, and aortic plaque. Adjusted-dose warfarin reduces the rate of stroke among patients with dense contrast and complex plaque. In patients with atrial fibrillation, the pathogenesis of stroke is multifactorial, and warfarin seems effective for the diverse mechanisms.","container-title":"Annals of internal medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["1998","4"]]},"language":"eng","page":"639-647","publisher-place":"United States, United States","title":"Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography.","type":"article-journal","volume":"128"},"uris":[""]}],"mendeley":{"formattedCitation":"(64)","plainTextFormattedCitation":"(64)","previouslyFormattedCitation":"(64)"},"properties":{"noteIndex":0},"schema":""}(64). Meanwhile, troponins are released as a following myocardial injury which may promote a pro-thrombotic state. Furthermore, elevated levels of troponin has been associated with impaired left atrial function, as assessed by cardiac magnetic resonance imaging (MRI) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1177/0004563217714004","ISSN":"1758-1001 (Electronic)","PMID":"28656817","abstract":"Background Left atrial function (LAF) plays an interactive role between pulmonary and systemic circulation. Cardiac biomarkers, such as amino-terminal pro-brain natriuretic peptide (NT-proBNP) and troponins, might reflect cardiac function. This study aims to evaluate the association between high sensitivity troponins (hsTn) and left atrial function in patients undergoing cardiac magnetic resonance imaging (cMRI). Methods Patients undergoing cardiac magnetic resonance imaging (cMRI) were enrolled prospectively. Patients with right ventricular dysfunction (<50%) were excluded. Blood samples for measurements of hsTn and NT-proBNP were collected at the time of cMRI. Results Eighty-four patients were included. Median LVEF was 59% (IQR 51-64%). HsTn correlated inversely with LAF within multivariable linear regression models (hsTnI: Beta -0.46; T -4.44; P = 0.0001; hsTnT: Beta -0.29; T -3.06; P = 0.003). High sensitivity troponins increased significantly according to decreasing stages of impaired LAF ( P = 0.0001). High sensitivity troponins discriminated patients with impaired LAF < 55% (hsTnT: AUC = 0.80; P = 0.0001; hsTnI: AUC = 0.74; P = 0.0001) and <45% (hsTnT: AUC = 0.75; P = 0.0001; hsTnI: AUC = 0.73; P = 0.001) and were still significantly associated in multivariable logistic regression models (LAF < 55%: hsTnT: OR = 21.78; P = 0.0001; hsTnI: OR = 5.96; P = 0.009; LAF < 45%: hsTnT: OR = 10.27; P = 0.0001; hsTnI: OR = 12.56; P = 0.001). Conclusions This study demonstrates that hsTn are able to reflect LAF being assessed by cardiac magnetic resonance imaging.","author":[{"dropping-particle":"","family":"Natale","given":"Michele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Behnes","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Seung-Hyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoffmann","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reckord","given":"Nadine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoffmann","given":"Ursula","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Budjan","given":"Johannes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lang","given":"Siegfried","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borggrefe","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Papavassiliu","given":"Theano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bertsch","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akin","given":"Ibrahim","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of clinical biochemistry","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2018","3"]]},"language":"eng","page":"264-275","publisher-place":"England, England","title":"High sensitivity troponin T and I reflect left atrial function being assessed by cardiac magnetic resonance imaging.","type":"article-journal","volume":"55"},"uris":[""]}],"mendeley":{"formattedCitation":"(65)","plainTextFormattedCitation":"(65)","previouslyFormattedCitation":"(65)"},"properties":{"noteIndex":0},"schema":""}(65). Renal functionAnother important biomarker in stroke risk stratification is renal function ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1378/chest.13-2103","ISSN":"19313543","PMID":"24356875","abstract":"Background: Atrial fibrillation (AF) is more likely to develop in patients with chronic kidney disease (CKD) than in individuals with normal renal function, and patients with CKD are more likely to suffer ischemic stroke (IS)/thromboembolism (TE). To our knowledge, no prior study has considered the impact of estimated glomerular filtration rate (eGFR) on bleeding. We investigated the relationship of eGFR to IS/TE, mortality, and bleeding in an AF population unrestricted by age or comorbidity. Methods: Patients with nonvalvular AF (NVAF) were stratified into five categories according to eGFR (≥90, 60-89, 30-59, 15-29, and < 15 mL/min/1.73 m2), analyzing risk factors, all-cause mortality, bleeding, and IS/TE. Of 8,962 eligible individuals, 5,912 had NVAF and available serum creatinine data, with 14,499 patient-years of follow-up. Results: The incidence rates of IS/TE were 7.4 and 7.2 per 1,000 person-years in individuals not receiving and receiving anticoagulation therapy, respectively. Rates of all-cause mortality were 13.4 and 9.4 per 1,000 person-years, respectively, and of major bleeding, 6.2 and 9.0 per 1,000 person-years, respectively. Rates increased with decreasing eGFR, with IS/TE rates being lower in individuals receiving oral anticoagulation (OAC) therapy. eGFR was not an independent predictor of IS/TE on multivariate analyses. When the benefit of IS reduction is balanced against the increased risk of hemorrhagic stroke, the net clinical benefit (NCB) was clearly positive in favor of OAC use. Conclusions: Incidence rates of IS/TE, mortality, and bleeding increased with reducing eGFR across the whole range of renal function. OAC use was associated with a lower incidence of IS/TE and mortality at 1 year compared with individuals not receiving anticoagulants in all categories of renal function as measured by eGFR. The NCB balancing IS against serious bleeding was positive in favor of OAC use among patients with renal impairment. ? 2014 American College of Chest Physicians.","author":[{"dropping-particle":"","family":"Banerjee","given":"Amitava","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fauchier","given":"Laurent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vourc'H","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andres","given":"Christian R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taillandier","given":"Sophie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halimi","given":"Jean Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H. H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2014","6"]]},"language":"eng","page":"1370-1382","publisher":"The American College of Chest Physicians","publisher-place":"United States, United States","title":"A prospective study of estimated glomerular filtration rate and outcomes in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project.","type":"article-journal","volume":"145"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1093/eurheartj/eht328","ISSN":"1522-9645 (Electronic)","PMID":"23966309","abstract":"AIMS: Limited data are available on the impact of renal function on the outcome of patients with atrial fibrillation (AF). METHODS AND RESULTS: AMADEUS was a multicentre, randomized, open-label non-inferiority study that compared fixed-dose idraparinux with conventional anticoagulation by dose-adjusted vitamin K antagonists. We performed a post hoc analysis to assess the impact of renal function on the outcomes of anticoagulated AF patients. The primary efficacy outcome was the composite of stroke/systemic embolism (SE). The principal safety outcome of this analysis was major bleeding. We calculated c-indexes, reflecting the ability for discriminating diseased vs. non-diseased patients, and the net reclassification improvement (NRI, an index of inferior/superior performance of risk estimation scores). Of 4576 patients, 45 strokes and 103 major bleeding events occurred following an average follow-up of 325 +/- 164 days. Patients with CrCl >90 mL/min had an annual stroke/SE rate of 0.6% compared with 0.8% for those with CrCl 60-90 mL/min and 2.2% for those with CrCl <60 mL/min (P < 0.001 for linear association). After adjusting for stroke risk factors, patients with CrCl <60 mL/min had more than two-fold higher risk of stroke/SE and almost 60% higher risk of major bleeding compared with those with CrCl >/=60. In patients with the CHA2DS2VASc score 1-2, CrCl <60 mL/min was associated with eight-fold higher stroke risk. When added to the CHA2DS2VASc or CHADS2 scores, CrCl <60 mL/min did not improve the c-indexes for CHADS2 (P = 0.054) or CHA2DS2VASc (P = 0.63) but resulted in significant NRI (0.26, P = 0.02) in this anticoagulated trial cohort. CONCLUSION: Renal impairment (CrCl <60 mL/min) doubles the risk of stroke and increased the risk of major bleeding by almost 60% in anticoagulated patients with AF. Renal impairment was additive to stroke risk prediction scores based on a significant NRI, but no significant improvement in discrimination ability (based on c-indexes) for CHA2DS2VASc or CHADS2 was observed.","author":[{"dropping-particle":"","family":"Apostolakis","given":"Stavros","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guo","given":"Yuotao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buller","given":"Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-2","issue":"46","issued":{"date-parts":[["2013","12"]]},"language":"eng","page":"3572-3579","publisher-place":"England","title":"Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial.","type":"article-journal","volume":"34"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1161/CIRCULATIONAHA.108.816082","ISSN":"1524-4539 (Electronic)","PMID":"19255343","abstract":"BACKGROUND: Atrial fibrillation (AF) substantially increases the risk of ischemic stroke, but this risk varies among individual patients with AF. Existing risk stratification schemes have limited predictive ability. Chronic kidney disease is a major cardiovascular risk factor, but whether it independently increases the risk for ischemic stroke in persons with AF is unknown. METHODS AND RESULTS: We examined how chronic kidney disease (reduced glomerular filtration rate or proteinuria) affects the risk of thromboembolism off anticoagulation in patients with AF. We estimated glomerular filtration rate using the Modification of Diet in Renal Disease equation and proteinuria from urine dipstick results found in laboratory databases. Patient characteristics, warfarin use, and thromboembolic events were ascertained from clinical databases, with validation of thromboembolism by chart review. During 33,165 person-years off anticoagulation among 10,908 patients with AF, we observed 676 incident thromboembolic events. After adjustment for known risk factors for stroke and other confounders, proteinuria increased the risk of thromboembolism by 54% (relative risk, 1.54; 95% CI, 1.29 to 1.85), and there was a graded, increased risk of stroke associated with a progressively lower level of estimated glomerular filtration rate compared with a rate > or =60 mL x min(-1) x 1.73 m(-2): relative risk of 1.16 (95% CI, 0.95 to 1.40) for estimated glomerular filtration rate of 45 to 59 mL x min(-1) x 1.73 m(-2) and 1.39 (95% CI, 1.13 to 1.71) for estimated glomerular filtration rate <45 mL x min(-1) x 1.73 m(-2) (P=0.0082 for trend). CONCLUSIONS: Chronic kidney disease increases the risk of thromboembolism in AF independently of other risk factors. Knowing the level of kidney function and the presence of proteinuria may improve risk stratification for decision making about the use of antithrombotic therapy for stroke prevention in AF.","author":[{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fang","given":"Margaret C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Udaltsova","given":"Natalia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pomernacki","given":"Niela K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borowsky","given":"Leila","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-3","issue":"10","issued":{"date-parts":[["2009","3","17"]]},"language":"eng","page":"1363-1369","publisher-place":"United States","title":"Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.","type":"article-journal","volume":"119"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1161/CIRCULATIONAHA.112.107128","ISSN":"00097322","PMID":"23212720","abstract":"BACKGROUND - : We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS - : In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R2CHADS2) improved net reclassification index by 6.2% compared with CHA2DS2VASc (C statistic=0.578) and by 8.2% compared with CHADS2 (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R2CHADS2 in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS2. CONCLUSIONS - : In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. ? 2013 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Piccini","given":"Jonathan P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stevens","given":"Susanna R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lokhnygina","given":"Yuliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Manesh R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahaffey","given":"Kenneth W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"Jonathan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Breithardt","given":"Günter Gunter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hankey","given":"Graeme J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hacke","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Becker","given":"Richard C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nessel","given":"Christopher C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fox","given":"Keith A.A. A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Califf","given":"Robert M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ROCKET AF Steering Committee and Investigators","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-4","issue":"2","issued":{"date-parts":[["2013","1","15"]]},"language":"eng","page":"224-232","publisher-place":"United States","title":"Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: Validation of the R2CHADS2 index in the ROCKET AF","type":"article-journal","volume":"127"},"uris":[""]}],"mendeley":{"formattedCitation":"(17,66–68)","plainTextFormattedCitation":"(17,66–68)","previouslyFormattedCitation":"(17,66–68)"},"properties":{"noteIndex":0},"schema":""}(17,66–68). Impaired renal function was demonstrated to be a strong predictor of stroke and systemic embolism in the ROCKET AF and ATRIA study cohorts, second only to prior stroke or TIA ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.112.107128","ISSN":"00097322","PMID":"23212720","abstract":"BACKGROUND - : We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS - : In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R2CHADS2) improved net reclassification index by 6.2% compared with CHA2DS2VASc (C statistic=0.578) and by 8.2% compared with CHADS2 (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R2CHADS2 in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS2. CONCLUSIONS - : In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. ? 2013 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Piccini","given":"Jonathan P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stevens","given":"Susanna R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lokhnygina","given":"Yuliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Manesh R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahaffey","given":"Kenneth W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"Jonathan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Breithardt","given":"Günter Gunter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hankey","given":"Graeme J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hacke","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Becker","given":"Richard C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nessel","given":"Christopher C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fox","given":"Keith A.A. A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Califf","given":"Robert M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ROCKET AF Steering Committee and Investigators","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013","1","15"]]},"language":"eng","page":"224-232","publisher-place":"United States","title":"Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: Validation of the R2CHADS2 index in the ROCKET AF","type":"article-journal","volume":"127"},"uris":[""]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"(17)"},"properties":{"noteIndex":0},"schema":""}(17). A meta-analysis of 18 studies involving 538,479 patients with AF demonstrated that estimated glomerular filtration rate (eGFR) was an independent risk factor for stroke or systemic embolism, with worsening chronic kidney disease (CKD) being associated with a greater increased risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/STROKEAHA.114.006881","ISSN":"15244628","PMID":"25424480","abstract":"Background and Purpose-Chronic kidney disease may increase the risk for ischemic stroke or systemic embolism in patients with nonvalular atrial fibrillation (AF). We conducted a meta-analysis to summarize all published studies to investigate the link between chronic kidney disease and risk of thromboembolic events in AF. Methods-We performed a literature search using MEDLINE (source PubMed, 1966 to July, 2014) and EMBASE (1980 to July 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Results-Eighteen studies involving 538 479 patients and 41 719 incident thromboembolic events were identified. From the pooled analysis, AF patients with estimated glomerular filtration rate <60 mL/min compared with those with estimated glomerular filtration rate 60 mL/min experienced a significantly increased risk for developing thromboembolic events (relative risk, 1.62 [95% confidence interval, 1.40-1.87; P<0.001]). The annual rate of thromboembolic events increased by 0.41% (95% confidence interval, 0.17%-0.65%) for a 10 mL/min decrease in renal function. Addition of renal impairment to CHADS2 slightly improved the stroke risk stratification. Conclusions-Impaired renal function is an independent predictor of stroke or systemic embolism in patients with nonvalvular AF. Consideration of renal function may improve stroke risk stratification in patients with AF.","author":[{"dropping-particle":"","family":"Zeng","given":"Wu-Tao Tao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"Xiu-Ting Ting","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tang","given":"Kai","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mei","given":"Wei-Yi Yi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Li-Juan Juan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Qing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheng","given":"Yun-Jiu Jiu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015","1","3"]]},"language":"eng","page":"157-163","publisher":"Lippincott Williams and Wilkins","publisher-place":"United States, United States","title":"Risk of thromboembolic events in atrial fibrillation with chronic kidney disease","type":"article-journal","volume":"46"},"uris":[""]}],"mendeley":{"formattedCitation":"(69)","plainTextFormattedCitation":"(69)","previouslyFormattedCitation":"(69)"},"properties":{"noteIndex":0},"schema":""}(69). Indeed AF patients with the most severe form of CKD requiring dialysis may have a dramatic increase of 9.8-fold in stroke risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ki.2009.185","ISSN":"1523-1755 (Electronic)","PMID":"19494800","abstract":"Despite the importance of cardiovascular disease in dialysis patients, the frequency of atrial fibrillation in incident dialysis patients has not been determined. We analyzed the prevalence of atrial fibrillation in patients starting dialysis over a 4-year period, its occurrence over the course of dialysis, and its influence on ischemic stroke and mortality. Factors predisposing to atrial fibrillation were noted, as was the influence of arrhythmia on mortality and presentation of ischemic stroke. Of the 256 patients studied, 31 had atrial fibrillation at the start of dialysis. Increased age, larger left atrium, and female gender were independently related to the presence of atrial fibrillation at dialysis inception. Of the 225 patients who were in sinus rhythm at the start of dialysis, 28 developed atrial fibrillation during a mean follow-up time of 2 years. The presence of valvular calcifications, bundle branch block, previous ischemic stroke, lower ejection fraction, higher pulse pressure, and lower hemoglobin concentration were predictors of the clinical evolution of atrial fibrillation. Overall, atrial fibrillation increased mortality risk 1.72-fold and ischemic stroke risk 9.8-fold. Therefore, it appears that atrial fibrillation is quite prevalent and its presence is associated with significant risk.","author":[{"dropping-particle":"","family":"Vazquez","given":"Eduardo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sanchez-Perales","given":"Carmen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garcia-Garcia","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Castellano","given":"Patricia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garcia-Cortes","given":"Maria-Jose","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liebana","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lozano","given":"Cristobal","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Kidney international","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2009","8"]]},"language":"eng","page":"324-330","publisher-place":"United States","title":"Atrial fibrillation in incident dialysis patients.","type":"article-journal","volume":"76"},"uris":[""]}],"mendeley":{"formattedCitation":"(70)","plainTextFormattedCitation":"(70)","previouslyFormattedCitation":"(70)"},"properties":{"noteIndex":0},"schema":""}(70). Chronic kidney disease promotes a pro-thrombotic state by its effects on the individual components of Virchow’s triad ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2016.06.057","ISSN":"1558-3597 (Electronic)","PMID":"27659468","abstract":"A bidirectional relationship exists between atrial fibrillation (AF) and chronic renal disease. Patients with AF have a higher incidence of renal dysfunction, and the latter predisposes to incident AF. The coexistence of both conditions results in a higher risk for thromboembolic-related adverse events but a paradoxical increased hemorrhagic risk. Oral anticoagulants (both vitamin K antagonists [VKAs] and non-VKA oral anticoagulants [NOACs]) have been demonstrated to be effective in mild to moderate renal dysfunction. Patients with severe renal impairment were excluded from the non-VKA oral anticoagulant trials, so limited data are available. In end-stage renal failure, the net clinical benefit of VKAs in dialysis-dependent patients remains uncertain, although some evidence suggests that such patients may do well with high-quality anticoagulation control. Risk stratification and careful follow-up of such patients are necessary to ensure a net clinical benefit from thromboprophylaxis.","author":[{"dropping-particle":"","family":"Lau","given":"Yee C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Proietti","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guiducci","given":"Elisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blann","given":"Andrew D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"13","issued":{"date-parts":[["2016","9"]]},"language":"eng","page":"1452-1464","publisher-place":"United States","title":"Atrial Fibrillation and Thromboembolism in Patients With Chronic Kidney Disease.","type":"article-journal","volume":"68"},"uris":[""]}],"mendeley":{"formattedCitation":"(71)","plainTextFormattedCitation":"(71)","previouslyFormattedCitation":"(71)"},"properties":{"noteIndex":0},"schema":""}(71). It has been found to be associated with stasis of the left atrium (LA) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjcard.2018.08.058","ISSN":"1879-1913 (Electronic)","PMID":"30293657","abstract":"Patients with chronic kidney disease (CKD) experiencing atrial arrhythmia are hypothesized to have elevated CHADS2 and CHA2DS2-VASc scores, thereby predisposed to left atrial (LA) thrombus formation and subsequent thromboembolism. We examined possible association of LA thrombogenic milieu (TM) with CKD in patients with nonvalvular atrial fibrillation. A total of 581 patients (181 women; mean age, 67 years) who underwent transesophageal echocardiography were examined. Patients were divided into 4 groups based on the estimated glomerular filtration rate (eGFR) (ml/min/1.73 m(2)): eGFR >/=90 (n=29), 60</= eGFR <90 (n=329), 30</= eGFR <60 (n=209), and eGFR <30 (n=14). TM was defined as the presence of LA thrombus, dense spontaneous echo contrast, or LA appendage velocity </=25 cm/s. Of 581 patients, 147 (25%) had TM. The prevalence of TM increased with decreasing eGFR (4%, 18%, 36%, and 86% for each group, p <0.001). Similar trends were observed for some of the clinical and echocardiographic variables including CHA2DS2-VASc score and LA size. Multivariate logistic regression analysis revealed that every 10 ml/min/1.73 m(2) decrement in eGFR was a significant independent correlate of TM (odds ratio 0.80, p=0.005), along with nonparoxysmal atrial fibrillation (AF) (odds ratio 0.45, p=0.004), higher CHA2DS2-VASc score (odds ratio 1.24, p=0.012), every 5 ml/m(2) increment in LA volume index (odds ratio 1.57, p <0.001), and every 10% decrement in left ventricular ejection fraction (odds ratio 0.51, p <0.001). In conclusion, CKD may be a significant risk factor for LA thrombus formation in patients with nonvalvular atrial fibrillation.","author":[{"dropping-particle":"","family":"Kizawa","given":"Shun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ito","given":"Takahide","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akamatsu","given":"Kanako","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ichihara","given":"Noboru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nogi","given":"Shimpei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyamura","given":"Masatoshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanzaki","given":"Yumiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sohmiya","given":"Koichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoshiga","given":"Masaaki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American journal of cardiology","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2018","12"]]},"language":"eng","page":"2062-2067","publisher-place":"United States, United States","title":"Chronic Kidney Disease as a Possible Predictor of Left Atrial Thrombogenic Milieu Among Patients with Nonvalvular Atrial Fibrillation.","type":"article-journal","volume":"122"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1159/000345434","ISSN":"1421-9751 (Electronic)","PMID":"23257736","abstract":"BACKGROUND: It is currently unknown if the increased risk of stroke in subjects with chronic kidney disease and atrial fibrillation (AF) is due to the presence of left atrial stasis or to any other vascular or systemic conditions. METHODS: This was a retrospective study of 372 subjects undergoing evaluation during an AF episode. The following markers of left atrial stasis were sought on transesophageal echocardiogram: left atrial or left atrial appendage thrombus (LAAT), dense spontaneous echocardiographic contrast (DSEC), and low flow velocities (LFV) in the left atrial appendage. Subgroup comparisons were performed according to the level of estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation as follows: >/=90, 45-89.9, and <45 ml/min/1.73 m2. RESULTS: LAAT was found in 11.6%, DSEC in 29.0%, and LFV in 14.9% of cases. A significant increase in the prevalence of DSEC was observed in the lower categories of eGFR: 37.8% in eGFR <45 ml/min, 30.7% in eGFR 45-89.9 ml/min, and 17.0% in eGFR >/=90 ml/min (p = 0.009; gamma for trend = 0.297, p = 0.002). The same was observed when assessing left atrial abnormality, i.e. the presence of at least one of the former transesophageal echocardiogram changes. On multivariate analysis, clinical parameters from CHADS2 (congestive heart failure, hypertension, age >/=75, diabetes mellitus and stroke) and CHA2DS2-VASc (age 65-74, history of vascular disease, and female gender along with the clinical variables from CHADS2) were predictors of transesophageal echocardiogram changes and an additive predictive value was found for eGFR. CONCLUSIONS: Our results suggest an association between compromised renal function as assessed through eGFR and markers of left atrial stasis in patients with AF. The increased risk of stroke in this population may be due to thromboembolism.","author":[{"dropping-particle":"","family":"Providencia","given":"Rui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fernandes","given":"Andreia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paiva","given":"Luis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faustino","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barra","given":"Sergio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Botelho","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trigo","given":"Joana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nascimento","given":"Jose","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leitao-Marques","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cardiology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2013"]]},"language":"eng","page":"3-10","publisher-place":"Switzerland, Switzerland","title":"Decreased glomerular filtration rate and markers of left atrial stasis in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"124"},"uris":[""]}],"mendeley":{"formattedCitation":"(72,73)","plainTextFormattedCitation":"(72,73)","previouslyFormattedCitation":"(72,73)"},"properties":{"noteIndex":0},"schema":""}(72,73), impaired endothelial function ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2215/CJN.12811216","ISSN":"1555-905X (Electronic)","PMID":"28784655","abstract":"BACKGROUND AND OBJECTIVES: CKD is associated with increased cardiovascular risk not fully attributable to traditional risk factors. We compared endothelium-dependent and -independent vascular function among individuals with advanced CKD with function in those with vascular disease but preserved kidney function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Matched cohort analysis randomly selected from 1259 participants at a single center with measurements of brachial artery flow-mediated dilation, an endothelium-dependent process, and nitroglycerin-mediated dilation, an endothelium-independent process. Patients with advanced CKD (n=70) were matched 1:1 to controls with preserved kidney function and (1) no overt vascular disease, (2) hypertension, and (3) coronary artery disease. RESULTS: The trend toward lower flow-mediated dilation (mean+/-SEM) in advanced CKD (5.4%+/-0.5%) compared with no overt vascular disease (7.3%+/-0.6%), hypertension (6.2%+/-0.5%), and coronary artery disease (5.8%+/-0.5%) did not reach statistical significance in adjusted analyses (P=0.05). Nitroglycerin-mediated dilation was lower in advanced CKD compared with in the other groups (adjusted nitroglycerin-mediated dilation: 6.9%+/-0.8%, 11.8%+/-0.9%, 11.0%+/-0.7%, and 10.5%+/-0.7% in advanced CKD, no overt vascular disease, hypertension, and coronary artery disease groups, respectively; P<0.001). Using tertiles generated from the full cohort and no overt vascular disease as the reference, the adjusted odds of flow-mediated dilation falling within the lowest tertile was higher in both the advanced CKD (odds ratio, 4.84; 95% confidence interval, 2.09 to 11.25) and coronary artery disease (odds ratio, 4.17; 95% confidence interval, 1.76 to 9.87) groups. In contrast, the adjusted odds of lowest tertile nitroglycerin-mediated dilation was higher in advanced CKD (odds ratio, 24.25; 95% confidence interval, 7.16 to 82.13) but not in the hypertension (odds ratio, 0.79; 95% confidence interval, 0.23 to 2.77) or coronary artery disease (odds ratio, 2.34; 95% confidence interval, 0.74 to 7.40) group. CONCLUSIONS: Impairment in endothelium-dependent vascular function is present in patients with CKD and those with clinically evident vascular disease but preserved kidney function. In contrast, substantial reduction in endothelium-independent function was observed only in the CKD group, suggesting differences in severity and pathophysiology of vascular dysfunction between CKD and other disea…","author":[{"dropping-particle":"","family":"Kopel","given":"Tal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"James S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hamburg","given":"Naomi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sampalis","given":"John S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vita","given":"Joseph A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dember","given":"Laura M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical journal of the American Society of Nephrology : CJASN","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2017","10"]]},"language":"eng","page":"1588-1594","publisher-place":"United States, United States","title":"Endothelium-Dependent and -Independent Vascular Function in Advanced Chronic Kidney Disease.","type":"article-journal","volume":"12"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1093/ndt/16.6.1189","ISSN":"0931-0509 (Print)","PMID":"11390719","abstract":"BACKGROUND: Chronic renal failure (CRF) is associated with an increased risk of ischaemic heart disease (IHD), but the mechanisms responsible are controversial. We investigated the relationship of two sets of candidate mechanisms-indices of LDL oxidation and markers of inflammatory activity-with vascular endothelial dysfunction (VED). METHODS: We carried out cross-sectional analysis of 23 dialysed and 16 non-dialysed CRF patients, 28 healthy controls, and 20 patients with stable angina and normal renal function. The following were determined: (i) LDL oxidation by Cu(2+) and ultraviolet light, serum autoantibodies to oxidized LDL (oxLDL); (ii) forearm flow-mediated vasodilatation, plasma concentrations of adhesion molecules, and von Willebrand factor (vWF); and (iii) circulating levels of TNF-alpha and IL-6, C-reactive protein (CRP), and fibrinogen. RESULTS: Endothelium-dependent vasodilatation (EDV) was lower in angina, pre-dialysis, and dialysis CRF patients than in controls (all P<0.005). Compared with controls, vWf (P<0.005) and adhesion molecules (vCAM-1, P<0.005; iCAM-1, P=0.01; E-selectin, P=0.05) were raised in dialysis, and vCAM-1 (P=0.01) in pre-dialysis CRF patients. Dialysed patients had lower HDL cholesterol (P=0.01) and higher triglyceride (P=0.05) than controls, but LDL-oxidation was similar in all groups. Autoantibodies to oxLDL were raised in angina (P<0.005) and pre-dialysis (P=0.006), but were absent in most dialysed patients. Concentrations of IL-6, TNF-alpha, CRP and fibrinogen were elevated in CRF compared with control and angina patients (P<0.005). In the whole population, IL-6 and TNF-alpha correlated negatively with EDV, HDL cholesterol, and positively with triglyceride, blood pressure, vWf, iCAM-1, vCAM-1 and E-selectin (r=-0.43 to +0.70, all P<0.05). CONCLUSIONS: Endothelial dysfunction is unrelated to LDL oxidation, suggesting that LDL oxidation might not be a major cause of VED in CRF. In contrast VED was more severe in CRF than in angina patients and is associated with increased acute-phase proteins and plasma cytokines, demonstrating a chronic inflammatory state. These observations may explain the VED and increased IHD risk of patients with CRF.","author":[{"dropping-particle":"","family":"Bolton","given":"Colin H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Downs","given":"Leonie G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Victory","given":"Jason G.G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dwight","given":"Jeremy F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tomson","given":"Charles R.V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mackness","given":"Michael I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pinkney","given":"Jonathan H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2001","6"]]},"language":"eng","page":"1189-1197","publisher-place":"England, England","title":"Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines.","type":"article-journal","volume":"16"},"uris":[""]},{"id":"ITEM-3","itemData":{"ISSN":"1875-6212 (Electronic)","PMID":"26759218","abstract":"BACKGROUND: Endothelial dysfunction is involved in the pathogenesis of atherosclerosis and cardiovascular complications in chronic kidney disease (CKD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered as a marker of endothelial dysfunction. The aim of this study was to evaluate serum ADMA, eNOS concentration and left ventricular structure and function in CKD patients and to assess the impact of the type of dialyzer on serum ADMA and eNOS concentrations after a haemodialysis (HD) session. MATERIAL AND METHODS: Peripheral blood was collected from 35 predialysis CKD patients, 40 CKD patients on HD and 15 healthy subjects. Patients on HD were divided into two groups according to the dialyzer used based on polynephron or cellulose membranes. Plasma ADMA and eNOS concentrations were assessed. All subjects underwent echocardiography and were evaluated for selected biochemical parameters. RESULTS: We found significantly higher serum ADMA (p<0.05) and significantly lower eNOS (p<0.05) concentration in CKD patients compared with healthy subjects. Both dialyzers significantly reduced serum ADMA concentration (p<0.05) but none of the analysed dialyzers showed superiority when comparing the results. We showed that stage V CKD patients, who had the highest serum ADMA concentration had the lowest left ventricle ejection fraction (LVEF) and the highest left ventricle mass (LVM) and left ventricular end diastolic diameter (LVEDd). CONCLUSIONS: Our results supports the presence of endothelial dysfunction in CKD patients. Correlation between elevated serum AMDA concentration and disadvantageous changes in left ventricular structure and function may indicate an important role of endothelial dysfunction in cardiovascular complications in CKD patients.","author":[{"dropping-particle":"","family":"Bartnicki","given":"Piotr","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kowalczyk","given":"Mariusz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franczyk-Skora","given":"Beata","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baj","given":"Zbigniew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rysz","given":"Jacek","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Current vascular pharmacology","id":"ITEM-3","issue":"4","issued":{"date-parts":[["2016"]]},"language":"eng","page":"360-367","publisher-place":"United Arab Emirates, United Arab Emirates","title":"Evaluation of Endothelial (dys)Function, Left Ventricular Structure and Function in Patients with Chronic Kidney Disease.","type":"article-journal","volume":"14"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.2215/CJN.06840711","ISSN":"1555-905X (Electronic)","PMID":"22193237","abstract":"BACKGROUND AND OBJECTIVES: Both prolactin clearance and production are altered in CKD. In nonrenal populations, emerging evidence suggests that prolactin participates in the atherosclerotic process. Given the elevated cardiovascular risk of CKD, this study examined links between prolactinemia, vascular derangements, and outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational study was conducted in two cohorts: one with 457 nondialyzed CKD patients (mean age 52+/-12 years; 229 men) with measurements of flow-mediated dilation (FMD) and carotid intima-media thickness and one with 173 hemodialysis patients (65+/-12 years; 111 men) with measurements of pulse wave velocity (PWV). Patients were followed for cardiovascular events (n=146, nondialyzed cohort) or death (n=79, hemodialysis cohort). RESULTS: Prolactin levels increased along with reduced kidney function. Prolactin significantly and independently contributed to explain the variance of both FMD (in nondialyzed patients) and PWV (in hemodialysis patients), but not intima-media thickness. In Cox analyses, the risk of cardiovascular events in nondialyzed patients increased by 27% (hazard ratio [HR], 1.27; 95% confidence interval [95% CI], 1.17-1.38) for each 10 ng/ml increment of prolactin. Similarly, the risk for all-cause and cardiovascular mortality in hemodialysis patients increased by 12% (HR, 1.12; 95% CI, 1.06-1.17) and 15% (HR, 1.15; 95% CI, 1.08-1.21), respectively. This was true after multivariate adjustment for confounders and after adjustment within the purported causal pathway (FMD or PWV). CONCLUSIONS: Prolactin levels directly associated with endothelial dysfunction/stiffness and with increased risk of cardiovascular events and mortality in two independent cohorts of CKD patients.","author":[{"dropping-particle":"","family":"Carrero","given":"Juan Jesus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kyriazis","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sonmez","given":"Alper","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tzanakis","given":"Ioannis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Qureshi","given":"Abdul Rashid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stenvinkel","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saglam","given":"Mutlu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stylianou","given":"Kostas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yaman","given":"Halil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taslipinar","given":"Abdullah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vural","given":"Abdulgaffar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gok","given":"Mahmut","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yenicesu","given":"Mujdat","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Daphnis","given":"Eugene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yilmaz","given":"Mahmut Ilker","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical journal of the American Society of Nephrology : CJASN","id":"ITEM-4","issue":"2","issued":{"date-parts":[["2012","2"]]},"language":"eng","page":"207-215","publisher-place":"United States, United States","title":"Prolactin levels, endothelial dysfunction, and the risk of cardiovascular events and mortality in patients with CKD.","type":"article-journal","volume":"7"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.3109/08860229409045079","ISSN":"0886-022X (Print)","PMID":"7938756","abstract":"The effect of preincubation of heparinized whole blood with endothelin-1 (ET-1) on the ADP (adenosine diphosphate) and epinephrine-induced platelet aggregation was examined in 20 healthy donors compared with 20 patients with chronic renal failure (CRF). ET-1 significantly stimulated ADP-induced aggregation in CRF: EC (effective concentration)25 = 2.3 +/- 0.20 with ET-1 vs. 2.7 +/- 0.22 mumol/L without ET-1; EC50: 3.8 +/- 0.18 with ET-1 vs. 4.4 +/- 0.24 mumol/L without ET-1; and EC75: 5.7 +/- 0.22 with ET-1 vs. 6.4 +/- 0.21 mumol/L without ET-1). In healthy donors only the EC25 was significantly increased: EC25 = 2.5 +/- 0.13 with ET-1 vs. 2.8 +/- 0.20 mumol/L without ET-1. No significant influence of ET-1 in epinephrine-induced aggregation was observed in CRF or in healthy donors. The basal values of determined ET-1 were significantly elevated in CRF: 6.99 +/- 0.29 pmol/mL vs. 5.65 +/- 0.33 pmol/mL in healthy donors. The high endogenous level of ET-1 in CRF patients together with an observed higher endogenous plasma level of cAMP (58 +/- 5.2 nmol/L compared to 29 +/- 2.0 nmol/L in healthy donors) may explain the enhanced pharmacological interaction of ET-1 and ADP in CRF patients. The data suggest that positive agonist interaction between ET-1 and ADP may result from effects on the concentrations of cAMP within the platelet rather than from direct interaction on the membrane receptors or the transmembrane coupling mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)","author":[{"dropping-particle":"","family":"Heintz","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmidt","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maurin","given":"N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirsten","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wieland","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sieberth","given":"H G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Renal failure","id":"ITEM-5","issue":"4","issued":{"date-parts":[["1994"]]},"language":"eng","page":"481-489","publisher-place":"England, England","title":"Endothelin-1 potentiates ADP-induced platelet aggregation in chronic renal failure.","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"(74–78)","plainTextFormattedCitation":"(74–78)","previouslyFormattedCitation":"(74–78)"},"properties":{"noteIndex":0},"schema":""}(74–78) and enhanced platelet activation ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0301-0430 (Print)","PMID":"18826858","abstract":"The high incidence of cardiovascular disease in patients with moderate renal impairment is not fully explained by traditional atherothrombotic risk factors. Independently from these factors, blood platelet activation may increase the cardiovascular disease risk of patients with mild-to-moderate renal impairment. Blood platelet activation has not been studied in nondiabetic patients with mild-to-moderate renal impairment. Therefore, we measured the extent of platelet activation by means of fluorescence cytometry in 93 nondiabetic patients with MDRD-estimated creatinine clearance ranging from 13 - 63 ml/min/1.73 m2. As platelet activation parameters we used the expression of CD62P (P-selectin), CD 63 (glycoprotein 53), PAC-1 (activated fibrinogen receptor), CD42b (von Willebrand factor receptor) and CD41 (fibrinogen receptor) on the platelet surface membrane. The expression of CD62p, CD63 and PAC-1 was statistically significantly inversely related to the estimated glomerular filtration rate in these patients (standardized b -0.28, -0.32 and -0.39, respectively). We conclude that nondiabetic mild-to-moderate renal impairment is associated with blood platelet activation. Whether this contributes to the increased cardiovascular risk in these patients needs further study.","author":[{"dropping-particle":"","family":"Thijs","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nanayakkara","given":"P W B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wee","given":"P M","non-dropping-particle":"Ter","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huijgens","given":"P C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guldener","given":"C","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stehouwer","given":"C D A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical nephrology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2008","10"]]},"language":"eng","page":"325-331","publisher-place":"Germany","title":"Mild-to-moderate renal impairment is associated with platelet activation: a cross-sectional study.","type":"article-journal","volume":"70"},"uris":[""]},{"id":"ITEM-2","itemData":{"ISSN":"1523-6838 (Electronic)","PMID":"14750089","abstract":"BACKGROUND: Studies in the general population suggest that low-grade inflammation, endothelial dysfunction, and platelet activation are associated with an increased risk of cardiovascular events. METHODS: Markers of inflammation, endothelial dysfunction, and platelet activation were measured in 334 patients with chronic kidney disease (serum creatinine >1.47 mg/dL [>130 micromol/L] at screening) and compared with 2 age- and sex-matched control groups, 1 comprising 92 patients with coronary artery disease and the other comprising 96 apparently healthy individuals with no history of cardiovascular or kidney disease. RESULTS: There was evidence of low-grade inflammation in the chronic renal impairment group compared with healthy controls, with higher concentrations of C-reactive protein (3.70 versus 2.18 mg/L, P < 0.01) and fibrinogen (3.48 versus 2.67 g/L, P < 0.001) and lower serum albumin concentration (41.8 versus 44.0 g/dL [418 versus 440 g/L], P < 0.001). More severe renal impairment was associated with a trend towards higher fibrinogen and lower albumin concentrations (both P < 0.001), although there was no association with higher C-reactive protein level. As compared to healthy controls, plasma von Willebrand factor (142 versus 108 IU/dL, P < 0.001) and soluble P-selectin concentrations (57.0 versus 43.3 ng/mL, P < 0.001) were also higher in the chronic renal impairment group. More severe renal impairment was associated with a trend towards higher levels of von Willebrand factor (P < 0.001) and of soluble P selectin (P < 0.05). CONCLUSION: This cross-sectional analysis demonstrates that chronic kidney disease is associated with low-grade inflammation, endothelial dysfunction, and platelet activation, even among patients with moderate renal impairment.","author":[{"dropping-particle":"","family":"Landray","given":"Martin J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wheeler","given":"David C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newman","given":"David J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blann","given":"Andrew D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGlynn","given":"Fiona J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ball","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Townend","given":"John N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baigent","given":"Colin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American journal of kidney diseases : the official journal of the National Kidney Foundation","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2004","2"]]},"language":"eng","page":"244-253","publisher-place":"United States","title":"Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study.","type":"article-journal","volume":"43"},"uris":[""]}],"mendeley":{"formattedCitation":"(79,80)","plainTextFormattedCitation":"(79,80)","previouslyFormattedCitation":"(79,80)"},"properties":{"noteIndex":0},"schema":""}(79,80). Furthermore, CKD is linked to the release of procoagulant and inflammatory biomarkers ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.cir.0000042700.48769.59","ISSN":"1524-4539 (Electronic)","PMID":"12515748","abstract":"BACKGROUND: Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease. METHODS AND RESULTS: The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged > or =65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P<0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar. CONCLUSION: Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.","author":[{"dropping-particle":"","family":"Shlipak","given":"Michael G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fried","given":"Linda F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crump","given":"Casey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bleyer","given":"Anthony J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manolio","given":"Teri A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tracy","given":"Russell P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furberg","given":"Curt D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Psaty","given":"Bruce M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2003","1"]]},"language":"eng","page":"87-92","publisher-place":"United States, United States","title":"Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency.","type":"article-journal","volume":"107"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1186/1471-2369-9-9","ISSN":"1471-2369 (Electronic)","PMID":"18681974","abstract":"BACKGROUND: Prior studies using creatinine-based estimated glomerular filtration rate (eGFR) have found limited associations between kidney function and markers of inflammation. Using eGFR and cystatin C, a novel marker of kidney function, the authors investigated the association of kidney function with multiple biomarkers in a diverse cohort. METHODS: The Multi-Ethnic Study of Atherosclerosis consists of 6,814 participants of white, African-American, Hispanic, and Chinese descent, enrolled from 2000-2002 from six U.S. communities. Measurements at the enrollment visit included serum creatinine, cystatin C, and six inflammatory and procoagulant biomarkers. Creatinine-based eGFR was estimated using the four-variable Modification of Diet in Renal Disease equation, and chronic kidney disease was defined by an eGFR < 60 mL/min/1.73 m2. RESULTS: Adjusted partial correlations between cystatin C and all biomarkers were statistically significant: C-reactive protein (r = 0.08), interleukin-6 (r = 0.16), tumor necrosis factor-alpha soluble receptor 1 (TNF-alphaR1; r = 0.75), intercellular adhesion molecule-1 (r = 0.21), fibrinogen (r = 0.14), and factor VIII (r = 0.11; two-sided p < 0.01 for all). In participants without chronic kidney disease, higher creatinine-based eGFR was associated only with higher TNF-alphaR1 levels. CONCLUSION: In a cohort characterized by ethnic diversity, cystatin C was directly associated with multiple procoagulant and inflammatory markers. Creatinine-based eGFR had similar associations with these biomarkers among subjects with chronic kidney disease.","author":[{"dropping-particle":"","family":"Keller","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Ronit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cushman","given":"Mary","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fried","given":"Linda F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shlipak","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMC nephrology","id":"ITEM-2","issued":{"date-parts":[["2008","8"]]},"language":"eng","page":"9","publisher-place":"England, England","title":"Association of kidney function with inflammatory and procoagulant markers in a diverse cohort: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA).","type":"article-journal","volume":"9"},"uris":[""]},{"id":"ITEM-3","itemData":{"ISSN":"1523-6838 (Electronic)","PMID":"14750089","abstract":"BACKGROUND: Studies in the general population suggest that low-grade inflammation, endothelial dysfunction, and platelet activation are associated with an increased risk of cardiovascular events. METHODS: Markers of inflammation, endothelial dysfunction, and platelet activation were measured in 334 patients with chronic kidney disease (serum creatinine >1.47 mg/dL [>130 micromol/L] at screening) and compared with 2 age- and sex-matched control groups, 1 comprising 92 patients with coronary artery disease and the other comprising 96 apparently healthy individuals with no history of cardiovascular or kidney disease. RESULTS: There was evidence of low-grade inflammation in the chronic renal impairment group compared with healthy controls, with higher concentrations of C-reactive protein (3.70 versus 2.18 mg/L, P < 0.01) and fibrinogen (3.48 versus 2.67 g/L, P < 0.001) and lower serum albumin concentration (41.8 versus 44.0 g/dL [418 versus 440 g/L], P < 0.001). More severe renal impairment was associated with a trend towards higher fibrinogen and lower albumin concentrations (both P < 0.001), although there was no association with higher C-reactive protein level. As compared to healthy controls, plasma von Willebrand factor (142 versus 108 IU/dL, P < 0.001) and soluble P-selectin concentrations (57.0 versus 43.3 ng/mL, P < 0.001) were also higher in the chronic renal impairment group. More severe renal impairment was associated with a trend towards higher levels of von Willebrand factor (P < 0.001) and of soluble P selectin (P < 0.05). CONCLUSION: This cross-sectional analysis demonstrates that chronic kidney disease is associated with low-grade inflammation, endothelial dysfunction, and platelet activation, even among patients with moderate renal impairment.","author":[{"dropping-particle":"","family":"Landray","given":"Martin J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wheeler","given":"David C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newman","given":"David J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blann","given":"Andrew D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGlynn","given":"Fiona J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ball","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Townend","given":"John N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baigent","given":"Colin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American journal of kidney diseases : the official journal of the National Kidney Foundation","id":"ITEM-3","issue":"2","issued":{"date-parts":[["2004","2"]]},"language":"eng","page":"244-253","publisher-place":"United States","title":"Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study.","type":"article-journal","volume":"43"},"uris":[""]}],"mendeley":{"formattedCitation":"(80–82)","plainTextFormattedCitation":"(80–82)","previouslyFormattedCitation":"(80–82)"},"properties":{"noteIndex":0},"schema":""}(80–82).It was previously suggested that the inclusion of CKD as a risk factor may improve stroke prediction models ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.112.107128","ISSN":"00097322","PMID":"23212720","abstract":"BACKGROUND - : We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS - : In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R2CHADS2) improved net reclassification index by 6.2% compared with CHA2DS2VASc (C statistic=0.578) and by 8.2% compared with CHADS2 (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R2CHADS2 in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS2. CONCLUSIONS - : In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. ? 2013 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Piccini","given":"Jonathan P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stevens","given":"Susanna R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lokhnygina","given":"Yuliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Manesh R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahaffey","given":"Kenneth W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"Jonathan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Breithardt","given":"Günter Gunter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hankey","given":"Graeme J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hacke","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Becker","given":"Richard C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nessel","given":"Christopher C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fox","given":"Keith A.A. A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Califf","given":"Robert M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ROCKET AF Steering Committee and Investigators","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013","1","15"]]},"language":"eng","page":"224-232","publisher-place":"United States","title":"Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: Validation of the R2CHADS2 index in the ROCKET AF","type":"article-journal","volume":"127"},"uris":[""]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"(17)"},"properties":{"noteIndex":0},"schema":""}(17). However, additional studies have found that it did not improve the discriminative capabilities of the CHADS2 and CHA2DS2-VASc scores ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1160/TH13-01-0054","ISSN":"2567-689X (Electronic)","PMID":"23572113","abstract":"Chronic Kidney Disease (CKD) constitutes an adverse risk factor in chronic anticoagulated atrial fibrillation (AF) patients, being related to adverse cardiovascular events, mortality and major bleeds. It is unclear if CKD adds independent prognostic information to stroke risk stratification schemes, as the risk factor components of the CHADS2 and CHA2DS2-VASc scores are themselves related to renal dysfunction. The aim of our study was to determine if CKD independently improves the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification scores in AF. We recruited consecutive patients (n=978) patients (49% male; median age 76) with permanent or paroxysmal AF on oral anticoagulants with acenocoumarol, from our out-patient anticoagulation clinic. After a median follow-up of 875 (IQR 706-1059) days, we recorded stroke/transient ischaemic attack (TIA), peripheral embolism, vascular events (acute coronary syndrome, acute heart failure and cardiac death) and all-cause mortality. During follow-up, 113 patients (4.82%/year) experienced an adverse cardiovascular event, of which 39 (1.66%/year) were strokes, 43 (1.83%/year) had an acute coronary syndrome and 32 (1.37%/year) had acute heart failure. Also, 102 patients (4.35%/year) died during the following up, 31 of them (1.32%/year) as a result of a thrombotic event. Based on c-statistics and the integrated discrimination improvement (IDI), CKD did not improve the prediction for stroke/systemic embolism, thrombotic events and all-cause mortality using the CHADS2 and CHA2DS2-VASc scores. In conclusion, evaluating renal function in AF patients is important as CKD would confer a poor overall prognosis in terms of thromboembolic events and all-cause mortality. Adding CKD to the CHADS2 and CHA2DS2-VASc stroke risk scores did not independently add predictive information.","author":[{"dropping-particle":"","family":"Roldan","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manzano-Fernandez","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fernandez","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallego","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"G Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2013","5"]]},"language":"eng","page":"956-960","publisher-place":"Germany","title":"Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation?","type":"article-journal","volume":"109"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jacc.2013.02.035","ISSN":"1558-3597 (Electronic)","PMID":"23524209","abstract":"OBJECTIVES: This study sought to determine the risk of ischemic stroke (IS)/thromboembolism (TE) associated with renal impairment and its incremental predictive value over established risk stratification scores (congestive heart failure, hypertension, age >/=75 years, diabetes, previous stroke [CHADS2] and congestive heart failure, hypertension, age >/=75 years, diabetes, previous stroke, vascular disease, age 65 to 74 years, sex category (female) [CHA(2)DS(2)-VASc]) in patients with atrial fibrillation (AF). BACKGROUND: Risk stratification schemes for prediction of IS/TE in patients with AF are validated but do not include renal impairment. METHODS: Patients diagnosed with nonvalvular AF and available estimated glomerular filtration rate (eGFR) data in a 4-hospital institution between 2000 and 2010 were identified. The study population was stratified by renal impairment defined by serum creatinine level and by eGFR measured at time of diagnosis of AF. Independent risk factors of IS/TE (including renal impairment) were investigated in Cox regression models. The incremental predictive value of renal impairment over CHADS(2) and CHA(2)DS(2)-VASc were assessed with the c-statistic, net reclassification improvement, and integrated discrimination improvement. We focused on the 1-year outcomes in our analyses. RESULTS: Of 8,962 eligible individuals, 5,912 (66%) had nonvalvular AF and available eGFR data. Renal impairment by both creatinine and eGFR definitions was associated with higher rates of IS/TE at 1 year, compared with normal renal function. After adjustment for CHADS(2) risk factors, renal impairment did not significantly increase the risk of IS/TE at 1 year (hazard ratio: 1.06; 95% confidence interval [CI]: 0.75 to 1.49 for renal impairment; and hazard ratio: 1.09; 95% CI: 0.84 to 1.41 for eGFR). When renal impairment was added to existing risk scoring systems for stroke/TE (CHADS(2) and CHA(2)DS(2)-VASc), it did not independently add to the predictive value of the scores, whether defined by serum creatinine level or eGFR. This was evident even when the analysis was confined to only those patients with at least 1 year of follow-up. CONCLUSIONS: Renal impairment was not an independent predictor of IS/TE in patients with AF and did not significantly improve the predictive ability of the CHADS(2) or CHA(2)DS(2)-VASc scores.","author":[{"dropping-particle":"","family":"Banerjee","given":"Amitava","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fauchier","given":"Laurent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vourc'h","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andres","given":"Christian R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taillandier","given":"Sophie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halimi","given":"Jean Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-2","issue":"20","issued":{"date-parts":[["2013","5"]]},"language":"eng","page":"2079-2087","publisher-place":"United States, United States","title":"Renal impairment and ischemic stroke risk assessment in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project.","type":"article-journal","volume":"61"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1093/eurheartj/eht328","ISSN":"1522-9645 (Electronic)","PMID":"23966309","abstract":"AIMS: Limited data are available on the impact of renal function on the outcome of patients with atrial fibrillation (AF). METHODS AND RESULTS: AMADEUS was a multicentre, randomized, open-label non-inferiority study that compared fixed-dose idraparinux with conventional anticoagulation by dose-adjusted vitamin K antagonists. We performed a post hoc analysis to assess the impact of renal function on the outcomes of anticoagulated AF patients. The primary efficacy outcome was the composite of stroke/systemic embolism (SE). The principal safety outcome of this analysis was major bleeding. We calculated c-indexes, reflecting the ability for discriminating diseased vs. non-diseased patients, and the net reclassification improvement (NRI, an index of inferior/superior performance of risk estimation scores). Of 4576 patients, 45 strokes and 103 major bleeding events occurred following an average follow-up of 325 +/- 164 days. Patients with CrCl >90 mL/min had an annual stroke/SE rate of 0.6% compared with 0.8% for those with CrCl 60-90 mL/min and 2.2% for those with CrCl <60 mL/min (P < 0.001 for linear association). After adjusting for stroke risk factors, patients with CrCl <60 mL/min had more than two-fold higher risk of stroke/SE and almost 60% higher risk of major bleeding compared with those with CrCl >/=60. In patients with the CHA2DS2VASc score 1-2, CrCl <60 mL/min was associated with eight-fold higher stroke risk. When added to the CHA2DS2VASc or CHADS2 scores, CrCl <60 mL/min did not improve the c-indexes for CHADS2 (P = 0.054) or CHA2DS2VASc (P = 0.63) but resulted in significant NRI (0.26, P = 0.02) in this anticoagulated trial cohort. CONCLUSION: Renal impairment (CrCl <60 mL/min) doubles the risk of stroke and increased the risk of major bleeding by almost 60% in anticoagulated patients with AF. Renal impairment was additive to stroke risk prediction scores based on a significant NRI, but no significant improvement in discrimination ability (based on c-indexes) for CHA2DS2VASc or CHADS2 was observed.","author":[{"dropping-particle":"","family":"Apostolakis","given":"Stavros","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guo","given":"Yuotao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buller","given":"Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-3","issue":"46","issued":{"date-parts":[["2013","12"]]},"language":"eng","page":"3572-3579","publisher-place":"England","title":"Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial.","type":"article-journal","volume":"34"},"uris":[""]}],"mendeley":{"formattedCitation":"(67,83,84)","plainTextFormattedCitation":"(67,83,84)","previouslyFormattedCitation":"(67,83,84)"},"properties":{"noteIndex":0},"schema":""}(67,83,84). To summarise prior results, a meta-analysis of eight studies found that the inclusion of CKD resulted in a slight improvement for stroke prediction by the CHADS2 score but not with the CHA2DS2-VASc score ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/STROKEAHA.114.006881","ISSN":"15244628","PMID":"25424480","abstract":"Background and Purpose-Chronic kidney disease may increase the risk for ischemic stroke or systemic embolism in patients with nonvalular atrial fibrillation (AF). We conducted a meta-analysis to summarize all published studies to investigate the link between chronic kidney disease and risk of thromboembolic events in AF. Methods-We performed a literature search using MEDLINE (source PubMed, 1966 to July, 2014) and EMBASE (1980 to July 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Results-Eighteen studies involving 538 479 patients and 41 719 incident thromboembolic events were identified. From the pooled analysis, AF patients with estimated glomerular filtration rate <60 mL/min compared with those with estimated glomerular filtration rate 60 mL/min experienced a significantly increased risk for developing thromboembolic events (relative risk, 1.62 [95% confidence interval, 1.40-1.87; P<0.001]). The annual rate of thromboembolic events increased by 0.41% (95% confidence interval, 0.17%-0.65%) for a 10 mL/min decrease in renal function. Addition of renal impairment to CHADS2 slightly improved the stroke risk stratification. Conclusions-Impaired renal function is an independent predictor of stroke or systemic embolism in patients with nonvalvular AF. Consideration of renal function may improve stroke risk stratification in patients with AF.","author":[{"dropping-particle":"","family":"Zeng","given":"Wu-Tao Tao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"Xiu-Ting Ting","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tang","given":"Kai","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mei","given":"Wei-Yi Yi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Li-Juan Juan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Qing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheng","given":"Yun-Jiu Jiu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015","1","3"]]},"language":"eng","page":"157-163","publisher":"Lippincott Williams and Wilkins","publisher-place":"United States, United States","title":"Risk of thromboembolic events in atrial fibrillation with chronic kidney disease","type":"article-journal","volume":"46"},"uris":[""]}],"mendeley":{"formattedCitation":"(69)","plainTextFormattedCitation":"(69)","previouslyFormattedCitation":"(69)"},"properties":{"noteIndex":0},"schema":""}(69). Therefore, there is currently insufficient evidence to justify the addition of CKD to the guideline-recommended CHA2DS2-VASc score. This is perhaps unsurprising given that CKD is associated with the individual component risk factors within the CHA2DS2-VASc score.HaemostasisStroke risk in AF is strongly related to the disruption of haemostasis, leading to a pro-thrombotic state. However, the haemostatic processes are complex and involve many different pathways. Therefore, it is important to understand which of these are affected in AF. D-dimer is a small protein fragment that is released following fibrinolysis. A prospective study of 509 patients with AF, found that those with a D-dimer level of <150 ng/ml had significantly lower risk of thromboembolic events compared to those with D-dimer level of ≥150 ng/ml, 0.7% per year compared to 3.8% per year ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ijcard.2005.05.049","ISSN":"0167-5273 (Print)","PMID":"15992948","abstract":"BACKGROUND: Elevated coagulative molecular markers could reflect the prothrombotic state in the cardiovascular system of patients with non-valvular atrial fibrillation (NVAF). A prospective, cooperative study was conducted to determine whether levels of coagulative markers alone or in combination with clinical risk factors could predict subsequent thromboembolic events in patients with NVAF. METHODS: Coagulative markers of prothrombin fragment 1+2, D-dimer, platelet factor 4, and beta-thromboglobulin were determined at the enrollment in the prospective study. RESULTS: Of 509 patients with NVAF (mean age, 66.6 +/- 10.3 years), 263 patients were treated with warfarin (mean international normalized ratio, 1.86), and 163 patients, with antiplatelet drugs. During an average follow-up period of 2.0 years, 31 thromboembolic events occurred. Event-free survival was significantly better in patients with D-dimer level < 150 ng/ml than in those with D-dimer level>or==150 ng/ml. Other coagulative markers, however, did not predict thromboembolic events. Age (>or==75 years), cardiomyopathies, and prior stroke or transient ischemic attack were independent, clinical risk factors for thromboembolism. Thromboembolic risk in patients without the clinical risk factors was quite low (0.7%/year) when D-dimer was < 150 ng/ml, but not low (3.8%/year) when D-dimer was >or==150 ng/ml. It was >5%/year in patients with the risk factors regardless of D-dimer levels. This was also true when analyses were confined to patients treated with warfarin. CONCLUSIONS: D-dimer level in combination with clinical risk factors could effectively predict subsequent thromboembolic events in patients with NVAF even when treated with warfarin.","author":[{"dropping-particle":"","family":"Nozawa","given":"Takashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inoue","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirai","given":"Tadakazu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwasa","given":"Atsushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okumura","given":"Ken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jong-Dae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimizu","given":"Akihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayano","given":"Motonobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yano","given":"Katsusuke","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International journal of cardiology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2006","4"]]},"language":"eng","page":"59-65","publisher-place":"Netherlands, Netherlands","title":"D-dimer level influences thromboembolic events in patients with atrial fibrillation.","type":"article-journal","volume":"109"},"uris":[""]}],"mendeley":{"formattedCitation":"(85)","plainTextFormattedCitation":"(85)","previouslyFormattedCitation":"(85)"},"properties":{"noteIndex":0},"schema":""}(85). Similar findings were demonstrated in other studies ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1160/TH03-06-0363","ISSN":"0340-6245 (Print)","PMID":"14652652","abstract":"Atrial fibrillation (AF) is associated with hemostatic abnormalities and increased risk of thrombotic cardiovascular events even during oral anticoagulant therapy (OAT). The aim of our study was to evaluate the predictive value of hemostatic markers for the risk of major cardiovascular events during OAT. The study group comprised 113 patients with chronic AF (70.2 +/- 5.4 years old, 60% men), referred for OAT. Established clinical risk factors and levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) antigen and activity, before and during OAT (after 3.9 +/- 0.7 months; INR 2.57 +/- 0.57) were determined. In all patients OAT significantly suppressed levels of F1+2 by 67%,TAT by 30% and D-dimer by 48% (all p <0.001). During an average follow-up of 44 months 22/111 (20%) patients suffered a combined cardiovascular event (stroke, myocardial infarction, peripheral vascular occlusion or vascular death). Patients with cardiovascular events were significantly older, had more frequent heart failure/systolic dysfunction and had significantly increased levels of D-dimer at entry (63 vs 39 ng/mL, p = 0.005) and during OAT (33 vs 18 ng/mL, p = 0.002), and of t-PA antigen at entry (14.3 vs 10.9 ng/mL, p = 0.02) and during OAT (15.0 vs 11.2 ng/mL, p = 0.05) (all values are medians). In multivariate Cox proportional hazard models, heart failure/systolic dysfunction (hazard ratio 2.91; 95% CI 1.17-7.26; p = 0.02), high levels of D-dimer on OAT (top vs. lower two quartiles) (hazard ratio 4.78, 95% CI 1.39-16.41; p = 0.01) and t-PA antigen levels (continuous variable) (hazard ratio 1.09; 95% CI 1.01-1.17; p = 0.02) were significantly associated with combined cardiovascular events. In conclusion, high levels of D-dimer and t-PA antigen during OAT are significant predictors of combined cardiovascular events in AF patients and, on this basis, could be useful additional markers of cardiovascular risk in such patients.","author":[{"dropping-particle":"","family":"Vene","given":"Nina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mavri","given":"Alenka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kosmelj","given":"Katarina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stegnar","given":"Mojca","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2003","12"]]},"language":"eng","page":"1163-1172","publisher-place":"Germany, Germany","title":"High D-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulant therapy.","type":"article-journal","volume":"90"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jacc.2009.12.049","ISSN":"07351097","author":[{"dropping-particle":"","family":"Sadanaga","given":"Tsuneaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sadanaga","given":"Motoaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogawa","given":"Satoshi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-2","issue":"20","issued":{"date-parts":[["2010"]]},"page":"2225-2231","title":"Evidence That D-Dimer Levels Predict Subsequent Thromboembolic and Cardiovascular Events in Patients With Atrial Fibrillation During Oral Anticoagulant Therapy","type":"article-journal","volume":"55"},"uris":[""]}],"mendeley":{"formattedCitation":"(86,87)","plainTextFormattedCitation":"(86,87)","previouslyFormattedCitation":"(86,87)"},"properties":{"noteIndex":0},"schema":""}(86,87). In contrast, You et al. reported that D-dimer was not an independent risk factor for ischaemic stroke in AF despite finding a positive correlation between D-dimer levels and stroke risk scores (CHADS2 and CHA2DS2-VASc) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/MD.0000000000012622","ISSN":"1536-5964 (Electronic)","PMID":"30412062","abstract":"This study aimed to explore the relationship of D-dimer level with the risk stratification of ischemic stroke, and determine whether high D-dimer levels could be used as a risk factor of ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF).This single-center, retrospective study recruited NVAF patients who did not undergo anticoagulant therapy. These patients were divided into 2 groups: ischemic stroke group and no-stroke group. The medical records of each patient were reviewed, demographic and clinical analyses were performed, and the laboratory results were summarized.A total of 323 eligible in-patients with NVAF, who did not receive anticoagulant therapy, were recruited (206 male and 117 female patients, median age was 75.18 +/- 10.46 years old). Among these patients, 78 patients suffered from acute ischemic stroke. D-dimer level increased with age, and was positively correlated with the risk stratification of stroke, CHADS2 score (rs = 0.441, P < .001), and CHA2DS2-VASC score (rs = 0.412, P < .001), even after adjustment for age and gender (rs = 0.422, P < .001). The difference in baseline D-dimer level between these 2 groups was not statistically significant (0.70 vs 0.66 mg/L, P = .330), but this significantly increased when patients suffered from stroke (1.34 vs 0.70 mg/L, P < .001). The D-dimer level after stroke (>/=6 months) was also higher than the baseline (1.16 vs 0.68 mg/L, P = .514) in 6 months, and this level nearly returned to baseline level after one year (0.69 vs 0.68 mg/L, P = .158). However, logistic regression revealed that only the D-dimer level at stroke onset and OMI were independent risk factors for ischemic stroke (P < .001), while the increase from baseline D-dimer levels was not an independent risk factor (P = .125).D-dimer level is positively correlated with the risk stratification of ischemic stroke, but has no predictive value on the occurrence of ischemic stroke in patients with NVAF.","author":[{"dropping-particle":"","family":"You","given":"Li-Rui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tang","given":"Mei","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Medicine","id":"ITEM-1","issue":"43","issued":{"date-parts":[["2018","10"]]},"language":"eng","page":"e12622","publisher-place":"United States, United States","title":"The association of high D-dimer level with high risk of ischemic stroke in nonvalvular atrial fibrillation patients: A retrospective study.","type":"article-journal","volume":"97"},"uris":[""]}],"mendeley":{"formattedCitation":"(88)","plainTextFormattedCitation":"(88)","previouslyFormattedCitation":"(88)"},"properties":{"noteIndex":0},"schema":""}(88). However, this study was retrospective in nature and only included non-anticoagulated patients. Overall, it does appear that D-dimer may be helpful for stroke risk stratification in AF.Given the role of platelets in haemostasis, it would seem likely that platelet count may be associated with stroke risk. However, in a study of 124 patients with AF on non-vitamin K oral anticoagulants (NOAC), Janion-Sadowska et al. found no association between thrombocytopenia (platelet count <100 x 109/L) and the risk of stroke or TIA over a 55-month follow-up period ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/FJC.0000000000000607","ISSN":"1533-4023 (Electronic)","PMID":"29985282","abstract":"AIMS: Thrombocytopenia was one of the exclusion criteria in randomized trials in which non-vitamin K antagonist oral anticoagulants (NOACs) were tested. The safety of NOACs in patients with atrial fibrillation (AF) and thrombocytopenia remains unclear. METHODS: We studied 62 patients with AF aged from 53 to 85 (mean 70.5) years with platelet count from 50 to 100 x 109/L who were treated with rivaroxaban 15 mg once daily (33.9%), dabigatran 110 mg twice daily (bid) (54.8%), or apixaban 2.5 mg bid (11.3%). Age- and sex-matched AF patients with normal platelet count and similar CHA2DS2-VASc scores who were treated with the recommended doses of NOACs served as a reference group. RESULTS: Patients were followed for a mean of 55 months (range, 23-64 months). In the thrombocytopenia group bleeding risk was higher (mean HAS-BLED score 2.0, vs. 1.0, P < 0.0001). During follow-up in thrombocytopenic and normocytopenic patients, we observed similar rates of major bleeding (1.8%/year vs. 2.7%/year, P = 0.49), clinically relevant nonmajor bleeding (CRNMB) (1.5%/year vs. 1.1%/year, P = 0.74), ischemic stroke and transient ischemic attacks (1.8%/year vs. 1.5%/year, P = 0.8), and death (1.06%/year vs. 1.11%/year, P = 0.96). The risk of bleeding and stroke was unaffected by the type of the NOAC used in both groups. Major bleedings and clinically relevant nonmajor bleeding in thrombocytopenic patients on NOACs were predicted only by age (hazard ratio 1.1, 95% confidence interval 1.0-1.3, P = 0.04). CONCLUSIONS: Our findings indicate that in AF patients with mild thrombocytopenia, anticoagulation with NOAC at reduced doses seems to be safe and effective.","author":[{"dropping-particle":"","family":"Janion-Sadowska","given":"Agnieszka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Papuga-Szela","given":"Elzbieta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lukaszuk","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chrapek","given":"Magdalena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Undas","given":"Anetta","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of cardiovascular pharmacology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018","9"]]},"language":"eng","page":"153-160","publisher-place":"United States","title":"Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Thrombocytopenia.","type":"article-journal","volume":"72"},"uris":[""]}],"mendeley":{"formattedCitation":"(89)","plainTextFormattedCitation":"(89)","previouslyFormattedCitation":"(89)"},"properties":{"noteIndex":0},"schema":""}(89). In contrast, Park et al. recently reported retrospective registry data on 10,978 patients with AF where patients with a platelet count <100 x 109/L had a significantly lower stroke risk compared to those with a normal platelet count ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.hrthm.2018.08.023","ISSN":"1556-3871 (Electronic)","PMID":"30170225","abstract":"BACKGROUND: The prognostic efficacy of quantitative platelet activity in atrial fibrillation (AF) remains unclear. OBJECTIVE: The purpose of this study was to evaluate the platelet count (PLT) as a prognostic indicator in patients with nonvalvular AF. METHODS: Data on 10,978 patients with nonvalvular AF were retrieved from a prospective registry of a single medical center in Korea. Cumulative risk for stroke and bleeding events were compared between patients with normal PLT (n = 8322), mild thrombocytopenia (n = 1791), and moderate to severe thrombocytopenia (n = 865) after propensity score matching. Prediction models for stroke were derived by conventional risk factors (model 1) and by combining PLT with model 1 (model 2), and model performance was assessed by area under the receiver operator characteristics curve (AUC). RESULTS: During the follow-up period, 7.3%, 7.0%, and 4.5% had stroke and 7.6%, 10.8%, and 17.2% had bleeding events in the normal PLT, mild, and moderate to severe thrombocytopenia groups, respectively. Compared to the normal PLT group, the moderate to severe thrombocytopenia group showed a lower risk of stroke (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.40-0.80; P = .002). A reverse relationship was found between PLT and bleeding risk (moderate to severe thrombocytopenia: HR 2.19; 95% CI 1.77-2.70; P <.001; mild thrombocytopenia: HR 1.43; 95% CI 1.18-1.73; P <.001). Compared to model 1, model 2 showed significant improvement in risk prediction (AUC 0.628 vs 0.644; P <.001). CONCLUSION: A lower PLT was associated with a lower risk of stroke and a higher risk of bleeding events. PLT combined with conventional risk factors showed significant improvement in prediction for stroke.","author":[{"dropping-particle":"","family":"Park","given":"Jiesuck","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cha","given":"Myung-Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"You-Jung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Euijae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moon","given":"Inki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwak","given":"Soongu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwon","given":"Soonil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Seokhun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Seoyoung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Eue-Keun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oh","given":"Seil","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart rhythm","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2019","2"]]},"language":"eng","page":"197-203","publisher-place":"United States","title":"Prognostic efficacy of platelet count in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"(90)","plainTextFormattedCitation":"(90)","previouslyFormattedCitation":"(90)"},"properties":{"noteIndex":0},"schema":""}(90). A major difference between the trials was in terms of the use of anticoagulation. About half of the patients (55.4%) in the latter trial were not anticoagulated and among those who were, warfarin was the main agent of choice (96.8%). There is limited evidence to base any firm conclusions at present although it could be that thrombocytopenia is protective against stroke in AF.Von Willebrand factor is a glycoprotein integral to haemostasis. Raised levels of vWF has been associated with a pro-thrombotic state in AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1042/CS20080372","ISSN":"1470-8736 (Electronic)","PMID":"18980576","abstract":"The aim of the present study was to determine the rates of stroke in patients with chronic NVAF (non-valvular atrial fibrillation), evaluating the relationship between plasma levels of inflammatory variables at admission and the occurrence of stroke during a 3-year follow-up. A total of 373 consecutive patients with chronic NVAF were enrolled. Blood samples were drawn within 72 h of admission, and we evaluated plasma levels of IL (interleukin)-1beta, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-10, E-selectin, P-selectin, ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and vWF (von Willebrand Factor). Subsequent patient events (stroke at follow-up) were monitored over a 3 year period. By multivariate analysis, only age, hypertension and high levels of IL-6, TNF-alpha and vWF remained significant predictors of a higher risk of experiencing ischaemic stroke at follow-up. Moreover, plasma values of TNF-alpha, IL-6 and vWF had a significant area under the ROC (receiver operating characteristic) curve. In conclusion, baseline plasma levels of TNF-alpha, IL-6 and vWF are predictors of new-onset ischaemic stroke at follow-up in patients with chronic NVAF.","author":[{"dropping-particle":"","family":"Pinto","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuttolomondo","given":"Antonino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casuccio","given":"Alessandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raimondo","given":"Domenico","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sciacca","given":"Riccardo","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnao","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Licata","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical science (London, England : 1979)","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2009","5"]]},"language":"eng","page":"781-789","publisher-place":"England, England","title":"Immuno-inflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF).","type":"article-journal","volume":"116"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jacc.2010.12.033","ISSN":"1558-3597 (Electronic)","PMID":"21497043","abstract":"OBJECTIVES: The purpose of this study was to evaluate the prognostic value of plasma von Willebrand factor (vWF) levels and fibrin d-dimer in a large cohort of anticoagulated permanent atrial fibrillation (AF) patients. BACKGROUND: In nonanticoagulated AF patients, plasma vWF levels have been related to stroke and vascular events. There are limited data on the prognostic role of biomarkers in anticoagulated AF patients in relation to adverse events (including thromboembolism), mortality, and major bleeding. METHODS: We studied 829 patients (50% male; median age 76 years) with permanent AF who were stabilized (for at least 6 months) on oral anticoagulation therapy (international normalized ratio: 2.0 to 3.0). Plasma d-dimer and vWF levels were quantified by enzyme-linked immunosorbent assay. Patients were followed for 2 years, and adverse events (thrombotic and vascular events, mortality, and major bleeding) were recorded. RESULTS: Patients were followed for a median of 828 days (range 18 to 1,085 days). On multivariate analysis, age 75 years and older, previous stroke, heart failure, and high plasma vWF levels (>/= 221 IU/dl) were associated with future adverse cardiovascular events (all p values <0.05). High plasma vWF levels, elderly patients, diabetes, hypercholesterolemia, and current smoking were associated with mortality (all p values <0.05). High plasma vWF levels were also an independent predictor of major bleeding (hazard ratio: 4.47, 95% confidence interval: 1.86 to 10.75; p < 0.001). High plasma vWF levels were able to refine clinical risk stratification schema for stroke (CHADS(2) [Congestive heart failure, Hypertension, Age >/= 75, Diabetes mellitus, and prior Stroke or transient ischemic attack (doubled)], CHA(2)DS(2)-VASc [Congestive heart failure, Hypertension, Age >/= 75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 to 74 years, Sex category]) and bleeding (HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly]). d-dimer did not show any significant impact on adverse events. CONCLUSIONS: High plasma vWF levels (>/=221 IU/dl) are an independent risk factor for adverse events in anticoagulated permanent AF patients. This biomarker may potentially be used to refine stroke and bleeding clinical risk stratification in AF.","author":[{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muina","given":"Begona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Torregrosa","given":"Jose Miguel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernandez-Romero","given":"Diana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-2","issue":"25","issued":{"date-parts":[["2011","6"]]},"language":"eng","page":"2496-2504","publisher-place":"United States","title":"Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients.","type":"article-journal","volume":"57"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1111/eci.12140","ISSN":"1365-2362 (Electronic)","PMID":"23961715","abstract":"BACKGROUND: Endothelial damage/dysfunction may contribute to a prothrombotic state in patients with atrial fibrillation (AF) and the increased risk of thromboembolism and cardiovascular events. Raised plasma von Willebrand factor (vWf), an established marker of endothelial damage/dysfunction, has been associated with stroke and vascular events, at least in a clinical trial population. Soluble E-selectin (sE-sel) is another biomarker of endothelial activation/dysfunction, with more limited data on prognostic outcomes in AF. OBJECTIVE: To assess the relationship between the levels of vWf, sE-sel and clinical adverse outcomes (including stroke, MI and all-cause mortality) in a 'real-world' community cohort of patients with AF. METHODS: We studied 423 patients (mean age 72.7 +/- 8.4 years, 55.6% male) with nonvalvular AF, with a median follow-up of 19 (9-31) months. Plasma vWf and sE-sel levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: There were 94 clinical adverse events (22.2%) observed during a median follow-up of 19 months. Patients with clinical events had significantly higher vWf (P < 0.001) and sE-sel levels at baseline (P < 0.001) compared with those who were event free. Kaplan-Meir analyses demonstrated that more clinical adverse events occurred in the upper tertile of vWf [upper vs. lowest tertile, RR 3.8, 95% CI (2.63-5.57), P < 0.001; upper vs. middle tertile, RR 10.5, 95% CI (5.33-20.60), P < 0.001]. Similarly, the highest tertile of sE-sel was associated with more adverse events [upper vs. lowest tertile, RR 3.7, 95% CI (2.51-5.31), P < 0.001; upper vs. middle tertile, RR 6.5, 95% CI (3.56-11.91), P < 0.001]. CONCLUSION: High plasma vWf and soluble E-selectin levels are associated with an increased risk of clinical adverse events (acute myocardial infarction, ischaemic stroke and all-cause mortality) in 'real-world' patients with AF. These soluble biomarkers may potentially aid clinical risk stratification in this common arrhythmia.","author":[{"dropping-particle":"","family":"Krishnamoorthy","given":"Suresh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khoo","given":"Chee Wah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Hoong S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Basili","given":"Stefania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European journal of clinical investigation","id":"ITEM-3","issue":"10","issued":{"date-parts":[["2013","10"]]},"language":"eng","page":"1032-1038","publisher-place":"England, England","title":"Prognostic role of plasma von Willebrand factor and soluble E-selectin levels for future cardiovascular events in a 'real-world' community cohort of patients with atrial fibrillation.","type":"article-journal","volume":"43"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1016/j.acvd.2017.08.004","ISSN":"1875-2128 (Electronic)","PMID":"29685722","abstract":"BACKGROUND: Heart failure and atrial fibrillation share common mechanisms that may contribute to hypercoagulability and thrombotic risk. Elevated von Willebrand factor (vWF) concentration has been associated with increased risk of thromboembolism and cardiovascular events. AIM: To investigate whether increased vWF plasma concentration predicts occurrence of a composite endpoint (all-cause death and stroke) in patients with non-valvular atrial fibrillation (NVAF). METHODS: We prospectively studied 122 patients (mean age 70+/-14years; 46% men) hospitalized with NVAF, and followed over a median (interquartile range) of 5.4 (2.3-9.0)years. Cox proportional models were used to estimate the association of vWF concentration with time to stroke and death. RESULTS: Forty-three patients (35%) had at least a stroke or died during the 5-year follow-up. Kaplan-Meier curves using vWF plasma concentration tertiles (</=191IU/dL;>191 to</=295IU/dL;>295IU/dL) showed that vWF plasma concentrations discriminated groups of patients with higher cardiovascular event rates (log-rank P=0.01). In the multivariable analysis, higher vWF concentrations (middle tertile hazard ratio [HR] 4.59, 95% confidence interval [CI] 1.55-13.50 [P=0.006]; upper tertile HR 4.10, 95% CI 1.43-11.75 [P=0.009]), age>/=75years (HR 5.02, 95% CI 1.53-16.49; P=0.008), heart failure (HR 2.05, 1.01-4.19; P=0.048), C-reactive protein, log2 per unit increase (HR 1.29, 95% CI 1.04-1.61; P=0.021), no warfarin at discharge (HR 4.96, 95% CI 2.02-12.20; P<0.0001) and no aspirin at discharge (HR 4.41, 95% CI 1.71-11.97; P=0.002) were independently associated with an increased risk of stroke and all-cause death, whereas female sex was a protective factor (HR 0.35, 0.16-0.78; P=0.01). CONCLUSIONS: High vWF plasma concentrations may discriminate patients with NVAF at greater risk of stroke or all-cause death.","author":[{"dropping-particle":"","family":"Ancedy","given":"Yann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berthelot","given":"Emmanuelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lang","given":"Sylvie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ederhy","given":"Stephane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boyer-Chatenet","given":"Louise","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Angelantonio","given":"Emanuele","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soulat-Dufour","given":"Laurie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Etienney","given":"Arnaud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adavane-Scheuble","given":"Saroumadi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boccara","given":"Franck","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cohen","given":"Ariel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of cardiovascular diseases","id":"ITEM-4","issue":"5","issued":{"date-parts":[["2018","5"]]},"language":"eng","page":"357-369","publisher-place":"Netherlands, Netherlands","title":"Is von Willebrand factor associated with stroke and death at mid-term in patients with non-valvular atrial fibrillation?","type":"article-journal","volume":"111"},"uris":[""]}],"mendeley":{"formattedCitation":"(91–94)","plainTextFormattedCitation":"(91–94)","previouslyFormattedCitation":"(91–94)"},"properties":{"noteIndex":0},"schema":""}(91–94). However, a limitation in many of these studies was that the primary outcome measure included events such as heart failure and all-cause death. Therefore, it was difficult to draw strong conclusions from them. Among those that evaluated stroke only outcomes, two studies found that high levels of vWF was linked to a greater risk of stroke ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1042/CS20080372","ISSN":"1470-8736 (Electronic)","PMID":"18980576","abstract":"The aim of the present study was to determine the rates of stroke in patients with chronic NVAF (non-valvular atrial fibrillation), evaluating the relationship between plasma levels of inflammatory variables at admission and the occurrence of stroke during a 3-year follow-up. A total of 373 consecutive patients with chronic NVAF were enrolled. Blood samples were drawn within 72 h of admission, and we evaluated plasma levels of IL (interleukin)-1beta, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-10, E-selectin, P-selectin, ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and vWF (von Willebrand Factor). Subsequent patient events (stroke at follow-up) were monitored over a 3 year period. By multivariate analysis, only age, hypertension and high levels of IL-6, TNF-alpha and vWF remained significant predictors of a higher risk of experiencing ischaemic stroke at follow-up. Moreover, plasma values of TNF-alpha, IL-6 and vWF had a significant area under the ROC (receiver operating characteristic) curve. In conclusion, baseline plasma levels of TNF-alpha, IL-6 and vWF are predictors of new-onset ischaemic stroke at follow-up in patients with chronic NVAF.","author":[{"dropping-particle":"","family":"Pinto","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuttolomondo","given":"Antonino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casuccio","given":"Alessandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raimondo","given":"Domenico","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sciacca","given":"Riccardo","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnao","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Licata","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical science (London, England : 1979)","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2009","5"]]},"language":"eng","page":"781-789","publisher-place":"England, England","title":"Immuno-inflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF).","type":"article-journal","volume":"116"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1111/eci.12140","ISSN":"1365-2362 (Electronic)","PMID":"23961715","abstract":"BACKGROUND: Endothelial damage/dysfunction may contribute to a prothrombotic state in patients with atrial fibrillation (AF) and the increased risk of thromboembolism and cardiovascular events. Raised plasma von Willebrand factor (vWf), an established marker of endothelial damage/dysfunction, has been associated with stroke and vascular events, at least in a clinical trial population. Soluble E-selectin (sE-sel) is another biomarker of endothelial activation/dysfunction, with more limited data on prognostic outcomes in AF. OBJECTIVE: To assess the relationship between the levels of vWf, sE-sel and clinical adverse outcomes (including stroke, MI and all-cause mortality) in a 'real-world' community cohort of patients with AF. METHODS: We studied 423 patients (mean age 72.7 +/- 8.4 years, 55.6% male) with nonvalvular AF, with a median follow-up of 19 (9-31) months. Plasma vWf and sE-sel levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: There were 94 clinical adverse events (22.2%) observed during a median follow-up of 19 months. Patients with clinical events had significantly higher vWf (P < 0.001) and sE-sel levels at baseline (P < 0.001) compared with those who were event free. Kaplan-Meir analyses demonstrated that more clinical adverse events occurred in the upper tertile of vWf [upper vs. lowest tertile, RR 3.8, 95% CI (2.63-5.57), P < 0.001; upper vs. middle tertile, RR 10.5, 95% CI (5.33-20.60), P < 0.001]. Similarly, the highest tertile of sE-sel was associated with more adverse events [upper vs. lowest tertile, RR 3.7, 95% CI (2.51-5.31), P < 0.001; upper vs. middle tertile, RR 6.5, 95% CI (3.56-11.91), P < 0.001]. CONCLUSION: High plasma vWf and soluble E-selectin levels are associated with an increased risk of clinical adverse events (acute myocardial infarction, ischaemic stroke and all-cause mortality) in 'real-world' patients with AF. These soluble biomarkers may potentially aid clinical risk stratification in this common arrhythmia.","author":[{"dropping-particle":"","family":"Krishnamoorthy","given":"Suresh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khoo","given":"Chee Wah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Hoong S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Basili","given":"Stefania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European journal of clinical investigation","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2013","10"]]},"language":"eng","page":"1032-1038","publisher-place":"England, England","title":"Prognostic role of plasma von Willebrand factor and soluble E-selectin levels for future cardiovascular events in a 'real-world' community cohort of patients with atrial fibrillation.","type":"article-journal","volume":"43"},"uris":[""]}],"mendeley":{"formattedCitation":"(91,93)","plainTextFormattedCitation":"(91,93)","previouslyFormattedCitation":"(91,93)"},"properties":{"noteIndex":0},"schema":""}(91,93). Despite demonstrating that higher levels of vWF were associated with a greater composite risk of all-cause death and stroke, Ancedy et al. found that the results were not significant when evaluated for stroke events only ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.acvd.2017.08.004","ISSN":"1875-2128 (Electronic)","PMID":"29685722","abstract":"BACKGROUND: Heart failure and atrial fibrillation share common mechanisms that may contribute to hypercoagulability and thrombotic risk. Elevated von Willebrand factor (vWF) concentration has been associated with increased risk of thromboembolism and cardiovascular events. AIM: To investigate whether increased vWF plasma concentration predicts occurrence of a composite endpoint (all-cause death and stroke) in patients with non-valvular atrial fibrillation (NVAF). METHODS: We prospectively studied 122 patients (mean age 70+/-14years; 46% men) hospitalized with NVAF, and followed over a median (interquartile range) of 5.4 (2.3-9.0)years. Cox proportional models were used to estimate the association of vWF concentration with time to stroke and death. RESULTS: Forty-three patients (35%) had at least a stroke or died during the 5-year follow-up. Kaplan-Meier curves using vWF plasma concentration tertiles (</=191IU/dL;>191 to</=295IU/dL;>295IU/dL) showed that vWF plasma concentrations discriminated groups of patients with higher cardiovascular event rates (log-rank P=0.01). In the multivariable analysis, higher vWF concentrations (middle tertile hazard ratio [HR] 4.59, 95% confidence interval [CI] 1.55-13.50 [P=0.006]; upper tertile HR 4.10, 95% CI 1.43-11.75 [P=0.009]), age>/=75years (HR 5.02, 95% CI 1.53-16.49; P=0.008), heart failure (HR 2.05, 1.01-4.19; P=0.048), C-reactive protein, log2 per unit increase (HR 1.29, 95% CI 1.04-1.61; P=0.021), no warfarin at discharge (HR 4.96, 95% CI 2.02-12.20; P<0.0001) and no aspirin at discharge (HR 4.41, 95% CI 1.71-11.97; P=0.002) were independently associated with an increased risk of stroke and all-cause death, whereas female sex was a protective factor (HR 0.35, 0.16-0.78; P=0.01). CONCLUSIONS: High vWF plasma concentrations may discriminate patients with NVAF at greater risk of stroke or all-cause death.","author":[{"dropping-particle":"","family":"Ancedy","given":"Yann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berthelot","given":"Emmanuelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lang","given":"Sylvie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ederhy","given":"Stephane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boyer-Chatenet","given":"Louise","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Angelantonio","given":"Emanuele","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soulat-Dufour","given":"Laurie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Etienney","given":"Arnaud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adavane-Scheuble","given":"Saroumadi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boccara","given":"Franck","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cohen","given":"Ariel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of cardiovascular diseases","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2018","5"]]},"language":"eng","page":"357-369","publisher-place":"Netherlands, Netherlands","title":"Is von Willebrand factor associated with stroke and death at mid-term in patients with non-valvular atrial fibrillation?","type":"article-journal","volume":"111"},"uris":[""]}],"mendeley":{"formattedCitation":"(94)","plainTextFormattedCitation":"(94)","previouslyFormattedCitation":"(94)"},"properties":{"noteIndex":0},"schema":""}(94). Consequently, the role of vWF for stroke risk stratification in AF requires additional investigation. InflammationThere is ample evidence to support the importance of inflammation in AF. However, use of inflammatory biomarkers to predict stroke risk in this condition has been met with conflicting results. An early pilot study demonstrated that IL-6 was an independent predictor of stroke risk in AF, but not CRP ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ahj.2004.01.026","ISSN":"1097-6744 (Electronic)","PMID":"15389233","abstract":"BACKGROUND: Atrial fibrillation (AF) is a risk factor for stroke and death. Inflammation has been associated with AF, but the prognostic significance of inflammatory mediators, such as interleukin-6 (IL-6) and C-reactive protein (CRP), among patients with AF is unknown. We hypothesized that increased plasma levels of IL-6 and CRP, as indexes of an inflammatory state, would be associated with an increased risk of stroke and death among patients with AF. METHODS: We undertook a pilot study to determine dates of stroke or death occurring among 77 AF cases, with stored plasma samples having initially been obtained during attendance at our specialist AF clinic between 1993 and 1995. Plasma IL-6 and CRP were measured by ELISA and a high-sensitivity latex particle turbidimetric assay, respectively. RESULTS: Patients were followed up for a median duration of 2305 days (interquartile range, 1692 to 2592) [equivalent to 6.3 (4.6 to 7.1) years]. During this period, there were 8 (10%) strokes, 22 (29%) deaths, and 28 (36%) patients who had stroke or death. Prior stroke and high (above median) IL-6 levels were independent predictors of stroke. Age was the only independent predictor of death. High (above median) IL-6 levels remained a significant predictor of stroke or death, even after adjustment for age (hazard ratio, 2.91; 95% CI, 1.20 to 6.51; P =.007), and was the only independent predictor of stroke or death. Trends toward increased risk with high plasma CRP did not reach statistical significance (P =.06 for stroke or death). CONCLUSIONS: In this pilot study, high plasma IL-6 levels were an independent predictor of stroke and the composite end point of stroke or death, suggesting that inflammation in AF may predict a poor prognosis.","author":[{"dropping-particle":"","family":"Conway","given":"Dwayne S g","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buggins","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hughes","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American heart journal","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2004","9"]]},"language":"eng","page":"462-466","publisher-place":"United States, United States","title":"Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation.","type":"article-journal","volume":"148"},"uris":[""]}],"mendeley":{"formattedCitation":"(95)","plainTextFormattedCitation":"(95)","previouslyFormattedCitation":"(95)"},"properties":{"noteIndex":0},"schema":""}(95). Subsequently, Pinto et al. evaluated this by comparing plasma levels of interleukin-1β, tumour necrosis factor-alpha, IL-6 and interleukin-10 (and E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vWF) in chronic AF patients with and without new-onset ischaemic stroke over a period of three years ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1042/CS20080372","ISSN":"1470-8736 (Electronic)","PMID":"18980576","abstract":"The aim of the present study was to determine the rates of stroke in patients with chronic NVAF (non-valvular atrial fibrillation), evaluating the relationship between plasma levels of inflammatory variables at admission and the occurrence of stroke during a 3-year follow-up. A total of 373 consecutive patients with chronic NVAF were enrolled. Blood samples were drawn within 72 h of admission, and we evaluated plasma levels of IL (interleukin)-1beta, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-10, E-selectin, P-selectin, ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and vWF (von Willebrand Factor). Subsequent patient events (stroke at follow-up) were monitored over a 3 year period. By multivariate analysis, only age, hypertension and high levels of IL-6, TNF-alpha and vWF remained significant predictors of a higher risk of experiencing ischaemic stroke at follow-up. Moreover, plasma values of TNF-alpha, IL-6 and vWF had a significant area under the ROC (receiver operating characteristic) curve. In conclusion, baseline plasma levels of TNF-alpha, IL-6 and vWF are predictors of new-onset ischaemic stroke at follow-up in patients with chronic NVAF.","author":[{"dropping-particle":"","family":"Pinto","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuttolomondo","given":"Antonino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casuccio","given":"Alessandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raimondo","given":"Domenico","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sciacca","given":"Riccardo","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnao","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Licata","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical science (London, England : 1979)","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2009","5"]]},"language":"eng","page":"781-789","publisher-place":"England, England","title":"Immuno-inflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF).","type":"article-journal","volume":"116"},"uris":[""]}],"mendeley":{"formattedCitation":"(91)","plainTextFormattedCitation":"(91)","previouslyFormattedCitation":"(91)"},"properties":{"noteIndex":0},"schema":""}(91). Following multivariable adjustment, only IL-6 and tumour necrosis factor-alpha remained significant predictors of stroke risk. In a separate study, Aulin et al. postulated that levels of inflammatory markers (IL-6, CRP and fibrinogen) may be related to the risk of thromboembolism in AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ahj.2015.09.018","ISSN":"1097-6744 (Electronic)","PMID":"26678637","abstract":"BACKGROUND: Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events in AF patients in the RE-LY study. METHODS: Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics. RESULTS: Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism (P = .0041), major bleedings (P = .0001), vascular death (P < .0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) (P < .0001). CRP was independently related to myocardial infarction (P = .0047), vascular death (P = .0004), and the composite thromboembolic outcome (P = .0001). When further adjusted for cardiac (troponin and N-terminal fragment B-type natriuretic peptide [NT-proBNP]) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death (P < .0001), major bleeding (P < .0170) and the composite thromboembolic outcome (P < .0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 (P = .0017) when adding IL-6 to the clinically used CHA2DS2-VASc risk score with net reclassification improvement of 28%. CONCLUSION: In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.","author":[{"dropping-particle":"","family":"Aulin","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huber","given":"Kurt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reilly","given":"Paul A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American heart journal","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2015","12"]]},"language":"eng","page":"1151-1160","publisher-place":"United States, United States","title":"Interleukin-6 and C-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation.","type":"article-journal","volume":"170"},"uris":[""]}],"mendeley":{"formattedCitation":"(96)","plainTextFormattedCitation":"(96)","previouslyFormattedCitation":"(96)"},"properties":{"noteIndex":0},"schema":""}(96). After adjustment for clinical risk factors, only IL-6 was found to be significant. However, use of other biomarkers (troponin, NT-proBNP and cystatin-C) attenuated the importance of IL-6 such that it was no longer predictive of stroke risk in AF. Other studies failed to demonstrate an association between thromboembolic risk in AF and levels of high-sensitivity CRP ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00392-011-0337-9","ISSN":"1861-0692 (Electronic)","PMID":"21725858","abstract":"INTRODUCTION: Atrial fibrillation (AF) is associated not only with inflammation but also with structural remodelling and altered endothelial activation which may contribute to clot formation, embolization and mortality. We aimed to determine the predictive value of single-time biomarker analysis for prediction of outcome in patients with AF. METHODS AND RESULTS: We conducted a prospective study to evaluate if biomarkers of structural, electrical or endothelial remodelling are predictive of cardiovascular events (composite primary endpoint of myocardial infarction, stroke, peripheral embolism or death). Secondary endpoint was all-cause mortality. Patients with any type of AF and without active inflammatory conditions were eligible. Plasma samples were collected for ELISA analysis of biomarkers (inflammation [hsCRP, sCD40L], structural [MMP-2] and endothelial remodelling [vWF, sVCAM-1]) at enrolment. Patients (n = 278) were followed for 28 +/- 12 (median 32) months. Eighty-eight individuals (32%) experienced a primary outcome event, including 8 (2.9%) with myocardial infarction, 13 (4.8%) with stroke and 4 (1.5%) with peripheral embolism. Predictors of the primary endpoint were age >75 years, CHADS(2)-score >2, LVEF <35%, diabetes, presence of an ICD/pacemaker, elevated vWF, sVCAM-1 and MMP-2 levels. On multivariate regression analysis, only age >75 years, sVCAM-1 and MMP-2 levels remained independently associated with the endpoint. There were 75 deaths during follow-up. Age >75 years, reduced LVEF, elevated sVCAM-1 and MMP-2 levels were predictors of all-cause mortality. CONCLUSION: In this cohort of AF patients, old age, elevated sVCAM-1 and MMP-2 levels were associated with cardiovascular events. Our data indicate that single-time biomarker assessment may be a useful tool to improve risk stratification schemes.","author":[{"dropping-particle":"","family":"Ehrlich","given":"Joachim R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaluzny","given":"Magdalena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baumann","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehmann","given":"Ralf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical research in cardiology : official journal of the German Cardiac Society","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2011","11"]]},"language":"eng","page":"1029-1036","publisher-place":"Germany, Germany","title":"Biomarkers of structural remodelling and endothelial dysfunction for prediction of cardiovascular events or death in patients with atrial fibrillation.","type":"article-journal","volume":"100"},"uris":[""]}],"mendeley":{"formattedCitation":"(97)","plainTextFormattedCitation":"(97)","previouslyFormattedCitation":"(97)"},"properties":{"noteIndex":0},"schema":""}(97), IL-6 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1538-7836.2012.04812.x","ISSN":"1538-7836 (Electronic)","PMID":"22681487","abstract":"UNLABELLED: There are limited data on the prognostic role of biomarkers in anticoagulated patients with atrial fibrillation (AF). We evaluated the prognostic value of high sensitivity TnT (hsTnT) and high-sensitivity interleukin-6 (hsIL6) in a large cohort of AF patients taking oral anticoagulant therapy (OAC) as both biomarkers have been associated with adverse cardiovascular events. METHODS: We studied 930 patients (51% male; median age 76) with permanent/ paroxysmal AF who were stabilized (for at least 6 months) on OAC (INRs 2.0-3.0). Plasma hsTnT and hsIL6 levels were quantified by electrochemiluminescense immunoassay at baseline. Patients were followed-up for up to 2 years, and adverse events (thrombotic and vascular events, mortality and major bleeding) were recorded. RESULTS: At follow-up, 96 patients (3.97%/year) died whilst 107 had an adverse cardiovascular event (3.14%/year). On multivariate analysis, high hsTnT and high hsIL6 remained significantly associated with prognosis even after adjusting for CHADS2 score: HR 2.21 (1.46-3.35, P<0.001) for high hsTnT and 1.97 (1.29-3.02, P=0.002) for high hsIL6, for adverse cardiovascular events. For all-cause mortality, the HRs were 1.79 (1.13-2.83, P=0.013) and 2.48 (1.60-3.85, P<0.001), respectively. The integrated discrimination index (IDI) values of clinical scores (CHADS2 and CHA2 DS2-VASc) were improved by the addition of hsTnT and/or hsIL6 (all P<0.05). CONCLUSION: In a large 'real world' cohort of anticoagulated AF patients, both hsTnT and hsIL6 levels provided prognostic information that was complementary to clinical risk scores for prediction of long-term cardiovascular events and death, suggesting that these biomarkers may potentially be used to refine clinical risk stratification in AF.","author":[{"dropping-particle":"","family":"Roldan","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diaz","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallego","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jover","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Romera","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manzano-Fernandez","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casas","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"G Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of thrombosis and haemostasis : JTH","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2012","8"]]},"language":"eng","page":"1500-1507","publisher-place":"England, England","title":"High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation.","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(55)","plainTextFormattedCitation":"(55)","previouslyFormattedCitation":"(55)"},"properties":{"noteIndex":0},"schema":""}(55) or fibrinogen ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.str.30.12.2547","ISBN":"0039-2499 (Print)\\r0039-2499 (Linking)","ISSN":"0039-2499 (Print)","PMID":"10582976","abstract":"BACKGROUND AND PURPOSE: Markers of thrombin generation and platelet activation are often elevated in patients with nonvalvular atrial fibrillation, but it is unclear whether such markers usefully predict stroke. Therefore, we undertook the present study to assess the relationship between prothrombin fragment F1.2 (F1.2), beta-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation with stroke in atrial fibrillation. METHODS: Specimens were obtained from 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. The results were correlated with patient features, antithrombotic therapy, and subsequent thromboembolism (ischemic stroke and systemic embolism) by multivariate analysis. RESULTS: Increased F1.2 levels were associated with age (P<0.001), female sex (P<0.001), systolic blood pressure (P=0.006), and heart failure (P=0.001). F1.2 were not affected by aspirin use and were not associated with thromboembolism after adjustment for age (P=0. 18). BTG levels were higher with advanced age (P=0.006), coronary artery disease (P=0.05), carotid disease (P=0.005), and heart failure (P<0.001), lower in regular alcohol users (P=0.05), and not significantly associated with thromboembolism. Fibrinogen levels were not significantly related to thromboembolism but were associated with elevated BTG levels (P<0.001). The factor V Leiden mutation was not associated with thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8). CONCLUSIONS: Elevated F1.2 levels were associated with clinical risk factors for stroke in atrial fibrillation, whereas increased BTG levels were linked to manifestations of atherosclerosis. In this large cohort of patients with atrial fibrillation who were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not independent, clinically useful predictors of stroke.","author":[{"dropping-particle":"","family":"Feinberg","given":"William M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"Lesly A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cushman","given":"Mary","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornell","given":"Elaine S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bovill","given":"Edwin G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"12","issued":{"date-parts":[["1999","12"]]},"language":"eng","page":"2547-2553","publisher":"Lippincott Williams and Wilkins","publisher-place":"United States, United States","title":"Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study.","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(98)","plainTextFormattedCitation":"(98)","previouslyFormattedCitation":"(98)"},"properties":{"noteIndex":0},"schema":""}(98). Given the current evidence, it appears that high levels of underlying inflammation as detected by IL-6 indicates a pro-thrombotic state in AF. There is no indication that CRP or fibrinogen are useful for this purpose.In addition to the biomarkers mentioned above, there are others that have been evaluated in AF. Many have limited supporting evidence and require further studies to confirm their possible predictive capabilities. These include mean platelet volume, matrix metalloproteinase-2, reduced nicotinamide adenine dinucleotide phosphate oxidase 2-derived peptide, soluble CD40 ligand and tissue plasminogen activator ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/clc.22759","ISSN":"1932-8737 (Electronic)","PMID":"28805957","abstract":"BACKGROUND: CHADS2 (congestive heart failure, hypertension, age >/= 75 years, diabetes mellitus, stroke) and CHA2 DS2 -VASc (congestive heart failure, hypertension, age >/= 75 years, diabetes mellitus, stroke, vascular disease, age 65 to 74 years, sex category) scores showed just moderate discrimination ability in predicting thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). HYPOTHESIS: To determine the association of antithrombin III (AT-III) deficiency and mean platelet volume (MPV) with the development of stroke or left atrial (LA) thrombus in patients with AF. METHODS: AT-III and MPV were analyzed in 352 patients with AF. The primary endpoint was a composite of ischemic stroke event and incidental LA thrombus. RESULTS: There were 50 events (14.2%) during a mean 35.4 months of follow-up. A significantly higher stroke or LA thrombus rate was observed in the low-AT-III group (<70%) than that in the high-AT-III group (>/=70%). A significantly higher stroke or LA thrombus rate was observed in the high-MPV group (>/=7.0 fL) than that in the low-MPV group (<7.0 fL). AF patients with an MPV >/=7.0 fL and AT-III deficiency had higher stroke or LA thrombus risk than those without an MPV >/=7.0 fL and AT-III deficiency. In the Cox proportional hazard analysis, high MPV was found to be an independent predictor of stroke or LA thrombus risk (hazard ratio: 6.408; 95% confidence interval: 2.874-14.286). Although AT-III deficiency was not an independent predictor of stroke or LA thrombus risk, a trend was observed. CONCLUSIONS: High MPV and AT-III deficiency were predictive markers for stroke or LA thrombus. Their predictive power for stroke was independent of antiplatelet treatment, anticoagulation therapy, and a high CHA2 DS2 -VASc score in patients with AF.","author":[{"dropping-particle":"","family":"Choi","given":"Seo-Won","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Bo-Bae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Dong-Hyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Geon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shin","given":"Byung Chul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Heesang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Dong-Min DongHun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Dong-Min DongHun","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical cardiology","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2017","11"]]},"language":"eng","page":"1013-1019","publisher-place":"United States, United States","title":"Stroke or left atrial thrombus prediction using antithrombin III and mean platelet volume in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"40"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1160/TH14-07-0571","ISSN":"2567-689X (Electronic)","PMID":"25392853","abstract":"There are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in atrial fibrillation (AF). The aim of this study was to analyse the role of urinary prostaglandin PGF2alpha (8-iso-PGF2alpha) and NOX2, markers of systemic oxidative stress, in predicting cardiovascular (CV) events and mortality in anticoagulated non-valvular AF patients. This was a prospective study including 1,002 anticoagulated AF patients, followed for a median time of 25.7 months (interquartile range: 14.8-50.9). All major CV events, CV deaths and all-cause deaths were considered as primary outcomes of the study. CV events included fatal/nonfatal ischaemic stroke, fatal/nonfatal myocardial infarction (MI), cardiac revascularisation and transient ischaemic attack (TIA). Oxidative stress biomarkers, such as urinary 8-iso-PGF2alpha and serum sNOX2-dp, a marker of NOX2 activation, were measured. A CV event occurred in 125 patients (12.5 %); 78 CV deaths and 31 non-CV deaths were registered. 8-iso-PGF2alpha and sNOX2-dp were correlated (Rs=0.765 p< 0.001). A significant increased cumulative incidence of CV events and CV deaths was observed across tertiles for 8-iso-PGF2alpha and sNOX2-dp. An increased rate of all-cause death was observed across tertiles of urinary 8-iso-PGF2alpha. In Cox or Fine and Gray models, 8-iso-PGF2alpha predicted CV events and CV and non-CV deaths. The addition of tertiles of 8-iso-PGF2alpha to CHA2DS2-VASc score improved ROC curves for each outcome and NRI for CV events (0.24 [0.06-0.53] p=0.0067). The study shows that in AF patients 8-iso-PGF2alpha and NOX2 levels are predictive of CV events and total mortality. F2-IsoP may complement conventional risk factors in prediction of CV events.","author":[{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pastori","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carnevale","given":"Roberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farcomeni","given":"Alessio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cangemi","given":"Roberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nocella","given":"Cristina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartimoccia","given":"Simona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicario","given":"Tommasa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saliola","given":"Mirella","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2015","3"]]},"language":"eng","page":"617-624","publisher-place":"Germany, Germany","title":"Serum NOX2 and urinary isoprostanes predict vascular events in patients with atrial fibrillation.","type":"article-journal","volume":"113"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1007/s00392-011-0337-9","ISSN":"1861-0692 (Electronic)","PMID":"21725858","abstract":"INTRODUCTION: Atrial fibrillation (AF) is associated not only with inflammation but also with structural remodelling and altered endothelial activation which may contribute to clot formation, embolization and mortality. We aimed to determine the predictive value of single-time biomarker analysis for prediction of outcome in patients with AF. METHODS AND RESULTS: We conducted a prospective study to evaluate if biomarkers of structural, electrical or endothelial remodelling are predictive of cardiovascular events (composite primary endpoint of myocardial infarction, stroke, peripheral embolism or death). Secondary endpoint was all-cause mortality. Patients with any type of AF and without active inflammatory conditions were eligible. Plasma samples were collected for ELISA analysis of biomarkers (inflammation [hsCRP, sCD40L], structural [MMP-2] and endothelial remodelling [vWF, sVCAM-1]) at enrolment. Patients (n = 278) were followed for 28 +/- 12 (median 32) months. Eighty-eight individuals (32%) experienced a primary outcome event, including 8 (2.9%) with myocardial infarction, 13 (4.8%) with stroke and 4 (1.5%) with peripheral embolism. Predictors of the primary endpoint were age >75 years, CHADS(2)-score >2, LVEF <35%, diabetes, presence of an ICD/pacemaker, elevated vWF, sVCAM-1 and MMP-2 levels. On multivariate regression analysis, only age >75 years, sVCAM-1 and MMP-2 levels remained independently associated with the endpoint. There were 75 deaths during follow-up. Age >75 years, reduced LVEF, elevated sVCAM-1 and MMP-2 levels were predictors of all-cause mortality. CONCLUSION: In this cohort of AF patients, old age, elevated sVCAM-1 and MMP-2 levels were associated with cardiovascular events. Our data indicate that single-time biomarker assessment may be a useful tool to improve risk stratification schemes.","author":[{"dropping-particle":"","family":"Ehrlich","given":"Joachim R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaluzny","given":"Magdalena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baumann","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehmann","given":"Ralf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical research in cardiology : official journal of the German Cardiac Society","id":"ITEM-3","issue":"11","issued":{"date-parts":[["2011","11"]]},"language":"eng","page":"1029-1036","publisher-place":"Germany, Germany","title":"Biomarkers of structural remodelling and endothelial dysfunction for prediction of cardiovascular events or death in patients with atrial fibrillation.","type":"article-journal","volume":"100"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.3109/09537104.2011.560306","ISSN":"1369-1635 (Electronic)","PMID":"21599611","abstract":"Platelet size, measured as mean platelet volume (MPV), is associated with platelet reactivity. MPV has been identified as an independent risk factor for future stroke and myocardial infarction. The aim of this study was to determine the association of MPV with the development of stoke in patients with atrial fibrillation (AF). MPV, N-terminal pro B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) were analysed in 200 patients with AF (mean age 69 years; 56% male). The primary endpoint was ischaemic stroke event. The mean MPV was 8.5 +/- 1.0 fL and the median NT-proBNP was 1916.5 (IQR 810-4427) pg/mL. The median hsCRP was 0.47 (IQR 0.32-2.46) mg/dL. There were 14 stroke events during a mean of 15.1 months of follow up. Kaplan-Meier analysis revealed that the higher tertile MPV group (>/=8.9 fL) had a significantly higher stroke rate compared to the lower tertile MPV group (<8.0 fL) (14.7% vs. 3.1%, log-rank: P = 0.01). A higher MPV was an independent predictor of stroke risk after adjusting for age, gender, and other CHADS(2) (congestive heart failure, hypertension, diabetes, and previous stroke or transient ischemic attack (TIA) history) score components (hazard ratio: 5.03, 95% CI 1.05-24.05, P = 0.043) in Cox proportional hazard analysis. When the MPV cut-off level was set to 8.85 fL using the receiver operating characteristic curve, the sensitivity was 71% and the specificity was 69% for differentiating between the group with stroke and the group without stroke. This value was more useful in patients with a low to intermediate traditional thromboembolic risk (CHADS(2) score <2). Furthermore, AF patients with an MPV over 8.85 fL had high stroke risk without anticoagulation, especially in the low thromboembolic risk group (Log-Rank <0.0001). The results of this study show that MPV was a predictive marker for stroke; its predictive power for stroke was independent of age, gender, and other CHADS(2) score components in patients with AF. These findings suggest that anticoagulation may be needed in patients with a high MPV, even if they have low to intermediate traditional thromboembolic risk (CHADS(2) score <2).","author":[{"dropping-particle":"","family":"Ha","given":"Sung-Il","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Dong-Hyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ki","given":"Young-Jae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Joon-Seung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Geon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Joong-Wha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koh","given":"Young-Youp","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Kyong-Sig","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hong","given":"Soon-Pyo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Platelets","id":"ITEM-4","issue":"6","issued":{"date-parts":[["2011"]]},"language":"eng","page":"408-414","publisher-place":"England, England","title":"Stroke prediction using mean platelet volume in patients with atrial fibrillation.","type":"article-journal","volume":"22"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1161/ATVBAHA.107.152777","ISSN":"1524-4636 (Electronic)","PMID":"17901373","abstract":"OBJECTIVE: Atrial fibrillation (AF) is associated with a high incidence of vascular disease that may be related to a prothrombotic and inflammatory state. Soluble CD40 ligand (sCD40L), which stems essentially from platelet activation, possesses inflammatory and prothrombotic properties. The aim of the study was to assess whether sCD40L is a predictor of stroke or myocardial infarction (MI) in patients with nonvalvular AF. METHODS AND RESULTS: Plasma levels of sCD40L were measured in 231 patients (177 [77%] had permanent or persistent AF, and 54 [23%] had paroxysmal AF). Patients were followed for a mean period of 27.8+/-8.8 months, and cardiovascular events such as fatal and nonfatal stroke and MI were recorded. AF population was divided in 2 groups according to sCD40L level above or below the median (4.76 ng/mL). The 2 patients' groups had similar distribution of cardiovascular risk factors, age, gender, medications, or serum C-reactive protein levels. During the follow-up period, vascular events occurred in 6 (2 nonfatal MI and 4 nonfatal ischemic strokes) of 116 patients with low levels of sCD40L (5.1%) and in 29 (11 fatal and 3 nonfatal MI; 3 fatal and 12 nonfatal ischemic strokes) of 115 patients with high levels (25.2%) (log-rank test: P<0.001). Using the COX proportional Hazards model, patients with sCD40L above the median were 4.63 times more likely to experience a vascular event (95% C.I.: 1.92 to 11.20). CONCLUSIONS: This study shows that enhanced soluble CD40L level is a predictor of vascular events in patients with nonvalvular AF, thus suggesting that enhanced platelet activation may play a role in its clinical progression.","author":[{"dropping-particle":"","family":"Ferro","given":"Domenico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Loffredo","given":"Lorenzo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Polimeni","given":"Licia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fimognari","given":"Filippo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Villari","given":"Paolo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fuster","given":"Valentin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Arteriosclerosis, thrombosis, and vascular biology","id":"ITEM-5","issue":"12","issued":{"date-parts":[["2007","12"]]},"language":"eng","page":"2763-2768","publisher-place":"United States, United States","title":"Soluble CD40 ligand predicts ischemic stroke and myocardial infarction in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"27"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"10.1160/TH03-06-0363","ISSN":"0340-6245 (Print)","PMID":"14652652","abstract":"Atrial fibrillation (AF) is associated with hemostatic abnormalities and increased risk of thrombotic cardiovascular events even during oral anticoagulant therapy (OAT). The aim of our study was to evaluate the predictive value of hemostatic markers for the risk of major cardiovascular events during OAT. The study group comprised 113 patients with chronic AF (70.2 +/- 5.4 years old, 60% men), referred for OAT. Established clinical risk factors and levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) antigen and activity, before and during OAT (after 3.9 +/- 0.7 months; INR 2.57 +/- 0.57) were determined. In all patients OAT significantly suppressed levels of F1+2 by 67%,TAT by 30% and D-dimer by 48% (all p <0.001). During an average follow-up of 44 months 22/111 (20%) patients suffered a combined cardiovascular event (stroke, myocardial infarction, peripheral vascular occlusion or vascular death). Patients with cardiovascular events were significantly older, had more frequent heart failure/systolic dysfunction and had significantly increased levels of D-dimer at entry (63 vs 39 ng/mL, p = 0.005) and during OAT (33 vs 18 ng/mL, p = 0.002), and of t-PA antigen at entry (14.3 vs 10.9 ng/mL, p = 0.02) and during OAT (15.0 vs 11.2 ng/mL, p = 0.05) (all values are medians). In multivariate Cox proportional hazard models, heart failure/systolic dysfunction (hazard ratio 2.91; 95% CI 1.17-7.26; p = 0.02), high levels of D-dimer on OAT (top vs. lower two quartiles) (hazard ratio 4.78, 95% CI 1.39-16.41; p = 0.01) and t-PA antigen levels (continuous variable) (hazard ratio 1.09; 95% CI 1.01-1.17; p = 0.02) were significantly associated with combined cardiovascular events. In conclusion, high levels of D-dimer and t-PA antigen during OAT are significant predictors of combined cardiovascular events in AF patients and, on this basis, could be useful additional markers of cardiovascular risk in such patients.","author":[{"dropping-particle":"","family":"Vene","given":"Nina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mavri","given":"Alenka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kosmelj","given":"Katarina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stegnar","given":"Mojca","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-6","issue":"6","issued":{"date-parts":[["2003","12"]]},"language":"eng","page":"1163-1172","publisher-place":"Germany, Germany","title":"High D-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulant therapy.","type":"article-journal","volume":"90"},"uris":[""]}],"mendeley":{"formattedCitation":"(86,97,99–102)","plainTextFormattedCitation":"(86,97,99–102)","previouslyFormattedCitation":"(86,97,99–102)"},"properties":{"noteIndex":0},"schema":""}(86,97,99–102). There are also biomarkers that have not been thoroughly evaluated but thus far not been convincingly shown to be associated with stroke risk in AF. These include soluble fibrin monomer complex, antithrombin III, E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, prothrombin fragment F1+2, thrombin-antithrombin complexes, plasminogen activator inhibitor-1 and β-thromboglobulin ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s11606-017-4279-4","ISSN":"1525-1497 (Electronic)","PMID":"29569024","abstract":"BACKGROUND: Soluble fibrin monomer complex (SFMC) is a biomarker of fibrin formation abnormally elevated in clinical situations of hypercoagulability. OBJECTIVE: We investigated the association and predictive performance of SFMC for stroke, adverse cardiovascular events, cardiovascular mortality and all-cause mortality in a cohort of patients with atrial fibrillation (AF) receiving vitamin K antagonist (VKA) anticoagulant therapy. DESIGN: During the second semester of 2007, we included 1226 AF outpatients stable on VKAs (INR 2.0-3.0) over a period of 6 months. SFMC levels were assessed at baseline. During 6.5 (IQR 4.4-8.0) years of follow-up, we recorded all ischemic strokes, adverse cardiovascular events (composite of stroke, acute heart failure, acute coronary syndrome and cardiovascular death), cardiovascular deaths and all-cause deaths. PARTICIPANTS: All patients were recruited consecutively. We excluded patients with rheumatic mitral valves, prosthetic heart valves, acute coronary syndrome, stroke, hemodynamic instability, hospital admissions or surgical interventions within the preceding 6 months. MAIN MEASURES: SFMC levels were measured in plasma by immunoturbidimetry in an automated coagulometer (STALiatestFM, Diagnostica Stago, Asnieres, France). KEY RESULTS: We recorded 121 (1.52%/year) ischemic strokes, 257 (3.23%/year) cardiovascular events, 67 (0.84%/year) cardiovascular deaths and 486 (6.10%/year) all-cause deaths. SFMC >12 mug/mL was not associated with stroke but was associated with higher risk of cardiovascular events (HR 1.72, 95% CI 1.31-2.26), cardiovascular mortality (HR 2.16, 95% CI 1.30-3.57) and all-cause mortality (HR 1.26, 95% CI 1.03-1.55). When SFMC >12 mug/mL was added to the CHA2DS2-VASc, there were significant improvements in predictive performance, sensitivity and reclassification for adverse cardiovascular events (c-index: 0.645 vs. 0.660, p = 0.010; IDI = 0.013, p < 0.001; NRI = 0.121, p < 0.001) and cardiovascular mortality (c-index: 0.661 vs. 0.691, p = 0.006; IDI = 0.009, p = 0.049; NRI = 0.217, p < 0.001), but decision curves demonstrated a similar net benefit and clinical usefulness. CONCLUSIONS: In AF patients taking VKAs, high SFMC levels were associated with the risk of adverse cardiovascular events, cardiovascular mortality and all-cause mortality. The addition of SFMC to the CHA2DS2-VASc score improved its predictive performance for these outcomes, but failed to show an improvement in clinical usefulness.","author":[{"dropping-particle":"","family":"Rivera-Caravaca","given":"Jose Miguel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Romera","given":"Marta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Esteve-Pastor","given":"Maria Asuncion","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of general internal medicine","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2018","6"]]},"language":"eng","page":"847-854","publisher-place":"United States, United States","title":"Soluble Fibrin Monomer Complex and Prediction of Cardiovascular Events in Atrial Fibrillation: The Observational Murcia Atrial Fibrillation Project.","type":"article-journal","volume":"33"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/clc.22759","ISSN":"1932-8737 (Electronic)","PMID":"28805957","abstract":"BACKGROUND: CHADS2 (congestive heart failure, hypertension, age >/= 75 years, diabetes mellitus, stroke) and CHA2 DS2 -VASc (congestive heart failure, hypertension, age >/= 75 years, diabetes mellitus, stroke, vascular disease, age 65 to 74 years, sex category) scores showed just moderate discrimination ability in predicting thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). HYPOTHESIS: To determine the association of antithrombin III (AT-III) deficiency and mean platelet volume (MPV) with the development of stroke or left atrial (LA) thrombus in patients with AF. METHODS: AT-III and MPV were analyzed in 352 patients with AF. The primary endpoint was a composite of ischemic stroke event and incidental LA thrombus. RESULTS: There were 50 events (14.2%) during a mean 35.4 months of follow-up. A significantly higher stroke or LA thrombus rate was observed in the low-AT-III group (<70%) than that in the high-AT-III group (>/=70%). A significantly higher stroke or LA thrombus rate was observed in the high-MPV group (>/=7.0 fL) than that in the low-MPV group (<7.0 fL). AF patients with an MPV >/=7.0 fL and AT-III deficiency had higher stroke or LA thrombus risk than those without an MPV >/=7.0 fL and AT-III deficiency. In the Cox proportional hazard analysis, high MPV was found to be an independent predictor of stroke or LA thrombus risk (hazard ratio: 6.408; 95% confidence interval: 2.874-14.286). Although AT-III deficiency was not an independent predictor of stroke or LA thrombus risk, a trend was observed. CONCLUSIONS: High MPV and AT-III deficiency were predictive markers for stroke or LA thrombus. Their predictive power for stroke was independent of antiplatelet treatment, anticoagulation therapy, and a high CHA2 DS2 -VASc score in patients with AF.","author":[{"dropping-particle":"","family":"Choi","given":"Seo-Won","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Bo-Bae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Dong-Hyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Geon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shin","given":"Byung Chul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Heesang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Dong-Min DongHun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Dong-Min DongHun","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical cardiology","id":"ITEM-2","issue":"11","issued":{"date-parts":[["2017","11"]]},"language":"eng","page":"1013-1019","publisher-place":"United States, United States","title":"Stroke or left atrial thrombus prediction using antithrombin III and mean platelet volume in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"40"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1111/eci.12140","ISSN":"1365-2362 (Electronic)","PMID":"23961715","abstract":"BACKGROUND: Endothelial damage/dysfunction may contribute to a prothrombotic state in patients with atrial fibrillation (AF) and the increased risk of thromboembolism and cardiovascular events. Raised plasma von Willebrand factor (vWf), an established marker of endothelial damage/dysfunction, has been associated with stroke and vascular events, at least in a clinical trial population. Soluble E-selectin (sE-sel) is another biomarker of endothelial activation/dysfunction, with more limited data on prognostic outcomes in AF. OBJECTIVE: To assess the relationship between the levels of vWf, sE-sel and clinical adverse outcomes (including stroke, MI and all-cause mortality) in a 'real-world' community cohort of patients with AF. METHODS: We studied 423 patients (mean age 72.7 +/- 8.4 years, 55.6% male) with nonvalvular AF, with a median follow-up of 19 (9-31) months. Plasma vWf and sE-sel levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: There were 94 clinical adverse events (22.2%) observed during a median follow-up of 19 months. Patients with clinical events had significantly higher vWf (P < 0.001) and sE-sel levels at baseline (P < 0.001) compared with those who were event free. Kaplan-Meir analyses demonstrated that more clinical adverse events occurred in the upper tertile of vWf [upper vs. lowest tertile, RR 3.8, 95% CI (2.63-5.57), P < 0.001; upper vs. middle tertile, RR 10.5, 95% CI (5.33-20.60), P < 0.001]. Similarly, the highest tertile of sE-sel was associated with more adverse events [upper vs. lowest tertile, RR 3.7, 95% CI (2.51-5.31), P < 0.001; upper vs. middle tertile, RR 6.5, 95% CI (3.56-11.91), P < 0.001]. CONCLUSION: High plasma vWf and soluble E-selectin levels are associated with an increased risk of clinical adverse events (acute myocardial infarction, ischaemic stroke and all-cause mortality) in 'real-world' patients with AF. These soluble biomarkers may potentially aid clinical risk stratification in this common arrhythmia.","author":[{"dropping-particle":"","family":"Krishnamoorthy","given":"Suresh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khoo","given":"Chee Wah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Hoong S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Basili","given":"Stefania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European journal of clinical investigation","id":"ITEM-3","issue":"10","issued":{"date-parts":[["2013","10"]]},"language":"eng","page":"1032-1038","publisher-place":"England, England","title":"Prognostic role of plasma von Willebrand factor and soluble E-selectin levels for future cardiovascular events in a 'real-world' community cohort of patients with atrial fibrillation.","type":"article-journal","volume":"43"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1007/s00392-011-0337-9","ISSN":"1861-0692 (Electronic)","PMID":"21725858","abstract":"INTRODUCTION: Atrial fibrillation (AF) is associated not only with inflammation but also with structural remodelling and altered endothelial activation which may contribute to clot formation, embolization and mortality. We aimed to determine the predictive value of single-time biomarker analysis for prediction of outcome in patients with AF. METHODS AND RESULTS: We conducted a prospective study to evaluate if biomarkers of structural, electrical or endothelial remodelling are predictive of cardiovascular events (composite primary endpoint of myocardial infarction, stroke, peripheral embolism or death). Secondary endpoint was all-cause mortality. Patients with any type of AF and without active inflammatory conditions were eligible. Plasma samples were collected for ELISA analysis of biomarkers (inflammation [hsCRP, sCD40L], structural [MMP-2] and endothelial remodelling [vWF, sVCAM-1]) at enrolment. Patients (n = 278) were followed for 28 +/- 12 (median 32) months. Eighty-eight individuals (32%) experienced a primary outcome event, including 8 (2.9%) with myocardial infarction, 13 (4.8%) with stroke and 4 (1.5%) with peripheral embolism. Predictors of the primary endpoint were age >75 years, CHADS(2)-score >2, LVEF <35%, diabetes, presence of an ICD/pacemaker, elevated vWF, sVCAM-1 and MMP-2 levels. On multivariate regression analysis, only age >75 years, sVCAM-1 and MMP-2 levels remained independently associated with the endpoint. There were 75 deaths during follow-up. Age >75 years, reduced LVEF, elevated sVCAM-1 and MMP-2 levels were predictors of all-cause mortality. CONCLUSION: In this cohort of AF patients, old age, elevated sVCAM-1 and MMP-2 levels were associated with cardiovascular events. Our data indicate that single-time biomarker assessment may be a useful tool to improve risk stratification schemes.","author":[{"dropping-particle":"","family":"Ehrlich","given":"Joachim R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaluzny","given":"Magdalena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baumann","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehmann","given":"Ralf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical research in cardiology : official journal of the German Cardiac Society","id":"ITEM-4","issue":"11","issued":{"date-parts":[["2011","11"]]},"language":"eng","page":"1029-1036","publisher-place":"Germany, Germany","title":"Biomarkers of structural remodelling and endothelial dysfunction for prediction of cardiovascular events or death in patients with atrial fibrillation.","type":"article-journal","volume":"100"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1042/CS20080372","ISSN":"1470-8736 (Electronic)","PMID":"18980576","abstract":"The aim of the present study was to determine the rates of stroke in patients with chronic NVAF (non-valvular atrial fibrillation), evaluating the relationship between plasma levels of inflammatory variables at admission and the occurrence of stroke during a 3-year follow-up. A total of 373 consecutive patients with chronic NVAF were enrolled. Blood samples were drawn within 72 h of admission, and we evaluated plasma levels of IL (interleukin)-1beta, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-10, E-selectin, P-selectin, ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and vWF (von Willebrand Factor). Subsequent patient events (stroke at follow-up) were monitored over a 3 year period. By multivariate analysis, only age, hypertension and high levels of IL-6, TNF-alpha and vWF remained significant predictors of a higher risk of experiencing ischaemic stroke at follow-up. Moreover, plasma values of TNF-alpha, IL-6 and vWF had a significant area under the ROC (receiver operating characteristic) curve. In conclusion, baseline plasma levels of TNF-alpha, IL-6 and vWF are predictors of new-onset ischaemic stroke at follow-up in patients with chronic NVAF.","author":[{"dropping-particle":"","family":"Pinto","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuttolomondo","given":"Antonino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casuccio","given":"Alessandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raimondo","given":"Domenico","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sciacca","given":"Riccardo","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnao","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Licata","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical science (London, England : 1979)","id":"ITEM-5","issue":"10","issued":{"date-parts":[["2009","5"]]},"language":"eng","page":"781-789","publisher-place":"England, England","title":"Immuno-inflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF).","type":"article-journal","volume":"116"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"10.1016/j.ijcard.2005.05.049","ISSN":"0167-5273 (Print)","PMID":"15992948","abstract":"BACKGROUND: Elevated coagulative molecular markers could reflect the prothrombotic state in the cardiovascular system of patients with non-valvular atrial fibrillation (NVAF). A prospective, cooperative study was conducted to determine whether levels of coagulative markers alone or in combination with clinical risk factors could predict subsequent thromboembolic events in patients with NVAF. METHODS: Coagulative markers of prothrombin fragment 1+2, D-dimer, platelet factor 4, and beta-thromboglobulin were determined at the enrollment in the prospective study. RESULTS: Of 509 patients with NVAF (mean age, 66.6 +/- 10.3 years), 263 patients were treated with warfarin (mean international normalized ratio, 1.86), and 163 patients, with antiplatelet drugs. During an average follow-up period of 2.0 years, 31 thromboembolic events occurred. Event-free survival was significantly better in patients with D-dimer level < 150 ng/ml than in those with D-dimer level>or==150 ng/ml. Other coagulative markers, however, did not predict thromboembolic events. Age (>or==75 years), cardiomyopathies, and prior stroke or transient ischemic attack were independent, clinical risk factors for thromboembolism. Thromboembolic risk in patients without the clinical risk factors was quite low (0.7%/year) when D-dimer was < 150 ng/ml, but not low (3.8%/year) when D-dimer was >or==150 ng/ml. It was >5%/year in patients with the risk factors regardless of D-dimer levels. This was also true when analyses were confined to patients treated with warfarin. CONCLUSIONS: D-dimer level in combination with clinical risk factors could effectively predict subsequent thromboembolic events in patients with NVAF even when treated with warfarin.","author":[{"dropping-particle":"","family":"Nozawa","given":"Takashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inoue","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirai","given":"Tadakazu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwasa","given":"Atsushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okumura","given":"Ken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jong-Dae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimizu","given":"Akihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayano","given":"Motonobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yano","given":"Katsusuke","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International journal of cardiology","id":"ITEM-6","issue":"1","issued":{"date-parts":[["2006","4"]]},"language":"eng","page":"59-65","publisher-place":"Netherlands, Netherlands","title":"D-dimer level influences thromboembolic events in patients with atrial fibrillation.","type":"article-journal","volume":"109"},"uris":[""]},{"id":"ITEM-7","itemData":{"DOI":"10.1160/TH03-06-0363","ISSN":"0340-6245 (Print)","PMID":"14652652","abstract":"Atrial fibrillation (AF) is associated with hemostatic abnormalities and increased risk of thrombotic cardiovascular events even during oral anticoagulant therapy (OAT). The aim of our study was to evaluate the predictive value of hemostatic markers for the risk of major cardiovascular events during OAT. The study group comprised 113 patients with chronic AF (70.2 +/- 5.4 years old, 60% men), referred for OAT. Established clinical risk factors and levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) antigen and activity, before and during OAT (after 3.9 +/- 0.7 months; INR 2.57 +/- 0.57) were determined. In all patients OAT significantly suppressed levels of F1+2 by 67%,TAT by 30% and D-dimer by 48% (all p <0.001). During an average follow-up of 44 months 22/111 (20%) patients suffered a combined cardiovascular event (stroke, myocardial infarction, peripheral vascular occlusion or vascular death). Patients with cardiovascular events were significantly older, had more frequent heart failure/systolic dysfunction and had significantly increased levels of D-dimer at entry (63 vs 39 ng/mL, p = 0.005) and during OAT (33 vs 18 ng/mL, p = 0.002), and of t-PA antigen at entry (14.3 vs 10.9 ng/mL, p = 0.02) and during OAT (15.0 vs 11.2 ng/mL, p = 0.05) (all values are medians). In multivariate Cox proportional hazard models, heart failure/systolic dysfunction (hazard ratio 2.91; 95% CI 1.17-7.26; p = 0.02), high levels of D-dimer on OAT (top vs. lower two quartiles) (hazard ratio 4.78, 95% CI 1.39-16.41; p = 0.01) and t-PA antigen levels (continuous variable) (hazard ratio 1.09; 95% CI 1.01-1.17; p = 0.02) were significantly associated with combined cardiovascular events. In conclusion, high levels of D-dimer and t-PA antigen during OAT are significant predictors of combined cardiovascular events in AF patients and, on this basis, could be useful additional markers of cardiovascular risk in such patients.","author":[{"dropping-particle":"","family":"Vene","given":"Nina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mavri","given":"Alenka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kosmelj","given":"Katarina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stegnar","given":"Mojca","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-7","issue":"6","issued":{"date-parts":[["2003","12"]]},"language":"eng","page":"1163-1172","publisher-place":"Germany, Germany","title":"High D-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulant therapy.","type":"article-journal","volume":"90"},"uris":[""]},{"id":"ITEM-8","itemData":{"DOI":"10.1161/01.str.30.12.2547","ISBN":"0039-2499 (Print)\\r0039-2499 (Linking)","ISSN":"0039-2499 (Print)","PMID":"10582976","abstract":"BACKGROUND AND PURPOSE: Markers of thrombin generation and platelet activation are often elevated in patients with nonvalvular atrial fibrillation, but it is unclear whether such markers usefully predict stroke. Therefore, we undertook the present study to assess the relationship between prothrombin fragment F1.2 (F1.2), beta-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation with stroke in atrial fibrillation. METHODS: Specimens were obtained from 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. The results were correlated with patient features, antithrombotic therapy, and subsequent thromboembolism (ischemic stroke and systemic embolism) by multivariate analysis. RESULTS: Increased F1.2 levels were associated with age (P<0.001), female sex (P<0.001), systolic blood pressure (P=0.006), and heart failure (P=0.001). F1.2 were not affected by aspirin use and were not associated with thromboembolism after adjustment for age (P=0. 18). BTG levels were higher with advanced age (P=0.006), coronary artery disease (P=0.05), carotid disease (P=0.005), and heart failure (P<0.001), lower in regular alcohol users (P=0.05), and not significantly associated with thromboembolism. Fibrinogen levels were not significantly related to thromboembolism but were associated with elevated BTG levels (P<0.001). The factor V Leiden mutation was not associated with thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8). CONCLUSIONS: Elevated F1.2 levels were associated with clinical risk factors for stroke in atrial fibrillation, whereas increased BTG levels were linked to manifestations of atherosclerosis. In this large cohort of patients with atrial fibrillation who were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not independent, clinically useful predictors of stroke.","author":[{"dropping-particle":"","family":"Feinberg","given":"William M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"Lesly A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cushman","given":"Mary","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornell","given":"Elaine S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bovill","given":"Edwin G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-8","issue":"12","issued":{"date-parts":[["1999","12"]]},"language":"eng","page":"2547-2553","publisher":"Lippincott Williams and Wilkins","publisher-place":"United States, United States","title":"Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study.","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(85,86,91,93,97–99,103)","plainTextFormattedCitation":"(85,86,91,93,97–99,103)","previouslyFormattedCitation":"(85,86,91,93,97–99,103)"},"properties":{"noteIndex":0},"schema":""}(85,86,91,93,97–99,103).Urine biomarkersFew urine biomarkers have been identified as possible predictors of stroke risk in AF. In the ATRIA study, presence of proteinuria was associated with a 1.5-fold increased risk of thromboembolism ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.108.816082","ISSN":"1524-4539 (Electronic)","PMID":"19255343","abstract":"BACKGROUND: Atrial fibrillation (AF) substantially increases the risk of ischemic stroke, but this risk varies among individual patients with AF. Existing risk stratification schemes have limited predictive ability. Chronic kidney disease is a major cardiovascular risk factor, but whether it independently increases the risk for ischemic stroke in persons with AF is unknown. METHODS AND RESULTS: We examined how chronic kidney disease (reduced glomerular filtration rate or proteinuria) affects the risk of thromboembolism off anticoagulation in patients with AF. We estimated glomerular filtration rate using the Modification of Diet in Renal Disease equation and proteinuria from urine dipstick results found in laboratory databases. Patient characteristics, warfarin use, and thromboembolic events were ascertained from clinical databases, with validation of thromboembolism by chart review. During 33,165 person-years off anticoagulation among 10,908 patients with AF, we observed 676 incident thromboembolic events. After adjustment for known risk factors for stroke and other confounders, proteinuria increased the risk of thromboembolism by 54% (relative risk, 1.54; 95% CI, 1.29 to 1.85), and there was a graded, increased risk of stroke associated with a progressively lower level of estimated glomerular filtration rate compared with a rate > or =60 mL x min(-1) x 1.73 m(-2): relative risk of 1.16 (95% CI, 0.95 to 1.40) for estimated glomerular filtration rate of 45 to 59 mL x min(-1) x 1.73 m(-2) and 1.39 (95% CI, 1.13 to 1.71) for estimated glomerular filtration rate <45 mL x min(-1) x 1.73 m(-2) (P=0.0082 for trend). CONCLUSIONS: Chronic kidney disease increases the risk of thromboembolism in AF independently of other risk factors. Knowing the level of kidney function and the presence of proteinuria may improve risk stratification for decision making about the use of antithrombotic therapy for stroke prevention in AF.","author":[{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fang","given":"Margaret C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Udaltsova","given":"Natalia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pomernacki","given":"Niela K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borowsky","given":"Leila","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2009","3","17"]]},"language":"eng","page":"1363-1369","publisher-place":"United States","title":"Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.","type":"article-journal","volume":"119"},"uris":[""]}],"mendeley":{"formattedCitation":"(68)","plainTextFormattedCitation":"(68)","previouslyFormattedCitation":"(68)"},"properties":{"noteIndex":0},"schema":""}(68). In addition, a retrospective study demonstrated that higher levels of albuminuria were associated with greater risk of thromboembolism among patients with newly diagnosed AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ijcard.2016.07.145","ISSN":"18741754","PMID":"27434352","abstract":"Background Accurate risk stratification is important in the management of patients with non-valvular atrial fibrillation (NVAF). However, one cohort study demonstrated an annual ischemic stroke rate of 1.61% in the group of patients classified in “the true low risk” according to CHA2DS2-VASc. We aimed to find out more indicators and evaluate their abilities in predicting thromboembolic events (TE). Methods We assigned 58 patients with TE to the thrombosis group, and 157 patients without TE to the non-thrombosis group. The clinical parameters of these patients were subjected to univariate analysis and unconditioned logistic regression analysis for screening the risk factor, which was urine albumin (UA) according to the result. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off point of the UA. Then we formed the CHA2DS2-VASc-UA2 score and made a comparison with CHA2DS2-VASc score. Results Mean UA of the thrombosis group was significantly higher than that of the non-thrombosis group (0.1 g/L vs 0.0 g/L, P < 0.01). The results of unconditioned logistic regression analysis showed that OR of UA was 40.98 (95% CI: 3.58–468.88, P < 0.01). The Area Under the Curve (AUC) of UA was 0.700 with an optimal cut-off point of 0.03 g/L. ROC curve analysis result showed that AUC of CHA2DS2-VASc-UA2 score was larger than that of CHA2DS2-VASc score (0.873 vs 0.860, P < 0.01). Conclusion UA ≥ 0.03 g/L is the independent predictive factor of TE for NVAF patients. And the CHA2DS2-VASc-UA2 score might perform better in predicting TE compared with the CHA2DS2-VASc score.","author":[{"dropping-particle":"","family":"He","given":"Haohui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guo","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Aidong","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Cardiology","id":"ITEM-1","issued":{"date-parts":[["2016","10"]]},"language":"eng","page":"827-830","publisher":"Elsevier Ireland Ltd","publisher-place":"Netherlands, Netherlands","title":"The value of urine albumin in predicting thromboembolic events for patients with non-valvular atrial fibrillation","type":"article-journal","volume":"221"},"uris":[""]}],"mendeley":{"formattedCitation":"(104)","plainTextFormattedCitation":"(104)","previouslyFormattedCitation":"(104)"},"properties":{"noteIndex":0},"schema":""}(104). Possible mechanisms are: 1) albuminuria reflects early-stage CKD which has been shown to be related to stroke risk; 2) albuminuria causes an imbalance between naturally occurring pro-thrombotic and anti-thrombotic factors, such as that seen in nephrotic syndrome ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2174/157016111203140518172048","ISSN":"1875-6212 (Electronic)","PMID":"22724465","abstract":"Patients with nephrotic syndrome are at increased risk for thromboembolic events such as deep venous and arterial thrombosis, renal vein thrombosis and pulmonary embolism. This thrombophilic phenomenon has been attributed to a \"hypercoagulable\" state in which an imbalance between naturally occurring pro-coagulant/pro-thrombotic factors and anti-coagulant/antithrombotic factors promotes in situ thrombosis in deep veins or arteries. Management of thromboembolic events may be divided in prophylactic and therapeutic strategies. Hypoalbuminemia is the most significant independent predictor factor of thrombotic risk, especially for values <2 g/dL. However, the most important question in these patients is whether to anticoagulate prophylactically or not. The decision depends on type of glomerulonephritis, proteinuria severity, other predisposing factors and prior history of thrombosis. Reviewing the recent literature, we suggest the best therapeutic management of anticoagulation for patients with nephrotic syndrome, focusing on prophylactic strategies.","author":[{"dropping-particle":"","family":"Gigante","given":"Antonietta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barbano","given":"Biagio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sardo","given":"Liborio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Martina","given":"Paola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gasperini","given":"Maria L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbadia","given":"Raffaella","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liberatori","given":"Marta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amoroso","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cianci","given":"Rosario","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Current vascular pharmacology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2014","5"]]},"language":"eng","page":"512-517","publisher-place":"United Arab Emirates, United Arab Emirates","title":"Hypercoagulability and nephrotic syndrome.","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"(105)","plainTextFormattedCitation":"(105)","previouslyFormattedCitation":"(105)"},"properties":{"noteIndex":0},"schema":""}(105). Pignatelli et al. showed that higher urinary prostaglandin F2α levels were associated with a greater composite risk of stroke, TIA, myocardial infarction and coronary revascularisation during a follow-up period of 26 months ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1160/TH14-07-0571","ISSN":"2567-689X (Electronic)","PMID":"25392853","abstract":"There are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in atrial fibrillation (AF). The aim of this study was to analyse the role of urinary prostaglandin PGF2alpha (8-iso-PGF2alpha) and NOX2, markers of systemic oxidative stress, in predicting cardiovascular (CV) events and mortality in anticoagulated non-valvular AF patients. This was a prospective study including 1,002 anticoagulated AF patients, followed for a median time of 25.7 months (interquartile range: 14.8-50.9). All major CV events, CV deaths and all-cause deaths were considered as primary outcomes of the study. CV events included fatal/nonfatal ischaemic stroke, fatal/nonfatal myocardial infarction (MI), cardiac revascularisation and transient ischaemic attack (TIA). Oxidative stress biomarkers, such as urinary 8-iso-PGF2alpha and serum sNOX2-dp, a marker of NOX2 activation, were measured. A CV event occurred in 125 patients (12.5 %); 78 CV deaths and 31 non-CV deaths were registered. 8-iso-PGF2alpha and sNOX2-dp were correlated (Rs=0.765 p< 0.001). A significant increased cumulative incidence of CV events and CV deaths was observed across tertiles for 8-iso-PGF2alpha and sNOX2-dp. An increased rate of all-cause death was observed across tertiles of urinary 8-iso-PGF2alpha. In Cox or Fine and Gray models, 8-iso-PGF2alpha predicted CV events and CV and non-CV deaths. The addition of tertiles of 8-iso-PGF2alpha to CHA2DS2-VASc score improved ROC curves for each outcome and NRI for CV events (0.24 [0.06-0.53] p=0.0067). The study shows that in AF patients 8-iso-PGF2alpha and NOX2 levels are predictive of CV events and total mortality. F2-IsoP may complement conventional risk factors in prediction of CV events.","author":[{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pastori","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carnevale","given":"Roberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farcomeni","given":"Alessio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cangemi","given":"Roberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nocella","given":"Cristina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartimoccia","given":"Simona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicario","given":"Tommasa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saliola","given":"Mirella","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015","3"]]},"language":"eng","page":"617-624","publisher-place":"Germany, Germany","title":"Serum NOX2 and urinary isoprostanes predict vascular events in patients with atrial fibrillation.","type":"article-journal","volume":"113"},"uris":[""]}],"mendeley":{"formattedCitation":"(100)","plainTextFormattedCitation":"(100)","previouslyFormattedCitation":"(100)"},"properties":{"noteIndex":0},"schema":""}(100). Furthermore, urinary 11-dehydro-thromboxane B2 has also been found to be related to a composite risk of stroke, TIA, myocardial infarction, coronary revascularisation and cardiovascular-related death among patients with AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ahj.2015.05.011","ISSN":"1097-6744 (Electronic)","PMID":"26385032","abstract":"BACKGROUND: Patients with nonvalvular atrial fibrillation (AF) show high residual cardiovascular (CV) risk despite oral anticoagulants. Urinary 11-dehydro-thromboxane B2 (TxB2) is associated with an increased risk of CV events (CVEs), but its predictive value in patients with anticoagulated AF is unknown. METHODS: A prospective single-center cohort study, including 837 patients with AF, was conducted. Mean time of follow-up was 30.0 months, yielding 2,062 person-years of observation. Urinary 11-dehydro-TxB2 was measured at baseline. The primary end point was the occurrence of a CVE including fatal/nonfatal myocardial infarction and ischemic stroke, transient ischemic attack, cardiac revascularization, and CV death. RESULTS: Mean age of patients was 73.1 years, and 43.6% were women. Median 11-dehydro-TxB2 levels were 100 (interquartile range 50-187) ng/mg of urinary creatinine. Overall, the anticoagulation control was adequate (63.9% of mean time in therapeutic range). A CVE occurred in 99 (11.8%) patients, and 55 were CV deaths. At baseline, 11-dehydro-TxB2 levels were higher in patients with a CVE compared with those without (186 [107-400] vs 98 [52-170], P < .001). An increased rate of CVEs (log-rank test, P < .001) and CV deaths (P < .001) was observed across tertiles of 11-dehydro-TxB2. Cardiovascular events were associated with age (hazard ratios [HR] 1.72 per 1 SD, 95% CI 1.33-2.21, P < .001), diabetes mellitus (HR 1.89, 95% CI 1.20-2.96, P = .005), heart failure (HR 1.60, 95% CI 1.01-2.54, P = .044), history of stroke/transient ischemic attack (HR 1.96, 95% CI 1.25-3.06, P = .003), and 11-dehydro-TxB2 (HR 1.64 per 1 SD, 95% CI 1.42-1.89, P < .001). CONCLUSIONS: Urinary 11-dehydro-TxB2 levels are associated with a residual risk of CVEs and CV mortality in patients with AF despite anticoagulant treatment.","author":[{"dropping-particle":"","family":"Pastori","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farcomeni","given":"Alessio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cangemi","given":"Roberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hiatt","given":"William R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartimoccia","given":"Simona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nocella","given":"Cristina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicario","given":"Tommasa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bucci","given":"Tommaso","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carnevale","given":"Roberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American heart journal","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015","9"]]},"language":"eng","page":"490-7.e1","publisher-place":"United States, United States","title":"Urinary 11-dehydro-thromboxane B2 is associated with cardiovascular events and mortality in patients with atrial fibrillation.","type":"article-journal","volume":"170"},"uris":[""]}],"mendeley":{"formattedCitation":"(106)","plainTextFormattedCitation":"(106)","previouslyFormattedCitation":"(106)"},"properties":{"noteIndex":0},"schema":""}(106). Overall, although urine biomarkers have not been comprehensively investigated in AF, they may represent an additional, simple and non-invasive method to aid stroke risk stratification.Structural biomarkersAtrial fibrillation causes significant structural changes including atrial remodelling that may be detected through a variety of imaging techniques. Some of these changes have been found to predict stroke risk in AF ( REF _Ref24900706 \r \h \* MERGEFORMAT Table 4), potentially by promoting abnormal blood stasis. Early studies in this area have relied predominantly on standard transthoracic echocardiography. Recently, advanced imaging modalities with increased accuracy such as trans-oesophageal echocardiography, computed tomography and MRI have become more widely available. This has allowed the discovery of new structural biomarkers such as LA fibrosis and left atrial appendage (LAA) morphology that may be used to refine stroke risk assessment in AF. The SPAF study evaluated the role of 14 echocardiographic parameters to predict incident ischaemic stroke or systemic embolism in AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.7326/0003-4819-116-1-6","ISSN":"0003-4819 (Print)","PMID":"1727097","abstract":"OBJECTIVE: To identify echocardiographic predictors of arterial thromboembolism in patients with nonrheumatic atrial fibrillation and to determine whether these add to clinical variables for risk stratification. DESIGN: Cohort study of patients assigned to placebo in a randomized clinical trial. SETTING: Five hundred sixty-eight inpatients and outpatients with nonrheumatic atrial fibrillation assigned to placebo therapy at 15 U.S. medical centers from 1987 to 1989 in the Stroke Prevention in Atrial Fibrillation study. Patients were followed for a mean of 1.3 years. MEASUREMENTS: M-mode and two-dimensional (2-D) echocardiograms performed at study entry and interpreted by local cardiologists. The predictive value of 14 echocardiographic variables for later ischemic stroke or systemic embolism was assessed by multivariate analysis. MAIN RESULTS: Left ventricular dysfunction from 2-D echocardiograms (P = 0.003) and the size of the left atrium from M-mode echocardiograms (P = 0.02) were the strongest independent predictors of later thromboembolism. Multivariate analysis of these two independent echocardiographic predictors with the three independent clinical predictors of thromboembolism (history of hypertension, recent congestive heart failure, previous thromboembolism) identified 26% of the cohort with a low risk for thromboembolism (1.0% per year; 95% Cl, 0.2% to 4.0%). Compared with risk stratification using clinical variables alone, echocardiographic results altered thromboembolic risk stratification in 18% of the entire cohort and in 38% of those without clinical risk factors. CONCLUSIONS: Both left ventricular and left atrial variables are significant predictors of thromboembolism in patients with nonvalvular atrial fibrillation. Our results challenge traditional views of the pathogenesis of ischemic stroke in patients with atrial fibrillation and suggest that standard echocardiography contributes to risk stratification, differentiating the one third of patients without clinical risk factors who are at increased risk for stroke from the remainder who may not need antithrombotic prophylaxis.","container-title":"Annals of internal medicine","id":"ITEM-1","issue":"1","issued":{"date-parts":[["1992","1"]]},"language":"eng","page":"6-12","publisher-place":"United States, United States","title":"Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators.","type":"article-journal","volume":"116"},"uris":[""]}],"mendeley":{"formattedCitation":"(107)","plainTextFormattedCitation":"(107)","previouslyFormattedCitation":"(107)"},"properties":{"noteIndex":0},"schema":""}(107). The authors reported that the presence of left ventricular dysfunction and higher LA size were found to be important. Furthermore, these parameters were able to identify patients without clinical risk factors who were at higher risk of stroke. A prospective study of 2,713 patients with AF demonstrated that LA enlargement (>45mm) was linked to a 1.7-fold increased risk of ischaemic stroke or systemic embolism ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/srep31042","ISSN":"2045-2322 (Electronic)","PMID":"27485817","abstract":"Controversy exists regarding whether left atrial enlargement (LAE) is a predictor of stroke/systemic embolism (SE) in atrial fibrillation (AF) patients. The Fushimi AF Registry, a community-based prospective survey, enrolled all AF patients in Fushmi-ku, Japan, from March 2011. Follow-up data and baseline echocardiographic data were available for 2,713 patients by August 2015. We compared backgrounds and incidence of events over a median follow-up of 976.5 days between patients with LAE (left atrial diameter > 45 mm; LAE group) and those without in the Fushimi AF Registry. The LAE group accounted for 39% (n = 1,049) of cohort. The LAE group was older and had longer AF duration, with more prevalent non-paroxysmal AF, higher CHADS2/CHA2DS2-VASc score, and oral anticoagulant (OAC) use. A higher risk of stroke/SE during follow-up in the LAE group was found (entire cohort; hazard ratio (HR): 1.92, 95% confidence interval (CI): 1.40-2.64; p < 0.01; without OAC; HR: 1.97, 95% CI: 1.18-3.25; p < 0.01; with OAC; HR: 1.83, 95% CI: 1.21-2.82; p < 0.01). LAE was independently associated with increased risk of stroke/SE (HR: 1.74, 95% CI: 1.25-2.42; p < 0.01) after adjustment by the components of CHA2DS2-VASc score and OAC use. In conclusion, LAE was an independent predictor of stroke/SE in large community cohort of AF patients.","author":[{"dropping-particle":"","family":"Hamatani","given":"Yasuhiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogawa","given":"Hisashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takabayashi","given":"Kensuke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamashita","given":"Yugo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takagi","given":"Daisuke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Esato","given":"Masahiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chun","given":"Yeong-Hwa Hwa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsuji","given":"Hikari","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wada","given":"Hiromichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hasegawa","given":"Koji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abe","given":"Mitsuru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H. H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akao","given":"Masaharu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific reports","id":"ITEM-1","issued":{"date-parts":[["2016","8","3"]]},"language":"eng","page":"31042","publisher":"Nature Publishing Group","publisher-place":"England, England","title":"Left atrial enlargement is an independent predictor of stroke and systemic embolism in patients with non-valvular atrial fibrillation.","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"(108)","plainTextFormattedCitation":"(108)","previouslyFormattedCitation":"(108)"},"properties":{"noteIndex":0},"schema":""}(108). Dakay et al. also found that more severe LA enlargement was associated with a greater risk of ischaemic stroke despite anticoagulation ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jstrokecerebrovasdis.2017.08.025","ISSN":"15328511","PMID":"28918087","abstract":"Background: Despite anticoagulation therapy, ischemic stroke risk in atrial fibrillation (AF) remains substantial. We hypothesize that left atrial enlargement (LAE) is more prevalent in AF patients admitted with ischemic stroke who are therapeutic, as opposed to nontherapeutic, on anticoagulation. Methods: We included consecutive patients with AF admitted with ischemic stroke between April 1, 2015, and December 31, 2016. Patients were divided into two groups based on whether they were therapeutic (warfarin with an international normalized ratio ≥ 2.0 or non–vitamin K oral anticoagulant with uninterrupted use in the prior 2 weeks) versus nontherapeutic on anticoagulation. Univariable and multivariable models were used to estimate associations between therapeutic anticoagulation and clinical factors, including CHADS2 score and LAE (none/mild versus moderate/severe). Results: We identified 225 patients during the study period; 52 (23.1%) were therapeutic on anticoagulation. Patients therapeutic on anticoagulation were more likely to have a larger left atrial diameter in millimeters (45.6 ± 9.2 versus 42.3 ± 8.6, P =.032) and a higher CHADS2 score (2.9 ± 1.1 versus 2.4 ± 1.1, P =.03). After adjusting for the CHADS2 score, patients who had a stroke despite therapeutic anticoagulation were more likely to have moderate to severe LAE (odds ratio, 2.05; 95% confidence interval, 1.01-4.16). Conclusion: LAE is associated with anticoagulation failure in AF patients admitted with an ischemic stroke. This provides indirect evidence that LAE may portend failure of anticoagulation therapy in patients with AF; further studies are needed to delineate the significance of this association and improve stroke prevention strategies.","author":[{"dropping-particle":"","family":"Dakay","given":"Katarina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Andrew D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hemendinger","given":"Morgan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cutting","given":"Shawna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McTaggart","given":"Ryan A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Jayaraman","given":"Mahesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chu","given":"Antony","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Panda","given":"Nikhil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merkler","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gialdini","given":"Gino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kummer","given":"Benjamin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lerario","given":"Michael P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kamel","given":"Hooman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Elkind","given":"Mitchell S.V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furie","given":"Karen L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yaghi","given":"Shadi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Stroke and Cerebrovascular Diseases","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018","1"]]},"language":"eng","page":"192-197","publisher":"Elsevier Inc.","publisher-place":"United States, United States","title":"Left Atrial Enlargement and Anticoagulation Status in Patients with Acute Ischemic Stroke and Atrial Fibrillation","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(109)","plainTextFormattedCitation":"(109)","previouslyFormattedCitation":"(109)"},"properties":{"noteIndex":0},"schema":""}(109). Interestingly, there appears to be an association between LA size and stroke risk even in the absence of AF. In the Framingham Heart study, non-AF patients with increased LA size were found to be at greater risk of stroke and mortality during the follow-up period of eight years ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.cir.92.4.835","ISBN":"1112131415161","ISSN":"0009-7322 (Print)","PMID":"7641364","abstract":"BACKGROUND: The medical literature contains conflicting reports on the association of left atrial (LA) enlargement with risk of stroke. The relation of LA size to risk of stroke and death in the general population remains largely unexplored. METHODS AND RESULTS: Subjects 50 years of age and older from the Framingham Heart Study were studied to assess the relations between echocardiographic LA size and risk of stroke and death. During 8 years of follow-up, 64 of 1371 (4.7%) men and 73 of 1728 (4.2%) women sustained a stroke, and 296 (21.6%) men and 271 (15.7%) women died. Sex-specific Cox proportional-hazards models were adjusted for age, hypertension, diabetes, atrial fibrillation, smoking, ECG left ventricular (LV) hypertrophy, and congestive heart failure or myocardial infarction. After multivariable adjustment, for every 10-mm increase in LA size, the relative risk of stroke was 2.4 in men (95% CI, 1.6 to 3.7) and 1.4 in women (95% CI, 0.9 to 2.1); the relative risk of death was 1.3 in men (95% CI, 1.0 to 1.5) and 1.4 in women (95% CI, 1.1 to 1.7). Adjusting for ECG LV mass/height attenuated the relation of LA size to stroke and death. CONCLUSIONS: After multivariable adjustment, LA enlargement remained a significant predictor of stroke in men and death in both sexes. The relation of LA enlargement to stroke and death appears to be partially mediated by LV mass.","author":[{"dropping-particle":"","family":"Benjamin","given":"Emelia J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Agostino","given":"Ralph B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Belanger","given":"Albert J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolf","given":"Philip A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levy","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"4","issued":{"date-parts":[["1995","8"]]},"language":"eng","page":"835-841","publisher-place":"United States, United States","title":"Left atrial size and the risk of stroke and death. The Framingham Heart Study.","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"(110)","plainTextFormattedCitation":"(110)","previouslyFormattedCitation":"(110)"},"properties":{"noteIndex":0},"schema":""}(110). The presence of LA enlargement may therefore be helpful to identify the subset of AF patients who remain at high-risk of stroke despite anticoagulation therapy. Furthermore, it can be assessed on transthoracic echocardiography without the need for more complex imaging techniques.The majority of cardioembolic strokes originate from the left atrium. In the LA, the most common site of thrombus formation is within the LAA. This is a small, complex, pouch-like sac attached to the anterior portion of the LA. Due to its complex anatomical structure and narrow inlet, the LAA is prone to abnormal blood stasis predisposing to thrombus formation. These thrombi may subsequently dislodge to cause a stroke. Therefore, it is perhaps unsurprising that certain LAA features have been shown to influence stroke risk. Unfortunately, these are rarely appreciated on standard transthoracic echocardiography which remains the most commonly used imaging method. The SPAF-III study demonstrated that among AF patients, ongoing arrhythmia during trans-oesophageal assessment was associated with a lower LAA peak antegrade flow velocity (Avp) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0894-7317(99)70105-7","ISSN":"0894-7317 (Print)","PMID":"10588784","abstract":"Stroke associated with atrial fibrillation (AF) is mainly due to embolism of thrombus formed during stasis of blood in the left atrial appendage (LAA). Pathophysiologic correlates of appendage flow velocity as assessed by transesophageal echocardiography (TEE) in patients with AF have not been defined. To evaluate the hypothesis that reduced velocity is associated with spontaneous echocardiographic contrast and thrombus in the LAA and with clinical embolic events, we measured LAA flow velocity by TEE in 721 patients with nonvalvular AF entering the Stroke Prevention in Atrial Fibrillation (SPAF-III) study. Patient features, TEE findings, and subsequent cardioembolic events were correlated with velocity by multivariate analysis. Patients in AF during TEE displayed lower peak antegrade (emptying) flow velocity (Anu(p)) than those with intermittent AF in sinus rhythm during TEE (33 cm/s vs 61 cm/s, respectively, P <.0001). Anu(p) < 20 cm/s was associated with dense spontaneous echocardiographic contrast (P <.001), appendage thrombus (P <.01), and subsequent cardioembolic events (P <.01). Independent predictors of Anu(p) < 20 cm/s included age (P =.009), systolic blood pressure (P <.001), sustained AF (P =.01), ischemic heart disease (P =.01), and left atrial area (P =.04). Multivariate analysis found both Anu(p) <20 cm/s (relative risk 2.6, P =.02) and clinical risk factors (relative risk 3.3, P =.002) independently associated with LAA thrombus. LAA Anu(p) is reduced in AF and associated with spontaneous echocardiographic contrast, appendage thrombus, and cardioembolic stroke. Systolic hypertension and aortic atherosclerosis, independent clinical predictors of stroke in patients with AF, also correlated with LAA Anu(p). Our results support the role of reduced LAA Anu(p) in the generation of stasis, thrombus formation, and embolism in patients with AF, although other mechanisms also contribute to stroke.","author":[{"dropping-particle":"","family":"Goldman","given":"M. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"L. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"R. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zabalgoitia","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asinger","given":"R. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Safford","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"J. L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Society of Echocardiography","id":"ITEM-1","issue":"12","issued":{"date-parts":[["1999","12"]]},"language":"eng","page":"1080-1087","publisher":"Mosby Inc.","publisher-place":"United States, United States","title":"Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The stroke prevention in atrial fibrillation [SPAF-III] study)","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"(111)","plainTextFormattedCitation":"(111)","previouslyFormattedCitation":"(111)"},"properties":{"noteIndex":0},"schema":""}(111). Furthermore, the authors found that an LAA Avp <20cm/s was related to the presence of spontaneous echo contrast and LAA thrombus, and increased risk of cardioembolic events. Predictors of Avp <20cm/s were increasing age, higher systolic blood pressure, ischaemic heart disease and greater LA area. All of which are known risk factors for AF. In addition, the presence of spontaneous echo contrast and LAA thrombus have both been independently shown to be linked to greater stroke risk in AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/0735-1097(94)90025-6","ISSN":"0735-1097 (Print)","PMID":"8077549","abstract":"OBJECTIVES: This study examined the influence of left atrial spontaneous echo contrast on the subsequent stroke or embolic event rate and on survival in patients with nonvalvular atrial fibrillation. BACKGROUND: Left atrial spontaneous echo contrast is associated with atrial fibrillation and a history of previous stroke or other embolic events. However, the prognostic implications of spontaneous contrast in patients with nonvalvular atrial fibrillation are unknown. METHOD: The study group comprised 272 consecutive patients with nonvalvular atrial fibrillation undergoing transesophageal echocardiography. Clinical and echocardiographic data were collected at baseline, and patients were prospectively followed up, and all strokes, other embolic events and deaths were documented. The relation between spontaneous contrast at baseline and subsequent stroke, other embolic events and survival was analyzed. RESULTS: Left atrial spontaneous echo contrast was detected at baseline in 161 patients (59%). The mean follow-up was 17.5 months. The stroke or other embolic event rate was 12%/year (15 strokes, 3 transient ischemic attacks, 2 peripheral embolisms) in patients with, compared with 3%/year (5 strokes) in patients without, baseline spontaneous contrast (p = 0.002). In 149 patients without previous thromboembolism, the event rate was 9.5%/year in patients with and 2.2%/year in patients without spontaneous contrast (p = 0.003). There were 25 deaths in patients with and 11 deaths in patients without spontaneous contrast. Patients with spontaneous contrast had significantly reduced survival (p = 0.025). On multivariate analysis, spontaneous contrast was the only positive predictor (odds ratio 3.5, p = 0.03) and warfarin therapy on follow-up the only negative predictor (odds ratio 0.23, p = 0.02) of subsequent stroke or other embolic events. CONCLUSIONS: Transesophageal echocardiography can risk stratify patients with nonvalvular atrial fibrillation by identifying left atrial spontaneous echo contrast. These patients have both a significantly higher risk of developing stroke or other embolic events and a reduced survival, and they may represent a subgroup in whom the risk/benefit ratio of anticoagulation may be most favorable.","author":[{"dropping-particle":"","family":"Leung","given":"Dominic Y C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Black","given":"Ian W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cranney","given":"Gregory B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hopkins","given":"Andrew P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walsh","given":"Warren F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["1994","9"]]},"language":"eng","page":"755-762","publisher-place":"United States, United States","title":"Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation.","type":"article-journal","volume":"24"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/s0735-1097(98)00146-6","ISSN":"0735-1097 (Print)","PMID":"9626843","abstract":"OBJECTIVES: This study explored the mechanisms linking clinical and precordial echocardiographic predictors to thromboembolism in atrial fibrillation (AF) by assessing transesophageal echocardiographic (TEE) correlations. BACKGROUND: Clinical predictors of thromboembolism in patients with nonvalvular AF have been identified, but their mechanistic links remain unclear. TEE provides imaging of the left atrium, its appendage and the proximal thoracic aorta, potentially clarifying stroke mechanisms in patients with AF. METHODS: Cross-sectional analysis of TEE features correlated with low, moderate and high thromboembolic risk during aspirin therapy among 786 participants undergoing TEE on entry into the Stroke Prevention in Atrial Fibrillation III trial. RESULTS: TEE features independently associated with increased thromboembolic risk were appendage thrombi (relative risk [RR] 2.5, p = 0.04), dense spontaneous echo contrast (RR 3.7, p < 0.001), left atrial appendage peak flow velocities < or = 20 cm/s (RR 1.7, p = 0.008) and complex aortic plaque (RR 2.1, p < 0.001). Patients with AF with a history of hypertension (conferring moderate risk) more frequently had atrial appendage thrombi (RR 2.6, p < 0.001) and reduced flow velocity (RR 1.8, p = 0.003) than low risk patients. Among low risk patients, those with intermittent AF had similar TEE features to those with constant AF. CONCLUSIONS: TEE findings indicative of atrial stasis or thrombosis and of aortic atheroma were independently associated with high thromboembolic risk in patients with AF. The increased stroke risk associated with a history of hypertension in AF appears to be mediated primarily through left atrial stasis and thrombi. The presence of complex aortic plaque distinguished patients with AF at high risk from those at moderate risk of thromboembolism.","author":[{"dropping-particle":"","family":"Zabalgoitia","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"L A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blackshear","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asinger","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"R G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-2","issue":"7","issued":{"date-parts":[["1998","6"]]},"language":"eng","page":"1622-1626","publisher-place":"United States, United States","title":"Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators.","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"(112,113)","plainTextFormattedCitation":"(112,113)","previouslyFormattedCitation":"(112,113)"},"properties":{"noteIndex":0},"schema":""}(112,113).It is now recognised that the LAA is a complex structure with significant variation between patients. A study by Di Biase et al. found that among AF patients planned for catheter ablation, LAA morphologies could be categorised into four main groups based on their appearances on computed tomography or MRI ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2012.04.032","ISSN":"07351097","PMID":"22858289","abstract":"Objectives: This study investigated the left atrial appendage (LAA) by computed tomography (CT) and magnetic resonance imaging (MRI) to categorize different LAA morphologies and to correlate the morphology with the history of stroke/transient ischemic attack (TIA). Background: LAA represents one of the major sources of cardiac thrombus formation responsible for TIA/stroke in patients with atrial fibrillation (AF). Methods: We studied 932 patients with drug-refractory AF who were planning to undergo catheter ablation. All patients underwent cardiac CT or MRI of the LAA and were screened for history of TIA/stroke. Four different morphologies were used to categorize LAA: Cactus, Chicken Wing, Windsock, and Cauliflower. Results: CT scans of 499 patients and MRI scans of 433 patients were analyzed (age 59 ± 10 years, 79% were male, and 14% had CHADS 2 [Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack] score <2). The distribution of different LAA morphologies was Cactus (278 [30%]), Chicken Wing (451 [48%]), Windsock (179 [19%]), and Cauliflower (24 [3%]). Of the 932 patients, 78 (8%) had a history of ischemic stroke or TIA. The prevalence of pre-procedure stroke/TIA in Cactus, Chicken Wing, Windsock, and Cauliflower morphologies was 12%, 4%, 10%, and 18%, respectively (p = 0.003). After controlling for CHADS 2 score, gender, and AF types in a multivariable logistic model, Chicken Wing morphology was found to be 79% less likely to have a stroke/TIA history (odd ratio: 0.21, 95% confidence interval: 0.05 to 0.91, p = 0.036). In a separate multivariate model, we entered Chicken Wing as the reference group and assessed the likelihood of stroke in other groups in relation to reference. Compared with Chicken Wing, Cactus was 4.08 times (p = 0.046), Windsock was 4.5 times (p = 0.038), and Cauliflower was 8.0 times (p = 0.056) more likely to have had a stroke/TIA. Conclusions: Patients with Chicken Wing LAA morphology are less likely to have an embolic event even after controlling for comorbidities and CHADS 2 score. If confirmed, these results could have a relevant impact on the anticoagulation management of patients with a low-intermediate risk for stroke/TIA. ? 2012 American College of Cardiology Foundation.","author":[{"dropping-particle":"","family":"Biase","given":"Luigi","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santangeli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anselmino","given":"Matteo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mohanty","given":"Prasant","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salvetti","given":"Ilaria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gili","given":"Sebastiano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horton","given":"Rodney","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sanchez","given":"Javier E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bai","given":"Rong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mohanty","given":"Sanghamitra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pump","given":"Agnes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cereceda Brantes","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallinghouse","given":"G. Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burkhardt","given":"J. David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cesarani","given":"Federico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scaglione","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Natale","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gaita","given":"Fiorenzo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2012","8","7"]]},"language":"eng","page":"531-538","publisher-place":"United States, United States","title":"Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study","type":"article-journal","volume":"60"},"uris":[""]}],"mendeley":{"formattedCitation":"(114)","plainTextFormattedCitation":"(114)","previouslyFormattedCitation":"(114)"},"properties":{"noteIndex":0},"schema":""}(114). In order of reducing frequency, these were called ‘chicken wing’ (48%), ‘cactus’ (30%), ‘windsock’ (19%) and ‘cauliflower’ (3%). After multivariable adjustment, a chicken wing morphology was associated with the lowest risk of stroke. In comparison, there was a four-fold increased stroke risk with the cactus and windsock morphologies, and eight-fold increased stroke risk with the cauliflower morphology. Similar findings were also reported elsewhere ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"2542-5641","PMID":"25533823","abstract":"BACKGROUND The left atrial appendage (LAA) is thought to be the main source of thrombi in patients with atrial fibrillation (AF). The purpose of this study was to describe the LAA orifice diameter, LAA length, and morphologic type of the LAA in Chinese patients with AF as well as to evaluate whether these LAA parameters are associated with a history of stroke in patients with AF from a single center in China. METHODS The study population consisted of 219 consecutive patients with drug-refractory, symptomatic paroxysmal, or persistent AF scheduled to undergo radiofrequency catheter ablation in our single center. All patients underwent extensive clinical assessment and multidetector computed tomography to fully explore the anatomy of the LAA. RESULTS Of the 219 patients who underwent catheter ablation procedures, chicken wing LAA morphology was found in 114 patients (52.2%), windsock in 52 (23.9%), cauliflower in 29 (13.0%), and cactus in 24 (10.9%). Compared with the windsock LAA morphology, cactus had a larger left atrial diameter ((42.40 ± 3.68) and (37.91 ± 4.32) mm, P = 0.005) and LAA orifice diameter ((27.38 ± 3.70) and (24.14 ± 3.58) mm, P = 0.048). The LAA length was significantly larger in the chicken wing morphology than in the windsock ((37.50 ± 6.74) and (31.33 ± 3.92) mm, P = 0.015) and cauliflower morphologies ((37.50 ± 6.74) and (31.33 ± 3.92) mm, P = 0.015). According to their medical records, 26 patients (11.9%) had suffered a prior stroke. Compared with patients who had no history of stroke, the prior-stroke patients were older (62.04 ± 8.07 and 58.24 ± 9.24, P = 0.047) and there were fewer patients with chicken wing (23.1% and 59.1%, P = 0.001) and more patients with cauliflower (26.9% and 9.8%, P = 0.046). Multivariate Logistic regression analysis demonstrated that age (odds ratio (OR) 1.26; 95% confidence interval (CI) 1.08-1.47; P = 0.003), non-chicken wing morphology (OR 5.82; 95% CI 1.61-21.03; P = 0.007), and LAA orifice diameter (OR 1.25; 95% CI 1.05-1.49; P = 0.014) were independent predictors of stroke after adjusting for all parameters that emerged as potential confounders with univariate analysis. CONCLUSION LAA analysis can potentially be used to inform guidance on the implication for stroke risk assessment.","author":[{"dropping-particle":"","family":"Kong","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"He","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Lei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fan","given":"Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mei","given":"Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Wanli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liao","given":"Jiafen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Dan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xing","given":"Dong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"He","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chinese medical journal","id":"ITEM-1","issue":"24","issued":{"date-parts":[["2014"]]},"page":"4210-4","title":"Left atrial appendage morphology in patients with atrial fibrillation in China: implications for stroke risk assessment from a single center study.","type":"article-journal","volume":"127"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.hrthm.2013.01.036","ISSN":"15563871","abstract":"BACKGROUND Strokes develop even in patients with low CHADS2 scores, and the left atrial appendage (LAA) is the embolic source 90% of the time. We focused on the LAA morphology as a new predictor of strokes. OBJECTIVE To clarify the anatomical characteristics of the LAA for risk stratification of strokes in patients with nonvalvular atrial fibrillation (AF) who have low CHADS2 scores. METHODS Among 80 patients who underwent catheter ablation of AF with contrast-enhanced computed tomography, the LAA characteristics were compared between 30 patients with histories of strokes and 50 age-matched controls. The LAA anatomy was classified into 4 types-\"cactus,\" \"cauliflower,\" \"chicken wing,\" and \"windsock\"- discriminated by the computed tomography measurements of the length, angle, and number of lobes of the LAA. RESULTS The average CHADS2 score did not differ significantly between patients with stroke and controls (0.8 ± 0.8 vs 0.6 ± 0.7; P = .277). Eight (26.7%) patients with stroke had CHA2DS2-VASc scores of 0. The left atrial size, LAA flow velocity, left ventricular function, and serum brain natriuretic peptide level were also unable to predict strokes. However, a \"cauliflower\" LAA, defined as a main lobe of less than 4 cm long without forked lobes, was significantly more common in patients with stroke (odds ratio 3.857; 95% confidence interval 1.482-10.037; P = .005). The CHA 2DS2-VASc score-adjusted logistic regression analysis revealed the cauliflower LAA as an independent predictor of a stroke (odds ratio 3.355; 95% confidence interval 1.243-9.055; P = .017). CONCLUSIONS The LAA anatomy might be useful for predicting strokes in patients with nonvalvular AF who have low CHADS2 scores. ? 2013 Heart Rhythm Society. All rights reserved.","author":[{"dropping-particle":"","family":"Kimura","given":"Takehiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takatsuki","given":"Seiji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inagawa","given":"Kohei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katsumata","given":"Yoshinori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishiyama","given":"Takahiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishiyama","given":"Nobuhiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fukumoto","given":"Kotaro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aizawa","given":"Yoshiyasu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanimoto","given":"Yoko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanimoto","given":"Kojiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jinzaki","given":"Masahiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fukuda","given":"Keiichi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart Rhythm","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2013"]]},"page":"921-925","publisher":"Elsevier","title":"Anatomical characteristics of the left atrial appendage in cardiogenic stroke with low CHADS2 scores","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(115,116)","plainTextFormattedCitation":"(115,116)","previouslyFormattedCitation":"(115,116)"},"properties":{"noteIndex":0},"schema":""}(115,116). However, a study by Khurram et al. failed to demonstrate any association between LAA morphology and risk of stroke or TIA ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.hrthm.2013.09.065","ISSN":"15475271","abstract":"Background Atrial fibrillation (AF) is an important cause of stroke. Given the morbidity and mortality associated with stroke, the risk stratification of patients based on left atrial appendage (LAA) characteristics is of great interest. Objective To explore the association between LAA morphology and LAA characteristics including the extent of trabeculations, orifice diameter, and length with prevalent stroke in a large cohort of patients with drug refractory AF who underwent AF ablation to develop mechanistic insight regarding the risk of stroke. Methods An institutional cohort of 1063 patients referred for AF ablation from 2003 to 2012 was reviewed to identify patients that underwent preprocedural cardiac computed tomography (CT). LAA morphology was characterized as chicken wing, cactus, windsock, or cauliflower by using previously reported methodology. Left atrial size and LAA trabeculations, morphology, orifice diameter, and length were compared between patients with prevalent stroke and patients without prevalent stroke. Results Of 678 patients with CT images, 65 (10%) had prior stroke or transient ischemic attack. In univariate analyses, prevalent heart failure (7.7% in cases vs 2.8% in controls; P =.033), smaller LAA orifice (2.26 ± 0.52 cm vs 2.78 ± 0.71 cm; P <.001), shorter LAA length (5.06 ± 1.17 cm vs 5.61 ± 1.17 cm; P <.001), and extensive LAA trabeculations (27.7% vs 14.4%; P =.019) were associated with stroke. LAA morphologies were unassociated with stroke risk. In multivariable analysis, smaller LAA orifice diameter and extensive LAA trabeculations remained independently associated with thromboembolic events. Conclusions The extent of LAA trabeculations and smaller LAA orifice diameter are associated with prevalent stroke and may mediate the previously described association of cauliflower LAA morphology with stroke. ? 2013 Heart Rhythm Society.","author":[{"dropping-particle":"","family":"Khurram","given":"Irfan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dewire","given":"Jane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mager","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maqbool","given":"Farhan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zimmerman","given":"Stefan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zipunnikov","given":"Vadim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beinart","given":"Roy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"E. Marine","given":"Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spragg","given":"David D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Ronald D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ashikaga","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nazarian","given":"Saman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calkins","given":"Hugh","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart Rhythm","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2013","12"]]},"page":"1843-1849","publisher":"Elsevier","title":"Relationship between left atrial appendage morphology and stroke in patients with atrial fibrillation","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(117)","plainTextFormattedCitation":"(117)","previouslyFormattedCitation":"(117)"},"properties":{"noteIndex":0},"schema":""}(117). In addition, the authors found that there was significant inter-observer variability during determination of LAA morphology, indicating that this may be an unreliable method of assessment. Limitations of the studies assessing LAA morphology above lies in the fact that they were all retrospective in nature and included only a subset of AF patients, specifically those undergoing catheter ablation. Therefore, future prospective studies are needed to confirm whether LAA morphology may be used for stroke risk stratification in a general cohort of AF patients.Other LAA parameters such as the number of lobes, neck dimension, overall dimension, volume, orifice diameter and trabeculations have also been studied but again further evaluation is required ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1540-8167.2010.01854.x","ISSN":"10453873","abstract":"Risk of Stroke/TIA in Patients With Atrial Fibrillation. Introduction: Most strokes in patients with atrial fibrillation (AF) arise from thrombus formation in left atrial appendage (LAA). Our aim was to identify LAA features associated with a higher stroke risk in patients with AF using magnetic resonance imaging and angiography (MRI/MRA). Methods: The study included 144 patients with nonvalvular AF who were not receiving warfarin and who underwent MRI/MRA prior to catheter ablation for AF. LAA volume, LAA depth, short and long axes of LAA neck, and numbers of lobes were measured. Results: Of the 144 patients, 18 had a prior stroke or transient ischemic attack (TIA) (13 and 5, respectively). Compared with patients who had no history of stroke/TIA, these patients were older, had higher prevalence of hypertension and hyperlipidemia and had higher LAA volume (22.9 ± 9.6 cm 3 vs. 14.5 ± 7.1 cm 3, P < 0.001). Their LAA depth (3.76 ± 0.9 cm vs. 3.21 ± 0.8 cm, P = 0.006) and the long and short axes of the LAA neck (3.12 ± 0.7 cm vs. 2.08 ± 0.7 cm, P < 0.001; 2.06 ± 0.5 cm vs. 1.37 ± 0.4 cm, P < 0.001, respectively) were larger. Using stepwise logistic regression model, the only statistically significant multivariable predictors of events were age (OR = 1.21 per year, 95% CI 1.06-1.38, P = 0.004), aspirin use (OR = 0.039, 95% CI 0.005-0.28, P = 0.001), and LAA neck dimensions (short axis × long axis) (OR = 3.59 per cm 2, 95% CI 1.93-6.69, P < 0.001). Conclusion: LAA dimensions predict strokes/TIAs in patients with AF. LAA assessment by MRI/MRA can potentially be used as an adjunctive tool for risk stratification for embolic events in AF patients. ? 2010 Wiley Periodicals, Inc.","author":[{"dropping-particle":"","family":"Beinart","given":"Roy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heist","given":"E. Kevin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newell","given":"John B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmvang","given":"Godtfred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruskin","given":"Jeremy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mansour","given":"Moussa","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Cardiovascular Electrophysiology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2011","1"]]},"page":"10-15","title":"Left atrial appendage dimensions predict the risk of Stroke/TIA in patients with atrial fibrillation","type":"article-journal","volume":"22"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.hrthm.2013.09.065","ISSN":"15475271","abstract":"Background Atrial fibrillation (AF) is an important cause of stroke. Given the morbidity and mortality associated with stroke, the risk stratification of patients based on left atrial appendage (LAA) characteristics is of great interest. Objective To explore the association between LAA morphology and LAA characteristics including the extent of trabeculations, orifice diameter, and length with prevalent stroke in a large cohort of patients with drug refractory AF who underwent AF ablation to develop mechanistic insight regarding the risk of stroke. Methods An institutional cohort of 1063 patients referred for AF ablation from 2003 to 2012 was reviewed to identify patients that underwent preprocedural cardiac computed tomography (CT). LAA morphology was characterized as chicken wing, cactus, windsock, or cauliflower by using previously reported methodology. Left atrial size and LAA trabeculations, morphology, orifice diameter, and length were compared between patients with prevalent stroke and patients without prevalent stroke. Results Of 678 patients with CT images, 65 (10%) had prior stroke or transient ischemic attack. In univariate analyses, prevalent heart failure (7.7% in cases vs 2.8% in controls; P =.033), smaller LAA orifice (2.26 ± 0.52 cm vs 2.78 ± 0.71 cm; P <.001), shorter LAA length (5.06 ± 1.17 cm vs 5.61 ± 1.17 cm; P <.001), and extensive LAA trabeculations (27.7% vs 14.4%; P =.019) were associated with stroke. LAA morphologies were unassociated with stroke risk. In multivariable analysis, smaller LAA orifice diameter and extensive LAA trabeculations remained independently associated with thromboembolic events. Conclusions The extent of LAA trabeculations and smaller LAA orifice diameter are associated with prevalent stroke and may mediate the previously described association of cauliflower LAA morphology with stroke. ? 2013 Heart Rhythm Society.","author":[{"dropping-particle":"","family":"Khurram","given":"Irfan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dewire","given":"Jane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mager","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maqbool","given":"Farhan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zimmerman","given":"Stefan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zipunnikov","given":"Vadim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beinart","given":"Roy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"E. Marine","given":"Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spragg","given":"David D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Ronald D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ashikaga","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nazarian","given":"Saman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calkins","given":"Hugh","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart Rhythm","id":"ITEM-2","issue":"12","issued":{"date-parts":[["2013","12"]]},"page":"1843-1849","publisher":"Elsevier","title":"Relationship between left atrial appendage morphology and stroke in patients with atrial fibrillation","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(117,118)","plainTextFormattedCitation":"(117,118)","previouslyFormattedCitation":"(117,118)"},"properties":{"noteIndex":0},"schema":""}(117,118). Left atrial fibrosis may also represent an additional biomarker for stroke risk stratification. In a study of 178 patients with AF, LA fibrosis was assessed using late gadolinium enhancement MRI and correlated to trans-oesophageal findings ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jce.12199","ISSN":"15408167","PMID":"23844972","abstract":"INTRODUCTION: Transesophageal echocardiography (TEE) is used to evaluate for left atrial appendage (LAA) thrombi prior to restoration of sinus rhythm in atrial fibrillation (AF). We examined the relationship of atrial fibrosis quantified using late gadolinium enhancement MRI (LGE-MRI) with TEE findings. METHODS AND RESULTS: We included 178 patients with AF, undergoing TEE and LGE-MRI prior to ablation or cardioversion. LGE-MRI and subsequent image processing was used to quantify atrial fibrosis based on signal intensity analysis. The mean CHADS2 score was 1.24 ± 1.08 and CHA2 DS2 -VASc was 2.08 ± 1.33. The LAA was classified as normal, spontaneous echocardiographic contrast (SEC) present or thrombus present. LAA thrombus was found in 12 patients (6.7%) while SEC was identified in 19 patients (10.7%). Patients with thrombus had higher atrial fibrosis compared to patients without thrombus (26.9 ± 17.4% vs 16.7 ± 10.5%; P < 0.01). Atrial fibrosis was also higher in patients with SEC (23.3 ± 13.7%) compared to those without SEC (16.7 ± 10.8%; P = 0.01). Patients with high atrial fibrosis (>20%) were more likely to have a LAA thrombus (odds ratio 4.6; P = 0.02) and SEC (odds ratio 2.6; P = 0.06). Multivariate logistic regression showed high fibrosis (odds ratio 3.6; P < 0.01) and CHADS2 ≥2 (odds ratio 3.5; P < 0.01) were significant predictors of TEE abnormalities (LAA thrombus or SEC). The area under the curve for the model including high fibrosis, AF type and CHADS2 ≥2 or CHA2 DS2 -VASc ≥2 was 0.73 compared to 0.63 and 0.65 for CHADS2 and CHA2 DS2 -VASc alone. CONCLUSIONS: Atrial fibrosis is independently associated with appendage thrombus and spontaneous contrast. It provides additional risk stratification not captured by clinical parameters.","author":[{"dropping-particle":"","family":"Akoum","given":"Nazem","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fernandez","given":"Genaro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilson","given":"Brent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mcgann","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kholmovski","given":"Eugene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marrouche","given":"Nassir","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of cardiovascular electrophysiology","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2013","10"]]},"language":"eng","page":"1104-1109","publisher-place":"United States, United States","title":"Association of atrial fibrosis quantified using LGE-MRI with atrial appendage thrombus and spontaneous contrast on transesophageal echocardiography in patients with atrial fibrillation","type":"article-journal","volume":"24"},"uris":[""]}],"mendeley":{"formattedCitation":"(119)","plainTextFormattedCitation":"(119)","previouslyFormattedCitation":"(119)"},"properties":{"noteIndex":0},"schema":""}(119). The authors reported that high atrial fibrosis (>20%) was linked to spontaneous echo contrast and LAA thrombus. Additionally, the presence of complex aortic plaques on trans-oesophageal echocardiography defined based on features of mobility, ulceration, pedunculation, thickness ≥4mm and location were found to be independently associated with a two-fold increased thromboembolic risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/s0735-1097(98)00146-6","ISSN":"0735-1097 (Print)","PMID":"9626843","abstract":"OBJECTIVES: This study explored the mechanisms linking clinical and precordial echocardiographic predictors to thromboembolism in atrial fibrillation (AF) by assessing transesophageal echocardiographic (TEE) correlations. BACKGROUND: Clinical predictors of thromboembolism in patients with nonvalvular AF have been identified, but their mechanistic links remain unclear. TEE provides imaging of the left atrium, its appendage and the proximal thoracic aorta, potentially clarifying stroke mechanisms in patients with AF. METHODS: Cross-sectional analysis of TEE features correlated with low, moderate and high thromboembolic risk during aspirin therapy among 786 participants undergoing TEE on entry into the Stroke Prevention in Atrial Fibrillation III trial. RESULTS: TEE features independently associated with increased thromboembolic risk were appendage thrombi (relative risk [RR] 2.5, p = 0.04), dense spontaneous echo contrast (RR 3.7, p < 0.001), left atrial appendage peak flow velocities < or = 20 cm/s (RR 1.7, p = 0.008) and complex aortic plaque (RR 2.1, p < 0.001). Patients with AF with a history of hypertension (conferring moderate risk) more frequently had atrial appendage thrombi (RR 2.6, p < 0.001) and reduced flow velocity (RR 1.8, p = 0.003) than low risk patients. Among low risk patients, those with intermittent AF had similar TEE features to those with constant AF. CONCLUSIONS: TEE findings indicative of atrial stasis or thrombosis and of aortic atheroma were independently associated with high thromboembolic risk in patients with AF. The increased stroke risk associated with a history of hypertension in AF appears to be mediated primarily through left atrial stasis and thrombi. The presence of complex aortic plaque distinguished patients with AF at high risk from those at moderate risk of thromboembolism.","author":[{"dropping-particle":"","family":"Zabalgoitia","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"L A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blackshear","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asinger","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"R G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["1998","6"]]},"language":"eng","page":"1622-1626","publisher-place":"United States, United States","title":"Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators.","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"(113)","plainTextFormattedCitation":"(113)","previouslyFormattedCitation":"(113)"},"properties":{"noteIndex":0},"schema":""}(113). Genetic markersImprovements in genomic technologies have seen an increasing role for genetic testing in certain diseases. This may provide an additional element for risk stratification in AF. However, there have been few genetics studies in AF to date and they have largely focused on chromosome 4q25. It has been suggested that genetic variants on this chromosome may be related with ischaemic stroke ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/ana.21480","ISSN":"1531-8249 (Electronic)","PMID":"18991354","abstract":"OBJECTIVE: To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome-wide association study. METHODS: We genotyped 1,661 Icelandic IS patients and 10,815 control subjects using the Infinium HumanHap300 chip (Illumina, San Diego, CA). A total of 310,881 single nucleotide polymorphisms (SNPs) were tested for association with IS, and the most significant signals were replicated in two large European IS sample sets (2,224 cases/2,583 control subjects). Two SNPs, rs2200733 and rs10033464, were tested further in additional European IS samples (2,327 patients and 16,760 control subjects). RESULTS: In the Icelandic samples and the two replication sets combined, rs2200733 associated significantly with cardioembolic stroke (CES) (odds ratio [OR], 1.54; p = 8.05 x 10(-9)). No other variants associated with IS or any of its subtypes. rs2200733 associated significantly with IS in all sample sets combined (OR, 1.26; p = 2.18 x 10(-10)), and both rs2200733 and its neighbour, rs10033464 associated strongly with CES (rs2200733: OR, 1.52; p = 5.8 x 10(-12); rs10033464: OR, 1.27; p = 6.1 x 10(-4)). Interestingly, rs2200733 also showed significant association to IS not classified as CES. INTERPRETATION: We discovered that variants previously shown to associate with atrial fibrillation (AF), rs2200733 and rs10033464, significantly associated with IS, with the strongest risk for CES. The association with noncardiogenic stroke is intriguing and suggests that atrial fibrillation may be underdiagnosed in patients presenting with stroke. This discovery may have implications for workup and treatment of IS.","author":[{"dropping-particle":"","family":"Gretarsdottir","given":"Solveig","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thorleifsson","given":"Gudmar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manolescu","given":"Andrei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Styrkarsdottir","given":"Unnur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Helgadottir","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gschwendtner","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kostulas","given":"Konstantinos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuhlenbaumer","given":"Gregor","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bevan","given":"Steve","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jonsdottir","given":"Thorbjorg","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bjarnason","given":"Hjordis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saemundsdottir","given":"Jona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palsson","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnar","given":"David O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holm","given":"Hilma","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thorgeirsson","given":"Gudmundur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdimarsson","given":"Einar Mar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sveinbjornsdottir","given":"Sigurlaug","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gieger","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Klaus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wichmann","given":"H-Erich","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hillert","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Markus","given":"Hugh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gulcher","given":"Jeffrey Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ringelstein","given":"E Bernd","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kong","given":"Augustine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dichgans","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gudbjartsson","given":"Daniel Fannar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thorsteinsdottir","given":"Unnur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stefansson","given":"Kari","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of neurology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2008","10"]]},"language":"eng","page":"402-409","publisher-place":"United States, United States","title":"Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke.","type":"article-journal","volume":"64"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1161/STROKEAHA.110.587980","ISSN":"1524-4628 (Electronic)","PMID":"20671249","abstract":"BACKGROUND AND PURPOSE: Genome-wide association studies recently identified 2 variants on chromosome 4q25 as susceptibility factors for atrial fibrillation. Interestingly, these variants were subsequently also shown to be associated with stroke. However, it remains unclear whether 4q25 associates with all the stroke subtypes or with cardioembolic stroke in particular, which is often attributable to atrial fibrillation. METHODS: We performed a large case-control association study in 4199 ischemic stroke patients, all subtyped according to Trial of Org 10172 in Acute Stroke Treatment criteria, and 3750 controls derived from 6 studies conducted in Australia, Austria, Belgium, Poland, Spain, and Sweden. Two variants on chromosome 4q25, rs1906591 and rs10033464, were genotyped. RESULTS: Within cases, the A-allele of rs1906591 was associated with atrial fibrillation (odds ratio, 1.64 [95% CI, 1.43 to 1.90]; P=9.2 . 10(-12)), whereas rs10033464 was only marginally associated. There was an association between overall ischemic stroke and rs1906591 (odds ratio, 1.20 [95% CI, 1.09 to 1.32]; P=1.2 . 10(-4)). However, this was probably caused by the large effect of stroke of cardioembolic etiology because no relation was obtained in any other subgroup of stroke. The rs10033464 variant failed to show any relationship with ischemic stroke. CONCLUSIONS: We replicated the association of the rs1906591 variant on chromosome 4q25 with atrial fibrillation and ischemic stroke of cardioembolic etiology. The 4q25 locus failed to associate with noncardiac subtypes of ischemic stroke.","author":[{"dropping-particle":"","family":"Lemmens","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buysschaert","given":"Ian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geelen","given":"Veerle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fernandez-Cadenas","given":"Israel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Montaner","given":"Joan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmidt","given":"Helena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmidt","given":"Reinhold","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Attia","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maguire","given":"Jane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levi","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jood","given":"Katarina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blomstrand","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jern","given":"Christina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wnuk","given":"Marcin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Slowik","given":"Agniezska","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lambrechts","given":"Diether","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thijs","given":"Vincent","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-2","issue":"9","issued":{"date-parts":[["2010","9"]]},"language":"eng","page":"1850-1857","publisher-place":"United States, United States","title":"The association of the 4q25 susceptibility variant for atrial fibrillation with stroke is limited to stroke of cardioembolic etiology.","type":"article-journal","volume":"41"},"uris":[""]}],"mendeley":{"formattedCitation":"(120,121)","plainTextFormattedCitation":"(120,121)","previouslyFormattedCitation":"(120,121)"},"properties":{"noteIndex":0},"schema":""}(120,121). In a case-control study of 1,059 AF patients, after adjusting for potential confounders, FGB 455 G/A polymorphism was associated with increased cardioembolic stroke potentially through elevated fibrinogen levels ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-17537-1","ISSN":"20452322","abstract":"Previous work has suggested that ischemic stroke (IS) may be more likely to occur in individuals with a genetic predisposition. In this study, we investigated the potential association of IS-relevant genetic risk factors with cardioembolic stroke (CES) in atrial fibrillation (AF) patients with low CHA2DS2-VaSc score. Genotyping was performed using the GenomeLab SNPstream genotyping platform for five IS-relevant SNPs (MMP-9 C1562T, ALOX5AP SG13S114A/T, MTHFR 677 C/T, FGB 455 G/A, and eNOS G298A) in 479 AF patients with CES and 580 age and sex-matched AF patients without CES. The multivariate analysis adjusted for potential confounders and demonstrated that FGB 455 G/A was independently associated with increased risk of CES in AF patients and the significance remained after Bonferroni correction in the additive, dominant, and recessive models with ORs of 1.548 (95% CI: 1.251-1.915, P = 0.001), 1.588 (95% CI: (1.226-2.057, P = 0.003), and 2.394 (95% CI: 1.357-4.223, P = 0.015), respectively. Plasma fibrinogen levels were significantly higher in patients with the A allele compared with patients with genotype of GG (3.29 ± 0.38 mg/dl vs. 2.87 ± 0.18 mg/dl, P < 0.001). We found for the first time that the A allele of FGB 455 G/A was a risk factor for CES in AF patients, probably by elevating the level of plasma fibrinogen.","author":[{"dropping-particle":"","family":"Hu","given":"Xiaofeng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Junjun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Yaguo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wu","given":"Jiong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Qiao","given":"Song","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Shanhu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Linhui","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017"]]},"page":"1-7","publisher":"Springer US","title":"The β-fibrinogen gene 455G/A polymorphism associated with cardioembolic stroke in atrial fibrillation with low CHA2DS2-VaSc score","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"(122)","plainTextFormattedCitation":"(122)","previouslyFormattedCitation":"(122)"},"properties":{"noteIndex":0},"schema":""}(122). Factor V Leiden mutation has not been found to be predictive of thromboembolism in AF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.str.30.12.2547","ISBN":"0039-2499 (Print)\\r0039-2499 (Linking)","ISSN":"0039-2499 (Print)","PMID":"10582976","abstract":"BACKGROUND AND PURPOSE: Markers of thrombin generation and platelet activation are often elevated in patients with nonvalvular atrial fibrillation, but it is unclear whether such markers usefully predict stroke. Therefore, we undertook the present study to assess the relationship between prothrombin fragment F1.2 (F1.2), beta-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation with stroke in atrial fibrillation. METHODS: Specimens were obtained from 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. The results were correlated with patient features, antithrombotic therapy, and subsequent thromboembolism (ischemic stroke and systemic embolism) by multivariate analysis. RESULTS: Increased F1.2 levels were associated with age (P<0.001), female sex (P<0.001), systolic blood pressure (P=0.006), and heart failure (P=0.001). F1.2 were not affected by aspirin use and were not associated with thromboembolism after adjustment for age (P=0. 18). BTG levels were higher with advanced age (P=0.006), coronary artery disease (P=0.05), carotid disease (P=0.005), and heart failure (P<0.001), lower in regular alcohol users (P=0.05), and not significantly associated with thromboembolism. Fibrinogen levels were not significantly related to thromboembolism but were associated with elevated BTG levels (P<0.001). The factor V Leiden mutation was not associated with thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8). CONCLUSIONS: Elevated F1.2 levels were associated with clinical risk factors for stroke in atrial fibrillation, whereas increased BTG levels were linked to manifestations of atherosclerosis. In this large cohort of patients with atrial fibrillation who were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not independent, clinically useful predictors of stroke.","author":[{"dropping-particle":"","family":"Feinberg","given":"William M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"Lesly A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cushman","given":"Mary","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornell","given":"Elaine S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bovill","given":"Edwin G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"12","issued":{"date-parts":[["1999","12"]]},"language":"eng","page":"2547-2553","publisher":"Lippincott Williams and Wilkins","publisher-place":"United States, United States","title":"Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study.","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(98)","plainTextFormattedCitation":"(98)","previouslyFormattedCitation":"(98)"},"properties":{"noteIndex":0},"schema":""}(98). Overall, more studies are needed to confirm these genetic findings. Even then, the use of genetic markers for stroke risk stratification in AF remains unrealistic at present.Bleeding risk assessmentA vital aspect of the management for AF includes stroke prevention. To this end, many patients require anticoagulation therapy. However, this approach is not without risk. A meta-analysis of eight RCTs found that the annual rates of major bleeding varied from 1.4 to 3.4% among patients with AF treated with warfarin ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1001/archinternmed.2012.121","ISSN":"00039926","PMID":"22450212","abstract":"Background: Although several new antithrombotic agents have been developed for stroke prevention in patients with nonvalvular atrial fibrillation (AF), many patients will continue to be treated with warfarin worldwide. Weperformed a meta-analysis of safety and efficacy outcomes in patients with AF treated with warfarin for stroke prevention in large contemporary randomized controlled trials (RCTs). Methods: We searched the MEDLINE, EMBASE, and Cochrane databases for relevant studies; RCTs comparing warfarin with an alternative thromboprophylaxis strategy with at least 400 patients in the warfarin arm and reporting stroke as an efficacy outcome were included. Results: Eight RCTs with 55 789 patient-years of warfarin therapy follow-up were included. Overall time spent in the therapeutic range was 55% to 68%. The annual incidence of stroke or systemic embolism in patients with AF taking warfarin was estimated to be 1.66% (95% CI, 1.41%- 1.91%). Major bleeding rates varied from 1.40% to 3.40%per year across the studies. The risk of stroke per year was significantly higher in elderly patients (2.27%), female patients (2.12%), patients with a history of stroke (2.64%), and patients reporting no previous exposure to vitamin K antagonists (1.96%). There was a significant increase in the annual incidence of stroke with progressively increasing CHADS 2 (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores. Conclusions: Current use of warfarin as a stroke prevention agent in patients with AF is associated with a low rate of residual stroke or systemic embolism estimated to be 1.66% per year. Compared with a previous meta-analysis, there has been significant improvement in the proportion of time spent in therapeutic anticoagulation, with a resultant decline in observed stroke rates. ?2012 American Medical Association. All rights reserved.","author":[{"dropping-particle":"","family":"Agarwal","given":"Shikhar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hachamovitch","given":"Rory","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Menon","given":"Venu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of Internal Medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2012","4"]]},"language":"eng","page":"623-631","publisher-place":"United States","title":"Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: A meta-analysis","type":"article-journal","volume":"172"},"uris":[""]}],"mendeley":{"formattedCitation":"(123)","plainTextFormattedCitation":"(123)","previouslyFormattedCitation":"(123)"},"properties":{"noteIndex":0},"schema":""}(123). The risk of ICH, the most serious form of bleeding, was estimated at 0.61% per year. Similar results were reported by Fang et al. in a cohort of 13,559 patients with AF treated with warfarin ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjmed.2006.07.034","ISSN":"1555-7162 (Electronic)","PMID":"17679129","abstract":"OBJECTIVES: Little is known about the outcomes of patients who have hemorrhagic complications while receiving warfarin therapy. We examined the rates of death and disability resulting from warfarin-associated intracranial and extracranial hemorrhages in a large cohort of patients with atrial fibrillation. METHODS: We assembled a cohort of 13,559 adults with nonvalvular atrial fibrillation and identified patients hospitalized for warfarin-associated intracranial and major extracranial hemorrhage. Data on functional disability at discharge and 30-day mortality were obtained from a review of medical charts and state death certificates. The relative odds of 30-day mortality by hemorrhage type were calculated using multivariable logistic regression. RESULTS: We identified 72 intracranial and 98 major extracranial hemorrhages occurring in more than 15,300 person-years of warfarin exposure. At hospital discharge, 76% of patients with intracranial hemorrhage had severe disability or died, compared with only 3% of those with major extracranial hemorrhage. Of the 40 deaths from warfarin-associated hemorrhage that occurred within 30 days, 35 (88%) were from intracranial hemorrhage. Compared with extracranial hemorrhages, intracranial events were strongly associated with 30-day mortality (odds ratio 20.8 [95% confidence interval, 6.0-72]) even after adjusting for age, sex, anticoagulation intensity on admission, and other coexisting illnesses. CONCLUSIONS: Among anticoagulated patients with atrial fibrillation, intracranial hemorrhages caused approximately 90% of the deaths from warfarin-associated hemorrhage and the majority of disability among survivors. When considering anticoagulation, patients and clinicians need to weigh the risk of intracranial hemorrhage far more than the risk of all major hemorrhages.","author":[{"dropping-particle":"","family":"Fang","given":"Margaret C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Go","given":"Alan S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henault","given":"Lori E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jensvold","given":"Nancy G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American journal of medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2007","8"]]},"language":"eng","page":"700-705","publisher-place":"United States, United States","title":"Death and disability from warfarin-associated intracranial and extracranial hemorrhages.","type":"article-journal","volume":"120"},"uris":[""]}],"mendeley":{"formattedCitation":"(124)","plainTextFormattedCitation":"(124)","previouslyFormattedCitation":"(124)"},"properties":{"noteIndex":0},"schema":""}(124). Despite the relatively low rates of ICH, 76% of these patients had severe disability or died, and ICH was associated with at least a 20-fold increased risk of 30-day mortality compared to other forms of bleeding. Given the detrimental consequences of anticoagulation-related bleeding in AF, especially with ICH, efforts should be directed at reducing this risk while maintaining adequate stroke prevention. The use of NOACs have been shown to be superior to warfarin in this regard. Two large meta-analysis have shown that NOACs, as a class of medications, have a better safety profile with less major bleeding and ICH when compared to warfarin ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1155/2013/640723","ISSN":"2090-1488 (Print)","PMID":"24455237","abstract":"Background. New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation in non-valvular atrial fibrillation (NVAF). Methods. MEDLINE and CENTRAL, regulatory agencies websites, clinical trials registers and conference proceedings were searched to identify randomised controlled trials of NOAC versus warfarin in NVAF. Two investigators reviewed all studies and extracted data on patient and study characteristics along with cardiovascular outcomes. Relative risks (RR) and 95% confidence intervals (CI) were estimated using a random effect meta-analysis. Results. Three clinical trials in 50,578 patients were included. The risk of non-hemorrhagic stroke and systemic embolic events (SEE) was similar with the NOAC and warfarin (RR = 0.93; 95% CI = 0.83-1.04), while the risk of intracranial bleeding (ICB) with the NOAC was lower than with warfarin (RR = 0.46; 95% CI = 0.33-0.65). We found differences in the effect size on all strokes and SEE depending on geographic region as well as on non-hemorrhagic stroke, SEE, bleeding and mortality depending on time in therapeutic range. Conclusion. The NOAC seem no more effective than warfarin for prevention of nonhemorrhagic stroke and SEE in the overall NVAF population, but are generally associated with a lower risk of ICB than warfarin.","author":[{"dropping-particle":"","family":"Gomez-Outes","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Terleira-Fernandez","given":"Ana Isabel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calvo-Rojas","given":"Gonzalo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suarez-Gea","given":"M Luisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vargas-Castrillon","given":"Emilio","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"language":"eng","page":"640723","publisher-place":"United States, United States","title":"Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups.","type":"article-journal","volume":"2013"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1161/STROKEAHA.119.026054","ISSN":"1524-4628 (Electronic)","PMID":"31422735","abstract":"Background and Purpose- Several randomized trials and real-world studies have reported the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in Asian patients with atrial fibrillation; and therefore, this meta-analysis was aimed to compare the effects of NOACs with warfarin for atrial fibrillation stroke prevention in Asians. Methods- The PubMed and Embase databases were searched from January 2009 to February 2019 for studies on comparisons of NOACs versus warfarin in Asians. Risk ratios (RRs) with 95% CIs were pooled using a random-effects model. Results- Five NOAC trials and 21 observational cohorts were included. For the NOAC trials, compared with warfarin, NOACs was associated with reduced risks of stroke or systemic embolism (RR, 0.73; 95% CI, 0.59-0.90), all-cause death (RR, 0.83; 95% CI, 0.73-0.95), major bleeding (RR, 0.59; 95% CI, 0.48-0.72), and intracranial bleeding (RR, 0.36; 95% CI, 0.26-0.49). For the real-world data, compared with warfarin, NOACs was associated with decreased rates of stroke or systemic embolism (RR, 0.75; 95% CI, 0.68-0.82), ischemic stroke (RR, 0.70; 95% CI, 0.59-0.83), myocardial infarction (RR, 0.74; 95% CI, 0.58-0.93), all-cause death (RR, 0.67; 95% CI, 0.59-0.77), major bleeding (RR, 0.63; 95% CI, 0.55-0.73), intracranial bleeding (RR, 0.50; 95% CI, 0.43-0.59), and gastrointestinal bleeding (RR, 0.65; 95% CI, 0.51-0.84). The results did not change in the subgroup analyses based on the type and dose of NOACs. Conclusions- Based on published NOAC trials and real-world studies, the use of NOACs is noninferior to warfarin in Asians with atrial fibrillation irrespective of the NOAC type and dose.","author":[{"dropping-particle":"","family":"Xue","given":"Zhengbiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Hao","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2019","10"]]},"language":"eng","page":"2819-2828","publisher-place":"United States, United States","title":"Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Asians With Atrial Fibrillation: Meta-Analysis of Randomized Trials and Real-World Studies.","type":"article-journal","volume":"50"},"uris":[""]}],"mendeley":{"formattedCitation":"(125,126)","plainTextFormattedCitation":"(125,126)","previouslyFormattedCitation":"(125,126)"},"properties":{"noteIndex":0},"schema":""}(125,126).It is also important to consider the timing of anticoagulation-related bleeding events. In this aspect, there appears to be an excess risk during the initial few months of treatment with vitamin K antagonist (VKA) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0140-6736(96)01109-9","ISSN":"01406736","PMID":"8709780","abstract":"BACKGROUND: Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications. We studied the frequency of bleeding complications in outpatients treated routinely in anticoagulation clinics. METHODS: In a prospective cohort from thirty-four Italian anticoagulation clinics, 2745 consecutive patients were studied from the start of their oral anticoagulation (warfarin in 64%, acenocourmarol in the rest). The target anticoagulation-intensity was low (international normalised ratio [INR] < or = 2.8) in 71% of the patients and high (> 2.8) in the remainder. We recorded demographic details and the main indication for treatment and, every 3-4 months, INR and outcome events. Such events included all complications (bleeding, thrombosis, other), although only bleeding events are reported here, and deaths. We divided bleeding into major and minor categories. FINDINGS: 43% of the patients were women. Nearly three-fifths of the patients were aged 60-79; 8% were over 80. The main indication for treatment was venous thrombolism (33%), followed by non-ischaemic heart disease (17%). Mean follow-up was 267 days. Over 2011 patient-years of follow-up, 153 bleeding complications occurred (7.6 per 100 patient-years). 5 were fatal (all cerebral haemorrhages, 0.25 per 100 patient-years), 23 were major (1.1), and 125 were minor (6.2). The rate of events was similar between sexes, coumarin type, size of enrolling centre, and target INR. The rate was higher in older patients: 10.5 per 100 patient-years in those aged 70 or over, 6.0 in those aged under 70 (relative risk 1.75, 95% Cl 1.29-2.39, p < 0.001). The rate was also higher when the indication was peripheral and/or cerebrovascular disease than venous thromboembolism plus other indications (12.5 vs 6.0 per 100 patient-years) (1.80, 1.2-2.7, p < 0.01), and during the first 90 days of treatment compared with later (11.0 vs 6.3, 1.75, 1.27-2.44, p < 0.001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR < 2, rate 7.7 per 100 patient-years of follow-up). The rates were 4.8, 9.5, 40.5, and 200 at INRs 2.0-2.9, 3-4.4, 4.5-6.9, and over 7, respectively (relative risks for INR > 4.5, 7.91, 5.44-11.5, p < 0.0001). INTERPRETATION: We saw fewer bleeding events than those recorded in other observational and experimental studies. Oral anticoagulation has become safer in recent years, especially if monitored in anticoagulation clinics.…","author":[{"dropping-particle":"","family":"Palareti","given":"Gualtiero","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leali","given":"Nicoletta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coccheri","given":"Sergio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Poggi","given":"Mario","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manotti","given":"Cesare","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Angelo","given":"Armando","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pengo","given":"Vittorio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Erba","given":"Nicoletta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moia","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ciavarella","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Devoto","given":"Gianluigi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berrettini","given":"Mauro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Musolesi","given":"Serena","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet","id":"ITEM-1","issue":"9025","issued":{"date-parts":[["1996","8"]]},"language":"eng","page":"423-428","publisher-place":"England, England","title":"Bleeding complications of oral anticoagulant treatment: An inception-cohort, prospective collaborative study (ISCOAT)","type":"article-journal","volume":"348"},"uris":[""]}],"mendeley":{"formattedCitation":"(127)","plainTextFormattedCitation":"(127)","previouslyFormattedCitation":"(127)"},"properties":{"noteIndex":0},"schema":""}(127). This may be due to poor anticoagulation control that eventually improves with time. However, there are likely to be additional factors involved as a similar effect was observed with dabigatran, where initial dose adjustments are rare ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1160/TH14-11-0954","ISSN":"2567-689X (Electronic)","PMID":"25739533","abstract":"The effectiveness and safety of dabigatran for stroke prevention in atrial fibrillation (SPAF) demonstrated in RE-LY needs to be confirmed in daily care. To evaluate treatment persistence, effectiveness and safety of dabigatran therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non-interventional registry of more than 2,500 patients on novel oral anticoagulants in daily care. Between October 1, 2011 and February 28, 2013, a total of 341 SPAF patients receiving dabigatran were enrolled. The combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.93/100 patient-years in the intention-to-treat analysis (95%-CI 1.6-4.9) and at 1.9/100 patient-years in the on treatment analysis (events within three days after last intake). On-treatment rates were higher in patients selected for 110 mg dabigatran (n=183) BID compared to the 158 patients selected for 150 mg BID (2.88 [95% CI 1.16- 5.93] vs 0.86/100 patient-years [95% CI 0.10, 3.12]). On treatment, major bleeding occurred at a rate of 2.3/100 patient-years and numerically more often in patients receiving the 110 mg BID dose compared to the 150 mg BID dose (2.9 vs 1.7/100 patient-years). Dabigatran treatment discontinuation occurred in a total of 124 patients during follow-up (25.8 per 100 patient-years in Kaplan Meier analysis). Main reasons for treatment discontinuation were non-bleeding side effects. Our data contribute to the confirmation of effectiveness and relative safety of dabigatran in unselected patients in daily care. However, discontinuation rates are not lower than those reported for patients treated with vitamin K antagonists.","author":[{"dropping-particle":"","family":"Beyer-Westendorf","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ebertz","given":"Franziska","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forster","given":"Kait","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gelbricht","given":"Vera","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Michalski","given":"Franziska","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kohler","given":"Christina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Werth","given":"Sebastian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Endig","given":"Heike","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pannach","given":"Sven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tittl","given":"Luise","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sahin","given":"Kurtulus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Daschkow","given":"Katharina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiss","given":"Norbert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2015","6"]]},"language":"eng","page":"1247-1257","publisher-place":"Germany, Germany","title":"Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry.","type":"article-journal","volume":"113"},"uris":[""]}],"mendeley":{"formattedCitation":"(128)","plainTextFormattedCitation":"(128)","previouslyFormattedCitation":"(128)"},"properties":{"noteIndex":0},"schema":""}(128). It is possible that the use of anticoagulation is simply unmasking high-risk individuals who were not identified using traditional assessment methods. Therefore, better risk profiling is necessary. Various factors based on clinical, biological and genetic markers have been shown to predict the risk of anticoagulation-related bleeding in patients with AF ( REF _Ref24900540 \r \h \* MERGEFORMAT Table 5). Some of these factors may also influence the stroke risk. There are several bleeding risk scores designed specifically for use in an AF cohort ( REF _Ref25595096 \r \h \* MERGEFORMAT Table 6). They have previously been summarised and include a combination of different clinical, biological and genetic markers ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjcard.2017.06.058","ISSN":"1879-1913 (Electronic)","PMID":"28800833","abstract":"Patients receiving oral anticoagulant (OAC) therapy for stroke prevention in atrial fibrillation (AF) and prevention of venous thromboembolism (VTE) face an increased risk of bleeding with OAC treatment. Clinicians need to weigh the benefits of OAC treatment against the risk of bleeding. To help formalize bleeding risk assessment, various bleeding risk scores have been developed to help predict the risk of bleeding in AF and VTE patients receiving OAC therapy. This review summarizes the literature involving original studies deriving bleeding risk scores and validation studies of these scores for stroke prevention in AF and treatment/prevention of VTE. To date, there are 10 bleeding risk scores, 6 for use in AF populations, 3 in VTE cohorts, and 1 for mixed indications; they differ markedly in the number of, and risk factors for, bleeding and complexity. In conclusion, many clinical prediction tools to assess bleeding risk prior to starting OAC treatment for either stroke prevention in AF or treatment of VTE are available and should be used in clinical practice to identify and manage modifiable risk factors.","author":[{"dropping-particle":"","family":"Zulkifly","given":"Hanis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American journal of cardiology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2017","10"]]},"language":"eng","page":"1139-1145","publisher-place":"United States","title":"Bleeding Risk Scores in Atrial Fibrillation and Venous Thromboembolism.","type":"article-journal","volume":"120"},"uris":[""]}],"mendeley":{"formattedCitation":"(129)","plainTextFormattedCitation":"(129)","previouslyFormattedCitation":"(129)"},"properties":{"noteIndex":0},"schema":""}(129). In general, each risk factor is assigned a score and the sum of these scores are used to estimate annual bleeding risk in an individual who is anticoagulated. It should be noted that there are differences in the way certain risk factors (e.g. age, renal dysfunction and hypertension) have been defined between the various risk scores. Furthermore, many risk factors for bleeding contribute as well to stroke risk in AF. This highlights the complex relationship between thrombogenesis and bleeding, and represent the challenges faced by physicians when weighing up the risk and benefits of anticoagulation therapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehw210","ISSN":"1522-9645 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Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.","type":"article-journal","volume":"37"},"uris":[""]}],"mendeley":{"formattedCitation":"(20)","plainTextFormattedCitation":"(20)","previouslyFormattedCitation":"(20)"},"properties":{"noteIndex":0},"schema":""}(20).Clinical markersAn early study investigating the risk factors for bleeding among patients treated with warfarin found that age ≥65 years, prior stroke, history of gastrointestinal bleeding, presence of serious comorbidity (such as recent myocardial infarction or renal impairment) and AF were important predictors ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0002-9343(89)80689-8","ISSN":"00029343","PMID":"2787958","abstract":"Purpose: To determine the incidence of major bleeding in outpatients treated with warfarin and to identify predictive factors known at the start of therapy. Patients and Methods: The records of 565 patients starting outpatient therapy with warfarin upon discharge from a university hospital were reviewed. Follow-up information was obtained for 562 patients (99.5%). Bleeding was classified as major or minor using explicit criteria. The cumulative incidence of bleeding was estimated by means of survival analysis. Independent risk factors for major bleeding were identified using Cox regression analysis in 375 randomly chosen patients; they were tested in the remaining 187 patients. Results: Major bleeding occurred in 65 patients (12%) and was fatal in 10 patients (2%). The cumulative incidences of major bleeding at one, 12, and 48 months were 3%, 11%, and 22%, respectively. The monthly risk of major bleeding decreased over time, from 3% during the first month of outpatient therapy to 0.3% per month after the first year of therapy. Five independent risk factors for major bleeding-age 65 years or greater, history of stroke, history of gastrointestinal bleeding, a serious comorbid condition (recent myocardial infarction, renal insufficiency, or severe anemia), atrial fibrillation-predicted major bleeding in the testing group; the cumulative incidence of major bleeding at 48 months was 2% in 57 low-risk patients, 17% in 110 middle-risk patients, and 63% in 20 high-risk patients. Conclusions: These findings provide a quantitative basis for evaluating the risk of major bleeding in individual patients at the start of outpatient therapy with warfarin. Whether the risk of bleeding can be reduced in high-risk patients without reducing the benefit of therapy remains to be determined. ? 1989 Reed Publishing USA.","author":[{"dropping-particle":"","family":"Landefeld","given":"C. Seth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldman","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldman","given":"Ohio Lee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldman","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American Journal of Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1989","8"]]},"language":"eng","page":"144-152","publisher-place":"United States, United States","title":"Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy","type":"article-journal","volume":"87"},"uris":[""]}],"mendeley":{"formattedCitation":"(130)","plainTextFormattedCitation":"(130)","previouslyFormattedCitation":"(130)"},"properties":{"noteIndex":0},"schema":""}(130). However, the study was limited by a small sample size and heterogenous cohort. Hughes et al. performed a systematic review of nine studies reporting on anticoagulation-related bleeding complications in AF to demonstrate that increasing age, uncontrolled hypertension, prior myocardial infarction or ischaemic heart disease, prior stroke, anaemia, history of bleeding and concomitant use of other drugs (e.g. antiplatelets) were independent risk factors for bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/qjmed/hcm076","ISSN":"1460-2725 (Print)","PMID":"17846060","abstract":"Atrial fibrillation (AF) is associated with an increased stroke risk that may be reduced by therapeutic anticoagulation. However, anticoagulation is associated with an increased risk of bleeding that in some patients may outweigh the benefits in reducing the risk of stroke. We systematically reviewed the literature for risk factors of anticoagulation-related bleeding complications in patients with AF, as part of the formulation of recently published national guidelines for the management of AF. We identified nine studies that reported anticoagulation-related bleeding complications in AF patients. The following patient characteristics were identified as having supporting evidence for being risk factors for anticoagulation-related bleeding complications: advanced age, uncontrolled hypertension, history of myocardial infarction or ischaemic heart disease, cerebrovascular disease, anaemia or a history of bleeding, and the concomitant use of other drugs such as antiplatelet agents. The presence of diabetes mellitus, controlled hypertension and gender were not identified as significant risk factors. Some of the risk factors for anticoagulation-related bleeding are also indications for the use of anticoagulants in AF patients. There is a need for further research in this area to help physicians to balance the risks and benefits of anticoagulation in AF patients.","author":[{"dropping-particle":"","family":"Hughes","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"G Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"QJM : monthly journal of the Association of Physicians","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2007","10"]]},"language":"eng","page":"599-607","publisher-place":"England, England","title":"Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review.","type":"article-journal","volume":"100"},"uris":[""]}],"mendeley":{"formattedCitation":"(131)","plainTextFormattedCitation":"(131)","previouslyFormattedCitation":"(131)"},"properties":{"noteIndex":0},"schema":""}(131). Unlike previous studies ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1001/archinte.159.5.457","ISSN":"0003-9926 (Print)","PMID":"10074953","abstract":"OBJECTIVES: To construct and validate the bleeding risk prediction score, which is based on variables identified in the literature that can be easily obtained before the institution of anticoagulant therapy, in a large independent cohort of patients who were treated with anticoagulant therapy for established venous thromboembolism to allow for quantitative assessment of the risks and benefits of the therapy and to adapt the patient's management accordingly. METHODS: We constructed a bleeding risk prediction score, based on variables and their odds ratios identified in the literature, which can be easily obtained before the institution of anticoagulant therapy (score = [ 1.6 X age] + [1.3 x sex] + [2.2 X malignancy]). Subsequently, we evaluated the score in a test group of 241 patients treated with anticoagulant therapy for venous thromboembolism to determine the optimal cutoff points for the prediction of hemorrhagic complications, using receiver operating characteristic curve analysis. We then validated this score in an independent cohort of 780 patients. A score of 3 or more points, 1 to 3 points, or 0 points represented a high, intermediate, or low bleeding risk, respectively. RESULTS: The score in about one fifth of the patients in the test group was classified as predicting high risk for bleeding complications. The risk of all bleeding complications was 26% in this group and the risk of major bleeding complications was 14%. The area under the curve was 0.75 (95% confidence interval, 0.64-0.84) and 0.82 (95% confidence interval, 0.66-0.98) for all bleeding complications and major bleeding complications, respectively. When validated, there was a moderate loss of predictive power of the score, but the categorization of the patients by the score remained clinically useful; 20% of the patients were classified as high risk, and the bleeding rate was 17% for all bleeding complications and 7% for major bleeding complications compared with 4% and 1%, respectively, in those categorized as low risk. CONCLUSIONS: With the use of 3 easily obtainable, clinical variables in a prediction model, it is possible to identify a subgroup of patients at the start of anticoagulant therapy who have a high risk of developing hemorrhagic complications. Further studies should address whether additional measures to prevent bleeding decrease the bleeding incidence without compromising efficacy.","author":[{"dropping-particle":"","family":"Kuijer","given":"P M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hutten","given":"B A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prins","given":"M H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buller","given":"H R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of internal medicine","id":"ITEM-1","issue":"5","issued":{"date-parts":[["1999","3"]]},"language":"eng","page":"457-460","publisher-place":"United States","title":"Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism.","type":"article-journal","volume":"159"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1378/chest.130.5.1390","ISSN":"0012-3692 (Print)","PMID":"17099015","abstract":"BACKGROUND AND PURPOSE: Develop and validate a contemporary bleeding risk model to guide the clinical use of warfarin in the elderly atrial fibrillation (AF) population. METHODS: Chart-abstracted data from the National Registry of Atrial Fibrillation was combined with Medicare part A claims to identify major bleeding events requiring hospitalization. Using a split-sample technique, candidate variables that provided statistically stable relationships with major bleeding events were selected for model development. Three risk categories were created and validated. The new model was compared to existing bleeding risk models using c-statistics and Kaplan-Meier curves. RESULTS: Model development and validation was conducted on 26,345 AF patients who were > 65 years of age and had been discharged from the hospital while receiving warfarin therapy. The following eight variables were included in the final risk score model: age > or = 70 years; gender; remote bleeding; recent (ie, during index hospitalization) bleeding; alcohol/drug abuse; diabetes; anemia; and antiplatelet use. Bleeding rates were 0.9%, 2.0%, and 5.4%, respectively, for the groups with low, moderate, and high risk, compared to the bleeding rates for groups with moderate risk (1.5% and 1.0%) and high risk (1.8% and 2.5%) from other models. CONCLUSIONS: Using a nationally derived data set, we developed a model based on contemporary practice standards for determining major bleeding risk among AF patients receiving warfarin therapy. The larger sample size afforded the opportunity to incorporate additional risk factors. In addition, since the majority of our population was > 65 years of age, we had greater ability to stratify risk among the elderly.","author":[{"dropping-particle":"","family":"Shireman","given":"Theresa I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahnken","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Howard","given":"Patricia A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kresowik","given":"Timothy F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hou","given":"Qingjiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ellerbeck","given":"Edward F","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-2","issue":"5","issued":{"date-parts":[["2006","11"]]},"language":"eng","page":"1390-1396","publisher-place":"United States, United States","title":"Development of a contemporary bleeding risk model for elderly warfarin recipients.","type":"article-journal","volume":"130"},"uris":[""]}],"mendeley":{"formattedCitation":"(132,133)","plainTextFormattedCitation":"(132,133)","previouslyFormattedCitation":"(132,133)"},"properties":{"noteIndex":0},"schema":""}(132,133), diabetes mellitus and sex were not found to be important predictors. Conversely, age and concomitant use of antiplatelets have been consistently shown to significantly increase the risk of anticoagulation-related major bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0140-6736(16)00741-8","ISSN":"1474-547X (Electronic)","PMID":"27056738","abstract":"BACKGROUND: The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischaemic stroke and increase in major bleeding. We aimed to develop and validate a new biomarker-based risk score to improve the prognostication of major bleeding in patients with atrial fibrillation. METHODS: We developed and internally validated a new biomarker-based risk score for major bleeding in 14,537 patients with atrial fibrillation randomised to apixaban versus warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomised to dabigatran versus warfarin in the RE-LY trial. Plasma samples for determination of candidate biomarker concentrations were obtained at randomisation. Major bleeding events were centrally adjudicated. The predictive values of biomarkers and clinical variables were assessed with Cox regression models. The most important variables were included in the score with weights proportional to the model coefficients. The ARISTOTLE and RE-LY trials are registered with , numbers NCT00412984 and NCT00262600, respectively. FINDINGS: The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0.68 [95% CI 0.66-0.70] vs 0.61 [0.59-0.63] vs 0.65 [0.62-0.67], respectively; ABC-bleeding vs HAS-BLED p<0.0001 and ABC-bleeding vs ORBIT p=0.0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0.71 [95% CI 0.68-0.73] vs 0.62 [0.59-0.64] for HAS-BLED vs 0.68 [0.65-0.70] for ORBIT; ABC-bleeding vs HAS-BLED p<0.0001 and ABC-bleeding vs ORBIT p=0.0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores. INTERPRETATION: The ABC-bleeding score, using age, history of bleeding, and three biomarkers (haemoglobin, cTn-hs, and GDF-15 or cystatin C/CKD-EPI) was internally and externally validated and calibrated in large cohorts of patients with atrial fibrillation receiving anticoagulation therapy. The …","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindback","given":"Johan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alexander","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelboom","given":"John W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael 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In order to elucidate the bleeding risk of users of antiplatelet drugs among users of coumarins, we assessed the odds ratio of major bleeding associated with use of antiplatelet drugs in users of the coumarins acenocoumarol and phenprocoumon. We used data from a Dutch record linkage system, including pharmacy and linked hospitalization records for approximately two million subjects, to conduct a nested case control study in a cohort of new users of coumarins. Cases were patients who were hospitalized with a primary diagnosis of major bleeding while taking coumarin and were matched with up to four control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CI). We identified 1848 case patients who were matched to 5818 controls. Users of clopidogrel or aspirin showed a significantly increased risk of hospitalization because of major bleeding (OR 2.9, 95% CI 1.2-6.9 and OR 1.6, 95% CI 1.3-1.9, respectively), whereas users of dipyridamole and combinations of antiplatelet drugs showed a strong trend (OR 1.5, 95% CI 1.0-2.3 and OR 1.8, 95 % CI 1.0-3.3, respectively). In all cases, the risks were greater for upper gastrointestinal bleedings than for other bleedings. In conclusion, the use of any antiplatelet drug increases the risk of hospitalization for major bleeding among users of coumarins. Concurrent use of clopidogrel or dipyridamole and coumarins is probably not safer than concurrent use of aspirin and coumarins.","author":[{"dropping-particle":"","family":"Schalekamp","given":"Tom","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klungel","given":"Olaf H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Souverein","given":"Patrick C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boer","given":"Anthonius","non-dropping-particle":"de","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2008","12"]]},"language":"eng","page":"1076-1083","publisher-place":"Germany, Germany","title":"Effect of oral antiplatelet agents on major bleeding in users of coumarins.","type":"article-journal","volume":"100"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1378/chest.130.5.1390","ISSN":"0012-3692 (Print)","PMID":"17099015","abstract":"BACKGROUND AND PURPOSE: Develop and validate a contemporary bleeding risk model to guide the clinical use of warfarin in the elderly atrial fibrillation (AF) population. METHODS: Chart-abstracted data from the National Registry of Atrial Fibrillation was combined with Medicare part A claims to identify major bleeding events requiring hospitalization. Using a split-sample technique, candidate variables that provided statistically stable relationships with major bleeding events were selected for model development. Three risk categories were created and validated. The new model was compared to existing bleeding risk models using c-statistics and Kaplan-Meier curves. RESULTS: Model development and validation was conducted on 26,345 AF patients who were > 65 years of age and had been discharged from the hospital while receiving warfarin therapy. The following eight variables were included in the final risk score model: age > or = 70 years; gender; remote bleeding; recent (ie, during index hospitalization) bleeding; alcohol/drug abuse; diabetes; anemia; and antiplatelet use. Bleeding rates were 0.9%, 2.0%, and 5.4%, respectively, for the groups with low, moderate, and high risk, compared to the bleeding rates for groups with moderate risk (1.5% and 1.0%) and high risk (1.8% and 2.5%) from other models. CONCLUSIONS: Using a nationally derived data set, we developed a model based on contemporary practice standards for determining major bleeding risk among AF patients receiving warfarin therapy. The larger sample size afforded the opportunity to incorporate additional risk factors. In addition, since the majority of our population was > 65 years of age, we had greater ability to stratify risk among the elderly.","author":[{"dropping-particle":"","family":"Shireman","given":"Theresa I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahnken","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Howard","given":"Patricia A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kresowik","given":"Timothy F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hou","given":"Qingjiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ellerbeck","given":"Edward F","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-3","issue":"5","issued":{"date-parts":[["2006","11"]]},"language":"eng","page":"1390-1396","publisher-place":"United States, United States","title":"Development of a contemporary bleeding risk model for elderly warfarin recipients.","type":"article-journal","volume":"130"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1001/archinte.159.5.457","ISSN":"0003-9926 (Print)","PMID":"10074953","abstract":"OBJECTIVES: To construct and validate the bleeding risk prediction score, which is based on variables identified in the literature that can be easily obtained before the institution of anticoagulant therapy, in a large independent cohort of patients who were treated with anticoagulant therapy for established venous thromboembolism to allow for quantitative assessment of the risks and benefits of the therapy and to adapt the patient's management accordingly. METHODS: We constructed a bleeding risk prediction score, based on variables and their odds ratios identified in the literature, which can be easily obtained before the institution of anticoagulant therapy (score = [ 1.6 X age] + [1.3 x sex] + [2.2 X malignancy]). Subsequently, we evaluated the score in a test group of 241 patients treated with anticoagulant therapy for venous thromboembolism to determine the optimal cutoff points for the prediction of hemorrhagic complications, using receiver operating characteristic curve analysis. We then validated this score in an independent cohort of 780 patients. A score of 3 or more points, 1 to 3 points, or 0 points represented a high, intermediate, or low bleeding risk, respectively. RESULTS: The score in about one fifth of the patients in the test group was classified as predicting high risk for bleeding complications. The risk of all bleeding complications was 26% in this group and the risk of major bleeding complications was 14%. The area under the curve was 0.75 (95% confidence interval, 0.64-0.84) and 0.82 (95% confidence interval, 0.66-0.98) for all bleeding complications and major bleeding complications, respectively. When validated, there was a moderate loss of predictive power of the score, but the categorization of the patients by the score remained clinically useful; 20% of the patients were classified as high risk, and the bleeding rate was 17% for all bleeding complications and 7% for major bleeding complications compared with 4% and 1%, respectively, in those categorized as low risk. CONCLUSIONS: With the use of 3 easily obtainable, clinical variables in a prediction model, it is possible to identify a subgroup of patients at the start of anticoagulant therapy who have a high risk of developing hemorrhagic complications. Further studies should address whether additional measures to prevent bleeding decrease the bleeding incidence without compromising efficacy.","author":[{"dropping-particle":"","family":"Kuijer","given":"P M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hutten","given":"B A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prins","given":"M H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buller","given":"H R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of internal medicine","id":"ITEM-4","issue":"5","issued":{"date-parts":[["1999","3"]]},"language":"eng","page":"457-460","publisher-place":"United States","title":"Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism.","type":"article-journal","volume":"159"},"uris":[""]}],"mendeley":{"formattedCitation":"(132–135)","plainTextFormattedCitation":"(132–135)","previouslyFormattedCitation":"(132–135)"},"properties":{"noteIndex":0},"schema":""}(132–135). Potential explanations for the increased risk of bleeding with age may relate to changes in metabolic clearance, higher prevalence of comorbidities, degenerative vascular changes, polypharmacy and cognitive decline ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1160/TH08-11-0730","ISSN":"0340-6245 (Print)","PMID":"19652877","abstract":"Anticoagulation with vitamin K antagonists (VKAs) has been shown to be effective in the prevention and treatment of thrombotic complications in various clinical settings, including atrial fibrillation (AF), venous thromboembolism (VTE), acute coronary syndromes and after invasive cardiac procedures. Bleeding is the most important complication of VKAs and a major concern for both physicians and patients. The occurrence of bleeding during treatment is not only important for the treated subjects, but also for a correct and complete use of this therapy in all the subjects who have a clear clinical indication for anticoagulation. This review analyses the treatment- and person-associated risk factors for bleeding during VKAs and their combination in clinical prediction rules that have been proposed in the attempt to identify those patients at higher risk for bleeding. The clinical prediction rules may help physicians stratify patients into categories of risk and thus to evaluate their individual risk/benefit ratio of starting or prolonging an anticoagulant treatment.","author":[{"dropping-particle":"","family":"Palareti","given":"Gualtiero","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cosmi","given":"Benilde","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2009","8"]]},"language":"eng","page":"268-278","publisher-place":"Germany, Germany","title":"Bleeding with anticoagulation therapy - who is at risk, and how best to identify such patients.","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"(136)","plainTextFormattedCitation":"(136)","previouslyFormattedCitation":"(136)"},"properties":{"noteIndex":0},"schema":""}(136). Meanwhile, concomitant use of antiplatelets will interfere with additional haemostatic pathways that are necessary to prevent bleeding. Additional anticoagulation-related bleeding risk factors that have previously been described include excess alcohol intake and thyroid disease ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1378/chest.130.5.1390","ISSN":"0012-3692 (Print)","PMID":"17099015","abstract":"BACKGROUND AND PURPOSE: Develop and validate a contemporary bleeding risk model to guide the clinical use of warfarin in the elderly atrial fibrillation (AF) population. METHODS: Chart-abstracted data from the National Registry of Atrial Fibrillation was combined with Medicare part A claims to identify major bleeding events requiring hospitalization. Using a split-sample technique, candidate variables that provided statistically stable relationships with major bleeding events were selected for model development. Three risk categories were created and validated. The new model was compared to existing bleeding risk models using c-statistics and Kaplan-Meier curves. RESULTS: Model development and validation was conducted on 26,345 AF patients who were > 65 years of age and had been discharged from the hospital while receiving warfarin therapy. The following eight variables were included in the final risk score model: age > or = 70 years; gender; remote bleeding; recent (ie, during index hospitalization) bleeding; alcohol/drug abuse; diabetes; anemia; and antiplatelet use. Bleeding rates were 0.9%, 2.0%, and 5.4%, respectively, for the groups with low, moderate, and high risk, compared to the bleeding rates for groups with moderate risk (1.5% and 1.0%) and high risk (1.8% and 2.5%) from other models. CONCLUSIONS: Using a nationally derived data set, we developed a model based on contemporary practice standards for determining major bleeding risk among AF patients receiving warfarin therapy. The larger sample size afforded the opportunity to incorporate additional risk factors. In addition, since the majority of our population was > 65 years of age, we had greater ability to stratify risk among the elderly.","author":[{"dropping-particle":"","family":"Shireman","given":"Theresa I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahnken","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Howard","given":"Patricia A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kresowik","given":"Timothy F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hou","given":"Qingjiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ellerbeck","given":"Edward F","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2006","11"]]},"language":"eng","page":"1390-1396","publisher-place":"United States, United States","title":"Development of a contemporary bleeding risk model for elderly warfarin recipients.","type":"article-journal","volume":"130"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1378/chest.10-0134","ISSN":"19313543","PMID":"20299623","abstract":"Objective: Despite extensive use of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and the increased bleeding risk associated with such OAC use, no handy quantification tool for assessing this risk exists. We aimed to develop a practical risk score to estimate the 1-year risk for major bleeding (intracranial, hospitalization, hemoglobin decrease >2 g/L, and/or transfusion) in a cohort of real-world patients with AF. Methods: Based on 3,978 patients in the Euro Heart Survey on AF with complete follow-up, all univariate bleeding risk factors in this cohort were used in a multivariate analysis along with historical bleeding risk factors. A new bleeding risk score termed HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (> 65 years), Drugs/alcohol concomitantly) was calculated, incorporating risk factors from the derivation cohort. Results: Fifty-three (1.5%) major bleeds occurred during 1-year follow-up. The annual bleeding rate increased with increasing risk factors. The predictive accuracy in the overall population using significant risk factors in the derivation cohort (C statistic 0.72) was consistent when applied in several subgroups. Application of the new bleeding risk score (HAS-BLED) gave similar C statistics except where patients were receiving antiplatelet agents alone or no antithrombotic therapy, with C statistics of 0.91 and 0.85, respectively. Conclusion: This simple, novel bleeding risk score (HAS-BLED) provides a practical tool to assess the individual bleeding risk of real-world patients with AF, potentially supporting clinical decision making regarding antithrombotic therapy in patients with AF. ? 2010 American College of Chest Physicians.","author":[{"dropping-particle":"","family":"Pisters","given":"Ron","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nieuwlaat","given":"Robby","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vos","given":"Cees B.","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crijns","given":"Harry J.G.M. 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Survey.","type":"article-journal","volume":"138"},"uris":[""]}],"mendeley":{"formattedCitation":"(133,137)","plainTextFormattedCitation":"(133,137)","previouslyFormattedCitation":"(133,137)"},"properties":{"noteIndex":0},"schema":""}(133,137). FallsPrior falls is perceived as a risk factor for anticoagulation-related bleeding, especially in elderly patients. Gage et al. demonstrated a significantly increased risk of ICH associated with the use of warfarin in AF patients deemed at high-risk of falls ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjmed.2005.02.022","ISSN":"0002-9343 (Print)","PMID":"15922692","abstract":"PURPOSE: Patients at high risk for falls are presumed to be at increased risk for intracranial hemorrhage, and high risk for falls is cited as a contraindication to antithrombotic therapy. Data substantiating this concern are lacking. METHODS: Quality improvement organizations identified 1245 Medicare beneficiaries who were documented in the medical record to be at high risk of falls and 18261 other patients with atrial fibrillation. The patients were elderly (mean 80 years), and 48% were prescribed warfarin at hospital discharge. The primary endpoint was subsequent hospitalization for an intracranial hemorrhage, based on ICD-9 codes. RESULTS: Rates (95% confidence interval [CI]) of intracranial hemorrhage per 100 patient-years were 2.8 (1.9-4.1) in patients at high risk for falls and 1.1 (1.0-1.3) in other patients. Rates (95% CI) of traumatic intracranial hemorrhage were 2.0 (1.3-3.1) in patients at high risk for falls and 0.34 (0.27-0.45) in other patients. Hazard ratios (95% CI) of other independent risk factors for intracranial hemorrhage were 1.4 (1.0-3.1) for neuropsychiatric disease, 2.1 (1.6-2.7) for prior stroke, and 1.9 (1.4-2.4) for prior major bleeding. Warfarin prescription was associated with intracranial hemorrhage mortality but not with intracranial hemorrhage occurrence. Ischemic stroke rates per 100 patient-years were 13.7 in patients at high risk for falls and 6.9 in other patients. Warfarin prescription in patients prone to fall who had atrial fibrillation and multiple additional stroke risk factors appeared to protect against a composite endpoint of stroke, intracranial hemorrhage, myocardial infarction, and death. CONCLUSION: Patients at high risk for falls with atrial fibrillation are at substantially increased risk of intracranial hemorrhage, especially traumatic intracranial hemorrhage. However, because of their high stroke rate, they appear to benefit from anticoagulant therapy if they have multiple stroke risk factors.","author":[{"dropping-particle":"","family":"Gage","given":"Brian F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Birman-Deych","given":"Elena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kerzner","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Radford","given":"Martha J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nilasena","given":"David S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rich","given":"Michael W","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American journal of medicine","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2005","6"]]},"language":"eng","page":"612-617","publisher-place":"United States","title":"Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall.","type":"article-journal","volume":"118"},"uris":[""]}],"mendeley":{"formattedCitation":"(138)","plainTextFormattedCitation":"(138)","previouslyFormattedCitation":"(138)"},"properties":{"noteIndex":0},"schema":""}(138). Based on this, such patients are often deprived of anticoagulant treatment for stroke prevention with the assumption that it is harmful. However, it is important to recognise that within the same study, there was overall improvement in clinical outcomes among patients at high-risk of falls who received anticoagulation therapy, despite the increased risk of ICH. In a separate study involving 7,156 patients with AF, a history of falls was independently associated with a 3.3-fold increased risk of major bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjmed.2014.05.035","ISSN":"1555-7162 (Electronic)","PMID":"24929021","abstract":"BACKGROUND: Patients with nonvalvular atrial fibrillation are often denied oral anticoagulation due to falls risk. The latter is variably defined, and existing studies have not compared the associated risk of bleeding with other cardiovascular events. There are no data about outcomes in individuals with nonvalvular atrial fibrillation with a prior history of (actual) falls, rather than being \"at risk of falls.\" Our objective was to evaluate the risk of cardiovascular outcomes associated with prior history of falls in patients with atrial fibrillation in a contemporary \"real world\" cohort. METHODS: Patients with nonvalvular atrial fibrillation in a 4-hospital institution between 2000 and 2010 were included. Stroke/thromboembolism event rates were calculated according to prior history of falls. Risk factors were investigated by Cox regression. RESULTS: Among 7156 atrial fibrillation patients, prior history of falls/trauma was uncommon (n = 76; 1.1%). Compared with patients without history of falls, those patients were older and less likely to be on oral anticoagulation; they also had higher risk scores for stroke/thromboembolism but not for bleeding. Compared with no prior history of falls, rates of stroke/thromboembolism (P = .01) and all-cause mortality (P < .0001) were significantly higher in patients with previous falls. In multivariable analyses, prior history of falls was independently associated with stroke/thromboembolism (hazard ratio [HR] 5.19; 95% confidence interval [CI], 2.1-12.6; P < .0001), major bleeding (HR 3.32 [1.23-8.91]; P = .02), and all-cause mortality (HR 3.69; 95% CI, 1.52-8.95; P = .04), but not hemorrhagic stroke (HR 4.20; 95% CI, 0.58-30.48; P = .16) in patients on oral anticoagulation. CONCLUSION: In this large \"real world\" atrial fibrillation cohort, prior history of falls was uncommon but independently increased risk of stroke/thromboembolism, bleeding, and mortality, but not hemorrhagic stroke in the presence of anticoagulation. Prior history of (actual) falls may be a more clinically useful risk prognosticator than \"being at risk of falls.\"","author":[{"dropping-particle":"","family":"Banerjee","given":"Amitava","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clementy","given":"Nicolas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haguenoer","given":"Ken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fauchier","given":"Laurent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American journal of medicine","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2014","10"]]},"language":"eng","page":"972-978","publisher-place":"United States","title":"Prior history of falls and risk of outcomes in atrial fibrillation: the Loire Valley Atrial Fibrillation Project.","type":"article-journal","volume":"127"},"uris":[""]}],"mendeley":{"formattedCitation":"(139)","plainTextFormattedCitation":"(139)","previouslyFormattedCitation":"(139)"},"properties":{"noteIndex":0},"schema":""}(139). The authors remarked that assessment of ‘actual falls’ may be more clinically useful than the ‘falls risk’. This may provide an explanation for lack of association between falls and major bleeding events in a prospective study involving 515 patients on oral anticoagulation, where falls risk was used ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjmed.2012.01.033","ISSN":"1555-7162 (Electronic)","PMID":"22840664","abstract":"BACKGROUND: The risk of falls is the most commonly cited reason for not providing oral anticoagulation, although the risk of bleeding associated with falls on oral anticoagulants is still debated. We aimed to evaluate whether patients on oral anticoagulation with high falls risk have an increased risk of major bleeding. METHODS: We prospectively studied consecutive adult medical patients who were discharged on oral anticoagulants. The outcome was the time to a first major bleed within a 12-month follow-up period adjusted for age, sex, alcohol abuse, number of drugs, concomitant treatment with antiplatelet agents, and history of stroke or transient ischemic attack. RESULTS: Among the 515 enrolled patients, 35 patients had a first major bleed during follow-up (incidence rate: 7.5 per 100 patient-years). Overall, 308 patients (59.8%) were at high risk of falls, and these patients had a nonsignificantly higher crude incidence rate of major bleeding than patients at low risk of falls (8.0 vs 6.8 per 100 patient-years, P=.64). In multivariate analysis, a high falls risk was not statistically significantly associated with the risk of a major bleed (hazard ratio 1.09; 95% confidence interval, 0.54-2.21). Overall, only 3 major bleeds occurred directly after a fall (incidence rate: 0.6 per 100 patient-years). CONCLUSIONS: In this prospective cohort, patients on oral anticoagulants at high risk of falls did not have a significantly increased risk of major bleeds. These findings suggest that being at risk of falls is not a valid reason to avoid oral anticoagulants in medical patients.","author":[{"dropping-particle":"","family":"Donze","given":"Jacques","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clair","given":"Carole","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hug","given":"Balthasar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodondi","given":"Nicolas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waeber","given":"Gerard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornuz","given":"Jacques","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aujesky","given":"Drahomir","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American journal of medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2012","8"]]},"language":"eng","page":"773-778","publisher-place":"United States, United States","title":"Risk of falls and major bleeds in patients on oral anticoagulation therapy.","type":"article-journal","volume":"125"},"uris":[""]}],"mendeley":{"formattedCitation":"(140)","plainTextFormattedCitation":"(140)","previouslyFormattedCitation":"(140)"},"properties":{"noteIndex":0},"schema":""}(140). Overall, the current evidence indicate that a history of falls may be an important risk factor for major bleeding but that this should not be the sole deterrent for anticoagulation in AF. In support of this, an earlier study by Man-Son-Hing et al. found that patients would need to fall an estimated 295 times per year for the risk of serious bleeding to outweigh the beneficial effects of warfarin ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1001/archinte.159.7.677","ISSN":"0003-9926 (Print)","PMID":"10218746","abstract":"OBJECTIVE: To determine whether the risk of falling (with a possible increased chance of subdural hematoma) should influence the choice of antithrombotic therapy in elderly patients with atrial fibrillation. DESIGN: A Markov decision analytic model was used to determine the preferred treatment strategy (no antithrombotic therapy, long-term aspirin use, or long-term warfarin use) for patients with atrial fibrillation who are 65 years of age and older, are at risk for falling, and have no other contraindications to antithrombotic therapy. Input data were obtained by systematic review of MEDLINE. Outcomes were expressed as quality-adjusted life-years. RESULTS: For patients with average risks of stroke and falling, warfarin therapy was associated with 12.90 quality-adjusted life-years per patient; aspirin therapy, 11.17 quality-adjusted life-years; and no antithrombotic therapy, 10.15 quality-adjusted life-years. Sensitivity analysis demonstrated that, regardless of the patients' age or baseline risk of stroke, the risk of falling was not an important factor in determining their optimal antithrombotic therapy. CONCLUSIONS: For elderly patients with atrial fibrillation, the choice of optimal therapy to prevent stroke depends on many clinical factors, especially their baseline risk of stroke. However, patients' propensity to fall is not an important factor in this decision.","author":[{"dropping-particle":"","family":"Man-Son-Hing","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nichol","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lau","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laupacis","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of internal medicine","id":"ITEM-1","issue":"7","issued":{"date-parts":[["1999","4"]]},"language":"eng","page":"677-685","publisher-place":"United States, United States","title":"Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls.","type":"article-journal","volume":"159"},"uris":[""]}],"mendeley":{"formattedCitation":"(141)","plainTextFormattedCitation":"(141)","previouslyFormattedCitation":"(141)"},"properties":{"noteIndex":0},"schema":""}(141).MalignancyPresence of a malignant disease has been associated with increased anticoagulation-related bleeding. A study by Gitter et al. found that patients with a malignant condition at the time of warfarin initiation had a four-fold greater risk of major haemorrhage during a 28-month follow-up period ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.4065/70.8.725","ISSN":"0025-6196 (Print)","PMID":"7630209","abstract":"OBJECTIVE: To estimate the incidence of and identify risk factors for hemorrhage and thromboembolism during long-term anticoagulant therapy. DESIGN: We conducted a population-based retrospective cohort study of all residents of Rochester, Minnesota, in whom a course of warfarin therapy intended to last for more than 4 weeks was initiated between Sept. 1, 1987, and Dec. 31, 1989. METHODS: Medical records were reviewed, and pertinent data were compiled. All bleeding complications were classified as minor or major on the basis of the bleeding severity index, and thromboembolic events were classified as major if they were fatal or life-threatening. Cumulative incidences of adverse events were analyzed statistically. RESULTS: During the study period, 261 patients had incident courses of anticoagulation (52% were male, 61% were 65 years of age or older, and 31% were 75 years of age or older), with 221 patient-years of warfarin exposure. The primary indications for anticoagulation were venous thromboembolism (39%); stroke or transient ischemic attack (21%); atrial fibrillation (11%); and coronary artery disease, procedures for coronary artery disease, or cardiomyopathy (7%). The cumulative incidence of major hemorrhage at 1, 3, 12, and 24 months was 1.6%, 3.3%, 5.3%, and 10.6%, respectively, and of major or minor thromboembolic events was 2.3%, 5.0%, 7.4%, and 13.1%, respectively. In multivariate analysis, (1) a malignant condition was significantly associated with major hemorrhage; (2) malignant disease and history of peptic ulcer were significantly associated with the combined outcome of major or minor hemorrhage; and (3) malignant disease was significantly associated with any thromboembolism. Age, sex, atrial fibrillation, history of gastrointestinal hemorrhage, history of peptic ulcer, alcohol abuse, hypertension, stroke, and the Charlson comorbidity index were not significantly associated with major hemorrhage. CONCLUSION: In this population-based study, including a high proportion of elderly patients, malignant disease at initiation of warfarin anticoagulation was significantly associated with both major hemorrhage and any thromboembolism. Advanced age is not a contraindication to anticoagulant therapy.","author":[{"dropping-particle":"","family":"Gitter","given":"M J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jaeger","given":"T M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Petterson","given":"T M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gersh","given":"B J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silverstein","given":"M D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Mayo Clinic proceedings","id":"ITEM-1","issue":"8","issued":{"date-parts":[["1995","8"]]},"language":"eng","page":"725-733","publisher-place":"England, England","title":"Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota.","type":"article-journal","volume":"70"},"uris":[""]}],"mendeley":{"formattedCitation":"(142)","plainTextFormattedCitation":"(142)","previouslyFormattedCitation":"(142)"},"properties":{"noteIndex":0},"schema":""}(142). Results from a secondary analysis of a prospective RCT demonstrated that the higher risk of bleeding was also observed with other anticoagulants such as heparin and danaparoid ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0340-6245 (Print)","PMID":"8950773","abstract":"OBJECTIVE: Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism. DESIGN: Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial. SETTING: One university and 2 regional teaching hospitals. PATIENTS: 188 patients treated with heparin or danaparoid for acute venous thromboembolism. MEASUREMENTS: The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively. RESULTS: Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders. CONCLUSIONS: A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.","author":[{"dropping-particle":"","family":"Wester","given":"J P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valk","given":"H W","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nieuwenhuis","given":"H K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brouwer","given":"C B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graaf","given":"Y","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meuwissen","given":"O J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"H C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sixma","given":"J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Banga","given":"J D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"5","issued":{"date-parts":[["1996","11"]]},"language":"eng","page":"682-688","publisher-place":"Germany, Germany","title":"Risk factors for bleeding during treatment of acute venous thromboembolism.","type":"article-journal","volume":"76"},"uris":[""]}],"mendeley":{"formattedCitation":"(143)","plainTextFormattedCitation":"(143)","previouslyFormattedCitation":"(143)"},"properties":{"noteIndex":0},"schema":""}(143). Despite the overall increased risk of anticoagulation-related bleeding with malignant conditions, there exist variations in terms of safety and efficacy between the different options for anticoagulation. In general, low-molecular weight heparin has a similar safety profile to VKA and is superior for prevention of recurrent thromboembolism ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa025313","ISSN":"1533-4406 (Electronic)","PMID":"12853587","abstract":"BACKGROUND: Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer. METHODS: Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months). RESULTS: During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oral-anticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group. CONCLUSIONS: In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.","author":[{"dropping-particle":"","family":"Lee","given":"Agnes Y Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levine","given":"Mark N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baker","given":"Ross I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bowden","given":"Chris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kakkar","given":"Ajay K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prins","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rickles","given":"Frederick R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Julian","given":"Jim A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haley","given":"Susan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kovacs","given":"Michael J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gent","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The New England journal of medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2003","7"]]},"language":"eng","page":"146-153","publisher-place":"United States, United States","title":"Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.","type":"article-journal","volume":"349"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.thromres.2015.07.011","ISSN":"1879-2472 (Electronic)","PMID":"26210891","abstract":"INTRODUCTION: Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE. METHODS: A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model. RESULTS: LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies. CONCLUSION: The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable. FUNDING: Austrian Science Fund (FWF-SFB-54).","author":[{"dropping-particle":"","family":"Posch","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Konigsbrugge","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zielinski","given":"Christoph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pabinger","given":"Ingrid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ay","given":"Cihan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis research","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2015","9"]]},"language":"eng","page":"582-589","publisher-place":"United States, United States","title":"Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants.","type":"article-journal","volume":"136"},"uris":[""]}],"mendeley":{"formattedCitation":"(144,145)","plainTextFormattedCitation":"(144,145)","previouslyFormattedCitation":"(144,145)"},"properties":{"noteIndex":0},"schema":""}(144,145). Non-vitamin K antagonist oral anticoagulants are a more convenient option to low-molecular weight heparin but may be associated with a higher risk of major bleeding with comparable effectiveness ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/14651858.CD006650.pub5","ISSN":"1469-493X (Electronic)","PMID":"29920657","abstract":"BACKGROUND: Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments. OBJECTIVES: To compare the efficacy and safety of low molecular weight heparins (LMWHs), direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the long-term treatment of venous thromboembolism (VTE) in people with cancer. SEARCH METHODS: We conducted a literature search including a major electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE (Ovid), and Embase (Ovid); handsearching conference proceedings; checking references of included studies; use of the 'related citation' feature in PubMed and a search for ongoing studies in trial registries. As part of the living systematic review approach, we run searches continually, incorporating new evidence after it is identified. Last search date 14 May 2018. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of long-term treatment with LMWHs, DOACs or VKAs in people with cancer and symptomatic VTE. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on study characteristics and risk of bias. Outcomes included: all-cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and health-related quality of life (QoL). We assessed the certainty of the evidence at the outcome level following the GRADE approach (GRADE handbook). MAIN RESULTS: Of 15,785 citations, including 7602 unique citations, 16 RCTs fulfilled the eligibility criteria. These trials enrolled 5167 people with cancer and VTE.Low molecular weight heparins versus vitamin K antagonistsEight studies enrolling 2327 participants compared LMWHs with VKAs. Meta-analysis of five studies probably did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on mortality up to 12 months of follow-up (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.13; risk difference (RD) 0 fewer per 1000, 95% CI 45 fewer to 48 more; moderate-certainty evidence). Meta-analysis of four studies did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on major bleeding (RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per 1000, 95% CI 19 fewer to 48 more, moderate-certainty evidence) or minor bleeding (RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per 1000, 95% CI 92 fewer to 47 more; low-certainty evidence), or thrombocytopenia (RR 0.94, 95% CI 0.52 to 1.69). Meta-analysis of five studies showe…","author":[{"dropping-particle":"","family":"Kahale","given":"Lara A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hakoum","given":"Maram B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsolakian","given":"Ibrahim G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matar","given":"Charbel F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Terrenato","given":"Irene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sperati","given":"Francesca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barba","given":"Maddalena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yosuico","given":"Victor Ed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schunemann","given":"Holger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akl","given":"Elie A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Cochrane database of systematic reviews","id":"ITEM-1","issued":{"date-parts":[["2018","6"]]},"language":"eng","page":"CD006650","publisher-place":"England, England","title":"Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer.","type":"article-journal","volume":"6"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.thromres.2018.02.144","ISSN":"1879-2472 (Electronic)","PMID":"29506866","abstract":"INTRODUCTION: It is unclear if direct oral anticoagulants (DOACs) are effective and safe alternatives to low-molecular-weight heparin (LMWHs) for the treatment of cancer-associated venous thromboembolism (VTE). We aim to synthesize existing literature that compared DOACs versus LMWHs in this high-risk population. MATERIALS AND METHODS: We conducted a systematic review using EMBASE, MEDLINE and CENTRAL for all observational studies and randomized controlled trials (RCTs) (PROSPERO: CRD42017080898). Two authors independently reviewed study eligibility, extracted data, and assessed bias. Primary outcomes included 6-month recurrent VTE and major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and mortality. RESULTS: We screened 426 articles, reviewed 25 in full-text, and selected 13 and 2 for qualitative and quantitative synthesis, respectively. Based on a meta-analysis of the 2 RCTs, DOACs had lower 6-month recurrent VTE (42/725) when compared to LMWH (64/727) (RR: 0.65 (0.42-1.01)). However, DOACs had higher major bleeding (40/725) when compared to LMWH (23/727) (RR 1.74 (1.05-2.88)). Similarly, CRNMB was higher (RR 2.31 (0.85-6.28)) for patients receiving DOACs. There was no difference in mortality (RR 1.03 (0.85-1.26)). Observational studies were heterogeneous with high risks of bias but showed recurrent VTE rates consistent with the meta-analysis. CONCLUSIONS: DOACs were more effective than LMWHs to prevent recurrent VTE but were associated with a significantly increased risk of major bleeding as well as a trend toward more CRNMB. The absolute risk differences were small (2-3%) for both primary outcomes and may reflect better compliance with DOACs than LMWHs.","author":[{"dropping-particle":"","family":"Li","given":"Ang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garcia","given":"David A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lyman","given":"Gary H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carrier","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis research","id":"ITEM-2","issued":{"date-parts":[["2019","1"]]},"language":"eng","page":"158-163","publisher-place":"United States, United States","title":"Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis.","type":"article-journal","volume":"173"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.thromres.2015.07.011","ISSN":"1879-2472 (Electronic)","PMID":"26210891","abstract":"INTRODUCTION: Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE. METHODS: A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model. RESULTS: LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies. CONCLUSION: The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable. FUNDING: Austrian Science Fund (FWF-SFB-54).","author":[{"dropping-particle":"","family":"Posch","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Konigsbrugge","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zielinski","given":"Christoph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pabinger","given":"Ingrid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ay","given":"Cihan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis research","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2015","9"]]},"language":"eng","page":"582-589","publisher-place":"United States, United States","title":"Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants.","type":"article-journal","volume":"136"},"uris":[""]}],"mendeley":{"formattedCitation":"(145–147)","plainTextFormattedCitation":"(145–147)","previouslyFormattedCitation":"(145–147)"},"properties":{"noteIndex":0},"schema":""}(145–147). Therefore, patients with malignant conditions who require anticoagulation therapy should be commenced on either low-molecular weight heparin or NOACs.EthnicityA previous study of 28,628 patients from the GARFIELD-AF registry demonstrated that those with an Asian background had reduced risk of major bleeding compared to other ethnicities ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0191592","ISSN":"1932-6203 (Electronic)","PMID":"29370229","abstract":"BACKGROUND: The factors influencing three major outcomes-death, stroke/systemic embolism (SE), and major bleeding-have not been investigated in a large international cohort of unselected patients with newly diagnosed atrial fibrillation (AF). METHODS AND RESULTS: In 28,628 patients prospectively enrolled in the GARFIELD-AF registry with 2-year follow-up, we aimed at analysing: (1) the variables influencing outcomes; (2) the extent of implementation of guideline-recommended therapies in comorbidities that strongly affect outcomes. Median (IQR) age was 71.0 (63.0 to 78.0) years, 44.4% of patients were female, median (IQR) CHA2DS2-VASc score was 3.0 (2.0 to 4.0); 63.3% of patients were on anticoagulants (ACs) with or without antiplatelet (AP) therapy, 24.5% AP monotherapy, and 12.2% no antithrombotic therapy. At 2 years, rates (95% CI) of death, stroke/SE, and major bleeding were 3.84 (3.68; 4.02), 1.27 (1.18; 1.38), and 0.71 (0.64; 0.79) per 100 person-years. Age, history of stroke/SE, vascular disease (VascD), and chronic kidney disease (CKD) were associated with the risks of all three outcomes. Congestive heart failure (CHF) was associated with the risks of death and stroke/SE. Smoking, non-paroxysmal forms of AF, and history of bleeding were associated with the risk of death, female sex and heavy drinking with the risk of stroke/SE. Asian race was associated with lower risks of death and major bleeding versus other races. AC treatment was associated with 30% and 28% lower risks of death and stroke/SE, respectively, compared with no AC treatment. Rates of prescription of guideline-recommended drugs were suboptimal in patients with CHF, VascD, or CKD. CONCLUSIONS: Our data show that several variables are associated with the risk of one or more outcomes, in terms of death, stroke/SE, and major bleeding. Comprehensive management of AF should encompass, besides anticoagulation, improved implementation of guideline-recommended therapies for comorbidities strongly associated with outcomes, namely CHF, VascD, and CKD. TRIAL REGISTRATION: NCT01090362.","author":[{"dropping-particle":"","family":"Bassand","given":"Jean-Pierre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Accetta","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahmeed","given":"Wael","non-dropping-particle":"Al","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Corbalan","given":"Ramon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelboom","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fitzmaurice","given":"David A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fox","given":"Keith A A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gao","given":"Haiyan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldhaber","given":"Samuel Z","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goto","given":"Shinya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haas","given":"Sylvia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kayani","given":"Gloria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pieper","given":"Karen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turpie","given":"Alexander G G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eickels","given":"Martin","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verheugt","given":"Freek W A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kakkar","given":"Ajay K","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PloS one","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018"]]},"language":"eng","page":"e0191592","publisher-place":"United States, United States","title":"Risk factors for death, stroke, and bleeding in 28,628 patients from the GARFIELD-AF registry: Rationale for comprehensive management of atrial fibrillation.","type":"article-journal","volume":"13"},"uris":[""]}],"mendeley":{"formattedCitation":"(148)","plainTextFormattedCitation":"(148)","previouslyFormattedCitation":"(148)"},"properties":{"noteIndex":0},"schema":""}(148). However, subsequent studies have found that while the risk of ICH is higher among non-whites in general, it was up to 4-fold higher in Asians compared to whites ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2007.01.098","ISSN":"1558-3597 (Electronic)","PMID":"17659197","abstract":"OBJECTIVES: This study was designed to study racial/ethnic differences in the risk for intracranial hemorrhage (ICH) and the effect of warfarin on ICH risk among patients with atrial fibrillation (AF). BACKGROUND: Nonwhites are at greater risk for ICH than whites in the general population. Whether this applies to patients with AF and whether warfarin therapy is associated with comparable risk of ICH in nonwhites are unknown. METHODS: We retrospectively identified a multiethnic stroke-free cohort hospitalized with nonrheumatic AF. Warfarin use and anticoagulation intensity were assessed by searching pharmacy and laboratory records. Crude ICH event rates were calculated by Poisson regression. Cox proportional hazard models were constructed to assess the independent effect of race/ethnicity on ICH after adjusting for age, gender, hypertension, diabetes, heart failure, and warfarin exposure. RESULTS: Between 1995 and 2000, we identified 18,867 qualifying AF hospitalizations (78.5% white, 8% black, 9.5% Hispanic, and 3.9% Asian) and 173 qualifying ICH events over 3.3 years follow-up. Achieved anticoagulation intensity was lower among blacks but not different between the other groups. Warfarin was associated with increased ICH risk in all races, but the magnitude of risk was greater among nonwhites. There were no gender differences. The hazard ratio for ICH with whites as referent was 4.06 for Asians (95% confidence interval [CI] 2.47 to 6.65), 2.06 for Hispanics (95% CI 1.31 to 3.24), and 2.04 (95% CI 1.25 to 3.35) for blacks. CONCLUSIONS: Nonwhites with AF were at greater risk for warfarin-related ICH. Blacks, Hispanics, and Asians were at successively greater ICH risk than whites.","author":[{"dropping-particle":"","family":"Shen","given":"Albert Yuh-Jer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yao","given":"Janis F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brar","given":"Somjot S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jorgensen","given":"Michael B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Wansu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2007","7"]]},"language":"eng","page":"309-315","publisher-place":"United States","title":"Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation.","type":"article-journal","volume":"50"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1159/000085310","ISSN":"0251-5350 (Print)","PMID":"15855802","abstract":"The sparseness of prospective data about hemorrhagic stroke (HS) risk among Asian American ethnic groups led to the investigation of 128,934 persons with self-classified ethnicity at health examinations in 1978-1985. Subsequently, 431 persons were hospitalized for HS; 31% for subarachnoid hemorrhage (SAH) and 69% for intracerebral hemorrhage (ICH). Ethnic predictors of HS were studied by Cox proportional hazard models with 7 covariates. With whites as reference, the adjusted relative risk (95% CI) of all Asians for HS was 1.6 (1.1-2.3, p = 0.01), due substantially to increased risks of SAH in Japanese people and ICH in Filipinos. These data mandate emphasis upon preventive measures in these groups.","author":[{"dropping-particle":"","family":"Klatsky","given":"Arthur L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friedman","given":"Gary D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sidney","given":"Stephen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kipp","given":"Harald","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kubo","given":"Ai","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Armstrong","given":"Mary Anne","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuroepidemiology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2005"]]},"language":"eng","page":"26-31","publisher-place":"Switzerland","title":"Risk of hemorrhagic stroke in Asian American ethnic groups.","type":"article-journal","volume":"25"},"uris":[""]}],"mendeley":{"formattedCitation":"(149,150)","plainTextFormattedCitation":"(149,150)","previouslyFormattedCitation":"(149,150)"},"properties":{"noteIndex":0},"schema":""}(149,150). Furthermore, the complication was associated with worse outcomes in this group of patients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/aje/154.11.1057","ISSN":"0002-9262 (Print)","PMID":"11724723","abstract":"Healthy People 2010 objectives for improving health include a goal to eliminate racial disparities in stroke mortality. Age-specific death rates by stroke subtype are not well documented among racial/ethnic minority populations in the United States. This report examines mortality rates by race/ethnicity for three stroke subtypes during 1995-1998. National Vital Statistics' death certificate data were used to calculate death rates for ischemic stroke (n = 507,256), intracerebral hemorrhage (n = 97,709), and subarachnoid hemorrhage (n = 27,334) among Hispanics, Blacks, American Indians/Alaska Natives, Asians/Pacific Islanders, and Whites by age and sex. Comparisons with Whites as the referent were made using age-standardized risk ratios and age-specific risk ratios. Age-standardized mortality rates for the three stroke subtypes were higher among Blacks than Whites. Death rates from intracerebral hemorrhage were also higher among Asians/Pacific Islanders than Whites. All minority populations had higher death rates from subarachnoid hemorrhage than did Whites. Among adults aged 25-44 years, Blacks and American Indians/Alaska Natives had higher risk ratios than did Whites for all three stroke subtypes. Increased public health attention is needed to reduce incidence and mortality for stroke, the third leading cause of death. Particular attention should be given to increasing awareness of stroke symptoms among young minority groups.","author":[{"dropping-particle":"","family":"Ayala","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Greenlund","given":"K J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Croft","given":"J B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keenan","given":"N L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Donehoo","given":"R S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giles","given":"W H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kittner","given":"S J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marks","given":"J S","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American journal of epidemiology","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2001","12"]]},"language":"eng","page":"1057-1063","publisher-place":"United States, United States","title":"Racial/ethnic disparities in mortality by stroke subtype in the United States, 1995-1998.","type":"article-journal","volume":"154"},"uris":[""]}],"mendeley":{"formattedCitation":"(151)","plainTextFormattedCitation":"(151)","previouslyFormattedCitation":"(151)"},"properties":{"noteIndex":0},"schema":""}(151). Given the current evidence, additional attention should be directed towards other modifiable bleeding risk factors in Asian patients commencing anticoagulation therapy. It may also be appropriate to consider NOACs in the first-instance as these have been found to be safer alternatives to VKA in this cohort ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.thromres.2018.04.008","ISSN":"1879-2472 (Electronic)","PMID":"29655001","abstract":"INTRODUCTION: The standard for treatment and secondary prevention of venous thromboembolism (VTE) has been vitamin K antagonist (VKA), which might be associated with a higher risk of bleeding particularly in Asian patients. Direct oral anticoagulants (DOAC) have been shown to be safer alternatives for VTE. It remains unclear whether this is the case in Asian ethnicity. MATERIALS AND METHODS: We performed a meta-analysis of randomized controlled trials to evaluate the efficacy and safety of DOACs in Asian and non-Asian patients with acute VTE. We searched MEDLINE, CENTRAL, and . The efficacy endpoint was recurrent VTE or VTE-related death. The safety endpoint was major bleedings or clinically relevant non-major bleedings. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS: We identified 6 studies that comprised 3542 Asian and 23,481 non-Asian patients. The efficacy of DOACs was comparable with VKA in both Asian and non-Asian patients (OR, 0.90; 95% CI, 0.55-1.49; P=0.69 for Asian patients; OR, 0.92; 95% CI, 0.78-1.08; P=0.32 for non-Asian patients; P interaction=0.94). DOACs significantly reduced the safety endpoint compared with VKA in Asian patients (OR, 0.64; 95% CI, 0.51-0.80; P<0.001), while DOACs were associated with non-significant reduction in non-Asian patients (OR, 0.73; 95% CI, 0.53-1.01; P=0.06), indicating that the reduction seemed numerically more prominent in Asian patients, although there was no statistically significant interaction (P interaction=0.49). CONCLUSIONS: The efficacy of DOACs was comparable with VKA irrespective of ethnicity, and DOACs could be safer alternatives in Asian patients.","author":[{"dropping-particle":"","family":"Yamashita","given":"Yugo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morimoto","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toyota","given":"Toshiaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shiomi","given":"Hiroki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Makiyama","given":"Takeru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ono","given":"Koh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kimura","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis research","id":"ITEM-1","issued":{"date-parts":[["2018","6"]]},"language":"eng","page":"37-42","publisher-place":"United States, United States","title":"Asian patients versus non-Asian patients in the efficacy and safety of direct oral anticoagulants relative to vitamin K antagonist for venous thromboembolism: A systemic review and meta-analysis.","type":"article-journal","volume":"166"},"uris":[""]}],"mendeley":{"formattedCitation":"(152)","plainTextFormattedCitation":"(152)","previouslyFormattedCitation":"(152)"},"properties":{"noteIndex":0},"schema":""}(152).WeightBody weight is known to influence the distribution and clearance of anticoagulants ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1365-2141.2011.08826.x","ISSN":"1365-2141 (Electronic)","PMID":"21848880","abstract":"The prevalence of obesity has increased substantially over recent years. Clinicians are increasingly being challenged with making uncertain anticoagulant dosing decisions, as the optimal dosing strategy for most anticoagulants in the obese patient population remains unknown. Research published to date suggests that the clearance of anticoagulants increases with weight. As obesity is associated with an increased risk of venous thromboembolism and arterial disease, there is an urgent need to establish appropriate anticoagulation regimens for this patient group. Research studies applying the method of pharmacokinetic-pharmacodynamic modelling and simulation could establish an appropriate evidence base and provide direction and reassurance to prescribing clinicians.","author":[{"dropping-particle":"","family":"Patel","given":"Jignesh P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roberts","given":"Lara N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arya","given":"Roopen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British journal of haematology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2011","10"]]},"language":"eng","page":"137-149","publisher-place":"England, England","title":"Anticoagulating obese patients in the modern era.","type":"article-journal","volume":"155"},"uris":[""]}],"mendeley":{"formattedCitation":"(153)","plainTextFormattedCitation":"(153)","previouslyFormattedCitation":"(153)"},"properties":{"noteIndex":0},"schema":""}(153). Therefore, there were concerns about the safety (and efficacy) of these medications in patients with extremes of body weight. However, studies on this topic have produced reassuring results. The risk of anticoagulation-related bleeding appears similar in underweight, and overweight or obese patients compared to those with normal body weight ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s40256-019-00362-4","ISSN":"1179-187X (Electronic)","PMID":"31342343","abstract":"OBJECTIVES: Concerns have arisen recently over the relationship between body mass index (BMI) and outcomes in atrial fibrillation (AF) patients with direct oral anticoagulants (DOACs). This meta-analysis aimed to explore if there is an \"obesity paradox\" in anticoagulated AF patients, and compare the treatment effects between DOACs and warfarin in AF patients across BMI categories. METHODS: We systematically searched the PubMed and Embase databases until February 26, 2019 for relevant studies. Risk ratios (RRs) with 95% confidence intervals (CIs) were extracted and pooled by a random-effects model. RESULTS: A total of nine studies were included. Compared with normal weight, underweight was associated with an increased risk of stroke or systemic embolism (SSE) (RR 1.98, 95% CI 1.19-3.28), whereas either overweight or obesity was related with reduced rates of SSE (overweight: RR 0.81, 95% CI 0.71-0.91; obesity: RR 0.69, 95% CI 0.61-0.78) and all-cause death (overweight: RR 0.73, 95% CI 0.64-0.83; obesity: RR 0.72, 95% CI 0.66-0.79). Compared with patients receiving warfarin, patients receiving DOACs who were underweight, normal weight or overweight all had decreased risks of SSE (underweight: RR 0.61, 95% CI 0.46-0.80; normal weight: RR 0.72, 95% CI 0.58-0.91; overweight: RR 0.87, 95% CI 0.76-0.99) and major bleeding (underweight: RR 0.67, 95% CI 0.55-0.81; normal weight: RR 0.72, 95% CI 0.58-0.90; overweight: RR 0.83, 95% CI 0.71-0.96), while obese DOAC users were at no higher risks for SSE and major bleeding. CONCLUSIONS: There may be an obesity paradox in anticoagulated patients with AF. DOACs have better efficacy and safety profiles than warfarin in underweight, normal weight and overweight patients, and are not inferior to warfarin in obese patients.","author":[{"dropping-particle":"","family":"Zhou","given":"Yue","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Jianyong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Wengen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American journal of cardiovascular drugs : drugs, devices, and other interventions","id":"ITEM-1","issued":{"date-parts":[["2019","7"]]},"language":"eng","publisher-place":"New Zealand, New Zealand","title":"Efficacy and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation Across BMI Categories: A Systematic Review and Meta-Analysis.","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1111/jth.13701","ISSN":"1538-7836 (Electronic)","PMID":"28407368","abstract":"Essentials The association of body weight and patient-important outcomes remains unknown. Phase III randomized controlled trials of direct oral anticoagulants (DOACs) were searched. Risk of outcomes varying among body weight subgroups is not attributable to anticoagulant type. Dose adjustment of DOACs, outside that recommended, is unlikely to improve the outcomes. Click to hear Dr Braunwald's perspective on antithrombotic therapy in cardiovascular disease SUMMARY: Background Concerns have arisen in direct oral anticoagulant (DOAC)-treated patients about safety and efficacy in extremes of body weight. The aims of this systematic review were to investigate the association of body weight and patient-important outcomes in patients treated with DOACs or warfarin, and to demonstrate the fixed-dose effect of DOACs. Methods MEDLINE and EMBASE were searched until November 2016. Phase III randomized controlled trials (RCTs) using DOACs in atrial fibrillation (AF) and acute venous thromboembolism (VTE) were included. Relative risk and 95% confidence interval were calculated. The pooled estimates were performed using a Mantel-Haenszel random effects model. Results A total of 11 phase III RCTs were included. Low body weight was associated with increased risk of thromboembolism compared with non-low body weight (relative risk [RR], 1.57; 95% confidence interval [CI], 1.34-1.85). High body weight was not associated with risk of thromboembolism compared with non-high body weight (RR, 0.88; 95% CI, 0.63-1.23). The subgroup of AF patients with high body weight had a lower risk of thromboembolism compared with non-high body weight (RR, 0.43; 95% CI, 0.28-0.67). Bleeding outcomes were comparable for all body weight comparisons. There were no clear interactions between types of anticoagulant in all outcomes. Conclusion The pooled effect of both the DOAC and comparison arms was likely to be attributable to differences in baseline thrombotic risk in each body weight category, rather than an effect of the type or dose of DOAC used for each indication. Dose adjustment of DOACs, outside that recommended in the package insert, is unlikely to improve safety or efficacy.","author":[{"dropping-particle":"","family":"Boonyawat","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caron","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chai-Adisaksopha","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iorio","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"R D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garcia","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crowther","given":"M A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of thrombosis and haemostasis : JTH","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2017","7"]]},"language":"eng","page":"1322-1333","publisher-place":"England, England","title":"Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis.","type":"article-journal","volume":"15"},"uris":[""]}],"mendeley":{"formattedCitation":"(154,155)","plainTextFormattedCitation":"(154,155)","previouslyFormattedCitation":"(154,155)"},"properties":{"noteIndex":0},"schema":""}(154,155). In fact, some studies have suggested that obesity may even be associated with reduced rates of bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/STROKEAHA.116.015984","ISSN":"1524-4628 (Electronic)","PMID":"28265017","abstract":"BACKGROUND AND PURPOSE: Obesity is a risk factor for all-cause and cardiovascular death but, despite this, an inverse relationship between overweight or obesity and a better cardiovascular prognosis in long-term follow-up studies has been observed; this phenomenon, described as obesity paradox, has also been found evident in atrial fibrillation cohorts. METHODS: We performed a systematic review on the relationship between body mass index and major adverse outcomes in atrial fibrillation patients. Moreover, we provided a meta-analysis of non-vitamin K antagonist oral anticoagulants (NOACs) trials. RESULTS: An obesity paradox was found for cardiovascular death and all-cause death in the subgroup analyses of randomized trial cohorts; however, observational studies fail to show this relationship. From the meta-analysis of NOAC trials, a significant obesity paradox was found, with both overweight and obese patients reporting a lower risk for stroke/systemic embolic event (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.66-0.84 and OR, 0.62; 95% CI, 0.54-0.70, respectively). For major bleeding, only obese patients were at lower risk compared with normal weight patients (OR, 0.84; 95% CI, 0.72-0.98). A significant treatment effect of NOACs was found in normal weight patients, both for stroke/systemic embolic event (OR, 0.66; 95% CI, 0.56-0.78) and for major bleeding (OR, 0.72; 95% CI, 0.54-0.95). Major bleeding risk was lower in overweight patients treated with NOACs (OR, 0.84; 95% CI, 0.71-1.00). CONCLUSIONS: There may be an obesity paradox in atrial fibrillation patients, particularly for all-cause and cardiovascular death outcomes. An obesity paradox was also evident for stroke/systemic embolic event outcome in NOAC trials, with a treatment effect favoring NOACs over warfarin for both efficacy and safety that was significant only for normal weight patients.","author":[{"dropping-particle":"","family":"Proietti","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guiducci","given":"Elisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheli","given":"Paola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017","4"]]},"language":"eng","page":"857-866","publisher-place":"United States, United States","title":"Is There an Obesity Paradox for Outcomes in Atrial Fibrillation? A Systematic Review and Meta-Analysis of Non-Vitamin K Antagonist Oral Anticoagulant Trials.","type":"article-journal","volume":"48"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.ijcard.2018.03.060","ISSN":"1874-1754 (Electronic)","PMID":"29622509","abstract":"Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism. Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions. Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1+/-542.9days; median 1004days). With increasing BMI (range 13.7-57.2kg/m(2)), the proportion of patients receiving standard (vs. reduced) NOAC dose increased from 64.7% (underweight) to 78.9% (obesity). Although obese patients had more cardiovascular risk factors compared to normal weight patients, on-treatment rates of clinical outcomes (CV, MB, all-cause-mortality) were lowest in overweight and obese patients. In a large set of real-life NOAC recipients we found no indication that high BMI is associated with inferior NOAC effectiveness or safety, which is in line with recent epidemiological data of a \"BMI paradox\" that indicates a somewhat protective effect of higher BMI regarding unfavourable outcomes also in patients receiving fixed dose NOAC anticoagulation without dose adjustment for higher BMI.","author":[{"dropping-particle":"","family":"Tittl","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Endig","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marten","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reitter","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beyer-Westendorf","given":"I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beyer-Westendorf","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International journal of cardiology","id":"ITEM-2","issued":{"date-parts":[["2018","7"]]},"language":"eng","page":"85-91","publisher-place":"Netherlands, Netherlands","title":"Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119).","type":"article-journal","volume":"262"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.amjmed.2016.08.017","ISSN":"1555-7162 (Electronic)","PMID":"27593608","abstract":"BACKGROUND: Several studies have demonstrated an association between body mass index (BMI) and warfarin therapeutic dose, but none evaluated the association of BMI with the clinically important outcome of major bleeding in a community setting. To address this evidence gap, we conducted a case-control study to evaluate the association between BMI and major bleeding risk among patients receiving warfarin. METHODS: We used a case-control study design to evaluate the association between obesity (BMI >30.0 kg/m(2)) and major bleeding risk among 265 cases and 305 controls receiving warfarin at Group Health, an integrated healthcare system in Washington State. Multivariate logistic regression was used to adjust for potential confounders derived from health plan records and a self-report survey. In exploratory analyses we evaluated the interaction between genetic variants potentially associated with warfarin bleeding (CYP2C9, VKORC1, and CYP4F2) and obesity on the risk of major bleeding. RESULTS: Overall, the sample was 55% male, 94% Caucasian, and mean age was 70 years. Cases and controls had an average of 3.4 and 3.7 years of warfarin use, respectively. Obese patients had significantly lower major bleeding risk relative to non-obese patients (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.39-0.92). The OR was 0.56 (95% CI 0.35-0.90) in patients with >/=1 year of warfarin use, and 0.78 (95% CI 0.40-1.54) in patients with <1 year of warfarin use. An exploratory analysis indicated a statistically significant interaction between CYP4F2*3 genetic status and obesity (P = .049), suggesting a protective effect of obesity on the risk of major bleeding among those wild type for CYP4F2*3, but not among variants. CONCLUSIONS: Our findings suggest that BMI is an important clinical factor in assessing and managing warfarin therapy. Future studies should confirm the major bleeding associations, including the interaction between obesity and CYP4F2*3 status identified in this study, and evaluate potential mechanisms.","author":[{"dropping-particle":"","family":"Hart","given":"Ragan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Veenstra","given":"David L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boudreau","given":"Denise M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roth","given":"Joshua A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American journal of medicine","id":"ITEM-3","issue":"2","issued":{"date-parts":[["2017","2"]]},"language":"eng","page":"222-228","publisher-place":"United States, United States","title":"Impact of Body Mass Index and Genetics on Warfarin Major Bleeding Outcomes in a Community Setting.","type":"article-journal","volume":"130"},"uris":[""]}],"mendeley":{"formattedCitation":"(156–158)","plainTextFormattedCitation":"(156–158)","previouslyFormattedCitation":"(156–158)"},"properties":{"noteIndex":0},"schema":""}(156–158). Furthermore, patients with obesity and AF who were treated with a NOAC had lower risk of thromboembolism, leading to the term ‘obesity paradox’ ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s40256-019-00362-4","ISSN":"1179-187X (Electronic)","PMID":"31342343","abstract":"OBJECTIVES: Concerns have arisen recently over the relationship between body mass index (BMI) and outcomes in atrial fibrillation (AF) patients with direct oral anticoagulants (DOACs). This meta-analysis aimed to explore if there is an \"obesity paradox\" in anticoagulated AF patients, and compare the treatment effects between DOACs and warfarin in AF patients across BMI categories. METHODS: We systematically searched the PubMed and Embase databases until February 26, 2019 for relevant studies. Risk ratios (RRs) with 95% confidence intervals (CIs) were extracted and pooled by a random-effects model. RESULTS: A total of nine studies were included. Compared with normal weight, underweight was associated with an increased risk of stroke or systemic embolism (SSE) (RR 1.98, 95% CI 1.19-3.28), whereas either overweight or obesity was related with reduced rates of SSE (overweight: RR 0.81, 95% CI 0.71-0.91; obesity: RR 0.69, 95% CI 0.61-0.78) and all-cause death (overweight: RR 0.73, 95% CI 0.64-0.83; obesity: RR 0.72, 95% CI 0.66-0.79). Compared with patients receiving warfarin, patients receiving DOACs who were underweight, normal weight or overweight all had decreased risks of SSE (underweight: RR 0.61, 95% CI 0.46-0.80; normal weight: RR 0.72, 95% CI 0.58-0.91; overweight: RR 0.87, 95% CI 0.76-0.99) and major bleeding (underweight: RR 0.67, 95% CI 0.55-0.81; normal weight: RR 0.72, 95% CI 0.58-0.90; overweight: RR 0.83, 95% CI 0.71-0.96), while obese DOAC users were at no higher risks for SSE and major bleeding. CONCLUSIONS: There may be an obesity paradox in anticoagulated patients with AF. DOACs have better efficacy and safety profiles than warfarin in underweight, normal weight and overweight patients, and are not inferior to warfarin in obese patients.","author":[{"dropping-particle":"","family":"Zhou","given":"Yue","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Jianyong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Wengen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American journal of cardiovascular drugs : drugs, devices, and other interventions","id":"ITEM-1","issued":{"date-parts":[["2019","7"]]},"language":"eng","publisher-place":"New Zealand, New Zealand","title":"Efficacy and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation Across BMI Categories: A Systematic Review and Meta-Analysis.","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1111/jth.13701","ISSN":"1538-7836 (Electronic)","PMID":"28407368","abstract":"Essentials The association of body weight and patient-important outcomes remains unknown. Phase III randomized controlled trials of direct oral anticoagulants (DOACs) were searched. Risk of outcomes varying among body weight subgroups is not attributable to anticoagulant type. Dose adjustment of DOACs, outside that recommended, is unlikely to improve the outcomes. Click to hear Dr Braunwald's perspective on antithrombotic therapy in cardiovascular disease SUMMARY: Background Concerns have arisen in direct oral anticoagulant (DOAC)-treated patients about safety and efficacy in extremes of body weight. The aims of this systematic review were to investigate the association of body weight and patient-important outcomes in patients treated with DOACs or warfarin, and to demonstrate the fixed-dose effect of DOACs. Methods MEDLINE and EMBASE were searched until November 2016. Phase III randomized controlled trials (RCTs) using DOACs in atrial fibrillation (AF) and acute venous thromboembolism (VTE) were included. Relative risk and 95% confidence interval were calculated. The pooled estimates were performed using a Mantel-Haenszel random effects model. Results A total of 11 phase III RCTs were included. Low body weight was associated with increased risk of thromboembolism compared with non-low body weight (relative risk [RR], 1.57; 95% confidence interval [CI], 1.34-1.85). High body weight was not associated with risk of thromboembolism compared with non-high body weight (RR, 0.88; 95% CI, 0.63-1.23). The subgroup of AF patients with high body weight had a lower risk of thromboembolism compared with non-high body weight (RR, 0.43; 95% CI, 0.28-0.67). Bleeding outcomes were comparable for all body weight comparisons. There were no clear interactions between types of anticoagulant in all outcomes. Conclusion The pooled effect of both the DOAC and comparison arms was likely to be attributable to differences in baseline thrombotic risk in each body weight category, rather than an effect of the type or dose of DOAC used for each indication. Dose adjustment of DOACs, outside that recommended in the package insert, is unlikely to improve safety or efficacy.","author":[{"dropping-particle":"","family":"Boonyawat","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caron","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chai-Adisaksopha","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iorio","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"R D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garcia","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crowther","given":"M A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of thrombosis and haemostasis : JTH","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2017","7"]]},"language":"eng","page":"1322-1333","publisher-place":"England, England","title":"Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis.","type":"article-journal","volume":"15"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1161/STROKEAHA.116.015984","ISSN":"1524-4628 (Electronic)","PMID":"28265017","abstract":"BACKGROUND AND PURPOSE: Obesity is a risk factor for all-cause and cardiovascular death but, despite this, an inverse relationship between overweight or obesity and a better cardiovascular prognosis in long-term follow-up studies has been observed; this phenomenon, described as obesity paradox, has also been found evident in atrial fibrillation cohorts. METHODS: We performed a systematic review on the relationship between body mass index and major adverse outcomes in atrial fibrillation patients. Moreover, we provided a meta-analysis of non-vitamin K antagonist oral anticoagulants (NOACs) trials. RESULTS: An obesity paradox was found for cardiovascular death and all-cause death in the subgroup analyses of randomized trial cohorts; however, observational studies fail to show this relationship. From the meta-analysis of NOAC trials, a significant obesity paradox was found, with both overweight and obese patients reporting a lower risk for stroke/systemic embolic event (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.66-0.84 and OR, 0.62; 95% CI, 0.54-0.70, respectively). For major bleeding, only obese patients were at lower risk compared with normal weight patients (OR, 0.84; 95% CI, 0.72-0.98). A significant treatment effect of NOACs was found in normal weight patients, both for stroke/systemic embolic event (OR, 0.66; 95% CI, 0.56-0.78) and for major bleeding (OR, 0.72; 95% CI, 0.54-0.95). Major bleeding risk was lower in overweight patients treated with NOACs (OR, 0.84; 95% CI, 0.71-1.00). CONCLUSIONS: There may be an obesity paradox in atrial fibrillation patients, particularly for all-cause and cardiovascular death outcomes. An obesity paradox was also evident for stroke/systemic embolic event outcome in NOAC trials, with a treatment effect favoring NOACs over warfarin for both efficacy and safety that was significant only for normal weight patients.","author":[{"dropping-particle":"","family":"Proietti","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guiducci","given":"Elisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheli","given":"Paola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-3","issue":"4","issued":{"date-parts":[["2017","4"]]},"language":"eng","page":"857-866","publisher-place":"United States, United States","title":"Is There an Obesity Paradox for Outcomes in Atrial Fibrillation? A Systematic Review and Meta-Analysis of Non-Vitamin K Antagonist Oral Anticoagulant Trials.","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"(154–156)","plainTextFormattedCitation":"(154–156)","previouslyFormattedCitation":"(154–156)"},"properties":{"noteIndex":0},"schema":""}(154–156).Biological markersThere are several biomarkers that may help predict anticoagulation-related bleeding. Some of these are linked to stroke risk and have already been described above (e.g. renal failure, IL-6, vWF). Perhaps one of the most important biomarkers associated with the use of VKA is the intensity of anticoagulation, measured as the international normalised ratio (INR). Higher INR levels have been found to increase the risk of anticoagulation-related bleeding, with relative risks (RR) for INR ≥4.5 of 7.9 (95% CI, 5.4 - 11.5) compared to INR <4.5 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0140-6736(96)01109-9","ISSN":"01406736","PMID":"8709780","abstract":"BACKGROUND: Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications. We studied the frequency of bleeding complications in outpatients treated routinely in anticoagulation clinics. METHODS: In a prospective cohort from thirty-four Italian anticoagulation clinics, 2745 consecutive patients were studied from the start of their oral anticoagulation (warfarin in 64%, acenocourmarol in the rest). The target anticoagulation-intensity was low (international normalised ratio [INR] < or = 2.8) in 71% of the patients and high (> 2.8) in the remainder. We recorded demographic details and the main indication for treatment and, every 3-4 months, INR and outcome events. Such events included all complications (bleeding, thrombosis, other), although only bleeding events are reported here, and deaths. We divided bleeding into major and minor categories. FINDINGS: 43% of the patients were women. Nearly three-fifths of the patients were aged 60-79; 8% were over 80. The main indication for treatment was venous thrombolism (33%), followed by non-ischaemic heart disease (17%). Mean follow-up was 267 days. Over 2011 patient-years of follow-up, 153 bleeding complications occurred (7.6 per 100 patient-years). 5 were fatal (all cerebral haemorrhages, 0.25 per 100 patient-years), 23 were major (1.1), and 125 were minor (6.2). The rate of events was similar between sexes, coumarin type, size of enrolling centre, and target INR. The rate was higher in older patients: 10.5 per 100 patient-years in those aged 70 or over, 6.0 in those aged under 70 (relative risk 1.75, 95% Cl 1.29-2.39, p < 0.001). The rate was also higher when the indication was peripheral and/or cerebrovascular disease than venous thromboembolism plus other indications (12.5 vs 6.0 per 100 patient-years) (1.80, 1.2-2.7, p < 0.01), and during the first 90 days of treatment compared with later (11.0 vs 6.3, 1.75, 1.27-2.44, p < 0.001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR < 2, rate 7.7 per 100 patient-years of follow-up). The rates were 4.8, 9.5, 40.5, and 200 at INRs 2.0-2.9, 3-4.4, 4.5-6.9, and over 7, respectively (relative risks for INR > 4.5, 7.91, 5.44-11.5, p < 0.0001). INTERPRETATION: We saw fewer bleeding events than those recorded in other observational and experimental studies. Oral anticoagulation has become safer in recent years, especially if monitored in anticoagulation clinics.…","author":[{"dropping-particle":"","family":"Palareti","given":"Gualtiero","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leali","given":"Nicoletta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coccheri","given":"Sergio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Poggi","given":"Mario","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manotti","given":"Cesare","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Angelo","given":"Armando","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pengo","given":"Vittorio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Erba","given":"Nicoletta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moia","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ciavarella","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Devoto","given":"Gianluigi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berrettini","given":"Mauro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Musolesi","given":"Serena","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet","id":"ITEM-1","issue":"9025","issued":{"date-parts":[["1996","8"]]},"language":"eng","page":"423-428","publisher-place":"England, England","title":"Bleeding complications of oral anticoagulant treatment: An inception-cohort, prospective collaborative study (ISCOAT)","type":"article-journal","volume":"348"},"uris":[""]}],"mendeley":{"formattedCitation":"(127)","plainTextFormattedCitation":"(127)","previouslyFormattedCitation":"(127)"},"properties":{"noteIndex":0},"schema":""}(127). It is estimated that every one unit increase in INR above 2.5 was associated with a two-fold increased risk of mortality ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.325.7372.1073","ISSN":"09598146","PMID":"12424167","abstract":"Objective: To study how mortality varies with different degrees of anticoagulation reflected by the international normalised ratio (INR). Design: Record linkage analysis with death hazard estimated as a continuous function of INR. Data sources: 46 anticoagulation clinics in Sweden with computerised medical records. Subjects: Records for 42 451 patients, 3533 deaths, and 1.25 million INR measurements. Main outcome measures: Mortality from all causes and from intracranial haemorrhage. Results: Mortality from all causes of death was strongly related to level of INR. Minimum risk of death was attained at 2.2 INR for all patients and 2.3 INR for patients with mechanical heart valve prostheses. A high INR was associated with an excess mortality: with an increase of 1 unit of INR above 2.5, the risks of death from cerebral bleeding (149 deaths) and from any cause were about doubled. Among patients with an INR of ≥3.0, 1069 deaths occurred within 7 weeks; if the risk coincided with that with an INR of 2.9, the expected number of deaths would have been 569. Thus at least 500 deaths were associated with a high INR value, but not necessarily caused by the treatment. Conclusions: The excess mortality associated with high INR values supports the use of less intensive treatment and a small therapeutic window, with INR close to 2.2-2.3 irrespective of the indication for anticoagulant treatment. More preventive actions should be taken to avoid episodes of high INR.","author":[{"dropping-particle":"","family":"Oden","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fahlen","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Odén","given":"Andersanders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fahlén","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oden","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fahlen","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Medical Journal","id":"ITEM-1","issue":"7372","issued":{"date-parts":[["2002","11"]]},"language":"eng","page":"1073-1075","publisher-place":"England, England","title":"Oral anticoagulation and risk of death: A medical record linkage study","type":"article-journal","volume":"325"},"uris":[""]}],"mendeley":{"formattedCitation":"(159)","plainTextFormattedCitation":"(159)","previouslyFormattedCitation":"(159)"},"properties":{"noteIndex":0},"schema":""}(159). Therefore, every effort should be taken to maintain the INR of AF patients within pre-defined ranges, often between 2 - 3 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehw210","ISSN":"1522-9645 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Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.","type":"article-journal","volume":"37"},"uris":[""]}],"mendeley":{"formattedCitation":"(20)","plainTextFormattedCitation":"(20)","previouslyFormattedCitation":"(20)"},"properties":{"noteIndex":0},"schema":""}(20). However, absolute INR levels alone can be misleading as a significant proportion of major bleeds occur despite the INR being in therapeutic range ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.str.31.11.2558","ISSN":"1524-4628 (Electronic)","PMID":"11062275","abstract":"BACKGROUND AND PURPOSE: Early survival of patients with intracerebral hemorrhage in general is known to be most strongly dependent on the Glasgow Coma Scale score on admission. The aim of this study was to examine the factors determining functional outcome and in-hospital mortality of patients admitted with an intracerebral hemorrhage related to oral anticoagulant (OAC) use. METHODS: Correlation studies and multiple logistic regression analyses were performed on data from a retrospective series of 42 patients admitted with OAC-related intracerebral hemorrhages over a 6-year period to a tertiary care center in the north of Scotland. RESULTS: The functional outcome after an OAC-related intracerebral hemorrhage was dependent on maximum diameter of hematoma on CT scan (R:=-0.72, P:<0. 001) and international normalized ratio (INR) (R:=-0.35, P:=0.024). Hematoma diameter and INR were not themselves strongly correlated (R:=0.31, P:=0.099). In-hospital mortality can be predicted by the Glasgow Coma Scale score alone (R:(2)=0.36, overall predictive accuracy 68%) but more accurately by a logistic regression model including hematoma diameter and CT signs of cerebrovascular disease (R:(2)=0.70, predictive accuracy 83%). CONCLUSIONS: Neither functional outcome nor in-hospital mortality appears to be strongly dependent on INR measured on admission. CT scan, however, provides essential information and allows accurate predictions about the short-term outcome of OAC-related intracerebral hemorrhages.","author":[{"dropping-particle":"","family":"Berwaerts","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dijkhuizen","given":"R S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robb","given":"O J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Webster","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2000","11"]]},"language":"eng","page":"2558-2562","publisher-place":"United States","title":"Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage.","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"(160)","plainTextFormattedCitation":"(160)","previouslyFormattedCitation":"(160)"},"properties":{"noteIndex":0},"schema":""}(160). More recently, INR variability has emerged as a more reliable assessment method for bleeding risk. A ‘labile INR’ as determined using time-in-therapeutic range (TTR) is strongly linked to future bleeding events ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1160/TH16-06-0489","ISSN":"2567-689X (Electronic)","PMID":"27652593","abstract":"High quality of warfarin treatment is important to prevent recurrence of venous thromboembolism (VTE) without bleeding complications. The aim of this study was to examine the effect of individual time in therapeutic range (iTTR) and International Normalised Ratio (INR) variability on bleeding risk and mortality in a large cohort of well-managed patients with warfarin due to VTE. A cohort of 16612 patients corresponding to 19502 treatment periods with warfarin due to VTE between January 1, 2006 and December 31, 2011 was retrieved from the Swedish national quality register AuriculA and matched with the Swedish National Patient Register for bleeding complications and background characteristics and the Cause of death register for occurrence and date of death. The rate of bleeding was 1.79 (confidence interval (CI) 95 % 1.66-1.93) per 100 treatment years among all patients. Those with poor warfarin treatment quality had a higher rate of clinically relevant bleeding, both when measured as iTTR below 70 %, 2.91 (CI 95 % 2.61-3.21) or as INR variability over the mean value 0.85, 2.61 (CI 95 % 2.36-2.86). Among those with both high INR variability and low iTTR the risk of clinically relevant bleeding was clearly increased hazard ratio (HR) 3.47 (CI 95 % 2.89-4.17). A similar result was found for all-cause mortality with a HR of 3.67 (CI 95 % 3.02-4.47). Both a low iTTR and a high INR variability increase the risk of bleeding complications or mortality. When combining the two treatment quality indicators patients at particular high risk of bleeding or death can be identified.","author":[{"dropping-particle":"","family":"Sanden","given":"Per","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Renlund","given":"Henrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svensson","given":"Peter J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sjalander","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017","1"]]},"language":"eng","page":"27-32","publisher-place":"Germany, Germany","title":"Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR.","type":"article-journal","volume":"117"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1001/jamacardio.2016.0199","ISSN":"2380-6591 (Electronic)","PMID":"27437888","abstract":"IMPORTANCE: Vitamin K antagonist (eg, warfarin) use is nowadays challenged by the non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). NOAC studies were based on comparisons with warfarin arms with times in therapeutic range (TTRs) of 55.2% to 64.9%, making the results less credible in health care systems with higher TTRs. OBJECTIVES: To evaluate the efficacy and safety of well-managed warfarin therapy in patients with nonvalvular AF, the risk of complications, especially intracranial bleeding, in patients with concomitant use of aspirin, and the impact of international normalized ratio (INR) control. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, multicenter cohort study based on Swedish registries, especially AuriculA, a quality register for AF and oral anticoagulation, was conducted. The register contains nationwide data, including that from specialized anticoagulation clinics and primary health care centers. A total of 40 449 patients starting warfarin therapy owing to nonvalvular AF during the study period were monitored until treatment cessation, death, or the end of the study. The study was conducted from January 1, 2006, to December 31, 2011, and data were analyzed between February 1 and November 15, 2015. Associating complications with risk factors and individual INR control, we evaluated the efficacy and safety of warfarin treatment in patients with concomitant aspirin therapy and those with no additional antiplatelet medications. EXPOSURES: Use of warfarin with and without concomitant therapy with aspirin. MAIN OUTCOMES AND MEASURES: Annual incidence of complications in association with individual TTR (iTTR), INR variability, and aspirin use and identification of factors indicating the probability of intracranial bleeding. RESULTS: Of the 40 449 patients included in the study, 16201 (40.0%) were women; mean (SD) age of the cohort was 72.5 (10.1) years, and the mean CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age >/=75 years [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65-74 years, and sex category [female]) score was 3.3 at baseline. The annual incidence, reported as percentage (95% CI) of all-cause mortality was 2.19% (2.07-2.31) and, for intracranial bleeding, 0.44% (0.39-0.49). Patients receiving concomitant aspirin had annual rates of any major bleeding of 3.07% (2.70-3.44) and thromboembolism of 4.90% (4.43-5.37), and those with renal failure …","author":[{"dropping-particle":"","family":"Bjorck","given":"Fredrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Renlund","given":"Henrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wester","given":"Per","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svensson","given":"Peter J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sjalander","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA cardiology","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2016","5"]]},"language":"eng","page":"172-180","publisher-place":"United States, United States","title":"Outcomes in a Warfarin-Treated Population With Atrial Fibrillation.","type":"article-journal","volume":"1"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1038/s41598-017-11683-2","ISSN":"2045-2322 (Electronic)","PMID":"28935868","abstract":"Bleeding risk with vitamin K antagonists (VKAs) is closely related to the quality of anticoagulation in atrial fibrillation (AF) patients, reflected by time in therapeutic range (TTR). Here we compared the discrimination performance of different bleeding risk scores and investigated if adding TTR would improve their predictive value and clinical usefulness. We included 1361 AF patients stables on VKA for at least 6 months. Bleeding risk was assessed by the HAS-BLED, ATRIA, ORBIT and HEMORR2HAGES scores. Major bleeding events were recorded after a median of 6.5 years follow-up. In this period 250 patients suffered major bleeds. Comparison of receiver operating characteristic (ROC) curves demonstrated that HAS-BLED had the best discrimination performance, but adding the 'labile INR' criteria (i.e. TTR <65%) to ATRIA, ORBIT and HEMORR2HAGES increased their ability of discrimination and predictive value, with significant improvements in reclassification and discriminatory performance. Decision curve analyses (DCA) showed improvements of the clinical usefulness and a net benefit of the modified risk scores. In summary, in AF patients taking VKAs, the HAS-BLED score had the best predictive ability. Adding 'labile INR' to ATRIA, ORBIT and HEMORR2HAGES improved their predictive value for major bleeding leading to improved clinical usefulness compared to the original scores.","author":[{"dropping-particle":"","family":"Rivera-Caravaca","given":"Jose Miguel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Esteve-Pastor","given":"Maria Asuncion","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific reports","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2017","9"]]},"language":"eng","page":"12066","publisher-place":"England, England","title":"Importance of time in therapeutic range on bleeding risk prediction using clinical risk scores in patients with atrial fibrillation.","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"(161–163)","plainTextFormattedCitation":"(161–163)","previouslyFormattedCitation":"(161–163)"},"properties":{"noteIndex":0},"schema":""}(161–163). However, there are several limitations of TTR that are worth bearing in mind ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jth.12041","ISSN":"1538-7836 (Electronic)","PMID":"23088617","abstract":"BACKGROUND: Anticoagulation control is often summarized using the percentage of time spent in a therapeutic range (TTR). This method does not describe the timing and severity of fluctuations in the International Normalised Ratio (INR). OBJECTIVE: To evaluate whether the TTR method can be improved by considering the patterns of INR over time. METHODS: The cohort included adults aged 40+ years with atrial fibrillation (AF) and laboratory records of INR as recorded in the UK Clinical Practice Research Datalink. Statistical clustering techniques based on simple INR measures were used to describe the patterns of INR. Nested case-control studies calculated the odds ratios (ORs) for the risk of stroke, bleeding and mortality with TTR and different INR patterns. It was also evaluated whether cluster analyses improved the prediction of outcomes over TTR. RESULTS: A number of 27 381 patients were studied with a mean age of 73 years. The OR for mortality was 3.76 (95% confidence interval [CI] 3.03-4.68) in patients with < 30% TTR compared with patients with 100% TTR. INR patterns were found to be best described by six different clusters. The cluster with the most unstable pattern was associated with the largest risk of mortality (OR 10.7, 95% CI 8.27-13.85) and stroke (OR 3.42, 95% CI 2.08-5.63). INR measures that predicted death independent of the TTR-included absolute difference between two subsequent INR measurements and change relative to the mean over time. CONCLUSION: Cluster analysis of INR patterns improved the prediction of clinical outcomes over TTR and may help to identify warfarin users who need additional anticoagulation monitoring.","author":[{"dropping-particle":"","family":"Ham","given":"H A","non-dropping-particle":"Van Den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klungel","given":"O H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leufkens","given":"H G M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Staa","given":"T P","non-dropping-particle":"Van","parse-names":false,"suffix":""}],"container-title":"Journal of thrombosis and haemostasis : JTH","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013","1"]]},"language":"eng","page":"107-115","publisher-place":"England, England","title":"The patterns of anticoagulation control and the risk of stroke, bleeding and mortality in patients with non-valvular atrial fibrillation.","type":"article-journal","volume":"11"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s11239-013-0900-5","ISSN":"1573-742X (Electronic)","PMID":"23456572","abstract":"Oral vitamin K antagonists are highly efficacious in the prevention and treatment of thromboembolic disease. Optimal use of these agents in clinical practice is challenged by their narrow therapeutic window. The proportion of time spent in the International Normalized Ratio (INR) range of 2.0-3.0 [time in the therapeutic range (TTR)] has been closely associated with adverse outcomes, i.e., stroke, hemorrhage, mortality. Although TTR is a validated marker, it has several limitations. TTR does not capture short-term risks associated with highly variable periods or periods characterized by extreme deviations in INR. Because TTR measurement is limited to consecutive periods of warfarin exposure, it does not inform the risks associated with gap periods of 56 days or greater as these time intervals are excluded from end-point rate calculations. Because individuals with gaps in monitoring represent a different patient population than those without gaps, e.g., less adherent, more acutely ill, more frequent transitions in health status, TTR analyses are likely most valid and informative for individuals with uninterrupted monitoring of the INR. Duration of warfarin therapy and patient-specific factors have also been shown to influence TTR. Younger age, female sex, lower income, black race, frequent hospitalizations, polypharmacy, active cancer, decompensated heart failure, substance abuse, psychiatric disorders, dementia, and chronic liver disease have all been associated with lower TTR. Targeted strategies to improve TTR are urgently needed.","author":[{"dropping-particle":"","family":"Hylek","given":"Elaine M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of thrombosis and thrombolysis","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2013","4"]]},"language":"eng","page":"333-335","publisher-place":"Netherlands, Netherlands","title":"Vitamin K antagonists and time in the therapeutic range: implications, challenges, and strategies for improvement.","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"(164,165)","plainTextFormattedCitation":"(164,165)","previouslyFormattedCitation":"(164,165)"},"properties":{"noteIndex":0},"schema":""}(164,165). Firstly, it assumes a linear relationship between INR measurements which may not be true. Secondly, it does not inform on short-term risks associated with extreme deviations in INR. Lastly, it fails to account for individuals with ‘missed’ monitoring periods who may represent a group at higher risk of bleeding due to reasons such as non-adherence.Given the importance of the liver and kidneys in regulating pharmacokinetics of drugs and maintaining haemostasis, it is inevitable that fluctuations in the functions of these organs could negatively impact on anticoagulation-related bleeding. A prospective, observational study of 8,466 AF patients treated with either VKA or NOACs suggests that both abnormal renal and liver functions were associated with increased risk of major bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmjopen-2018-022478","ISSN":"2044-6055 (Electronic)","PMID":"30928922","abstract":"OBJECTIVES: We identified factors associated with thromboembolic and bleeding events in two contemporary cohorts of anticoagulated patients with atrial fibrillation (AF), treated with either vitamin K antagonists (VKA) or non-VKA oral anticoagulants (NOACs). DESIGN: Prospective, multicentre observational study. SETTING: 461 centres in seven European countries. PARTICIPANTS: 5310 patients receiving a VKA (PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF), derivation cohort) and 3156 patients receiving a NOAC (PREFER in AF Prolongation, validation cohort) for stroke prevention in AF. OUTCOME MEASURES: Risk factors for thromboembolic events (ischaemic stroke, systemic embolism) and major bleeding (gastrointestinal bleeding, intracerebral haemorrhage and other life-threatening bleeding). RESULTS: The mean age of patients enrolled in the PREFER in AF registry was 72+/-10 years, 40% were female and the mean CHA2DS2-VASc Score was 3.5+/-1.7. The incidence of thromboembolic and major bleeding events was 2.34% (95% CI 1.93% to 2.74%) and 2.84% (95% CI 2.41% to 3.33%) after 1-year of follow-up, respectively.Abnormal liver function, prior stroke or transient ischaemic attack, labile international normalised ratio (INR), concomitant therapy with antiplatelet or non-steroidal anti-inflammatory drugs, heart failure and older age (>/=75 years) were independently associated with both thromboembolic and major bleeding events.With the exception of unstable INR values, these risk factors were validated in patients treated with NOACs (PREFER in AF Prolongation Study, 72+/-9 years, 40% female, CHA2DS2-VASc 3.3+/-1.6). For each single point decrease on a modifiable bleeding risk scale we observed a 30% lower risk for major bleeding events (OR 0.70, 95% CI 0.64 to 0.76, p<0.01) and a 28% lower rate of thromboembolic events (OR 0.72, 95% CI 0.66 to 0.82, p<0.01). CONCLUSION: Attending to modifiable risk factors is an important treatment target in anticoagulated AF patients to reduce thromboembolic and bleeding events. Initiation of anticoagulation in those at risk of stroke should not be prevented by elevated bleeding risk scores.","author":[{"dropping-particle":"","family":"Rohla","given":"Miklos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiss","given":"Thomas W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pecen","given":"Ladislav","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patti","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siller-Matula","given":"Jolanta M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schnabel","given":"Renate B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schilling","given":"Richard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kotecha","given":"Dipak","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lucerna","given":"Markus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huber","given":"Kurt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caterina","given":"Raffaele","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirchhof","given":"Paulus","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMJ open","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2019","3"]]},"language":"eng","page":"e022478","publisher-place":"England, England","title":"Risk factors for thromboembolic and bleeding events in anticoagulated patients with atrial fibrillation: the prospective, multicentre observational PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF).","type":"article-journal","volume":"9"},"uris":[""]}],"mendeley":{"formattedCitation":"(166)","plainTextFormattedCitation":"(166)","previouslyFormattedCitation":"(166)"},"properties":{"noteIndex":0},"schema":""}(166). The study authors defined abnormal renal function as serum creatinine >2.3 mg/dL (200 μmol/L), prior renal transplantation or receiving chronic dialysis, and abnormal liver function as cirrhosis, elevated liver transaminases or alkaline phosphatase >3 times above the upper limit of normal, or bilirubin >2 times above the upper limit of normal. Similar findings were reported in a separate large cohort study of 7,141 AF patients receiving rivaroxaban ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00380-019-01425-x","ISSN":"1615-2573 (Electronic)","PMID":"31127325","abstract":"For Japanese patients with non-valvular atrial fibrillation (NVAF), the risk of stroke and major bleeding events was assessed by using the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The risk factors for embolism and major bleeding under DOAC may be different from current reports. We analyzed the data set of the EXPAND Study to determine the risk factors for events among Japanese NVAF patients in the era of direct oral anticoagulant. Using the data of EXPAND Study, the validity for predictability of the CHADS2, CHA2DS2-VASc, and HAS-BLED scores was identified using the receiver operating characteristic curve analysis. Multivariate analysis was performed with the Cox proportional hazard model to determine the independent risk factors for stroke/systemic embolism and major bleeding among NVAF patients receiving rivaroxaban. Explanatory variables were selected based on the univariate analysis. A total of 7141 patients (mean age 71.6 +/- 9.4 years, women 32.3%, and rivaroxaban 15 mg per day 56.5%) were included. Incidence rates of stroke/systemic embolism and major bleeding were 1.0%/year and 1.2%/year, respectively. The multivariate analysis revealed that only history of stroke was associated with stroke/systemic embolism (hazard ratio 3.4, 95% confidence interval 2.5-4.7, p < 0.0001). By contrast, age (1.7, 1.1-2.6, p = 0.0263), creatinine clearance (CrCl) 30-49 mL/min (1.6, 1.2-2.2, p = 0.0011), liver dysfunction (1.7, 1.1-2.8, p = 0.0320), history/disposition of bleeding (1.8, 1.0-3.0, p = 0.0348), and concomitant use of antiplatelet agents (1.6, 1.2-2.3, p = 0.0030) were associated with major bleeding. This sub-analysis showed that some components of the HAS-BLED score were independently associated with major bleeding in Japanese NVAF patients receiving anticoagulation therapy by rivaroxaban. Additionally, CrCl value of 30-49 mL/min was an independent predictor of major bleeding in patients receiving rivaroxaban.","author":[{"dropping-particle":"","family":"Sakuma","given":"Ichiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Uchiyama","given":"Shinichiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Atarashi","given":"Hirotsugu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inoue","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kitazono","given":"Takanari","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamashita","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimizu","given":"Wataru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ikeda","given":"Takanori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kamouchi","given":"Masahiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaikita","given":"Koichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fukuda","given":"Koji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Origasa","given":"Hideki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimokawa","given":"Hiroaki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart and vessels","id":"ITEM-1","issued":{"date-parts":[["2019","5"]]},"language":"eng","publisher-place":"Japan, Japan","title":"Clinical risk factors of stroke and major bleeding in patients with non-valvular atrial fibrillation under rivaroxaban: the EXPAND Study sub-analysis.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(167)","plainTextFormattedCitation":"(167)","previouslyFormattedCitation":"(167)"},"properties":{"noteIndex":0},"schema":""}(167). Furthermore, Banerjee et al. reported that lower levels of eGFR were related to a greater risk of major bleeding over a study period of 2.5 years ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1378/chest.13-2103","ISSN":"19313543","PMID":"24356875","abstract":"Background: Atrial fibrillation (AF) is more likely to develop in patients with chronic kidney disease (CKD) than in individuals with normal renal function, and patients with CKD are more likely to suffer ischemic stroke (IS)/thromboembolism (TE). To our knowledge, no prior study has considered the impact of estimated glomerular filtration rate (eGFR) on bleeding. We investigated the relationship of eGFR to IS/TE, mortality, and bleeding in an AF population unrestricted by age or comorbidity. Methods: Patients with nonvalvular AF (NVAF) were stratified into five categories according to eGFR (≥90, 60-89, 30-59, 15-29, and < 15 mL/min/1.73 m2), analyzing risk factors, all-cause mortality, bleeding, and IS/TE. Of 8,962 eligible individuals, 5,912 had NVAF and available serum creatinine data, with 14,499 patient-years of follow-up. Results: The incidence rates of IS/TE were 7.4 and 7.2 per 1,000 person-years in individuals not receiving and receiving anticoagulation therapy, respectively. Rates of all-cause mortality were 13.4 and 9.4 per 1,000 person-years, respectively, and of major bleeding, 6.2 and 9.0 per 1,000 person-years, respectively. Rates increased with decreasing eGFR, with IS/TE rates being lower in individuals receiving oral anticoagulation (OAC) therapy. eGFR was not an independent predictor of IS/TE on multivariate analyses. When the benefit of IS reduction is balanced against the increased risk of hemorrhagic stroke, the net clinical benefit (NCB) was clearly positive in favor of OAC use. Conclusions: Incidence rates of IS/TE, mortality, and bleeding increased with reducing eGFR across the whole range of renal function. OAC use was associated with a lower incidence of IS/TE and mortality at 1 year compared with individuals not receiving anticoagulants in all categories of renal function as measured by eGFR. The NCB balancing IS against serious bleeding was positive in favor of OAC use among patients with renal impairment. ? 2014 American College of Chest Physicians.","author":[{"dropping-particle":"","family":"Banerjee","given":"Amitava","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fauchier","given":"Laurent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vourc'H","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andres","given":"Christian R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taillandier","given":"Sophie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halimi","given":"Jean Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H. H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2014","6"]]},"language":"eng","page":"1370-1382","publisher":"The American College of Chest Physicians","publisher-place":"United States, United States","title":"A prospective study of estimated glomerular filtration rate and outcomes in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project.","type":"article-journal","volume":"145"},"uris":[""]}],"mendeley":{"formattedCitation":"(66)","plainTextFormattedCitation":"(66)","previouslyFormattedCitation":"(66)"},"properties":{"noteIndex":0},"schema":""}(66).Anaemia has also been linked to increased bleeding risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0002-9343(89)80689-8","ISSN":"00029343","PMID":"2787958","abstract":"Purpose: To determine the incidence of major bleeding in outpatients treated with warfarin and to identify predictive factors known at the start of therapy. Patients and Methods: The records of 565 patients starting outpatient therapy with warfarin upon discharge from a university hospital were reviewed. Follow-up information was obtained for 562 patients (99.5%). Bleeding was classified as major or minor using explicit criteria. The cumulative incidence of bleeding was estimated by means of survival analysis. Independent risk factors for major bleeding were identified using Cox regression analysis in 375 randomly chosen patients; they were tested in the remaining 187 patients. Results: Major bleeding occurred in 65 patients (12%) and was fatal in 10 patients (2%). The cumulative incidences of major bleeding at one, 12, and 48 months were 3%, 11%, and 22%, respectively. The monthly risk of major bleeding decreased over time, from 3% during the first month of outpatient therapy to 0.3% per month after the first year of therapy. Five independent risk factors for major bleeding-age 65 years or greater, history of stroke, history of gastrointestinal bleeding, a serious comorbid condition (recent myocardial infarction, renal insufficiency, or severe anemia), atrial fibrillation-predicted major bleeding in the testing group; the cumulative incidence of major bleeding at 48 months was 2% in 57 low-risk patients, 17% in 110 middle-risk patients, and 63% in 20 high-risk patients. Conclusions: These findings provide a quantitative basis for evaluating the risk of major bleeding in individual patients at the start of outpatient therapy with warfarin. Whether the risk of bleeding can be reduced in high-risk patients without reducing the benefit of therapy remains to be determined. ? 1989 Reed Publishing USA.","author":[{"dropping-particle":"","family":"Landefeld","given":"C. Seth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldman","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldman","given":"Ohio Lee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldman","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American Journal of Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1989","8"]]},"language":"eng","page":"144-152","publisher-place":"United States, United States","title":"Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy","type":"article-journal","volume":"87"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1093/qjmed/hcm076","ISSN":"1460-2725 (Print)","PMID":"17846060","abstract":"Atrial fibrillation (AF) is associated with an increased stroke risk that may be reduced by therapeutic anticoagulation. However, anticoagulation is associated with an increased risk of bleeding that in some patients may outweigh the benefits in reducing the risk of stroke. We systematically reviewed the literature for risk factors of anticoagulation-related bleeding complications in patients with AF, as part of the formulation of recently published national guidelines for the management of AF. We identified nine studies that reported anticoagulation-related bleeding complications in AF patients. The following patient characteristics were identified as having supporting evidence for being risk factors for anticoagulation-related bleeding complications: advanced age, uncontrolled hypertension, history of myocardial infarction or ischaemic heart disease, cerebrovascular disease, anaemia or a history of bleeding, and the concomitant use of other drugs such as antiplatelet agents. The presence of diabetes mellitus, controlled hypertension and gender were not identified as significant risk factors. Some of the risk factors for anticoagulation-related bleeding are also indications for the use of anticoagulants in AF patients. There is a need for further research in this area to help physicians to balance the risks and benefits of anticoagulation in AF patients.","author":[{"dropping-particle":"","family":"Hughes","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"G Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"QJM : monthly journal of the Association of Physicians","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2007","10"]]},"language":"eng","page":"599-607","publisher-place":"England, England","title":"Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review.","type":"article-journal","volume":"100"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1111/jth.12874","ISSN":"1538-7836 (Electronic)","PMID":"25683276","abstract":"BACKGROUND: Anemia may predispose to thromboembolic events or bleeding in anticoagulated patients with atrial fibrillation (AF). OBJECTIVES: To investigate whether anemia is associated with thromboembolic events and bleeding in patients with AF. PATIENTS AND METHODS: We retrospectively analyzed the RE-LY trial database, which randomized 18 113 patients with AF and a risk of stroke to receive dabigatran or warfarin for a median follow-up of 2 years. Cox regression analysis was used to determine whether anemia predicted cardiovascular events and bleeding complications in these patients. RESULTS: Anemia was present in 12% of the population at baseline, and the presence of anemia was associated with a higher risk of thromboembolic cardiovascular events, including the composite endpoint of all-cause mortality or myocardial infarction (adjusted hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.32-1.71) and the primary RE-LY outcome of stroke or systemic embolism (adjusted HR 1.41, 95% CI 1.12-1.78). Anemia was also associated with a higher risk of major bleeding complications (adjusted HR 2.14, 95% CI 1.87-2.46) and discontinuation of anticoagulants (adjusted HR 1.40, 95% CI 1.28-1.79). The association between anemia and outcome was similar irrespective of cardiovascular comorbidities, randomized treatment allocation, or prior use of warfarin. The incidence of events was lower in patients with transient anemia than in patients in whom anemia was sustained (adjusted HR 0.66, 95% CI 0.49-0.91). CONCLUSIONS: Anemia is associated with an increased risk of thromboembolic events, bleeding complications and mortality in anticoagulated patients with AF. These findings suggest that patients with anemia should be monitored closely during all types of anticoagulant treatment.","author":[{"dropping-particle":"","family":"Westenbrink","given":"B D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alings","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"S J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelboom","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"M D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pongue","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilst","given":"W H","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"Journal of thrombosis and haemostasis : JTH","id":"ITEM-3","issue":"5","issued":{"date-parts":[["2015","5"]]},"language":"eng","page":"699-707","publisher-place":"England, England","title":"Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial.","type":"article-journal","volume":"13"},"uris":[""]}],"mendeley":{"formattedCitation":"(130,131,168)","plainTextFormattedCitation":"(130,131,168)","previouslyFormattedCitation":"(130,131,168)"},"properties":{"noteIndex":0},"schema":""}(130,131,168). The underlying mechanism remains unclear but there is some evidence to suggest that platelet aggregation is impaired by a reduced red blood cell count ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0006-4971 (Print)","PMID":"8639780","abstract":"Previous studies on patients with storage pool deficiency (SPD) who are specifically deficient in platelet dense granules (delta-SPD) have suggested a role for dense granule substances, in all likelihood adenosine diphosphate (ADP), in mediating thrombus formation on subendothelium at high shear rates. The role of dense granule substances in mediating platelet adhesion appears to be more complicated Previous studies in delta-SPD suggested an adhesion defect that was strongly influenced by the patient's hematocrit (Hct) value. To explore further the possibility that red blood cells (RBCs) may influence the role that platelet storage granules play in mediating adhesion at high shear rates, we have measured adhesion (and thrombus formation) throughout a preselected range of Hct values (30% to 60%) in normal subjects and in patients with delta-SPD. The present studies confirm the defect in platelet adhesion in patients with delta-SPD, most significantly at Hct values of 30% to 40%. This defect (but not that of thrombus formation) can be completely corrected by the addition of RBCs. The correction of the platelet adhesion defect by RBCs was specific for delta-SPD; it was not observed in either von Willebrand's disease or thrombasthenia. Studies performed on normal blood under conditions that could be expected to block any effect of ADP on adhesion and an analysis of the type of adhesion defect in delta-SPD suggest that ADP may be involved in the process required for platelet spreading on the subendothelium. The corrective effect of RBCs on platelet adhesion in delta-SPD appears to be chemical rather than physical in nature, possibly due to shear-induced release of RBC ADP or to other recently described properties of RBCs that enhance collagen-induced platelet interactions.","author":[{"dropping-particle":"","family":"Weiss","given":"H J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lages","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoffmann","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turitto","given":"V T","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-1","issue":"10","issued":{"date-parts":[["1996","5"]]},"language":"eng","page":"4214-4222","publisher-place":"United States, United States","title":"Correction of the platelet adhesion defect in delta-storage pool deficiency at elevated hematocrit--possible role of adenosine diphosphate.","type":"article-journal","volume":"87"},"uris":[""]}],"mendeley":{"formattedCitation":"(169)","plainTextFormattedCitation":"(169)","previouslyFormattedCitation":"(169)"},"properties":{"noteIndex":0},"schema":""}(169). Furthermore, the anaemia may indicate concealed bleeding that becomes manifest with anticoagulation therapy. The use of IL-6 as a predictor of anticoagulation-related bleeding remains controversial. A large cohort study in AF patients found that IL-6 was independently associated with bleeding following adjustment for clinical risk factors and other biomarkers (troponin, NT-proBNP and cystatin-C) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ahj.2015.09.018","ISSN":"1097-6744 (Electronic)","PMID":"26678637","abstract":"BACKGROUND: Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events in AF patients in the RE-LY study. METHODS: Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics. RESULTS: Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism (P = .0041), major bleedings (P = .0001), vascular death (P < .0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) (P < .0001). CRP was independently related to myocardial infarction (P = .0047), vascular death (P = .0004), and the composite thromboembolic outcome (P = .0001). When further adjusted for cardiac (troponin and N-terminal fragment B-type natriuretic peptide [NT-proBNP]) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death (P < .0001), major bleeding (P < .0170) and the composite thromboembolic outcome (P < .0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 (P = .0017) when adding IL-6 to the clinically used CHA2DS2-VASc risk score with net reclassification improvement of 28%. CONCLUSION: In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.","author":[{"dropping-particle":"","family":"Aulin","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huber","given":"Kurt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reilly","given":"Paul A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American heart journal","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2015","12"]]},"language":"eng","page":"1151-1160","publisher-place":"United States, United States","title":"Interleukin-6 and C-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation.","type":"article-journal","volume":"170"},"uris":[""]}],"mendeley":{"formattedCitation":"(96)","plainTextFormattedCitation":"(96)","previouslyFormattedCitation":"(96)"},"properties":{"noteIndex":0},"schema":""}(96). Meanwhile, although a separate large cohort study initially demonstrated the relationship between IL-6 and bleeding, the results were not statistically significant once other biomarkers were taken into account ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/heartjnl-2015-308887","ISSN":"1468201X","PMID":"26839066","abstract":"Objective: Atrial fibrillation (AF) is a risk factor for stroke and mortality and the prothrombotic state has been linked to inflammation. In this study we evaluated the relationship between inflammatory biomarkers at baseline and future risk of cardiovascular events in the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Methods: The ARISTOTLE trial randomised 18 201 patients with AF to apixaban or warfarin. Interleukin 6 (IL-6) and C reactive protein (CRP) were analysed in plasma obtained at randomisation from 14 954 participants, and median follow-up was 1.9 years. Association between quartile groups of IL-6 and CRP and outcomes were analysed by Cox regression adjusted for clinical risk factors and other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Results: The IL-6 median level was 2.3 ng/L (IQR 1.5-3.9), median CRP level was 2.2 mg/L (1.0-4.8). IL-6 and CRP were significantly associated with all-cause mortality independent of clinical risk factors and other biomarkers (HR (95% CI) 1.93 (1.57 to 2.37) and 1.49 (1.24 to 1.79), respectively, Q4 vs Q1). IL-6 was associated with myocardial infarction, cardiovascular mortality, and major bleeding beyond clinical risk factors but not in the presence of cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Neither inflammatory biomarker was associated with stroke/systemic embolism. Risk prediction for stroke, death and major bleeding was not improved by IL-6 or CRP when added to clinical risk factors and the other cardiovascular biomarkers (NTproBNP, troponin, GDF-15, cystatin C). Conclusions: In patients with AF on anticoagulation, after accounting for clinical risk factors and other biomarkers, biomarkers of inflammation were significantly associated with an increased risk of mortality. However, there were no associations with the risk of stroke or major bleeding.","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aulin","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alexander","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gersh","given":"Bernard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanna","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horowitz","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"Renato D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2016","4"]]},"language":"eng","page":"508-517","publisher-place":"England, England","title":"Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"(170)","plainTextFormattedCitation":"(170)","previouslyFormattedCitation":"(170)"},"properties":{"noteIndex":0},"schema":""}(170). Neither of these studies found CRP to be important in the relationship with bleeding.Similar to the stroke findings as discussed above, the study by Janion-Sadowska et al. found no association between thrombocytopenia (platelet count <100 x 109/L) and risk of bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/FJC.0000000000000607","ISSN":"1533-4023 (Electronic)","PMID":"29985282","abstract":"AIMS: Thrombocytopenia was one of the exclusion criteria in randomized trials in which non-vitamin K antagonist oral anticoagulants (NOACs) were tested. The safety of NOACs in patients with atrial fibrillation (AF) and thrombocytopenia remains unclear. METHODS: We studied 62 patients with AF aged from 53 to 85 (mean 70.5) years with platelet count from 50 to 100 x 109/L who were treated with rivaroxaban 15 mg once daily (33.9%), dabigatran 110 mg twice daily (bid) (54.8%), or apixaban 2.5 mg bid (11.3%). Age- and sex-matched AF patients with normal platelet count and similar CHA2DS2-VASc scores who were treated with the recommended doses of NOACs served as a reference group. RESULTS: Patients were followed for a mean of 55 months (range, 23-64 months). In the thrombocytopenia group bleeding risk was higher (mean HAS-BLED score 2.0, vs. 1.0, P < 0.0001). During follow-up in thrombocytopenic and normocytopenic patients, we observed similar rates of major bleeding (1.8%/year vs. 2.7%/year, P = 0.49), clinically relevant nonmajor bleeding (CRNMB) (1.5%/year vs. 1.1%/year, P = 0.74), ischemic stroke and transient ischemic attacks (1.8%/year vs. 1.5%/year, P = 0.8), and death (1.06%/year vs. 1.11%/year, P = 0.96). The risk of bleeding and stroke was unaffected by the type of the NOAC used in both groups. Major bleedings and clinically relevant nonmajor bleeding in thrombocytopenic patients on NOACs were predicted only by age (hazard ratio 1.1, 95% confidence interval 1.0-1.3, P = 0.04). CONCLUSIONS: Our findings indicate that in AF patients with mild thrombocytopenia, anticoagulation with NOAC at reduced doses seems to be safe and effective.","author":[{"dropping-particle":"","family":"Janion-Sadowska","given":"Agnieszka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Papuga-Szela","given":"Elzbieta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lukaszuk","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chrapek","given":"Magdalena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Undas","given":"Anetta","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of cardiovascular pharmacology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018","9"]]},"language":"eng","page":"153-160","publisher-place":"United States","title":"Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Thrombocytopenia.","type":"article-journal","volume":"72"},"uris":[""]}],"mendeley":{"formattedCitation":"(89)","plainTextFormattedCitation":"(89)","previouslyFormattedCitation":"(89)"},"properties":{"noteIndex":0},"schema":""}(89). In contrast, Park et al. reported that patients with a platelet count <100 x 109/L had a significantly increased risk of bleeding events compared to those with a normal platelet count (HR 2.19 (95% CI, 1.77 - 2.70)) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.hrthm.2018.08.023","ISSN":"1556-3871 (Electronic)","PMID":"30170225","abstract":"BACKGROUND: The prognostic efficacy of quantitative platelet activity in atrial fibrillation (AF) remains unclear. OBJECTIVE: The purpose of this study was to evaluate the platelet count (PLT) as a prognostic indicator in patients with nonvalvular AF. METHODS: Data on 10,978 patients with nonvalvular AF were retrieved from a prospective registry of a single medical center in Korea. Cumulative risk for stroke and bleeding events were compared between patients with normal PLT (n = 8322), mild thrombocytopenia (n = 1791), and moderate to severe thrombocytopenia (n = 865) after propensity score matching. Prediction models for stroke were derived by conventional risk factors (model 1) and by combining PLT with model 1 (model 2), and model performance was assessed by area under the receiver operator characteristics curve (AUC). RESULTS: During the follow-up period, 7.3%, 7.0%, and 4.5% had stroke and 7.6%, 10.8%, and 17.2% had bleeding events in the normal PLT, mild, and moderate to severe thrombocytopenia groups, respectively. Compared to the normal PLT group, the moderate to severe thrombocytopenia group showed a lower risk of stroke (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.40-0.80; P = .002). A reverse relationship was found between PLT and bleeding risk (moderate to severe thrombocytopenia: HR 2.19; 95% CI 1.77-2.70; P <.001; mild thrombocytopenia: HR 1.43; 95% CI 1.18-1.73; P <.001). Compared to model 1, model 2 showed significant improvement in risk prediction (AUC 0.628 vs 0.644; P <.001). CONCLUSION: A lower PLT was associated with a lower risk of stroke and a higher risk of bleeding events. PLT combined with conventional risk factors showed significant improvement in prediction for stroke.","author":[{"dropping-particle":"","family":"Park","given":"Jiesuck","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cha","given":"Myung-Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"You-Jung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Euijae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moon","given":"Inki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwak","given":"Soongu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwon","given":"Soonil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Seokhun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Seoyoung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Eue-Keun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oh","given":"Seil","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart rhythm","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2019","2"]]},"language":"eng","page":"197-203","publisher-place":"United States","title":"Prognostic efficacy of platelet count in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"(90)","plainTextFormattedCitation":"(90)","previouslyFormattedCitation":"(90)"},"properties":{"noteIndex":0},"schema":""}(90). Despite limited evidence on the matter, it seems likely that a low platelet count could increase the risk of bleeding in AF.In addition to the biomarkers above, there are several others that have been associated with anticoagulation-related bleeding including vWF, high-sensitivity troponin and growth differentiation factor-15 (marker of oxidative stress). Roldan et al. showed that patients with high levels of vWF had a 4.5-fold increased risk of major bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2010.12.033","ISSN":"1558-3597 (Electronic)","PMID":"21497043","abstract":"OBJECTIVES: The purpose of this study was to evaluate the prognostic value of plasma von Willebrand factor (vWF) levels and fibrin d-dimer in a large cohort of anticoagulated permanent atrial fibrillation (AF) patients. BACKGROUND: In nonanticoagulated AF patients, plasma vWF levels have been related to stroke and vascular events. There are limited data on the prognostic role of biomarkers in anticoagulated AF patients in relation to adverse events (including thromboembolism), mortality, and major bleeding. METHODS: We studied 829 patients (50% male; median age 76 years) with permanent AF who were stabilized (for at least 6 months) on oral anticoagulation therapy (international normalized ratio: 2.0 to 3.0). Plasma d-dimer and vWF levels were quantified by enzyme-linked immunosorbent assay. Patients were followed for 2 years, and adverse events (thrombotic and vascular events, mortality, and major bleeding) were recorded. RESULTS: Patients were followed for a median of 828 days (range 18 to 1,085 days). On multivariate analysis, age 75 years and older, previous stroke, heart failure, and high plasma vWF levels (>/= 221 IU/dl) were associated with future adverse cardiovascular events (all p values <0.05). High plasma vWF levels, elderly patients, diabetes, hypercholesterolemia, and current smoking were associated with mortality (all p values <0.05). High plasma vWF levels were also an independent predictor of major bleeding (hazard ratio: 4.47, 95% confidence interval: 1.86 to 10.75; p < 0.001). High plasma vWF levels were able to refine clinical risk stratification schema for stroke (CHADS(2) [Congestive heart failure, Hypertension, Age >/= 75, Diabetes mellitus, and prior Stroke or transient ischemic attack (doubled)], CHA(2)DS(2)-VASc [Congestive heart failure, Hypertension, Age >/= 75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 to 74 years, Sex category]) and bleeding (HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly]). d-dimer did not show any significant impact on adverse events. CONCLUSIONS: High plasma vWF levels (>/=221 IU/dl) are an independent risk factor for adverse events in anticoagulated permanent AF patients. This biomarker may potentially be used to refine stroke and bleeding clinical risk stratification in AF.","author":[{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muina","given":"Begona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Torregrosa","given":"Jose Miguel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernandez-Romero","given":"Diana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"25","issued":{"date-parts":[["2011","6"]]},"language":"eng","page":"2496-2504","publisher-place":"United States","title":"Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients.","type":"article-journal","volume":"57"},"uris":[""]}],"mendeley":{"formattedCitation":"(92)","plainTextFormattedCitation":"(92)","previouslyFormattedCitation":"(92)"},"properties":{"noteIndex":0},"schema":""}(92). Using the ARISTOTLE cohort, Hijazi et al. demonstrated that both high-sensitivity troponin and growth differentiation factor-15 were the strongest predictors of major bleeding when compared to traditional risk factors such as age, haemoglobin, previous bleeding, congestive heart failure, previous stroke or TIA, hypertension and diabetes mellitus ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0140-6736(16)00741-8","ISSN":"1474-547X (Electronic)","PMID":"27056738","abstract":"BACKGROUND: The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischaemic stroke and increase in major bleeding. We aimed to develop and validate a new biomarker-based risk score to improve the prognostication of major bleeding in patients with atrial fibrillation. METHODS: We developed and internally validated a new biomarker-based risk score for major bleeding in 14,537 patients with atrial fibrillation randomised to apixaban versus warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomised to dabigatran versus warfarin in the RE-LY trial. Plasma samples for determination of candidate biomarker concentrations were obtained at randomisation. Major bleeding events were centrally adjudicated. The predictive values of biomarkers and clinical variables were assessed with Cox regression models. The most important variables were included in the score with weights proportional to the model coefficients. The ARISTOTLE and RE-LY trials are registered with , numbers NCT00412984 and NCT00262600, respectively. FINDINGS: The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0.68 [95% CI 0.66-0.70] vs 0.61 [0.59-0.63] vs 0.65 [0.62-0.67], respectively; ABC-bleeding vs HAS-BLED p<0.0001 and ABC-bleeding vs ORBIT p=0.0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0.71 [95% CI 0.68-0.73] vs 0.62 [0.59-0.64] for HAS-BLED vs 0.68 [0.65-0.70] for ORBIT; ABC-bleeding vs HAS-BLED p<0.0001 and ABC-bleeding vs ORBIT p=0.0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores. INTERPRETATION: The ABC-bleeding score, using age, history of bleeding, and three biomarkers (haemoglobin, cTn-hs, and GDF-15 or cystatin C/CKD-EPI) was internally and externally validated and calibrated in large cohorts of patients with atrial fibrillation receiving anticoagulation therapy. The …","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindback","given":"Johan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alexander","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelboom","given":"John W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Held","given":"Claes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"Renato D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindb?ck","given":"Johan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alexander","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelboom","given":"John W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Held","given":"Claes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"Renato D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindback","given":"Johan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alexander","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelboom","given":"John W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Held","given":"Claes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"Renato D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet (London, England)","id":"ITEM-1","issue":"10035","issued":{"date-parts":[["2016","6"]]},"language":"eng","page":"2302-2311","publisher-place":"England, England","title":"The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study.","type":"article-journal","volume":"387"},"uris":[""]}],"mendeley":{"formattedCitation":"(134)","plainTextFormattedCitation":"(134)","previouslyFormattedCitation":"(134)"},"properties":{"noteIndex":0},"schema":""}(134). Studies on NT-proBNP have not found it to be useful for predicting anticoagulation-related bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/STROKEAHA.113.003338","ISSN":"1524-4628 (Electronic)","PMID":"24519407","abstract":"BACKGROUND AND PURPOSE: Oral anticoagulation is highly effective in reducing stroke and mortality in atrial fibrillation (AF). Several risk stratification schemes have been developed using clinical characteristics. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) are important markers of increased mortality and morbidity in congestive heart failure and general community population. The aim of our study was to assess the predictive value of NT-proBNP levels in an unselected real-world cohort of anticoagulated patients with AF. METHODS: We studied 1172 patients (49% male; median age, 76 years) with permanent AF who were well stabilized on oral anticoagulation (international normalized ratio, 2.0-3.0). Plasma NT-proBNP levels were quantified at baseline. We recorded thrombotic and vascular events, mortality, and major bleeding. The best cutoff points were assessed by receiver-operating characteristic curves. RESULTS: Median levels (interquartile range) of NT-proBNP were 610 (318-1037) pg/mL. Median follow-up was 1007 (806-1279) days. On multivariate analysis, high NT-proBNP was significantly associated with the risk of stroke (hazards ratio, 2.71; P=0.001) and composite vascular events (acute coronary syndrome or acute heart failure; hazards ratio, 1.85; P=0.016), as well as a significant association with mortality (adjusted hazards ratio, 1.66; P=0.006). No association with bleeding was found (P=0.637). The integrated discrimination improvement (IDI) analysis demonstrated that NT-proBNP improved the Congestive heart failure, Hypertension, Age>/=75 (doubled), Diabetes mellitus, Stroke (doubled)-Vascular disease and Sex category (female); CHA2DS2-VASc score for predicting embolic events (relative IDI, 2.8%; P=0.001) and all-cause death (relative IDI, 1.8%; P=0.001). CONCLUSIONS: In real-world cohort of anticoagulated patients with AF, NT-proBNP provided complementary prognostic information to an established clinical risk score (CHA2DS2-VASc) for the prediction of stroke/systemic embolism. NT-proBNP was also predictive of all-cause mortality, suggesting that this biomarker may potentially be used to refine clinical risk stratification in anticoagulated patients with AF.","author":[{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vilchez","given":"Juan Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manzano-Fernandez","given":"Sergio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jover","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galvez","given":"Josefa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Puche","given":"Carmen M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2014","3"]]},"language":"eng","page":"696-701","publisher-place":"United States, United States","title":"Usefulness of N-terminal pro-B-type natriuretic Peptide levels for stroke risk prediction in anticoagulated patients with atrial fibrillation.","type":"article-journal","volume":"45"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jacc.2012.11.082","ISSN":"1558-3597 (Electronic)","PMID":"23563134","abstract":"OBJECTIVES: This study sought to assess the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and the treatment effect of apixaban according to NT-proBNP levels. BACKGROUND: Natriuretic peptides are associated with mortality and cardiovascular events in several cardiac diseases. METHODS: In the ARISTOTLE trial, 18,201 patients with AF were randomized to apixaban or warfarin. Plasma samples at randomization were available from 14,892 patients. The association between NT-proBNP concentrations and clinical outcomes was evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors. RESULTS: Quartiles of NT-proBNP were: Q1, </=363 ng/l; Q2, 364 to 713 ng/l; Q3, 714 to 1,250 ng/l; and Q4, >1,250 ng/l. During 1.9 years, the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile, an adjusted hazard ratio of 2.35 (95% confidence interval [CI]: 1.62 to 3.40; p < 0.0001). Annual rates of cardiac death ranged from 0.86% in Q1 to 4.14% in Q4, with an adjusted hazard ratio of 2.50 (95% CI: 1.81 to 3.45; p < 0.0001). Adding NT-proBNP levels to the CHA2DS2VASc score improved C-statistics from 0.62 to 0.65 (p = 0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p < 0.0001). Apixaban reduced stroke, mortality, and bleeding regardless of the NT-proBNP level. CONCLUSIONS: NT-proBNP levels are often elevated in AF and independently associated with an increased risk of stroke and mortality. NT-proBNP improves risk stratification beyond the CHA2DS2VASc score and might be a novel tool for improved stroke prediction in AF. The efficacy of apixaban compared with warfarin is independent of the NT-proBNP level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984).","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christersson","given":"Christina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Justin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gersh","given":"Bernard J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanna","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horowitz","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huber","given":"Kurt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"Renato D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"McMurray","given":"John J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-2","issue":"22","issued":{"date-parts":[["2013","6"]]},"language":"eng","page":"2274-2284","publisher-place":"United States, United States","title":"N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation).","type":"article-journal","volume":"61"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1161/CIRCULATIONAHA.111.038729","ISSN":"1524-4539 (Electronic)","PMID":"22374183","abstract":"BACKGROUND: Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. METHODS AND RESULTS: Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS(2) and CHA(2)DS(2)-VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 mug/L, n=2663; 0.010 to 0.019 mug/L, n=2006; 0.020 to 0.039 mug/L, n=1023; >/=0.040 mug/L, n=497; and on NT-proBNP concentration quartiles: <387; 387 to 800; 801 to 1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17-3.39]; P=0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41-4.07]; P=0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05-6.29]; P<0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95-11.49]; P<0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P<0.0001, for a composite of thromboembolic events. CONCLUSIONS: Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables.","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reilly","given":"Paul A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinereanu","given":"Dragos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-3","issue":"13","issued":{"date-parts":[["2012","4"]]},"language":"eng","page":"1605-1616","publisher-place":"United States, United States","title":"Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy.","type":"article-journal","volume":"125"},"uris":[""]}],"mendeley":{"formattedCitation":"(56–58)","plainTextFormattedCitation":"(56–58)","previouslyFormattedCitation":"(56–58)"},"properties":{"noteIndex":0},"schema":""}(56–58). Overall, there is limited research to support the ‘real world’ role of these biomarkers in relation to bleeding risk assessment, given that bleeding risk is dynamic and changes with addressing modifiable risks, and that many biomarkers are non-specific and likely to reflect a sick patient or ‘sick heart’.Genetic markersPolymorphism of cytochrome P450 2C9 has been linked to an increased risk of major bleeding through its effects on the metabolism and action of warfarin ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2165/00003088-200140080-00003","ISSN":"0312-5963 (Print)","PMID":"11523725","abstract":"Warfarin is one of the most widely prescribed oral anticoagulants. However, optimal use of the drug has been hampered by its >10-fold interpatient variability in the doses required to attain therapeutic responses. Pharmacogenetic polymorphism of cytochrome P450 (CYP) may be associated with impaired elimination of warfarin and exaggerated anticoagulatory responses to the drug in certain patients. Clinically available warfarin is a racemic mixture of (R)- and (S)-warfarin, and the (S)-enantiomer has 3 to 5 times greater anticoagulation potency than its optical congener. Both enantiomers are eliminated extensively via hepatic metabolism with low clearance relative to hepatic blood flow. CYP2C9 is almost exclusively responsible for the metabolism of the pharmacologically more active (S)-enantiomer. Several human allelic variants of CYP2C9 have been cloned, designated as CYP2C9*1 (reference sequence or wild-type allele), CYP2C9*2, CYP2C9*3 and CYP2C9*4, respectively. The allelic frequencies for these variants differ considerably among different ethnic populations. Caucasians appear to carry the CYP 2C9*2 (8 to 20%) and CYP2C9*3 (6 to 10%) variants more frequently than do Asians (0% and 2 to 5%, respectively). The metabolic activities of the CYP2C9 variants have been investigated in vitro. The catalytic activity of CYP2C9*3 expressed from cDNA was significantly less than that of CYP2C9*1. Human liver microsomes obtained from individuals heterozygous for CYP2C9*3 showed significantly reduced (S)-warfarin 7-hydroxylation as compared with those obtained from individuals genotyped as CYP2C9*1. The influence of the CYP2C9*3 allele on the in vivo pharmacokinetics of (S)-warfarin has been studied in Japanese patients. Patients with the homozygous CYP2C9*3 genotype, as well as those with the heterozygous CYP2C9*1/*3 genotype, had significantly reduced clearance of (S)-warfarin (by 90 and 60%, respectively) compared with those with homozygous CYP2C9*1. The maintenance dosages of warfarin required in Japanese patients with heterozygous and homozygous CYP2C9*3 mutations were significantly lower than those in patients with CYP2C9*1/*1. In addition, 86% of British patients exhibiting adequate therapeutic responses with lower maintenance dosages of warfarin (<1.5 mg/day) had either the CYP2C9*2 or CYP2C9*3 mutation singly or in combination, whereas only 38% of randomly selected patients receiving warfarin carried the corresponding mutations. Furthermore, the former group s…","author":[{"dropping-particle":"","family":"Takahashi","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Echizen","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical pharmacokinetics","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2001"]]},"language":"eng","page":"587-603","publisher-place":"Switzerland, Switzerland","title":"Pharmacogenetics of warfarin elimination and its clinical implications.","type":"article-journal","volume":"40"},"uris":[""]}],"mendeley":{"formattedCitation":"(171)","plainTextFormattedCitation":"(171)","previouslyFormattedCitation":"(171)"},"properties":{"noteIndex":0},"schema":""}(171). It may also have important implications on warfarin dose requirements ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00228-008-0584-5","ISSN":"1432-1041 (Electronic)","PMID":"19031075","abstract":"PURPOSE: To quantify the influence of common cytochrome P450 2C9 (CYP2C9) polymorphisms on warfarin dose requirements. METHODS: A systematic review and a meta-analysis, calculating the warfarin dose reduction associated with the five most common variant CYP2C9 genotypes. RESULTS: Thirty-nine studies (7,907 patients) were included in the meta-analysis. Compared to the CYP2C9*1/*1 genotype, the CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 required warfarin doses that were 19.6 (95% confidence interval 17.4, 21.9), 33.7 (29.4, 38.1), 36.0 (29.9, 42.0), 56.7 (49.1, 64.3), and 78.1% (72.0, 84.3) lower, respectively. The impact of CYP2C9 genotype tended to be larger in patients without interacting drugs. CONCLUSIONS: Previous studies have rarely been powered to determine the quantitative influence of specific CYP2C9 genotypes on warfarin dose requirements. The results from our pooled analysis are likely to be the most accurate to date and the methodology could serve as a model for future pharmacogenetic meta-analyses.","author":[{"dropping-particle":"","family":"Lindh","given":"Jonatan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holm","given":"Lennart","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Marine L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rane","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European journal of clinical pharmacology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2009","4"]]},"language":"eng","page":"365-375","publisher-place":"Germany, Germany","title":"Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis.","type":"article-journal","volume":"65"},"uris":[""]}],"mendeley":{"formattedCitation":"(172)","plainTextFormattedCitation":"(172)","previouslyFormattedCitation":"(172)"},"properties":{"noteIndex":0},"schema":""}(172). However, as mentioned above, there is currently limited evidence on the role for genetic markers in AF.Limitations of risk scoresRisk scores are useful as they provide a rapid tool to guide treatment decisions in AF and highlight bleeding risk factors that deserve attention. However, it is important to recognise that the risk scores in AF have been simplified to provide physicians with a reliable yet useable tool for daily clinical practice. As a result, most are subject to several limitations and are at best, only modestly robust at predicting individual stroke risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehy731","ISSN":"1522-9645 (Electronic)","PMID":"30508086","abstract":"Despite the demonstrable success of oral anticoagulants in reducing the rate of stroke in patients with atrial fibrillation, they continue to be seriously underutilized. Indications for their use as stated in the guidelines incorporate a number of risk score algorithms, the most widely used being the CHA2DS2-VASc score. Nonetheless there are several limitations to the various scores currently in clinical use and a critique of these is the focus of this review. In this review we discuss the pathophysiology of atrial fibrillation and its role in thromboembolic stroke risk. We amalgamate this with the basis of major professional society anticoagulation recommendations with regards to the strengths and limitations of current risk stratification strategies and discuss gaps in our current evidence base and next steps to address those gaps.","author":[{"dropping-particle":"","family":"Killu","given":"Ammar M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gersh","given":"Bernard J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"16","issued":{"date-parts":[["2019","4"]]},"language":"eng","page":"1294-1302","publisher-place":"England, England","title":"Risk stratification for stroke in atrial fibrillation: a critique.","type":"article-journal","volume":"40"},"uris":[""]}],"mendeley":{"formattedCitation":"(173)","plainTextFormattedCitation":"(173)","previouslyFormattedCitation":"(173)"},"properties":{"noteIndex":0},"schema":""}(173). First, not all risk factors may be included in certain risk scores. Second, they use a ‘one size fits all’ approach and do not account for the heterogenous nature within the AF population. Third, they fail to adequately consider the differential weight of individual risk factors. Fourth, they fail to consider the degree or severity of individual risk factors. Fifth, many risk scores were developed using older definition of diseases that may have subsequently evolved over time. Finally, studies have often correlated stroke occurrences during long periods of follow-up to risk factors measured at baseline, and risk changes with increasing age and incident risk factors. Indeed, recent attention has been directed towards the dynamic nature of risk profiles in AF patients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1055/s-0038-1636534","ISSN":"2567-689X (Electronic)","PMID":"29510426","abstract":"AIM: When assessing bleeding risk in patients with atrial fibrillation (AF), risk stratification is often based on the baseline risks. We aimed to investigate changes in bleeding risk factors and alterations in the HAS-BLED score in AF patients. We hypothesized that a follow-up HAS-BLED score and the 'delta HAS-BLED score' (reflecting the change in score between baseline and follow-up) would be more predictive of major bleeding, when compared with baseline HAS-BLED score. METHODS AND RESULTS: A total of 19,566 AF patients receiving warfarin and baseline HAS-BLED score </=2 were studied. After a follow-up of 93,783 person-years, 3,032 major bleeds were observed. The accuracies of baseline, follow-up, and delta HAS-BLED scores as well as cumulative numbers of baseline modifiable bleeding risk factors, in predicting subsequent major bleeding, were analysed and compared. The mean baseline HAS-BLED score was 1.43 which increased to 2.45 with a mean 'delta HAS-BLED score' of 1.03. The HAS-BLED score remained unchanged in 38.2% of patients. Of those patients experiencing major bleeding, 76.6% had a 'delta HAS-BLED' score >/=1, compared with only 59.0% in patients without major bleeding (p < 0.001). For prediction of major bleeding, AUC was significantly higher for the follow-up HAS-BLED (0.63) or delta HAS-BLED (0.62) scores, compared with baseline HAS-BLED score (0.54). The number of baseline modifiable risk factors was non-significantly predictive of major bleeding (AUC = 0.49). CONCLUSION: In this 'real-world' nationwide AF cohort, follow-up HAS-BLED or 'delta HAS-BLED score' was more predictive of major bleeding compared with baseline HAS-BLED or the simple determination of 'modifiable bleeding risk factors'. Bleeding risk in AF is a dynamic process and use of the HAS-BLED score should be to 'flag up' patients potentially at risk for more regular review and follow-up, and to address the modifiable bleeding risk factors during follow-up visits.","author":[{"dropping-particle":"","family":"Chao","given":"Tze-Fan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Yenn-Jiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Shih-Lin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lo","given":"Li-Wei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Yu-Feng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuan","given":"Ta-Chuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liao","given":"Jo-Nan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Fa-Po","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Tzeng-Ji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Shih-Ann","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2018","4"]]},"language":"eng","page":"768-777","publisher-place":"Germany","title":"Incident Risk Factors and Major Bleeding in Patients with Atrial Fibrillation Treated with Oral Anticoagulants: A Comparison of Baseline, Follow-up and Delta HAS-BLED Scores with an Approach Focused on Modifiable Bleeding Risk Factors.","type":"article-journal","volume":"118"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1055/s-0038-1651482","ISSN":"2567-689X (Electronic)","PMID":"29723875","abstract":"BACKGROUND: Stroke risk in atrial fibrillation (AF) is often assessed at initial presentation, and risk stratification performed as a 'one off'. In validation studies of risk prediction, baseline values are often used to 'predict' events that occur many years later. Many clinical variables have 'dynamic' changes over time, as the patient is followed up. These dynamic changes in risk factors may increase the CHA2DS2-VASc score, stroke risk category and absolute ischaemic stroke rate. OBJECTIVE: This article evaluates the 'dynamic' changes of CHA2DS2-VASc variables and its effect on prediction of stroke risk. PATIENTS AND METHODS: From the Korea National Health Insurance Service database, a total of 167,262 oral anticoagulant-naive non-valvular AF patients aged >/= 18 years old were enrolled between January 1, 2002, and December 31, 2005. These patients were followed up until December 31, 2015. RESULTS: At baseline, the proportions of subjects categorized as 'low', 'intermediate' or 'high risk' by CHA2DS2-VASc score were 15.4, 10.6 and 74.0%, respectively. Mean CHA2DS2-VASc score increased annually by 0.14, particularly due to age and hypertension. During follow-up of 10 years, 46.6% of 'low-risk' patients and 72.0% of 'intermediate risk' patients were re-classified to higher stroke risk categories. Among the original 'low-risk' patients, annual ischaemic stroke rates were significantly higher in the re-classified 'intermediate' (1.17 per 100 person-years, p < 0.001) or re-classified 'high-risk' groups (1.44 per 100 person-years, p = 0.048) than consistently 'low-risk' group (0.29 per 100 person-years). The most recent CHA2DS2-VASc score and the score change with the longest follow-up had the best prediction for ischaemic stroke. CONCLUSION: In AF patients, stroke risk as assessed by the CHA2DS2-VASc score is dynamic and changes over time. Rates of ischaemic stroke increased when patients accumulated risk factors, and were re-classified into higher CHA2DS2-VASc score categories. Stroke risk assessment is needed at every patient contact, as accumulation of risk factors with increasing CHA2DS2-VASc score translates to greater stroke risks over time.","author":[{"dropping-particle":"","family":"Yoon","given":"Minjae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Pil-Sung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jang","given":"Eunsun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Hee Tae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Tae-Hoon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Uhm","given":"Jae-Sun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Jong-Youn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pak","given":"Hui-Nam","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Moon-Hyoung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Joung","given":"Boyoung","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2018","7"]]},"language":"eng","page":"1296-1304","publisher-place":"Germany","title":"Dynamic Changes of CHA2DS2-VASc Score and the Risk of Ischaemic Stroke in Asian Patients with Atrial Fibrillation: A Nationwide Cohort Study.","type":"article-journal","volume":"118"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.jacc.2017.10.085","ISSN":"1558-3597 (Electronic)","PMID":"29325634","abstract":"BACKGROUND: When assessing ischemic stroke risk in patients with atrial fibrillation (AF), the CHA2DS2-VASc score is calculated based on the baseline risk factors, and the outcomes are determined after a follow-up period. However, the stroke risk in patients with AF does not remain static, and with time, patients get older and accumulate more comorbidities. OBJECTIVES: This study hypothesized that the \"Delta CHA2DS2-VASc score,\" which reflects the change in score between baseline and follow-up, would be more predictive of ischemic stroke compared with the baseline CHA2DS2-VASc score. METHODS: A total of 31,039 patients with AF who did not receive antiplatelet agents or oral anticoagulants, and who did not have comorbidities of the CHA2DS2-VASc score except for age and sex, were studied. The Delta CHA2DS2-VASc scores were defined as the differences between the baseline and follow-up CHA2DS2-VASc scores. During 171,956 person-years, 4,103 patients experienced ischemic stroke. The accuracies of baseline, follow-up, and Delta CHA2DS2-VASc scores in predicting ischemic stroke were analyzed and compared. RESULTS: The mean baseline CHA2DS2-VASc score was 1.29, which increased to 2.31 during the follow-up, with a mean Delta CHA2DS2-VASc score of 1.02. The CHA2DS2-VASc score remained unchanged in only 40.8% of patients. Among 4,103 patients who experienced ischemic stroke, 89.4% had a Delta CHA2DS2-VASc score >/=1 compared with only 54.6% in patients without ischemic stroke, and 2,643 (64.4%) patients had >/=1 new-onset comorbidity, the most common being hypertension. The Delta CHA2DS2-VASc score was a significant predictor of ischemic stroke that performed better than baseline or follow-up CHA2DS2-VASc scores, as assessed by the C-index and the net reclassification index. CONCLUSIONS: In this AF cohort, the authors demonstrated that the CHA2DS2-VASc score was not static, and that most patients with AF developed >/=1 new stroke risk factor before presentation with ischemic stroke. The Delta CHA2DS2-VASc score, reflecting the change in score between baseline and follow-up, was strongly predictive of ischemic stroke, reflecting how stroke risk in AF is a dynamic process due to increasing age and incident comorbidities.","author":[{"dropping-particle":"","family":"Chao","given":"Tze-Fan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Chia-Jen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Yenn-Jiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Shih-Lin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lo","given":"Li-Wei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Yu-Feng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuan","given":"Ta-Chuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liao","given":"Jo-Nan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Fa-Po","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Tzeng-Ji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Shih-Ann","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-3","issue":"2","issued":{"date-parts":[["2018","1"]]},"language":"eng","page":"122-132","publisher-place":"United States","title":"Relationship of Aging and Incident Comorbidities to Stroke Risk in Patients With Atrial Fibrillation.","type":"article-journal","volume":"71"},"uris":[""]}],"mendeley":{"formattedCitation":"(174–176)","plainTextFormattedCitation":"(174–176)","previouslyFormattedCitation":"(174–176)"},"properties":{"noteIndex":0},"schema":""}(174–176). Chao et al. found the majority of patients with AF (89.4%) developed ≥1 new risk factor(s) prior to presenting with an ischaemic stroke ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2017.10.085","ISSN":"1558-3597 (Electronic)","PMID":"29325634","abstract":"BACKGROUND: When assessing ischemic stroke risk in patients with atrial fibrillation (AF), the CHA2DS2-VASc score is calculated based on the baseline risk factors, and the outcomes are determined after a follow-up period. However, the stroke risk in patients with AF does not remain static, and with time, patients get older and accumulate more comorbidities. OBJECTIVES: This study hypothesized that the \"Delta CHA2DS2-VASc score,\" which reflects the change in score between baseline and follow-up, would be more predictive of ischemic stroke compared with the baseline CHA2DS2-VASc score. METHODS: A total of 31,039 patients with AF who did not receive antiplatelet agents or oral anticoagulants, and who did not have comorbidities of the CHA2DS2-VASc score except for age and sex, were studied. The Delta CHA2DS2-VASc scores were defined as the differences between the baseline and follow-up CHA2DS2-VASc scores. During 171,956 person-years, 4,103 patients experienced ischemic stroke. The accuracies of baseline, follow-up, and Delta CHA2DS2-VASc scores in predicting ischemic stroke were analyzed and compared. RESULTS: The mean baseline CHA2DS2-VASc score was 1.29, which increased to 2.31 during the follow-up, with a mean Delta CHA2DS2-VASc score of 1.02. The CHA2DS2-VASc score remained unchanged in only 40.8% of patients. Among 4,103 patients who experienced ischemic stroke, 89.4% had a Delta CHA2DS2-VASc score >/=1 compared with only 54.6% in patients without ischemic stroke, and 2,643 (64.4%) patients had >/=1 new-onset comorbidity, the most common being hypertension. The Delta CHA2DS2-VASc score was a significant predictor of ischemic stroke that performed better than baseline or follow-up CHA2DS2-VASc scores, as assessed by the C-index and the net reclassification index. CONCLUSIONS: In this AF cohort, the authors demonstrated that the CHA2DS2-VASc score was not static, and that most patients with AF developed >/=1 new stroke risk factor before presentation with ischemic stroke. The Delta CHA2DS2-VASc score, reflecting the change in score between baseline and follow-up, was strongly predictive of ischemic stroke, reflecting how stroke risk in AF is a dynamic process due to increasing age and incident comorbidities.","author":[{"dropping-particle":"","family":"Chao","given":"Tze-Fan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Chia-Jen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Yenn-Jiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Shih-Lin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lo","given":"Li-Wei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Yu-Feng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuan","given":"Ta-Chuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liao","given":"Jo-Nan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Fa-Po","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Tzeng-Ji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Shih-Ann","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2018","1"]]},"language":"eng","page":"122-132","publisher-place":"United States","title":"Relationship of Aging and Incident Comorbidities to Stroke Risk in Patients With Atrial Fibrillation.","type":"article-journal","volume":"71"},"uris":[""]}],"mendeley":{"formattedCitation":"(176)","plainTextFormattedCitation":"(176)","previouslyFormattedCitation":"(176)"},"properties":{"noteIndex":0},"schema":""}(176). Indeed, a change in CHA2DS2-VASc score was demonstrated to be strongly predictive of ischaemic stroke. The study highlights the importance of regular stroke risk assessments in AF. Therefore, stroke and bleeding risk stratification should be undertaken by clinicians as a continuous process with specific focus on preventing the development of additional risk factors. Furthermore, in addition to the dynamic nature of risk, therapeutic options for AF are expanding. As more effective and safer therapies are introduced, we may need to re-evaluate the threshold for initiating anticoagulation.ConclusionIn conclusion, there are a variety of clinical, electrical, biological and genetic markers to guide stroke and bleeding risk assessments in AF. Furthermore, risk schemas provide a structured, standardised and rapid tool for this purpose.DisclosuresWYD and SLH: None declared. DG: Speaker for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Biosense Webster and Boston Scientific. Proctor for Abbott. Research Grants from Medtronic, Biosense Webster and Boston Scientific.GYHL: Consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are directly received personally.DL has received investigator-initiated educational grants from Bristol-Myers Squibb and Boehringer Ingelheim; has been a speaker for Boehringer Ingelheim, Bayer, and Bristol-Myers Squibb/Pfizer; and has consulted for Bristol-Myers Squibb, Bayer, Boehringer Ingelheim, and Daiichi-Sankyo.? The funders had NO role in the submitted paper. All authors declare no conflict of interest.ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. 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Racial/ethnic disparities in mortality by stroke subtype in the United States, 1995-1998. Am J Epidemiol. 2001 Dec;154(11):1057–63. 152. Yamashita Y, Morimoto T, Toyota T, Shiomi H, Makiyama T, Ono K, et al. Asian patients versus non-Asian patients in the efficacy and safety of direct oral anticoagulants relative to vitamin K antagonist for venous thromboembolism: A systemic review and meta-analysis. Thromb Res. 2018 Jun;166:37–42. 153. Patel JP, Roberts LN, Arya R. Anticoagulating obese patients in the modern era. Br J Haematol. 2011 Oct;155(2):137–49. 154. Zhou Y, Ma J, Zhu W. Efficacy and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation Across BMI Categories: A Systematic Review and Meta-Analysis. Am J Cardiovasc Drugs. 2019 Jul; 155. Boonyawat K, Caron F, Li A, Chai-Adisaksopha C, Lim W, Iorio A, et al. Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis. J Thromb Haemost. 2017 Jul;15(7):1322–33. 156. Proietti M, Guiducci E, Cheli P, Lip GYH. Is There an Obesity Paradox for Outcomes in Atrial Fibrillation? A Systematic Review and Meta-Analysis of Non-Vitamin K Antagonist Oral Anticoagulant Trials. Stroke. 2017 Apr;48(4):857–66. 157. Tittl L, Endig S, Marten S, Reitter A, Beyer-Westendorf I, Beyer-Westendorf J. Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119). Int J Cardiol. 2018 Jul;262:85–91. 158. Hart R, Veenstra DL, Boudreau DM, Roth JA. Impact of Body Mass Index and Genetics on Warfarin Major Bleeding Outcomes in a Community Setting. Am J Med. 2017 Feb;130(2):222–8. 159. Oden A, Fahlen M, Odén A, Fahlén M, Oden A, Fahlen M. Oral anticoagulation and risk of death: A medical record linkage study. Br Med J. 2002 Nov;325(7372):1073–5. 160. Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J. Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage. Stroke. 2000 Nov;31(11):2558–62. 161. Sanden P, Renlund H, Svensson PJ, Sjalander A. Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR. Thromb Haemost. 2017 Jan;117(1):27–32. 162. Bjorck F, Renlund H, Lip GYH, Wester P, Svensson PJ, Sjalander A. Outcomes in a Warfarin-Treated Population With Atrial Fibrillation. JAMA Cardiol. 2016 May;1(2):172–80. 163. Rivera-Caravaca JM, Roldan V, Esteve-Pastor MA, Valdes M, Vicente V, Lip GYH, et al. Importance of time in therapeutic range on bleeding risk prediction using clinical risk scores in patients with atrial fibrillation. Sci Rep. 2017 Sep;7(1):12066. 164. Van Den Ham HA, Klungel OH, Leufkens HGM, Van Staa TP. The patterns of anticoagulation control and the risk of stroke, bleeding and mortality in patients with non-valvular atrial fibrillation. J Thromb Haemost. 2013 Jan;11(1):107–15. 165. Hylek EM. Vitamin K antagonists and time in the therapeutic range: implications, challenges, and strategies for improvement. J Thromb Thrombolysis. 2013 Apr;35(3):333–5. 166. Rohla M, Weiss TW, Pecen L, Patti G, Siller-Matula JM, Schnabel RB, et al. Risk factors for thromboembolic and bleeding events in anticoagulated patients with atrial fibrillation: the prospective, multicentre observational PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF). BMJ Open. 2019 Mar;9(3):e022478. 167. Sakuma I, Uchiyama S, Atarashi H, Inoue H, Kitazono T, Yamashita T, et al. Clinical risk factors of stroke and major bleeding in patients with non-valvular atrial fibrillation under rivaroxaban: the EXPAND Study sub-analysis. Heart Vessels. 2019 May; 168. Westenbrink BD, Alings M, Connolly SJ, Eikelboom J, Ezekowitz MD, Oldgren J, et al. Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial. J Thromb Haemost. 2015 May;13(5):699–707. 169. Weiss HJ, Lages B, Hoffmann T, Turitto VT. Correction of the platelet adhesion defect in delta-storage pool deficiency at elevated hematocrit--possible role of adenosine diphosphate. Blood. 1996 May;87(10):4214–22. 170. Hijazi Z, Aulin J, Andersson U, Alexander JH, Gersh B, Granger CB, et al. Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation. Heart. 2016 Apr;102(7):508–17. 171. Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet. 2001;40(8):587–603. 172. Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis. Eur J Clin Pharmacol. 2009 Apr;65(4):365–75. 173. Killu AM, Granger CB, Gersh BJ. Risk stratification for stroke in atrial fibrillation: a critique. Eur Heart J. 2019 Apr;40(16):1294–302. 174. Chao T-F, Lip GYH, Lin Y-J, Chang S-L, Lo L-W, Hu Y-F, et al. Incident Risk Factors and Major Bleeding in Patients with Atrial Fibrillation Treated with Oral Anticoagulants: A Comparison of Baseline, Follow-up and Delta HAS-BLED Scores with an Approach Focused on Modifiable Bleeding Risk Factors. Thromb Haemost. 2018 Apr;118(4):768–77. 175. Yoon M, Yang P-S, Jang E, Yu HT, Kim T-H, Uhm J-S, et al. Dynamic Changes of CHA2DS2-VASc Score and the Risk of Ischaemic Stroke in Asian Patients with Atrial Fibrillation: A Nationwide Cohort Study. Thromb Haemost. 2018 Jul;118(7):1296–304. 176. Chao T-F, Lip GYH, Liu C-J, Lin Y-J, Chang S-L, Lo L-W, et al. Relationship of Aging and Incident Comorbidities to Stroke Risk in Patients With Atrial Fibrillation. J Am Coll Cardiol. 2018 Jan;71(2):122–32. 177. Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011 Jul;58(4):395–401. 178. Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, et al. Clinical classification schemes for predicting hemorrhage: Results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006 Mar;151(3):713–9. Figure LegendCentral illustration of risk factors associated with stroke in AFAF, atrial fibrillation; eGFR, estimated glomerular filtration rate; IL-6, interleukin-6; LA, left atrial; LAA, left atrial appendage; LV, left ventricle; MMP-2, matrix metalloproteinase-2; NOX2, reduced nicotinamide adenine dinucleotide phosphate oxidase 2; sCD40L, soluble CD40 ligand; SR, sinus rhythm; TE, thromboembolism; TIA, transient ischaemic attack; tPA, tissue plasminogen activator; vWF, von Willebrand factor.* Dashed lines indicate possible risk factors and the size of individual shapes reflect the degree of risk (Created with BioRender)TablesRisk factors for stroke in AFRisk factorPossible risk factorClinical markersPrior stroke, TIA or TEVascular disease+Increasing ageCongestive heart failureHypertensionDiabetes mellitusFemale sex* Electrical markersAF burdenCardioversion to SRAF typeAF morphologyBiological markersBlood markersTroponins I and TBNP and NT-proBNPReduced eGFRD-dimerInterleukin-6von Willebrand factorMean platelet volumeMMP-2NOX2-derived peptideSoluble CD40 ligandTumour necrosis factor-αtPAβ-thromboglobulinUrine markersAlbuminuriaProstaglandin F2α11-dehydro-thromboxane B2Imaging markersLAA thrombiLA spontaneous echo contrastLAA flow velocityLAA morphologyLV dysfunctionLA enlargementLA fibrosisLAA dimensionsComplex aortic plaqueGenetic markerGenetic variants on chromosome 4q25FGB 455 G/A polymorphism~AF, atrial fibrillation; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; LA, left atrial; LAA, left atrial appendage; LV, left ventricle; MMP-2, matrix metalloproteinase-2; NOX2, reduced nicotinamide adenine dinucleotide phosphate oxidase 2; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SR, sinus rhythm; TE, thromboembolism; TIA, transient ischaemic attack; tPA, tissue plasminogen activator.*Risk modifier+Includes prior myocardial infarction, peripheral artery disease, or aortic plaqueElectrical markers relating to AF and stroke riskStudy, year (ref)DesignStudy populationn% male; mean (SD) or median (IQR) age, yearsRelevant outcome measuresFollow-up durationElectrical markerFindingsChu, 2019 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.hrtlng.2019.07.007","ISSN":"01479563","PMID":"31376922","abstract":"BACKGROUND: Atrial fibrillation (AF) burden might link to increased risk of systemic embolism. Current scoring systems for evaluating stroke risks such as CHA2DS2-VASc do not incorporate AF burden partly because of the difficulty to assess these data. Patients with dual-chamber pacemakers implanted have opportunities to acquire incidence and duration of AF. OBJECTIVES: We aimed to evaluate the AF burden and its association with thromboembolism in patients with dual-chamber pacemakers. METHODS: This retrospective cohort study enrolled patients who underwent dual-chamber pacemaker implantation at our center between October 2003 and May 2017. We excluded patients with prior thromboembolism or receiving anticoagulants. The incidence and duration of pacemaker-detected AF were compared between patients with and without thromboembolic outcomes. Propensity score matching (1:1) was conducted based on clinical characteristics. Multivariate regressions were performed to determine the predictors of thromboembolic outcomes. Survival free from stroke and thromboembolism was assessed using Kaplan-Meier analysis in groups with different AF burden. RESULTS: Among the 152 patients enrolled (43.4% women; age 73.2+/-13.3 years), ten experienced thromboembolic events within a median follow-up of 67 months. Patients with thromboembolisms had higher CHA2DS2-VASc scores but not higher AF burden. Higher CHA2DS2-VASc score was associated with increased risk for systemic thromboembolism [hazard ratio (HR), 1.87; 95% confidence interval (CI), 1.07-3.24; P=0.027). In the propensity score-matched cohort with comparable CHA2DS2-VASc score, patients with thromboembolism had higher AF burden. Pacemaker-detected AF was associated with increased risk for thromboembolism (propensity-adjusted HR, 9.33; 95% CI, 1.19-72.99; P=0.033). Experiencing AF episodes lasting >6 min was a predictor of significantly higher risk of future stroke or thromboembolism (propensity-adjusted HR, 6.75; 95% CI, 1.30-35.11; P=0.023). CONCLUSION: In patients with dual-chamber pacemakers and comparable CHA2DS2-VASc score, pacemaker-detected AF burden is associated with elevated risk for thromboembolism. Further research is needed to clarify how pacemaker-detected AF burden could incorporate with CHA2DS2-VASc score variables and help to guide anticoagulation.","author":[{"dropping-particle":"","family":"Chu","given":"Song-Yun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiang","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Yu-Ling","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheng","given":"Qin-Hui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhou","given":"Jing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ding","given":"Yan-Sheng","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart & Lung","id":"ITEM-1","issued":{"date-parts":[["2019","7"]]},"language":"eng","publisher":"Elsevier Inc.","publisher-place":"United States, United States","title":"Pacemaker-detected atrial fibrillation burden and risk of ischemic stroke or thromboembolic events—A cohort study","type":"article-journal","volume":"000"},"uris":[""]}],"mendeley":{"formattedCitation":"(45)","plainTextFormattedCitation":"(45)","previouslyFormattedCitation":"(45)"},"properties":{"noteIndex":0},"schema":""}(45)Retrospective cohortUndergoing pacemaker implantation15256.4;73.2 (13.3)Ischaemic stroke, TIA or SE67 monthsAF burdenHigher AF burden was associated with greater risk of ischaemic stroke, TIA or SEGo, 2018 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1001/jamacardio.2018.1176","ISSN":"2380-6591 (Electronic)","PMID":"29799942","abstract":"Importance: Atrial fibrillation is a potent risk factor for stroke, but whether the burden of atrial fibrillation in patients with paroxysmal atrial fibrillation independently influences the risk of thromboembolism remains controversial. Objective: To determine if the burden of atrial fibrillation characterized using noninvasive, continuous ambulatory monitoring is associated with the risk of ischemic stroke or arterial thromboembolism in adults with paroxysmal atrial fibrillation. Design, Setting, and Participants: This retrospective cohort study conducted from October 2011 and October 2016 at 2 large integrated health care delivery systems used an extended continuous cardiac monitoring system to identify adults who were found to have paroxysmal atrial fibrillation on 14-day continuous ambulatory electrocardiographic monitoring. Exposures: The burden of atrial fibrillation was defined as the percentage of analyzable wear time in atrial fibrillation or flutter during the up to 14-day monitoring period. Main Outcomes and Measures: Ischemic stroke and other arterial thromboembolic events occurring while patients were not taking anticoagulation were identified through November 2016 using electronic medical records and were validated by manual review. We evaluated the association of the burden of atrial fibrillation with thromboembolism while not taking anticoagulation after adjusting for the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) or CHA2DS2-VASc stroke risk scores. Results: Among 1965 adults with paroxysmal atrial fibrillation, the mean (SD) age was 69 (11.8) years, 880 (45%) were women, 496 (25%) were persons of color, the median ATRIA stroke risk score was 4 (interquartile range [IQR], 2-7), and the median CHA2DS2-VASc score was 3 (IQR, 1-4). The median burden of atrial fibrillation was 4.4% (IQR ,1.1%-17.23%). Patients with a higher burden of atrial fibrillation were less likely to be women or of Hispanic ethnicity, but had more prior cardioversion attempts compared with those who had a lower burden. After adjusting for either ATRIA or CHA2DS2-VASc stroke risk scores, the highest tertile of atrial fibrillation burden (>/=11.4%) was associated with a more than 3-fold higher adjusted rate of thromboembolism while not taking anticoagulants (adjusted hazard ratios, 3.13 [95% CI, 1.50-6.56] and 3.16 [95% CI, 1.51-6.62], respectively) compared with the combined lower 2 tertiles of atrial fibrillation burden. Results were consistent ac…","author":[{"dropping-particle":"","family":"Go","given":"Alan S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reynolds","given":"Kristi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Jingrong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gupta","given":"Nigel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lenane","given":"Judith","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sung","given":"Sue Hee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harrison","given":"Teresa N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Taylor I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Solomon","given":"Matthew D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA cardiology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2018","7"]]},"language":"eng","page":"601-608","publisher-place":"United States, United States","title":"Association of Burden of Atrial Fibrillation With Risk of Ischemic Stroke in Adults With Paroxysmal Atrial Fibrillation: The KP-RHYTHM Study.","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"(44)","plainTextFormattedCitation":"(44)","previouslyFormattedCitation":"(44)"},"properties":{"noteIndex":0},"schema":""}(44)Retrospective cohortAF on 14-day ambulatory ECG monitoring1,96555.2;68.8 (11.8)Ischaemic stroke and SENA (retrospective)AF burdenHigher AF burden was associated with greater risk of ischaemic stroke or SELink, 2017 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCEP.116.004267","ISSN":"19413084","PMID":"28077507","abstract":"Background - Whether the pattern of atrial fibrillation (AF) modifies the risk/benefit of anticoagulation is controversial. In ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48), the factor Xa inhibitor edoxaban was noninferior to warfarin in preventing stroke or systemic embolic events and significantly reduced bleeding and cardiovascular mortality. However, detailed analyses by AF pattern have not been reported. Methods and Results - The 21 105 patients were categorized as having paroxysmal (<7 days duration), persistent (≥7 days but <1 year), or permanent (≥1 year or failed cardioversion) AF patterns at randomization. Efficacy and safety outcomes were evaluated during the 2.8 years median follow-up and compared by AF pattern. The primary end point of stroke/systemic embolic event was lower in those patients with paroxysmal AF (1.49%/year), compared with persistent (1.83%/year; P-adj =0.015) and permanent AF (1.95%/year; P-adj =0.004). Overall, all-cause mortality also was lower with paroxysmal (3.0%/year) compared with persistent (4.4%/year; P-adj <0.001) and permanent AF (4.4%/year; P-adj <0.001). Annualized major bleeding rates were similar across AF patterns (2.86% versus 2.65% versus 2.73%). There was no effect modification by treatment assignment. Conclusions - In ENGAGE AF-TIMI 48 trial, patients with paroxysmal AF suffered fewer thromboembolic events and deaths compared with those with persistent and permanent AF. The efficacy and safety profile of edoxaban as compared with warfarin was consistent across the 3 patterns of AF.","author":[{"dropping-particle":"","family":"Link","given":"Mark S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giugliano","given":"Robert P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruff","given":"Christian T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scirica","given":"Benjamin M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huikuri","given":"Heikke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oto","given":"Ali","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crompton","given":"Andrea E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murphy","given":"Sabina A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lanz","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mercuri","given":"Michele F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Antman","given":"Elliott M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Braunwald","given":"Eugene","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation: Arrhythmia and Electrophysiology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017","1"]]},"language":"eng","page":"1-7","publisher-place":"United States, United States","title":"Stroke and Mortality Risk in Patients with Various Patterns of Atrial Fibrillation: Results from the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48)","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(39)","plainTextFormattedCitation":"(39)","previouslyFormattedCitation":"(39)"},"properties":{"noteIndex":0},"schema":""}(39)Sub-analysis of RCTAF with at least 2 stroke risk factors21,10561.9;70.6 (NA)Stroke or SE2.8 yearsAF typeParoxysmal AF was associated with lower risk of stroke or SE compared to persistent and permanent AFBoriani, 2014 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/eht491","ISSN":"1522-9645 (Electronic)","PMID":"24334432","abstract":"OBJECTIVE: The aim of this study was to assess the association between maximum daily atrial fibrillation (AF) burden and risk of ischaemic stroke. BACKGROUND: Cardiac implanted electronic devices (CIEDs) enhance detection of AF, providing a comprehensive measure of AF burden. DESIGN, SETTING, AND PATIENTS: A pooled analysis of individual patient data from five prospective studies was performed. Patients without permanent AF, previously implanted with CIEDs, were included if they had at least 3 months of follow-up. A total of 10 016 patients (median age 70 years) met these criteria. The risk of ischaemic stroke associated with pre-specified cut-off points of AF burden (5 min, 1, 6, 12, and 23 h, respectively) was assessed. RESULTS: During a median follow-up of 24 months, 43% of 10 016 patients experienced at least 1 day with at least 5 min of AF burden and for them the median time to the maximum AF burden was 6 months (inter-quartile range: 1.3-14). A Cox regression analysis adjusted for the CHADS2 score and anticoagulants at baseline demonstrated that AF burden was an independent predictor of ischaemic stroke. Among the thresholds of AF burden that we evaluated, 1 h was associated with the highest hazard ratio (HR) for ischaemic stroke, i.e. 2.11 (95% CI: 1.22-3.64, P = 0.008). CONCLUSIONS: Device-detected AF burden is associated with an increased risk of ischaemic stroke in a relatively unselected population of CIEDs patients. This finding may add to the basis for timely and clinically appropriate decision-making on anticoagulation treatment.","author":[{"dropping-particle":"","family":"Boriani","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Glotzer","given":"Taya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santini","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"West","given":"Teena M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Melis","given":"Mirko","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sepsi","given":"Milan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gasparini","given":"Maurizio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewalter","given":"Thorsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Camm","given":"John A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2014","2"]]},"language":"eng","page":"508-516","publisher-place":"England, England","title":"Device-detected atrial fibrillation and risk for stroke: an analysis of >10,000 patients from the SOS AF project (Stroke preventiOn Strategies based on Atrial Fibrillation information from implanted devices).","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"(43)","plainTextFormattedCitation":"(43)","previouslyFormattedCitation":"(43)"},"properties":{"noteIndex":0},"schema":""}(43)Pooled analysis of 5 prospective studiesPacemaker or ICD in situ10,01669;70 (61 - 76)Ischaemic stroke24 monthsAF burdenHigher AF burden was associated with greater risk of ischaemic strokeHealey, 2012 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa1105575","ISSN":"15334406","PMID":"22475610","abstract":"Background: One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation. Methods: We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing. Results: By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P = 0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P = 0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation. Conclusions: Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. (Funded by St. Jude Medical; ASSERT number, NCT00256152.) Copyright ? 2012 Massachusetts Medical Society. All rights reserved.","author":[{"dropping-particle":"","family":"Healey","given":"Jeff S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gold","given":"Michael R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Israel","given":"Carsten W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gelder","given":"Isabelle C.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Capucci","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lau","given":"C. P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fain","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Sean","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bailleul","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morillo","given":"Carlos A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carlson","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Themeles","given":"Ellison","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"Elizabeth S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012","1"]]},"language":"eng","page":"120-129","publisher-place":"United States","title":"Subclinical atrial fibrillation and the risk of stroke","type":"article-journal","volume":"366"},"uris":[""]}],"mendeley":{"formattedCitation":"(41)","plainTextFormattedCitation":"(41)","previouslyFormattedCitation":"(41)"},"properties":{"noteIndex":0},"schema":""}(41)RCTAged ≥65 years, known HTN and recent pacemaker or ICD implanatation2,58058.4;76.1 (NA)Ischaemic stroke or SE2.5 yearsAHRE (>190 bpm for >6 minutes)Presence of AHREs were associated with a 5.6-fold greater risk of ischaemic stroke or SEFriberg, 2010 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/ehn599","ISSN":"1522-9645 (Electronic)","PMID":"19176537","abstract":"AIMS: Knowledge about stroke risk in paroxysmal atrial fibrillation (PxAF) is limited. Although current guideline recommendations advocate the same treatment as in permanent atrial fibrillation (PermAF), most patients with PxAF do not receive prophylactic anticoagulation. The aim of this study is to investigate whether there are differences in stroke risk between PxAF and PermAF. METHODS AND RESULTS: All patients with PxAF (n = 855) and PermAF (n = 1126) treated for atrial fibrillation (AF) during 2002 at one of Scandinavia's largest hospitals were followed-up for 3.6 years regarding incidence of stroke. Information about type of AF, comorbidity, medication, and clinical events during follow-up was acquired from medical records and the National Register of Hospital Discharges. The incidence of ischaemic stroke was similar in PxAF and PermAF (26 vs. 29 events/1000 patient years). The multivariable-adjusted hazard ratio (HR) for ischaemic stroke in PxAF compared with PermAF was 1.07 (95% CI 0.71-1.61) in subjects without prior stroke. The corresponding HR for any stroke, ischaemic or haemorrhagic, was 0.89 (95% CI 0.61-1.30). Compared with the general population, ischaemic stroke was twice as common as expected in PxAF after standardization for age and sex (standardized incidence ratio 2.12, 95% CI 1.52-2.71). PxAF patients who took warfarin had approximately half as many ischaemic strokes as those who did not take warfarin (HR 0.44, 95% CI 0.30-0.65). CONCLUSION: Ischaemic stroke is about as common in PxAF as in PermAF, and about twice as common as in the general population. Yet, PxAF patients do not receive protective anticoagulant treatment as often as patients with PermAF do. It is therefore important to increase the use of anticoagulants among PxAF patients in accordance with current guideline recommendations.","author":[{"dropping-particle":"","family":"Friberg","given":"Leif","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hammar","given":"Niklas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenqvist","given":"Marten","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2010","4"]]},"language":"eng","page":"967-975","publisher-place":"England, England","title":"Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation.","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"(34)","plainTextFormattedCitation":"(34)","previouslyFormattedCitation":"(34)"},"properties":{"noteIndex":0},"schema":""}(34)Retrospective cohortAF (or atrial flutter)1,981NA;75.8 (NA)Ischaemic stroke3.6 yearsAF typeNo association with ischaemic strokeYilmaz, 2007 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000095416","ISSN":"1421-9751 (Electronic)","PMID":"16943646","abstract":"BACKGROUND: Atrial fibrillation (AF) is a frequent arrhythmia, associated with morbidity and mortality. It is identified by two types on surface electrocardiogram as fine and coarse AF. We aimed to search the association of subtypes of AF with clinical parameters. METHODS: Eight hundred and eleven consecutive patients, who had AF attack which lasted longer than 24 h or more, were evaluated along with clinical and laboratory data. RESULTS: Coarse AF was noticed in 51.7% (n = 419), and fine AF in 48.3% (n = 392). Sex was associated with subtype of AF such that coarse AF was present in 46.5% of male patients, but in 56.1% of female patients (p = 0.009). Coarse AF was present in 85.3% of patients with mitral stenosis, whereas it was present in 35.3% of patients with normal heart valve (p < 0.001). ). Patients having fine AF were significantly older than those having coarse AF (64 +/- 12, 57 +/- 13 years, p < 0.001). 19.6% of those with coarse AF had history of cerebrovascular event (CVE), whereas 13.5% of those with fine AF had history of CVE (p = 0.021). After controlling for age in the multivariable logistic regression analysis, presence of coarse AF (B = 1.585, p = 0.031) was found to be independently associated with the history of CVE. CONCLUSION: AF is identified by two morphological forms on the surface electrocardiogram. These two forms were found to be associated with different clinical parameters, acting on vascular endpoints differently.","author":[{"dropping-particle":"","family":"Yilmaz","given":"Mehmet Birhan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guray","given":"Yesim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guray","given":"Umit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cay","given":"Serkan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caldir","given":"Vedat","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Biyikoglu","given":"Senay Funda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sasmaz","given":"Hatice","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Korkmaz","given":"Sule","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cardiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2007"]]},"language":"eng","page":"193-196","publisher-place":"Switzerland, Switzerland","title":"Fine vs. coarse atrial fibrillation: which one is more risky?","type":"article-journal","volume":"107"},"uris":[""]}],"mendeley":{"formattedCitation":"(50)","plainTextFormattedCitation":"(50)","previouslyFormattedCitation":"(50)"},"properties":{"noteIndex":0},"schema":""}(50)Retrospective cohortAF lasting longer than 24 hours81145.9;60 (13)History of stroke or TIANA (retrospective)Coarse or fine AFCoarse AF was associated with greater risk of stroke or TIAHohnloser, 2007 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2007.07.076","ISSN":"07351097","PMID":"18036454","abstract":"Objectives: Our goal was to determine the risk of stroke or non-cerebral embolism associated with paroxysmal compared with sustained atrial fibrillation (AF). Background: The risk of stroke and non-cerebral embolism and the efficacy of oral anticoagulation (OAC) in paroxysmal AF as compared with sustained AF are not precisely known. Methods: The ACTIVE W (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) was a trial comparing OAC to combined antiplatelet therapy with aspirin and clopidogrel for prevention of vascular events in 6,706 AF patients. The incidence of thromboembolic events and major bleeds were compared in patients with paroxysmal AF (n = 1,202) and persistent or permanent AF (n = 5,495). Results: Patients with paroxysmal AF were younger, had a shorter AF history, more hypertension, and less valvular disease, heart failure, and diabetes mellitus than patients with sustained AF. At baseline, patients with paroxysmal AF had a CHADS2 (cardiac failure, hypertension, age, diabetes, stroke [doubled]) risk score of 1.79 ± 1.03 compared with 2.04 ± 1.12 in patients with sustained AF (p < 0.00001). The annualized risk of stroke or non-central nervous system (CNS) systemic embolism was 2.0 in paroxysmal AF compared with 2.2 in sustained AF (relative risk 0.87, 95% confidence interval [CI] 0.59 to 1.30, p = 0.496). After adjusting for confounding baseline variables, the relative risk was 0.94 (95% CI 0.63 to 1.40, p = 0.755). The incidence of stroke and non-CNS embolism was lower for patients treated with OAC irrespective of type of AF. There were more bleedings of any type in patients receiving clopidogrel plus aspirin, irrespective of the type of AF. Conclusions: Patients with paroxysmal AF treated with aspirin plus clopidogrel or OAC have a similar risk for thromboembolic events than patients with sustained AF. This risk can be significantly lowered with OAC. (The ACTIVE W trial; ; NCT00243178). ? 2007 American College of Cardiology Foundation.","author":[{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pajitnev","given":"Dimitri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pogue","given":"Janice","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Healey","given":"Jeff S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pfeffer","given":"Marc A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2007","11"]]},"language":"eng","page":"2156-2161","publisher-place":"United States, United States","title":"Incidence of Stroke in Paroxysmal Versus Sustained Atrial Fibrillation in Patients Taking Oral Anticoagulation or Combined Antiplatelet Therapy. An ACTIVE W Substudy","type":"article-journal","volume":"50"},"uris":[""]}],"mendeley":{"formattedCitation":"(36)","plainTextFormattedCitation":"(36)","previouslyFormattedCitation":"(36)"},"properties":{"noteIndex":0},"schema":""}(36)RCTAF with at least 1 stroke risk factor6,70666;70.2 (NA)Stroke or SE 1.3 yearsAF typeNo association with stroke or SECapucci, 2005 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2005.07.044","ISSN":"1558-3597 (Electronic)","PMID":"16286180","abstract":"OBJECTIVES: The aim of our study was to evaluate arterial embolism (AE) occurrence rates and predictors in patients suffering from bradycardia and wearing a pacemaker with antitachycardia pacing therapies. BACKGROUND: Atrial fibrillation (AF) is associated with a high incidence of AE. METHODS: A total of 725 patients (360 men, age 71 +/- 11 years) were implanted with a DDDRP pacemaker (Medtronic AT500, Medtronic Inc., Minneapolis, Minnesota). At baseline 225 (31.0%) patients received antiplatelet therapy and 264 (36.4%) patients received anticoagulation agents. RESULTS: Over a median 22-month follow-up (25th to 75th interquartile range 16 to 30 months), AE occurred in 14 (1.9%) patients: 7 patients suffered a nonfatal ischemic stroke (0.6% per year), 4 patients had transient ischemic attack (0.34% per year), and 3 patients had embolic complications. Among baseline patients' characteristics, multivariate logistic analysis showed that embolic events are independently associated to ischemic heart disease (7.0 odds ratio [OR], 95% confidence interval [CI] 2.3 to 21.3, p = 0.001), prior embolic event (7.3 OR, 95% CI 1.2 to 43.9, p = 0.029), diabetes (5.0 OR, 95% CI 1.2 to 15.7, p = 0.032), and hypertension (4.1 OR, 95% CI 1.1 to 15.6, p = 0.036). The risk of embolism, adjusted for known risk factors, was 3.1 times increased (95% CI 1.1 to 10.5, p = 0.044) in patients with device-detected atrial fibrillation episodes longer than one day during follow-up. CONCLUSIONS: In a cohort of patients with bradycardia and AF, arterial embolism was common in patients with ischemic cardiopathy, hypertension, diabetes mellitus, and in patients with known stroke risk factors. Atrial fibrillation occurrences longer than one day were independently associated with embolic events.","author":[{"dropping-particle":"","family":"Capucci","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santini","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Padeletti","given":"Luigi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gulizia","given":"Michele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Botto","given":"GianLuca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boriani","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ricci","given":"Renato","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Favale","given":"Stefano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zolezzi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Belardino","given":"Natale","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Molon","given":"Giulio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drago","given":"Fabrizio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Villani","given":"Giovanni Q","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mazzini","given":"Elena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vimercati","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grammatico","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2005","11"]]},"language":"eng","page":"1913-1920","publisher-place":"United States","title":"Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers.","type":"article-journal","volume":"46"},"uris":[""]}],"mendeley":{"formattedCitation":"(42)","plainTextFormattedCitation":"(42)","previouslyFormattedCitation":"(42)"},"properties":{"noteIndex":0},"schema":""}(42)Prospective cohortIndication for pacemaker and history of symptomatic atrial tachyarrhythmias72549.7;71 (11)Ischaemic stroke, TIA or SE22 monthsAF durationAF duration longer than 24 hours was associated with greater risk of ischaemic stroke, TIA or SEGlotzer, 2003 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.CIR.0000057981.70380.45","ISSN":"00097322","PMID":"12668495","abstract":"Background - Some current pacing systems can automatically detect and record atrial tachyarrhythmias that may be asymptomatic. We prospectively studied a 312-patient (pt) subgroup of MOST (MOde Selection Trial), a 2010-patient, 6-year randomized trial of DDDR versus VVIR pacing in sinus node dysfunction (SND). The purpose of the study was to correlate atrial high rate events (AHREs) detected by pacemaker diagnostics with clinical outcomes. Methods and Results - Pacemakers were programmed to log an AHRE when the atrial rate was >220 bpm for 10 consecutive beats. Analysis was confined to patients with at least 1 AHRE duration exceeding 5 minutes. The 312 patients were median age 74 years, 55% female, and 60% had a history of SVT. 160 of 312 (51.3%) patients enrolled had at least 1 AHRE > 5 minutes duration over median follow-up of 27 months. Cox proportional hazards analysis assessed the relationship of AHREs with clinical events, adjusting for prognostic variables and baseline covariates. The presence of any AHRE was an independent predictor of the following: total mortality (hazard ratio AHRE versus no AHRE and 95% confidence intervals=2.48 [1.25, 4.91], P = 0.0092); death or nonfatal stroke (2.79 [1.51, 5.15], P = 0.0011); and atrial fibrillation (5.93 [2.88, 12.2], P = 0.0001). There was no significant effect of pacing mode on the presence or absence of AHREs. Conclusions - AHRE detected by pacemakers in patients with SND identify patients that are more than twice as likely to die or have a stroke, and 6 times as likely to develop atrial fibrillation as similar patients without AHRE.","author":[{"dropping-particle":"V.","family":"Glotzer","given":"Taya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hellkamp","given":"Anne S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zimmerman","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sweeney","given":"Michael O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yee","given":"Raymond","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marinchak","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cook","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paraschos","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Love","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Radoslovich","given":"Glauco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Kerry L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamas","given":"Gervasio A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2003","4"]]},"language":"eng","page":"1614-1619","publisher-place":"United States","title":"Atrial high rate episodes detected by pacemaker diagnostics predict death and stroke: Report of the atrial diagnostics ancillary study of the MOde Selection Trial (MOST)","type":"article-journal","volume":"107"},"uris":[""]}],"mendeley":{"formattedCitation":"(40)","plainTextFormattedCitation":"(40)","previouslyFormattedCitation":"(40)"},"properties":{"noteIndex":0},"schema":""}(40)RCTSND undergoing pacemaker implantation31245;74 (NA)Death of non-fatal stroke33.1 monthsAHRE (>220 bpm for 10 consecutive beats)Presence of AHREs were associated with greater risk of composite endpointHart, 2000 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0735-1097(99)00489-1","ISSN":"07351097","PMID":"10636278","abstract":"OBJECTIVE: This study was performed to characterize the risk of stroke in elderly patients with recurrent intermittent atrial fibrillation (AF). BACKGROUND: Although intermittent AF is common, relatively little is known about the attendant risk of stroke. METHODS: A longitudinal cohort study was performed comparing 460 participants with intermittent AF with 1,552 with sustained AF treated with aspirin in the Stroke Prevention in Atrial Fibrillation studies and followed for a mean of two years. Independent risk factors for ischemic stroke were identified by multivariate analysis. RESULTS: Patients with intermittent AF were, on average, younger (66 vs. 70 years, p < 0.001), were more often women (37% vs. 26% p < 0.001) and less often had heart failure (11% vs. 21%, p < 0.001) than those with sustained AF. The annualized rate of ischemic stroke was similar for those with intermittent (3.2%) and sustained AF (3.3%). In patients with intermittent AF, independent predictors of ischemic stroke were advancing age (relative risk [RR] = 2.1 per decade, p < 0.001), hypertension (RR = 3.4, p = 0.003) and prior stroke (RR = 4.1, p = 0.01). Of those with intermittent AF predicted to be high risk (24%), the observed stroke rate was 7.8% per year (95% confidence interval 4.5 to 14). CONCLUSIONS: In this large cohort of AF patients given aspirin, those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors. Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation. High-risk patients with intermittent AF can be identified using the same clinical criteria that apply to patients with sustained AF.","author":[{"dropping-particle":"","family":"Hart","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"Lesly A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rothbart","given":"Robert M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McAnulty","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asinger","given":"Richard W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"Jonathan L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2000","1"]]},"language":"eng","page":"183-187","publisher-place":"United States, United States","title":"Stroke with intermittent atrial fibrillation: Incidence and predictors during aspirin therapy","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"(35)","plainTextFormattedCitation":"(35)","previouslyFormattedCitation":"(35)"},"properties":{"noteIndex":0},"schema":""}(35)Prospective cohortAF2,01271.5;69.1 (NA)Ischaemic stroke2 yearsAF typeNo association with ischaemic stroke AF, atrial fibrillation; AHRE, atrial high rate episode; ECG, electrocardiogram; HTN, hypertension; ICD, implantable cardioverter defibrillator; IQR, interquartile range; NA, not applicable or available; RCT, randomised controlled trial; SD, standard deviation; SE, systemic embolism; SND, sinus node disease; TIA, transient ischaemic attack.Blood-based biomarkers for stroke risk in AFStudy, year (ref)DesignStudy populationn% male; mean (SD) or median (IQR) age, yearsRelevant outcome measuresFollow-up durationBiomarkerFindingsPark, 2019 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.hrthm.2018.08.023","ISSN":"1556-3871 (Electronic)","PMID":"30170225","abstract":"BACKGROUND: The prognostic efficacy of quantitative platelet activity in atrial fibrillation (AF) remains unclear. OBJECTIVE: The purpose of this study was to evaluate the platelet count (PLT) as a prognostic indicator in patients with nonvalvular AF. METHODS: Data on 10,978 patients with nonvalvular AF were retrieved from a prospective registry of a single medical center in Korea. Cumulative risk for stroke and bleeding events were compared between patients with normal PLT (n = 8322), mild thrombocytopenia (n = 1791), and moderate to severe thrombocytopenia (n = 865) after propensity score matching. Prediction models for stroke were derived by conventional risk factors (model 1) and by combining PLT with model 1 (model 2), and model performance was assessed by area under the receiver operator characteristics curve (AUC). RESULTS: During the follow-up period, 7.3%, 7.0%, and 4.5% had stroke and 7.6%, 10.8%, and 17.2% had bleeding events in the normal PLT, mild, and moderate to severe thrombocytopenia groups, respectively. Compared to the normal PLT group, the moderate to severe thrombocytopenia group showed a lower risk of stroke (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.40-0.80; P = .002). A reverse relationship was found between PLT and bleeding risk (moderate to severe thrombocytopenia: HR 2.19; 95% CI 1.77-2.70; P <.001; mild thrombocytopenia: HR 1.43; 95% CI 1.18-1.73; P <.001). Compared to model 1, model 2 showed significant improvement in risk prediction (AUC 0.628 vs 0.644; P <.001). CONCLUSION: A lower PLT was associated with a lower risk of stroke and a higher risk of bleeding events. PLT combined with conventional risk factors showed significant improvement in prediction for stroke.","author":[{"dropping-particle":"","family":"Park","given":"Jiesuck","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cha","given":"Myung-Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"You-Jung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Euijae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moon","given":"Inki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwak","given":"Soongu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwon","given":"Soonil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Seokhun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Seoyoung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Eue-Keun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oh","given":"Seil","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart rhythm","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2019","2"]]},"language":"eng","page":"197-203","publisher-place":"United States","title":"Prognostic efficacy of platelet count in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"(90)","plainTextFormattedCitation":"(90)","previouslyFormattedCitation":"(90)"},"properties":{"noteIndex":0},"schema":""}(90)Prospective registryAF10,97863.6;73.5 (11.8)Stroke42.6 monthsPlatelet count (<100 x 109/L)Lower platelet counts were associated with lower risk of strokeJanion-Sadowska, 2018 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/FJC.0000000000000607","ISSN":"1533-4023 (Electronic)","PMID":"29985282","abstract":"AIMS: Thrombocytopenia was one of the exclusion criteria in randomized trials in which non-vitamin K antagonist oral anticoagulants (NOACs) were tested. The safety of NOACs in patients with atrial fibrillation (AF) and thrombocytopenia remains unclear. METHODS: We studied 62 patients with AF aged from 53 to 85 (mean 70.5) years with platelet count from 50 to 100 x 109/L who were treated with rivaroxaban 15 mg once daily (33.9%), dabigatran 110 mg twice daily (bid) (54.8%), or apixaban 2.5 mg bid (11.3%). Age- and sex-matched AF patients with normal platelet count and similar CHA2DS2-VASc scores who were treated with the recommended doses of NOACs served as a reference group. RESULTS: Patients were followed for a mean of 55 months (range, 23-64 months). In the thrombocytopenia group bleeding risk was higher (mean HAS-BLED score 2.0, vs. 1.0, P < 0.0001). During follow-up in thrombocytopenic and normocytopenic patients, we observed similar rates of major bleeding (1.8%/year vs. 2.7%/year, P = 0.49), clinically relevant nonmajor bleeding (CRNMB) (1.5%/year vs. 1.1%/year, P = 0.74), ischemic stroke and transient ischemic attacks (1.8%/year vs. 1.5%/year, P = 0.8), and death (1.06%/year vs. 1.11%/year, P = 0.96). The risk of bleeding and stroke was unaffected by the type of the NOAC used in both groups. Major bleedings and clinically relevant nonmajor bleeding in thrombocytopenic patients on NOACs were predicted only by age (hazard ratio 1.1, 95% confidence interval 1.0-1.3, P = 0.04). CONCLUSIONS: Our findings indicate that in AF patients with mild thrombocytopenia, anticoagulation with NOAC at reduced doses seems to be safe and effective.","author":[{"dropping-particle":"","family":"Janion-Sadowska","given":"Agnieszka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Papuga-Szela","given":"Elzbieta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lukaszuk","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chrapek","given":"Magdalena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Undas","given":"Anetta","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of cardiovascular pharmacology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018","9"]]},"language":"eng","page":"153-160","publisher-place":"United States","title":"Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Thrombocytopenia.","type":"article-journal","volume":"72"},"uris":[""]}],"mendeley":{"formattedCitation":"(89)","plainTextFormattedCitation":"(89)","previouslyFormattedCitation":"(89)"},"properties":{"noteIndex":0},"schema":""}(89)Prospective cohortAF on NOAC12433.1; 70.3 (NA)Stroke or TIA55 monthsPlatelet count (<100 x 109/L)No association with stroke or TIARivera-Caravaca, 2018 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s11606-017-4279-4","ISSN":"1525-1497 (Electronic)","PMID":"29569024","abstract":"BACKGROUND: Soluble fibrin monomer complex (SFMC) is a biomarker of fibrin formation abnormally elevated in clinical situations of hypercoagulability. OBJECTIVE: We investigated the association and predictive performance of SFMC for stroke, adverse cardiovascular events, cardiovascular mortality and all-cause mortality in a cohort of patients with atrial fibrillation (AF) receiving vitamin K antagonist (VKA) anticoagulant therapy. DESIGN: During the second semester of 2007, we included 1226 AF outpatients stable on VKAs (INR 2.0-3.0) over a period of 6 months. SFMC levels were assessed at baseline. During 6.5 (IQR 4.4-8.0) years of follow-up, we recorded all ischemic strokes, adverse cardiovascular events (composite of stroke, acute heart failure, acute coronary syndrome and cardiovascular death), cardiovascular deaths and all-cause deaths. PARTICIPANTS: All patients were recruited consecutively. We excluded patients with rheumatic mitral valves, prosthetic heart valves, acute coronary syndrome, stroke, hemodynamic instability, hospital admissions or surgical interventions within the preceding 6 months. MAIN MEASURES: SFMC levels were measured in plasma by immunoturbidimetry in an automated coagulometer (STALiatestFM, Diagnostica Stago, Asnieres, France). KEY RESULTS: We recorded 121 (1.52%/year) ischemic strokes, 257 (3.23%/year) cardiovascular events, 67 (0.84%/year) cardiovascular deaths and 486 (6.10%/year) all-cause deaths. SFMC >12 mug/mL was not associated with stroke but was associated with higher risk of cardiovascular events (HR 1.72, 95% CI 1.31-2.26), cardiovascular mortality (HR 2.16, 95% CI 1.30-3.57) and all-cause mortality (HR 1.26, 95% CI 1.03-1.55). When SFMC >12 mug/mL was added to the CHA2DS2-VASc, there were significant improvements in predictive performance, sensitivity and reclassification for adverse cardiovascular events (c-index: 0.645 vs. 0.660, p = 0.010; IDI = 0.013, p < 0.001; NRI = 0.121, p < 0.001) and cardiovascular mortality (c-index: 0.661 vs. 0.691, p = 0.006; IDI = 0.009, p = 0.049; NRI = 0.217, p < 0.001), but decision curves demonstrated a similar net benefit and clinical usefulness. CONCLUSIONS: In AF patients taking VKAs, high SFMC levels were associated with the risk of adverse cardiovascular events, cardiovascular mortality and all-cause mortality. The addition of SFMC to the CHA2DS2-VASc score improved its predictive performance for these outcomes, but failed to show an improvement in clinical usefulness.","author":[{"dropping-particle":"","family":"Rivera-Caravaca","given":"Jose Miguel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Romera","given":"Marta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Esteve-Pastor","given":"Maria Asuncion","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of general internal medicine","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2018","6"]]},"language":"eng","page":"847-854","publisher-place":"United States, United States","title":"Soluble Fibrin Monomer Complex and Prediction of Cardiovascular Events in Atrial Fibrillation: The Observational Murcia Atrial Fibrillation Project.","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"(103)","plainTextFormattedCitation":"(103)","previouslyFormattedCitation":"(103)"},"properties":{"noteIndex":0},"schema":""}(103)Prospective cohortAF on OAC, attending clinic1,22649.7; 76 (70 - 81)Ischaemic stroke6.5 yearsSoluble fibrin monomer complexNo association with ischaemic strokeYou, 2018 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/MD.0000000000012622","ISSN":"1536-5964 (Electronic)","PMID":"30412062","abstract":"This study aimed to explore the relationship of D-dimer level with the risk stratification of ischemic stroke, and determine whether high D-dimer levels could be used as a risk factor of ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF).This single-center, retrospective study recruited NVAF patients who did not undergo anticoagulant therapy. These patients were divided into 2 groups: ischemic stroke group and no-stroke group. The medical records of each patient were reviewed, demographic and clinical analyses were performed, and the laboratory results were summarized.A total of 323 eligible in-patients with NVAF, who did not receive anticoagulant therapy, were recruited (206 male and 117 female patients, median age was 75.18 +/- 10.46 years old). Among these patients, 78 patients suffered from acute ischemic stroke. D-dimer level increased with age, and was positively correlated with the risk stratification of stroke, CHADS2 score (rs = 0.441, P < .001), and CHA2DS2-VASC score (rs = 0.412, P < .001), even after adjustment for age and gender (rs = 0.422, P < .001). The difference in baseline D-dimer level between these 2 groups was not statistically significant (0.70 vs 0.66 mg/L, P = .330), but this significantly increased when patients suffered from stroke (1.34 vs 0.70 mg/L, P < .001). The D-dimer level after stroke (>/=6 months) was also higher than the baseline (1.16 vs 0.68 mg/L, P = .514) in 6 months, and this level nearly returned to baseline level after one year (0.69 vs 0.68 mg/L, P = .158). However, logistic regression revealed that only the D-dimer level at stroke onset and OMI were independent risk factors for ischemic stroke (P < .001), while the increase from baseline D-dimer levels was not an independent risk factor (P = .125).D-dimer level is positively correlated with the risk stratification of ischemic stroke, but has no predictive value on the occurrence of ischemic stroke in patients with NVAF.","author":[{"dropping-particle":"","family":"You","given":"Li-Rui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tang","given":"Mei","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Medicine","id":"ITEM-1","issue":"43","issued":{"date-parts":[["2018","10"]]},"language":"eng","page":"e12622","publisher-place":"United States, United States","title":"The association of high D-dimer level with high risk of ischemic stroke in nonvalvular atrial fibrillation patients: A retrospective study.","type":"article-journal","volume":"97"},"uris":[""]}],"mendeley":{"formattedCitation":"(88)","plainTextFormattedCitation":"(88)","previouslyFormattedCitation":"(88)"},"properties":{"noteIndex":0},"schema":""}(88)Case-controlled studyNon-anticoagulated AF32363.8;75.2 (NA)Ischaemic strokeNA(retrospective)D-dimerNo association with ischaemic strokeAncedy, 2018 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.acvd.2017.08.004","ISSN":"1875-2128 (Electronic)","PMID":"29685722","abstract":"BACKGROUND: Heart failure and atrial fibrillation share common mechanisms that may contribute to hypercoagulability and thrombotic risk. Elevated von Willebrand factor (vWF) concentration has been associated with increased risk of thromboembolism and cardiovascular events. AIM: To investigate whether increased vWF plasma concentration predicts occurrence of a composite endpoint (all-cause death and stroke) in patients with non-valvular atrial fibrillation (NVAF). METHODS: We prospectively studied 122 patients (mean age 70+/-14years; 46% men) hospitalized with NVAF, and followed over a median (interquartile range) of 5.4 (2.3-9.0)years. Cox proportional models were used to estimate the association of vWF concentration with time to stroke and death. RESULTS: Forty-three patients (35%) had at least a stroke or died during the 5-year follow-up. Kaplan-Meier curves using vWF plasma concentration tertiles (</=191IU/dL;>191 to</=295IU/dL;>295IU/dL) showed that vWF plasma concentrations discriminated groups of patients with higher cardiovascular event rates (log-rank P=0.01). In the multivariable analysis, higher vWF concentrations (middle tertile hazard ratio [HR] 4.59, 95% confidence interval [CI] 1.55-13.50 [P=0.006]; upper tertile HR 4.10, 95% CI 1.43-11.75 [P=0.009]), age>/=75years (HR 5.02, 95% CI 1.53-16.49; P=0.008), heart failure (HR 2.05, 1.01-4.19; P=0.048), C-reactive protein, log2 per unit increase (HR 1.29, 95% CI 1.04-1.61; P=0.021), no warfarin at discharge (HR 4.96, 95% CI 2.02-12.20; P<0.0001) and no aspirin at discharge (HR 4.41, 95% CI 1.71-11.97; P=0.002) were independently associated with an increased risk of stroke and all-cause death, whereas female sex was a protective factor (HR 0.35, 0.16-0.78; P=0.01). CONCLUSIONS: High vWF plasma concentrations may discriminate patients with NVAF at greater risk of stroke or all-cause death.","author":[{"dropping-particle":"","family":"Ancedy","given":"Yann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berthelot","given":"Emmanuelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lang","given":"Sylvie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ederhy","given":"Stephane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boyer-Chatenet","given":"Louise","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Angelantonio","given":"Emanuele","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soulat-Dufour","given":"Laurie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Etienney","given":"Arnaud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adavane-Scheuble","given":"Saroumadi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boccara","given":"Franck","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cohen","given":"Ariel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of cardiovascular diseases","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2018","5"]]},"language":"eng","page":"357-369","publisher-place":"Netherlands, Netherlands","title":"Is von Willebrand factor associated with stroke and death at mid-term in patients with non-valvular atrial fibrillation?","type":"article-journal","volume":"111"},"uris":[""]}],"mendeley":{"formattedCitation":"(94)","plainTextFormattedCitation":"(94)","previouslyFormattedCitation":"(94)"},"properties":{"noteIndex":0},"schema":""}(94)Prospective cohortHospitalised AF12246;70 (14)Composite of all-cause death and stroke; stroke5 yearsvWFHigher vWF levels were associated with greater risk of composite endpointNo association with stroke risk onlyHayashi, 2018 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1253/circj.CJ-17-1085","ISSN":"1347-4820 (Electronic)","PMID":"29491320","abstract":"BACKGROUND: B-type natriuretic peptide (BNP) may be a predictor of stroke risk in patients with nonvalvular atrial fibrillation (NVAF); because heart failure is associated with the incidence of stroke in AF patients. However, limited data exist regarding the association between BNP at baseline and risks of thromboembolic events (TE) and death in NVAF patients. Methods and Results: We prospectively studied 1,013 NVAF patients (725 men, 72.8+/-9.7 years old) from the Hokuriku-plus AF Registry to determine the relationship between BNP at baseline and prognosis among Japanese NVAF patients. During the follow-up period (median, 751 days); 31 patients experienced TE and there were 81 cases of TE/all-cause death. For each endpoint we constructed receiver-operating characteristic curves that gave cutoff points of BNP for TE (170 pg/mL) and TE/all-cause death (147 pg/mL). Multivariate analysis with the Cox-proportional hazards model indicated that high BNP was significantly associated with risks of TE (hazard ratio [HR] 3.86; 95% confidence interval [CI] 1.83-8.67; P=0.0003) and TE/all-cause death (HR 2.27; 95% CI 1.45-3.56; P=0.0003). Based on the C-index and net reclassification improvement, the addition of BNP to CHA2DS2-VASc statistically improved the prediction of TE. CONCLUSIONS: In a real-world cohort of Japanese NVAF patients, high BNP was significantly associated with TE and death. Plasma BNP might be a useful biomarker for these adverse clinical events.","author":[{"dropping-particle":"","family":"Hayashi","given":"Kenshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsuda","given":"Toyonobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nomura","given":"Akihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fujino","given":"Noboru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nohara","given":"Atsushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sakata","given":"Kenji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Konno","given":"Tetsuo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakanishi","given":"Chiaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tada","given":"Hayato","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagata","given":"Yoji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teramoto","given":"Ryota","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanaka","given":"Yoshihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawashiri","given":"Masa-Aki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamagishi","given":"Masakazu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation journal : official journal of the Japanese Circulation Society","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2018","4"]]},"language":"eng","page":"1271-1278","publisher-place":"Japan, Japan","title":"Impact of B-Type Natriuretic Peptide Level on Risk Stratification of Thromboembolism and Death in Patients With Nonvalvular Atrial Fibrillation- The Hokuriku-Plus AF Registry.","type":"article-journal","volume":"82"},"uris":[""]}],"mendeley":{"formattedCitation":"(59)","plainTextFormattedCitation":"(59)","previouslyFormattedCitation":"(59)"},"properties":{"noteIndex":0},"schema":""}(59)Prospective registryAF1,01371.6;72.8 (9.7)Stroke, TIA or SE25 monthsBNPHigh BNP levels were associated with a 3.9-fold greater risk of stroke, TIA or SEChoi, 2017 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/clc.22759","ISSN":"1932-8737 (Electronic)","PMID":"28805957","abstract":"BACKGROUND: CHADS2 (congestive heart failure, hypertension, age >/= 75 years, diabetes mellitus, stroke) and CHA2 DS2 -VASc (congestive heart failure, hypertension, age >/= 75 years, diabetes mellitus, stroke, vascular disease, age 65 to 74 years, sex category) scores showed just moderate discrimination ability in predicting thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). HYPOTHESIS: To determine the association of antithrombin III (AT-III) deficiency and mean platelet volume (MPV) with the development of stroke or left atrial (LA) thrombus in patients with AF. METHODS: AT-III and MPV were analyzed in 352 patients with AF. The primary endpoint was a composite of ischemic stroke event and incidental LA thrombus. RESULTS: There were 50 events (14.2%) during a mean 35.4 months of follow-up. A significantly higher stroke or LA thrombus rate was observed in the low-AT-III group (<70%) than that in the high-AT-III group (>/=70%). A significantly higher stroke or LA thrombus rate was observed in the high-MPV group (>/=7.0 fL) than that in the low-MPV group (<7.0 fL). AF patients with an MPV >/=7.0 fL and AT-III deficiency had higher stroke or LA thrombus risk than those without an MPV >/=7.0 fL and AT-III deficiency. In the Cox proportional hazard analysis, high MPV was found to be an independent predictor of stroke or LA thrombus risk (hazard ratio: 6.408; 95% confidence interval: 2.874-14.286). Although AT-III deficiency was not an independent predictor of stroke or LA thrombus risk, a trend was observed. CONCLUSIONS: High MPV and AT-III deficiency were predictive markers for stroke or LA thrombus. Their predictive power for stroke was independent of antiplatelet treatment, anticoagulation therapy, and a high CHA2 DS2 -VASc score in patients with AF.","author":[{"dropping-particle":"","family":"Choi","given":"Seo-Won","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Bo-Bae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Dong-Hyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Geon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shin","given":"Byung Chul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Heesang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Dong-Min DongHun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Dong-Min DongHun","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical cardiology","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2017","11"]]},"language":"eng","page":"1013-1019","publisher-place":"United States, United States","title":"Stroke or left atrial thrombus prediction using antithrombin III and mean platelet volume in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"40"},"uris":[""]}],"mendeley":{"formattedCitation":"(99)","plainTextFormattedCitation":"(99)","previouslyFormattedCitation":"(99)"},"properties":{"noteIndex":0},"schema":""}(99)Prospective cohortAF35257.4;68.4 (12.1)Composite of ischaemic stroke and incidental LA thrombus35.4 monthsAntithrombin IIINo association with composite endpointMPVHigh MPV levels were associated with a 6.4-fold greater risk of composite endpointAulin, 2015 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ahj.2015.09.018","ISSN":"1097-6744 (Electronic)","PMID":"26678637","abstract":"BACKGROUND: Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events in AF patients in the RE-LY study. METHODS: Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics. RESULTS: Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism (P = .0041), major bleedings (P = .0001), vascular death (P < .0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) (P < .0001). CRP was independently related to myocardial infarction (P = .0047), vascular death (P = .0004), and the composite thromboembolic outcome (P = .0001). When further adjusted for cardiac (troponin and N-terminal fragment B-type natriuretic peptide [NT-proBNP]) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death (P < .0001), major bleeding (P < .0170) and the composite thromboembolic outcome (P < .0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 (P = .0017) when adding IL-6 to the clinically used CHA2DS2-VASc risk score with net reclassification improvement of 28%. CONCLUSION: In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.","author":[{"dropping-particle":"","family":"Aulin","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huber","given":"Kurt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reilly","given":"Paul A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American heart journal","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2015","12"]]},"language":"eng","page":"1151-1160","publisher-place":"United States, United States","title":"Interleukin-6 and C-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation.","type":"article-journal","volume":"170"},"uris":[""]}],"mendeley":{"formattedCitation":"(96)","plainTextFormattedCitation":"(96)","previouslyFormattedCitation":"(96)"},"properties":{"noteIndex":0},"schema":""}(96)Sub-study of RCTAF with at least 1 stroke risk factor6,18763.7;72 (67 - 77)Stroke or SE2 yearsIL-6Higher IL-6 levels were associated with greater risk of stroke or SECRPNo association with stroke or SEFibrinogenNo association with stroke or SEPignatelli, 2015 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1160/TH14-07-0571","ISSN":"2567-689X (Electronic)","PMID":"25392853","abstract":"There are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in atrial fibrillation (AF). The aim of this study was to analyse the role of urinary prostaglandin PGF2alpha (8-iso-PGF2alpha) and NOX2, markers of systemic oxidative stress, in predicting cardiovascular (CV) events and mortality in anticoagulated non-valvular AF patients. This was a prospective study including 1,002 anticoagulated AF patients, followed for a median time of 25.7 months (interquartile range: 14.8-50.9). All major CV events, CV deaths and all-cause deaths were considered as primary outcomes of the study. CV events included fatal/nonfatal ischaemic stroke, fatal/nonfatal myocardial infarction (MI), cardiac revascularisation and transient ischaemic attack (TIA). Oxidative stress biomarkers, such as urinary 8-iso-PGF2alpha and serum sNOX2-dp, a marker of NOX2 activation, were measured. A CV event occurred in 125 patients (12.5 %); 78 CV deaths and 31 non-CV deaths were registered. 8-iso-PGF2alpha and sNOX2-dp were correlated (Rs=0.765 p< 0.001). A significant increased cumulative incidence of CV events and CV deaths was observed across tertiles for 8-iso-PGF2alpha and sNOX2-dp. An increased rate of all-cause death was observed across tertiles of urinary 8-iso-PGF2alpha. In Cox or Fine and Gray models, 8-iso-PGF2alpha predicted CV events and CV and non-CV deaths. The addition of tertiles of 8-iso-PGF2alpha to CHA2DS2-VASc score improved ROC curves for each outcome and NRI for CV events (0.24 [0.06-0.53] p=0.0067). The study shows that in AF patients 8-iso-PGF2alpha and NOX2 levels are predictive of CV events and total mortality. F2-IsoP may complement conventional risk factors in prediction of CV events.","author":[{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pastori","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carnevale","given":"Roberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farcomeni","given":"Alessio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cangemi","given":"Roberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nocella","given":"Cristina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartimoccia","given":"Simona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicario","given":"Tommasa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saliola","given":"Mirella","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015","3"]]},"language":"eng","page":"617-624","publisher-place":"Germany, Germany","title":"Serum NOX2 and urinary isoprostanes predict vascular events in patients with atrial fibrillation.","type":"article-journal","volume":"113"},"uris":[""]}],"mendeley":{"formattedCitation":"(100)","plainTextFormattedCitation":"(100)","previouslyFormattedCitation":"(100)"},"properties":{"noteIndex":0},"schema":""}(100)Prospective cohortAF95055.5;73.3 (8.8)Composite of stroke, TIA, MI and coronary revascularization25.7 monthsSerum NOX2-derived peptideHigher serum NOX2-derived peptide levels were associated with greater risk of composite endpointBanerjee, 2014 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1378/chest.13-2103","ISSN":"19313543","PMID":"24356875","abstract":"Background: Atrial fibrillation (AF) is more likely to develop in patients with chronic kidney disease (CKD) than in individuals with normal renal function, and patients with CKD are more likely to suffer ischemic stroke (IS)/thromboembolism (TE). To our knowledge, no prior study has considered the impact of estimated glomerular filtration rate (eGFR) on bleeding. We investigated the relationship of eGFR to IS/TE, mortality, and bleeding in an AF population unrestricted by age or comorbidity. Methods: Patients with nonvalvular AF (NVAF) were stratified into five categories according to eGFR (≥90, 60-89, 30-59, 15-29, and < 15 mL/min/1.73 m2), analyzing risk factors, all-cause mortality, bleeding, and IS/TE. Of 8,962 eligible individuals, 5,912 had NVAF and available serum creatinine data, with 14,499 patient-years of follow-up. Results: The incidence rates of IS/TE were 7.4 and 7.2 per 1,000 person-years in individuals not receiving and receiving anticoagulation therapy, respectively. Rates of all-cause mortality were 13.4 and 9.4 per 1,000 person-years, respectively, and of major bleeding, 6.2 and 9.0 per 1,000 person-years, respectively. Rates increased with decreasing eGFR, with IS/TE rates being lower in individuals receiving oral anticoagulation (OAC) therapy. eGFR was not an independent predictor of IS/TE on multivariate analyses. When the benefit of IS reduction is balanced against the increased risk of hemorrhagic stroke, the net clinical benefit (NCB) was clearly positive in favor of OAC use. Conclusions: Incidence rates of IS/TE, mortality, and bleeding increased with reducing eGFR across the whole range of renal function. OAC use was associated with a lower incidence of IS/TE and mortality at 1 year compared with individuals not receiving anticoagulants in all categories of renal function as measured by eGFR. The NCB balancing IS against serious bleeding was positive in favor of OAC use among patients with renal impairment. ? 2014 American College of Chest Physicians.","author":[{"dropping-particle":"","family":"Banerjee","given":"Amitava","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fauchier","given":"Laurent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vourc'H","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andres","given":"Christian R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taillandier","given":"Sophie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halimi","given":"Jean Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H. H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chest","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2014","6"]]},"language":"eng","page":"1370-1382","publisher":"The American College of Chest Physicians","publisher-place":"United States, United States","title":"A prospective study of estimated glomerular filtration rate and outcomes in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project.","type":"article-journal","volume":"145"},"uris":[""]}],"mendeley":{"formattedCitation":"(66)","plainTextFormattedCitation":"(66)","previouslyFormattedCitation":"(66)"},"properties":{"noteIndex":0},"schema":""}(66)Prospective cohortAF5,91262.9;70.9 (NA)Ischaemic stroke or TE2.5 yearseGFR (MDRD)Lower levels of renal function were associated with greater risk of ischaemic stroke or TERoldan, 2014 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/STROKEAHA.113.003338","ISSN":"1524-4628 (Electronic)","PMID":"24519407","abstract":"BACKGROUND AND PURPOSE: Oral anticoagulation is highly effective in reducing stroke and mortality in atrial fibrillation (AF). Several risk stratification schemes have been developed using clinical characteristics. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) are important markers of increased mortality and morbidity in congestive heart failure and general community population. The aim of our study was to assess the predictive value of NT-proBNP levels in an unselected real-world cohort of anticoagulated patients with AF. METHODS: We studied 1172 patients (49% male; median age, 76 years) with permanent AF who were well stabilized on oral anticoagulation (international normalized ratio, 2.0-3.0). Plasma NT-proBNP levels were quantified at baseline. We recorded thrombotic and vascular events, mortality, and major bleeding. The best cutoff points were assessed by receiver-operating characteristic curves. RESULTS: Median levels (interquartile range) of NT-proBNP were 610 (318-1037) pg/mL. Median follow-up was 1007 (806-1279) days. On multivariate analysis, high NT-proBNP was significantly associated with the risk of stroke (hazards ratio, 2.71; P=0.001) and composite vascular events (acute coronary syndrome or acute heart failure; hazards ratio, 1.85; P=0.016), as well as a significant association with mortality (adjusted hazards ratio, 1.66; P=0.006). No association with bleeding was found (P=0.637). The integrated discrimination improvement (IDI) analysis demonstrated that NT-proBNP improved the Congestive heart failure, Hypertension, Age>/=75 (doubled), Diabetes mellitus, Stroke (doubled)-Vascular disease and Sex category (female); CHA2DS2-VASc score for predicting embolic events (relative IDI, 2.8%; P=0.001) and all-cause death (relative IDI, 1.8%; P=0.001). CONCLUSIONS: In real-world cohort of anticoagulated patients with AF, NT-proBNP provided complementary prognostic information to an established clinical risk score (CHA2DS2-VASc) for the prediction of stroke/systemic embolism. NT-proBNP was also predictive of all-cause mortality, suggesting that this biomarker may potentially be used to refine clinical risk stratification in anticoagulated patients with AF.","author":[{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vilchez","given":"Juan Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manzano-Fernandez","given":"Sergio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jover","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galvez","given":"Josefa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Puche","given":"Carmen M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2014","3"]]},"language":"eng","page":"696-701","publisher-place":"United States, United States","title":"Usefulness of N-terminal pro-B-type natriuretic Peptide levels for stroke risk prediction in anticoagulated patients with atrial fibrillation.","type":"article-journal","volume":"45"},"uris":[""]}],"mendeley":{"formattedCitation":"(58)","plainTextFormattedCitation":"(58)","previouslyFormattedCitation":"(58)"},"properties":{"noteIndex":0},"schema":""}(58)Prospective cohortAF on OAC, attending clinic1,17249;76 (71 - 81)Stroke or TIA34 monthsNT-proBNPHigh NT-proBNP levels were associated with a 2.7-fold greater stroke or TIA riskApostolakis, 2013 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/eurheartj/eht328","ISSN":"1522-9645 (Electronic)","PMID":"23966309","abstract":"AIMS: Limited data are available on the impact of renal function on the outcome of patients with atrial fibrillation (AF). METHODS AND RESULTS: AMADEUS was a multicentre, randomized, open-label non-inferiority study that compared fixed-dose idraparinux with conventional anticoagulation by dose-adjusted vitamin K antagonists. We performed a post hoc analysis to assess the impact of renal function on the outcomes of anticoagulated AF patients. The primary efficacy outcome was the composite of stroke/systemic embolism (SE). The principal safety outcome of this analysis was major bleeding. We calculated c-indexes, reflecting the ability for discriminating diseased vs. non-diseased patients, and the net reclassification improvement (NRI, an index of inferior/superior performance of risk estimation scores). Of 4576 patients, 45 strokes and 103 major bleeding events occurred following an average follow-up of 325 +/- 164 days. Patients with CrCl >90 mL/min had an annual stroke/SE rate of 0.6% compared with 0.8% for those with CrCl 60-90 mL/min and 2.2% for those with CrCl <60 mL/min (P < 0.001 for linear association). After adjusting for stroke risk factors, patients with CrCl <60 mL/min had more than two-fold higher risk of stroke/SE and almost 60% higher risk of major bleeding compared with those with CrCl >/=60. In patients with the CHA2DS2VASc score 1-2, CrCl <60 mL/min was associated with eight-fold higher stroke risk. When added to the CHA2DS2VASc or CHADS2 scores, CrCl <60 mL/min did not improve the c-indexes for CHADS2 (P = 0.054) or CHA2DS2VASc (P = 0.63) but resulted in significant NRI (0.26, P = 0.02) in this anticoagulated trial cohort. CONCLUSION: Renal impairment (CrCl <60 mL/min) doubles the risk of stroke and increased the risk of major bleeding by almost 60% in anticoagulated patients with AF. Renal impairment was additive to stroke risk prediction scores based on a significant NRI, but no significant improvement in discrimination ability (based on c-indexes) for CHA2DS2VASc or CHADS2 was observed.","author":[{"dropping-particle":"","family":"Apostolakis","given":"Stavros","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guo","given":"Yuotao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buller","given":"Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European heart journal","id":"ITEM-1","issue":"46","issued":{"date-parts":[["2013","12"]]},"language":"eng","page":"3572-3579","publisher-place":"England","title":"Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial.","type":"article-journal","volume":"34"},"uris":[""]}],"mendeley":{"formattedCitation":"(67)","plainTextFormattedCitation":"(67)","previouslyFormattedCitation":"(67)"},"properties":{"noteIndex":0},"schema":""}(67)Post-hoc analysis of RCTAF4,57666.5;70 (9)Stroke or SE10.8 monthsCrCl, eGFR (MDRD, CKD-EPI)Lower levels of renal function were associated with greater risk of stroke or SEKrishnamoorthy, 2013 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/eci.12140","ISSN":"1365-2362 (Electronic)","PMID":"23961715","abstract":"BACKGROUND: Endothelial damage/dysfunction may contribute to a prothrombotic state in patients with atrial fibrillation (AF) and the increased risk of thromboembolism and cardiovascular events. Raised plasma von Willebrand factor (vWf), an established marker of endothelial damage/dysfunction, has been associated with stroke and vascular events, at least in a clinical trial population. Soluble E-selectin (sE-sel) is another biomarker of endothelial activation/dysfunction, with more limited data on prognostic outcomes in AF. OBJECTIVE: To assess the relationship between the levels of vWf, sE-sel and clinical adverse outcomes (including stroke, MI and all-cause mortality) in a 'real-world' community cohort of patients with AF. METHODS: We studied 423 patients (mean age 72.7 +/- 8.4 years, 55.6% male) with nonvalvular AF, with a median follow-up of 19 (9-31) months. Plasma vWf and sE-sel levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: There were 94 clinical adverse events (22.2%) observed during a median follow-up of 19 months. Patients with clinical events had significantly higher vWf (P < 0.001) and sE-sel levels at baseline (P < 0.001) compared with those who were event free. Kaplan-Meir analyses demonstrated that more clinical adverse events occurred in the upper tertile of vWf [upper vs. lowest tertile, RR 3.8, 95% CI (2.63-5.57), P < 0.001; upper vs. middle tertile, RR 10.5, 95% CI (5.33-20.60), P < 0.001]. Similarly, the highest tertile of sE-sel was associated with more adverse events [upper vs. lowest tertile, RR 3.7, 95% CI (2.51-5.31), P < 0.001; upper vs. middle tertile, RR 6.5, 95% CI (3.56-11.91), P < 0.001]. CONCLUSION: High plasma vWf and soluble E-selectin levels are associated with an increased risk of clinical adverse events (acute myocardial infarction, ischaemic stroke and all-cause mortality) in 'real-world' patients with AF. These soluble biomarkers may potentially aid clinical risk stratification in this common arrhythmia.","author":[{"dropping-particle":"","family":"Krishnamoorthy","given":"Suresh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khoo","given":"Chee Wah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Hoong S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lane","given":"Deirdre A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Basili","given":"Stefania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European journal of clinical investigation","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2013","10"]]},"language":"eng","page":"1032-1038","publisher-place":"England, England","title":"Prognostic role of plasma von Willebrand factor and soluble E-selectin levels for future cardiovascular events in a 'real-world' community cohort of patients with atrial fibrillation.","type":"article-journal","volume":"43"},"uris":[""]}],"mendeley":{"formattedCitation":"(93)","plainTextFormattedCitation":"(93)","previouslyFormattedCitation":"(93)"},"properties":{"noteIndex":0},"schema":""}(93)Prospective cohortAF, attending clinic42355.6;72.7 (8.4)Composite of stroke, acute MI and all-cause mortality; ischaemic stroke19 monthsvWFHigher vWF levels were associated with greater risk of composite endpoint and ischaemic strokeSoluble E-selectinHigher soluble E-selectin levels were associated with greater risk of composite endpoint and ischaemic strokeHijazi, 2013 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2012.11.082","ISSN":"1558-3597 (Electronic)","PMID":"23563134","abstract":"OBJECTIVES: This study sought to assess the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and the treatment effect of apixaban according to NT-proBNP levels. BACKGROUND: Natriuretic peptides are associated with mortality and cardiovascular events in several cardiac diseases. METHODS: In the ARISTOTLE trial, 18,201 patients with AF were randomized to apixaban or warfarin. Plasma samples at randomization were available from 14,892 patients. The association between NT-proBNP concentrations and clinical outcomes was evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors. RESULTS: Quartiles of NT-proBNP were: Q1, </=363 ng/l; Q2, 364 to 713 ng/l; Q3, 714 to 1,250 ng/l; and Q4, >1,250 ng/l. During 1.9 years, the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile, an adjusted hazard ratio of 2.35 (95% confidence interval [CI]: 1.62 to 3.40; p < 0.0001). Annual rates of cardiac death ranged from 0.86% in Q1 to 4.14% in Q4, with an adjusted hazard ratio of 2.50 (95% CI: 1.81 to 3.45; p < 0.0001). Adding NT-proBNP levels to the CHA2DS2VASc score improved C-statistics from 0.62 to 0.65 (p = 0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p < 0.0001). Apixaban reduced stroke, mortality, and bleeding regardless of the NT-proBNP level. CONCLUSIONS: NT-proBNP levels are often elevated in AF and independently associated with an increased risk of stroke and mortality. NT-proBNP improves risk stratification beyond the CHA2DS2VASc score and might be a novel tool for improved stroke prediction in AF. The efficacy of apixaban compared with warfarin is independent of the NT-proBNP level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984).","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christersson","given":"Christina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Justin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gersh","given":"Bernard J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanna","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horowitz","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huber","given":"Kurt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"Renato D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"McMurray","given":"John J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2013","6"]]},"language":"eng","page":"2274-2284","publisher-place":"United States, United States","title":"N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation).","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"(57)","plainTextFormattedCitation":"(57)","previouslyFormattedCitation":"(57)"},"properties":{"noteIndex":0},"schema":""}(57)Sub-study of RCTAF with at least 1 CHADS2 risk factor14,89264.4;NAStroke or SE1.9 yearsNT-proBNPHigher NT-proBNP levels were associated with greater risk of stroke or SEHighest quartile of NT-proBNP was associated with 2.4-fold greater risk of stroke or SE compared to lowest quartilePiccini, 2013 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.112.107128","ISSN":"00097322","PMID":"23212720","abstract":"BACKGROUND - : We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS - : In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R2CHADS2) improved net reclassification index by 6.2% compared with CHA2DS2VASc (C statistic=0.578) and by 8.2% compared with CHADS2 (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R2CHADS2 in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS2. CONCLUSIONS - : In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. ? 2013 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Piccini","given":"Jonathan P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stevens","given":"Susanna R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lokhnygina","given":"Yuliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Manesh R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahaffey","given":"Kenneth W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"Jonathan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Breithardt","given":"Günter Gunter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hankey","given":"Graeme J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hacke","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Becker","given":"Richard C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nessel","given":"Christopher C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fox","given":"Keith A.A. A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Califf","given":"Robert M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ROCKET AF Steering Committee and Investigators","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013","1","15"]]},"language":"eng","page":"224-232","publisher-place":"United States","title":"Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: Validation of the R2CHADS2 index in the ROCKET AF","type":"article-journal","volume":"127"},"uris":[""]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"(17)"},"properties":{"noteIndex":0},"schema":""}(17) Sub-study of RCTAF with at least 1 stroke risk factor14,26460.7;73 (NA)Stroke or SE1.9 yearsCrCl, eGFR (MDRD)Lower levels of renal function were associated with greater risk of stroke or SE; every 10-mL/min decrease in CrCl resulted in 1.12-fold increase in risk; every 5mL/min/1.73 m2 decrease in eGFR (MDRD) resulted in 1.09-fold increase in riskHijazi, 2012 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.111.038729","ISSN":"1524-4539 (Electronic)","PMID":"22374183","abstract":"BACKGROUND: Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. METHODS AND RESULTS: Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS(2) and CHA(2)DS(2)-VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 mug/L, n=2663; 0.010 to 0.019 mug/L, n=2006; 0.020 to 0.039 mug/L, n=1023; >/=0.040 mug/L, n=497; and on NT-proBNP concentration quartiles: <387; 387 to 800; 801 to 1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17-3.39]; P=0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41-4.07]; P=0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05-6.29]; P<0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95-11.49]; P<0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P<0.0001, for a composite of thromboembolic events. CONCLUSIONS: Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables.","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andersson","given":"Ulrika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reilly","given":"Paul A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinereanu","given":"Dragos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallentin","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"13","issued":{"date-parts":[["2012","4"]]},"language":"eng","page":"1605-1616","publisher-place":"United States, United States","title":"Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy.","type":"article-journal","volume":"125"},"uris":[""]}],"mendeley":{"formattedCitation":"(56)","plainTextFormattedCitation":"(56)","previouslyFormattedCitation":"(56)"},"properties":{"noteIndex":0},"schema":""}(56)Sub-study of RCTAF with at least 1 stroke risk factor6,18963.7;72 (67 - 77)Stroke2.2 yearsNT-proBNPHigher NT-proBNP levels were associated with greater stroke riskHighest quartile of NT-proBNP was associated with 2.4-fold greater risk of stroke compared to lowest quartileTroponin IHigher troponin I levels were associated with greater stroke riskHighest quartile of troponin I was associated with 2.0-fold greater risk of stroke compared to lowest quartileRoldan, 2012 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1538-7836.2012.04812.x","ISSN":"1538-7836 (Electronic)","PMID":"22681487","abstract":"UNLABELLED: There are limited data on the prognostic role of biomarkers in anticoagulated patients with atrial fibrillation (AF). We evaluated the prognostic value of high sensitivity TnT (hsTnT) and high-sensitivity interleukin-6 (hsIL6) in a large cohort of AF patients taking oral anticoagulant therapy (OAC) as both biomarkers have been associated with adverse cardiovascular events. METHODS: We studied 930 patients (51% male; median age 76) with permanent/ paroxysmal AF who were stabilized (for at least 6 months) on OAC (INRs 2.0-3.0). Plasma hsTnT and hsIL6 levels were quantified by electrochemiluminescense immunoassay at baseline. Patients were followed-up for up to 2 years, and adverse events (thrombotic and vascular events, mortality and major bleeding) were recorded. RESULTS: At follow-up, 96 patients (3.97%/year) died whilst 107 had an adverse cardiovascular event (3.14%/year). On multivariate analysis, high hsTnT and high hsIL6 remained significantly associated with prognosis even after adjusting for CHADS2 score: HR 2.21 (1.46-3.35, P<0.001) for high hsTnT and 1.97 (1.29-3.02, P=0.002) for high hsIL6, for adverse cardiovascular events. For all-cause mortality, the HRs were 1.79 (1.13-2.83, P=0.013) and 2.48 (1.60-3.85, P<0.001), respectively. The integrated discrimination index (IDI) values of clinical scores (CHADS2 and CHA2 DS2-VASc) were improved by the addition of hsTnT and/or hsIL6 (all P<0.05). CONCLUSION: In a large 'real world' cohort of anticoagulated AF patients, both hsTnT and hsIL6 levels provided prognostic information that was complementary to clinical risk scores for prediction of long-term cardiovascular events and death, suggesting that these biomarkers may potentially be used to refine clinical risk stratification in AF.","author":[{"dropping-particle":"","family":"Roldan","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diaz","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallego","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jover","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Romera","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manzano-Fernandez","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casas","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"G Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of thrombosis and haemostasis : JTH","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2012","8"]]},"language":"eng","page":"1500-1507","publisher-place":"England, England","title":"High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation.","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(55)","plainTextFormattedCitation":"(55)","previouslyFormattedCitation":"(55)"},"properties":{"noteIndex":0},"schema":""}(55)Prospective cohortAF on OAC, attending clinic93051;76 (70 - 81)Stroke or TIA2 yearsTroponin THigh troponin T levels were associated with a 2.4-fold greater stroke or TIA riskIL-6No association with stroke or TIAEhrlich, 2011 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00392-011-0337-9","ISSN":"1861-0692 (Electronic)","PMID":"21725858","abstract":"INTRODUCTION: Atrial fibrillation (AF) is associated not only with inflammation but also with structural remodelling and altered endothelial activation which may contribute to clot formation, embolization and mortality. We aimed to determine the predictive value of single-time biomarker analysis for prediction of outcome in patients with AF. METHODS AND RESULTS: We conducted a prospective study to evaluate if biomarkers of structural, electrical or endothelial remodelling are predictive of cardiovascular events (composite primary endpoint of myocardial infarction, stroke, peripheral embolism or death). Secondary endpoint was all-cause mortality. Patients with any type of AF and without active inflammatory conditions were eligible. Plasma samples were collected for ELISA analysis of biomarkers (inflammation [hsCRP, sCD40L], structural [MMP-2] and endothelial remodelling [vWF, sVCAM-1]) at enrolment. Patients (n = 278) were followed for 28 +/- 12 (median 32) months. Eighty-eight individuals (32%) experienced a primary outcome event, including 8 (2.9%) with myocardial infarction, 13 (4.8%) with stroke and 4 (1.5%) with peripheral embolism. Predictors of the primary endpoint were age >75 years, CHADS(2)-score >2, LVEF <35%, diabetes, presence of an ICD/pacemaker, elevated vWF, sVCAM-1 and MMP-2 levels. On multivariate regression analysis, only age >75 years, sVCAM-1 and MMP-2 levels remained independently associated with the endpoint. There were 75 deaths during follow-up. Age >75 years, reduced LVEF, elevated sVCAM-1 and MMP-2 levels were predictors of all-cause mortality. CONCLUSION: In this cohort of AF patients, old age, elevated sVCAM-1 and MMP-2 levels were associated with cardiovascular events. Our data indicate that single-time biomarker assessment may be a useful tool to improve risk stratification schemes.","author":[{"dropping-particle":"","family":"Ehrlich","given":"Joachim R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaluzny","given":"Magdalena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baumann","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehmann","given":"Ralf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohnloser","given":"Stefan H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical research in cardiology : official journal of the German Cardiac Society","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2011","11"]]},"language":"eng","page":"1029-1036","publisher-place":"Germany, Germany","title":"Biomarkers of structural remodelling and endothelial dysfunction for prediction of cardiovascular events or death in patients with atrial fibrillation.","type":"article-journal","volume":"100"},"uris":[""]}],"mendeley":{"formattedCitation":"(97)","plainTextFormattedCitation":"(97)","previouslyFormattedCitation":"(97)"},"properties":{"noteIndex":0},"schema":""}(97)Prospective cohortAF27863;70 (11)Composite of stroke, MI, SE and all-cause death28 monthshsCRPNo association with composite endpointsCD40LNo association with composite endpointMMP-2Higher MMP-2 levels were associated with greater risk of composite endpointvWFNo association with composite endpointsVCAM-1Higher sVCAM-1 levels were associated with greater risk of composite endpointRoldan, 2011 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2010.12.033","ISSN":"1558-3597 (Electronic)","PMID":"21497043","abstract":"OBJECTIVES: The purpose of this study was to evaluate the prognostic value of plasma von Willebrand factor (vWF) levels and fibrin d-dimer in a large cohort of anticoagulated permanent atrial fibrillation (AF) patients. BACKGROUND: In nonanticoagulated AF patients, plasma vWF levels have been related to stroke and vascular events. There are limited data on the prognostic role of biomarkers in anticoagulated AF patients in relation to adverse events (including thromboembolism), mortality, and major bleeding. METHODS: We studied 829 patients (50% male; median age 76 years) with permanent AF who were stabilized (for at least 6 months) on oral anticoagulation therapy (international normalized ratio: 2.0 to 3.0). Plasma d-dimer and vWF levels were quantified by enzyme-linked immunosorbent assay. Patients were followed for 2 years, and adverse events (thrombotic and vascular events, mortality, and major bleeding) were recorded. RESULTS: Patients were followed for a median of 828 days (range 18 to 1,085 days). On multivariate analysis, age 75 years and older, previous stroke, heart failure, and high plasma vWF levels (>/= 221 IU/dl) were associated with future adverse cardiovascular events (all p values <0.05). High plasma vWF levels, elderly patients, diabetes, hypercholesterolemia, and current smoking were associated with mortality (all p values <0.05). High plasma vWF levels were also an independent predictor of major bleeding (hazard ratio: 4.47, 95% confidence interval: 1.86 to 10.75; p < 0.001). High plasma vWF levels were able to refine clinical risk stratification schema for stroke (CHADS(2) [Congestive heart failure, Hypertension, Age >/= 75, Diabetes mellitus, and prior Stroke or transient ischemic attack (doubled)], CHA(2)DS(2)-VASc [Congestive heart failure, Hypertension, Age >/= 75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 to 74 years, Sex category]) and bleeding (HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly]). d-dimer did not show any significant impact on adverse events. CONCLUSIONS: High plasma vWF levels (>/=221 IU/dl) are an independent risk factor for adverse events in anticoagulated permanent AF patients. This biomarker may potentially be used to refine stroke and bleeding clinical risk stratification in AF.","author":[{"dropping-particle":"","family":"Roldan","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marin","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muina","given":"Begona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Torregrosa","given":"Jose Miguel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernandez-Romero","given":"Diana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valdes","given":"Mariano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vicente","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"25","issued":{"date-parts":[["2011","6"]]},"language":"eng","page":"2496-2504","publisher-place":"United States","title":"Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients.","type":"article-journal","volume":"57"},"uris":[""]}],"mendeley":{"formattedCitation":"(92)","plainTextFormattedCitation":"(92)","previouslyFormattedCitation":"(92)"},"properties":{"noteIndex":0},"schema":""}(92)Prospective cohortAF on OAC, attending clinic82950;76 (70 - 80)Composite of TE, acute MI and acute HF27.6 monthsvWFHigh vWF levels were associated with a greater risk of composite endpointHa, 2011 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3109/09537104.2011.560306","ISSN":"1369-1635 (Electronic)","PMID":"21599611","abstract":"Platelet size, measured as mean platelet volume (MPV), is associated with platelet reactivity. MPV has been identified as an independent risk factor for future stroke and myocardial infarction. The aim of this study was to determine the association of MPV with the development of stoke in patients with atrial fibrillation (AF). MPV, N-terminal pro B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) were analysed in 200 patients with AF (mean age 69 years; 56% male). The primary endpoint was ischaemic stroke event. The mean MPV was 8.5 +/- 1.0 fL and the median NT-proBNP was 1916.5 (IQR 810-4427) pg/mL. The median hsCRP was 0.47 (IQR 0.32-2.46) mg/dL. There were 14 stroke events during a mean of 15.1 months of follow up. Kaplan-Meier analysis revealed that the higher tertile MPV group (>/=8.9 fL) had a significantly higher stroke rate compared to the lower tertile MPV group (<8.0 fL) (14.7% vs. 3.1%, log-rank: P = 0.01). A higher MPV was an independent predictor of stroke risk after adjusting for age, gender, and other CHADS(2) (congestive heart failure, hypertension, diabetes, and previous stroke or transient ischemic attack (TIA) history) score components (hazard ratio: 5.03, 95% CI 1.05-24.05, P = 0.043) in Cox proportional hazard analysis. When the MPV cut-off level was set to 8.85 fL using the receiver operating characteristic curve, the sensitivity was 71% and the specificity was 69% for differentiating between the group with stroke and the group without stroke. This value was more useful in patients with a low to intermediate traditional thromboembolic risk (CHADS(2) score <2). Furthermore, AF patients with an MPV over 8.85 fL had high stroke risk without anticoagulation, especially in the low thromboembolic risk group (Log-Rank <0.0001). The results of this study show that MPV was a predictive marker for stroke; its predictive power for stroke was independent of age, gender, and other CHADS(2) score components in patients with AF. These findings suggest that anticoagulation may be needed in patients with a high MPV, even if they have low to intermediate traditional thromboembolic risk (CHADS(2) score <2).","author":[{"dropping-particle":"","family":"Ha","given":"Sung-Il","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Dong-Hyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ki","given":"Young-Jae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Joon-Seung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Geon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Joong-Wha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koh","given":"Young-Youp","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Kyong-Sig","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hong","given":"Soon-Pyo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Platelets","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2011"]]},"language":"eng","page":"408-414","publisher-place":"England, England","title":"Stroke prediction using mean platelet volume in patients with atrial fibrillation.","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(101)","plainTextFormattedCitation":"(101)","previouslyFormattedCitation":"(101)"},"properties":{"noteIndex":0},"schema":""}(101)Prospective cohortAF20056;68.9 (11.7)Ischaemic stroke15.1 monthsMPVHigher MPV levels were associated with greater ischaemic stroke riskHighest tertile of MPV was associated with a 5.0-fold greater risk of ischaemic stroke compared to lowest quartileSadanaga, 2011 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00380-010-0084-2","ISSN":"1615-2573 (Electronic)","PMID":"21188387","abstract":"The aim of the present study was to assess whether elevated B-type natriuretic peptide (BNP) levels, as an objective marker of heart failure, is a predictor of subsequent thromboembolic events in patients with atrial fibrillation (AF) during oral anticoagulant therapy. This was a post hoc analysis of a single-center, prospective, observational study. Consecutive patients with AF (261 patients, 74 +/- 9 years old, 153 paroxysmal AF) treated with warfarin were included for the analysis. BNP level at baseline examination was measured to assess the relationship of this parameter with subsequent thromboembolic events. BNP levels at the time of entry were 161 +/- 188 (5-1,500, median 105) pg/ml. During an average follow-up time of 762 +/- 220 (median 742) days, nine (1.8%/year) thromboembolic events occurred. Receiver operating characteristic curve showed that an optimal cut-off value for BNP to predict thromboembolic events was 218 pg/ml. There were six thromboembolic events observed among patients with a baseline BNP levels >/=200 pg/ml (n = 73) as compared to three such events in those with baseline BNP levels <200 pg/ml (n = 188). Kaplan-Meier curves for BNP level showed that elevated BNP level (>/=200 pg/ml) was significantly associated with thromboembolic events (p < 0.01). Cox-proportional hazard analysis also revealed that a high BNP level (>/=200 pg/ml) was a significant predictor of subsequent thromboembolic events (hazard ratio 5.32, p = 0.018). Elevated BNP levels (>/=200 pg/ml) could be a useful marker of subsequent thromboembolic events in patients with AF during oral anticoagulant therapy. However, the number of patients and events in this study was small and drawing a definite conclusion was not possible with this small sample size. Therefore, further larger-scale, multicenter studies are needed to confirm these findings.","author":[{"dropping-particle":"","family":"Sadanaga","given":"Tsuneaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kohsaka","given":"Shun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mitamura","given":"Hideo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogawa","given":"Satoshi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart and vessels","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2011","9"]]},"language":"eng","page":"530-535","publisher-place":"Japan, Japan","title":"Elevated B-type natriuretic peptide level as a marker of subsequent thromboembolic events in patients with atrial fibrillation.","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"(54)","plainTextFormattedCitation":"(54)","previouslyFormattedCitation":"(54)"},"properties":{"noteIndex":0},"schema":""}(54)Post-hoc analysis of prospective cohortAF on OAC26156;74 (9)Ischaemic stroke, TIA or SE24.7 monthsBNPHigh BNP levels were associated with a 5.3-fold greater risk of ischaemic stroke, TIA or SESadanaga, 2010 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2009.12.049","ISSN":"07351097","author":[{"dropping-particle":"","family":"Sadanaga","given":"Tsuneaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sadanaga","given":"Motoaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogawa","given":"Satoshi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"20","issued":{"date-parts":[["2010"]]},"page":"2225-2231","title":"Evidence That D-Dimer Levels Predict Subsequent Thromboembolic and Cardiovascular Events in Patients With Atrial Fibrillation During Oral Anticoagulant Therapy","type":"article-journal","volume":"55"},"uris":[""]}],"mendeley":{"formattedCitation":"(87)","plainTextFormattedCitation":"(87)","previouslyFormattedCitation":"(87)"},"properties":{"noteIndex":0},"schema":""}(87)Prospective cohortAF on OAC26957;74 (9)Ischaemic stroke, TIA or SE25.2 monthsD-dimerHigh D-dimer levels were associated with a 15.8-fold greater risk of ischaemic stroke, TIA or SEGo, 2009 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.108.816082","ISSN":"1524-4539 (Electronic)","PMID":"19255343","abstract":"BACKGROUND: Atrial fibrillation (AF) substantially increases the risk of ischemic stroke, but this risk varies among individual patients with AF. Existing risk stratification schemes have limited predictive ability. Chronic kidney disease is a major cardiovascular risk factor, but whether it independently increases the risk for ischemic stroke in persons with AF is unknown. METHODS AND RESULTS: We examined how chronic kidney disease (reduced glomerular filtration rate or proteinuria) affects the risk of thromboembolism off anticoagulation in patients with AF. We estimated glomerular filtration rate using the Modification of Diet in Renal Disease equation and proteinuria from urine dipstick results found in laboratory databases. Patient characteristics, warfarin use, and thromboembolic events were ascertained from clinical databases, with validation of thromboembolism by chart review. During 33,165 person-years off anticoagulation among 10,908 patients with AF, we observed 676 incident thromboembolic events. After adjustment for known risk factors for stroke and other confounders, proteinuria increased the risk of thromboembolism by 54% (relative risk, 1.54; 95% CI, 1.29 to 1.85), and there was a graded, increased risk of stroke associated with a progressively lower level of estimated glomerular filtration rate compared with a rate > or =60 mL x min(-1) x 1.73 m(-2): relative risk of 1.16 (95% CI, 0.95 to 1.40) for estimated glomerular filtration rate of 45 to 59 mL x min(-1) x 1.73 m(-2) and 1.39 (95% CI, 1.13 to 1.71) for estimated glomerular filtration rate <45 mL x min(-1) x 1.73 m(-2) (P=0.0082 for trend). CONCLUSIONS: Chronic kidney disease increases the risk of thromboembolism in AF independently of other risk factors. Knowing the level of kidney function and the presence of proteinuria may improve risk stratification for decision making about the use of antithrombotic therapy for stroke prevention in AF.","author":[{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fang","given":"Margaret C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Udaltsova","given":"Natalia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pomernacki","given":"Niela K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borowsky","given":"Leila","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2009","3","17"]]},"language":"eng","page":"1363-1369","publisher-place":"United States","title":"Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.","type":"article-journal","volume":"119"},"uris":[""]}],"mendeley":{"formattedCitation":"(68)","plainTextFormattedCitation":"(68)","previouslyFormattedCitation":"(68)"},"properties":{"noteIndex":0},"schema":""}(68)Sub-study of prospective cohortAF10,90857.2;71.6 (NA)TE3 yearseGFR (MDRD)Lower levels of renal function were associated with greater TE riskPinto, 2009 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1042/CS20080372","ISSN":"1470-8736 (Electronic)","PMID":"18980576","abstract":"The aim of the present study was to determine the rates of stroke in patients with chronic NVAF (non-valvular atrial fibrillation), evaluating the relationship between plasma levels of inflammatory variables at admission and the occurrence of stroke during a 3-year follow-up. A total of 373 consecutive patients with chronic NVAF were enrolled. Blood samples were drawn within 72 h of admission, and we evaluated plasma levels of IL (interleukin)-1beta, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-10, E-selectin, P-selectin, ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and vWF (von Willebrand Factor). Subsequent patient events (stroke at follow-up) were monitored over a 3 year period. By multivariate analysis, only age, hypertension and high levels of IL-6, TNF-alpha and vWF remained significant predictors of a higher risk of experiencing ischaemic stroke at follow-up. Moreover, plasma values of TNF-alpha, IL-6 and vWF had a significant area under the ROC (receiver operating characteristic) curve. In conclusion, baseline plasma levels of TNF-alpha, IL-6 and vWF are predictors of new-onset ischaemic stroke at follow-up in patients with chronic NVAF.","author":[{"dropping-particle":"","family":"Pinto","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuttolomondo","given":"Antonino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casuccio","given":"Alessandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raimondo","given":"Domenico","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sciacca","given":"Riccardo","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnao","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Licata","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical science (London, England : 1979)","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2009","5"]]},"language":"eng","page":"781-789","publisher-place":"England, England","title":"Immuno-inflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF).","type":"article-journal","volume":"116"},"uris":[""]}],"mendeley":{"formattedCitation":"(91)","plainTextFormattedCitation":"(91)","previouslyFormattedCitation":"(91)"},"properties":{"noteIndex":0},"schema":""}(91)Prospective cohortChronic AF37363.5;66.1 (7.4)Ischaemic stroke3 yearsIL-1βNo association with ischaemic strokeTNF-αHigher TNF-α levels were associated with greater ischaemic stroke riskIL-6Higher IL-6 levels were associated with greater ischaemic stroke riskIL-10No association with ischaemic strokeE-selectinNo association with ischaemic strokeP-selectinNo association with ischaemic strokeICAM-1No association with ischaemic strokeVCAM-1No association with ischaemic strokevWFHigher vWF levels were associated with greater ischaemic stroke riskFerro, 2007 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/ATVBAHA.107.152777","ISSN":"1524-4636 (Electronic)","PMID":"17901373","abstract":"OBJECTIVE: Atrial fibrillation (AF) is associated with a high incidence of vascular disease that may be related to a prothrombotic and inflammatory state. Soluble CD40 ligand (sCD40L), which stems essentially from platelet activation, possesses inflammatory and prothrombotic properties. The aim of the study was to assess whether sCD40L is a predictor of stroke or myocardial infarction (MI) in patients with nonvalvular AF. METHODS AND RESULTS: Plasma levels of sCD40L were measured in 231 patients (177 [77%] had permanent or persistent AF, and 54 [23%] had paroxysmal AF). Patients were followed for a mean period of 27.8+/-8.8 months, and cardiovascular events such as fatal and nonfatal stroke and MI were recorded. AF population was divided in 2 groups according to sCD40L level above or below the median (4.76 ng/mL). The 2 patients' groups had similar distribution of cardiovascular risk factors, age, gender, medications, or serum C-reactive protein levels. During the follow-up period, vascular events occurred in 6 (2 nonfatal MI and 4 nonfatal ischemic strokes) of 116 patients with low levels of sCD40L (5.1%) and in 29 (11 fatal and 3 nonfatal MI; 3 fatal and 12 nonfatal ischemic strokes) of 115 patients with high levels (25.2%) (log-rank test: P<0.001). Using the COX proportional Hazards model, patients with sCD40L above the median were 4.63 times more likely to experience a vascular event (95% C.I.: 1.92 to 11.20). CONCLUSIONS: This study shows that enhanced soluble CD40L level is a predictor of vascular events in patients with nonvalvular AF, thus suggesting that enhanced platelet activation may play a role in its clinical progression.","author":[{"dropping-particle":"","family":"Ferro","given":"Domenico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Loffredo","given":"Lorenzo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Polimeni","given":"Licia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fimognari","given":"Filippo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Villari","given":"Paolo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pignatelli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fuster","given":"Valentin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Violi","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Arteriosclerosis, thrombosis, and vascular biology","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2007","12"]]},"language":"eng","page":"2763-2768","publisher-place":"United States, United States","title":"Soluble CD40 ligand predicts ischemic stroke and myocardial infarction in patients with nonvalvular atrial fibrillation.","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(102)","plainTextFormattedCitation":"(102)","previouslyFormattedCitation":"(102)"},"properties":{"noteIndex":0},"schema":""}(102)Prospective cohortAF23148;72.4 (10.3)Composite of stroke and MI27.8 monthssCD40LHigh sCD40L levels were associated with a 4.6-fold greater risk of composite endpointNozawa, 2006 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ijcard.2005.05.049","ISSN":"0167-5273 (Print)","PMID":"15992948","abstract":"BACKGROUND: Elevated coagulative molecular markers could reflect the prothrombotic state in the cardiovascular system of patients with non-valvular atrial fibrillation (NVAF). A prospective, cooperative study was conducted to determine whether levels of coagulative markers alone or in combination with clinical risk factors could predict subsequent thromboembolic events in patients with NVAF. METHODS: Coagulative markers of prothrombin fragment 1+2, D-dimer, platelet factor 4, and beta-thromboglobulin were determined at the enrollment in the prospective study. RESULTS: Of 509 patients with NVAF (mean age, 66.6 +/- 10.3 years), 263 patients were treated with warfarin (mean international normalized ratio, 1.86), and 163 patients, with antiplatelet drugs. During an average follow-up period of 2.0 years, 31 thromboembolic events occurred. Event-free survival was significantly better in patients with D-dimer level < 150 ng/ml than in those with D-dimer level>or==150 ng/ml. Other coagulative markers, however, did not predict thromboembolic events. Age (>or==75 years), cardiomyopathies, and prior stroke or transient ischemic attack were independent, clinical risk factors for thromboembolism. Thromboembolic risk in patients without the clinical risk factors was quite low (0.7%/year) when D-dimer was < 150 ng/ml, but not low (3.8%/year) when D-dimer was >or==150 ng/ml. It was >5%/year in patients with the risk factors regardless of D-dimer levels. This was also true when analyses were confined to patients treated with warfarin. CONCLUSIONS: D-dimer level in combination with clinical risk factors could effectively predict subsequent thromboembolic events in patients with NVAF even when treated with warfarin.","author":[{"dropping-particle":"","family":"Nozawa","given":"Takashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inoue","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirai","given":"Tadakazu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwasa","given":"Atsushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okumura","given":"Ken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jong-Dae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimizu","given":"Akihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayano","given":"Motonobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yano","given":"Katsusuke","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International journal of cardiology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2006","4"]]},"language":"eng","page":"59-65","publisher-place":"Netherlands, Netherlands","title":"D-dimer level influences thromboembolic events in patients with atrial fibrillation.","type":"article-journal","volume":"109"},"uris":[""]}],"mendeley":{"formattedCitation":"(85)","plainTextFormattedCitation":"(85)","previouslyFormattedCitation":"(85)"},"properties":{"noteIndex":0},"schema":""}(85)Prospective cohortAF50964.8;66.6 (10.3)Composite of clinically evident stroke, TIA and SE2 yearsD-dimerHigh D-dimer levels were associated with a greater risk of composite endpointF1+2No association with composite endpointPlatelet factor 4No association with composite endpointβ-thromboglobulinNo association with composite endpointConway, 2004 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ahj.2004.01.026","ISSN":"1097-6744 (Electronic)","PMID":"15389233","abstract":"BACKGROUND: Atrial fibrillation (AF) is a risk factor for stroke and death. Inflammation has been associated with AF, but the prognostic significance of inflammatory mediators, such as interleukin-6 (IL-6) and C-reactive protein (CRP), among patients with AF is unknown. We hypothesized that increased plasma levels of IL-6 and CRP, as indexes of an inflammatory state, would be associated with an increased risk of stroke and death among patients with AF. METHODS: We undertook a pilot study to determine dates of stroke or death occurring among 77 AF cases, with stored plasma samples having initially been obtained during attendance at our specialist AF clinic between 1993 and 1995. Plasma IL-6 and CRP were measured by ELISA and a high-sensitivity latex particle turbidimetric assay, respectively. RESULTS: Patients were followed up for a median duration of 2305 days (interquartile range, 1692 to 2592) [equivalent to 6.3 (4.6 to 7.1) years]. During this period, there were 8 (10%) strokes, 22 (29%) deaths, and 28 (36%) patients who had stroke or death. Prior stroke and high (above median) IL-6 levels were independent predictors of stroke. Age was the only independent predictor of death. High (above median) IL-6 levels remained a significant predictor of stroke or death, even after adjustment for age (hazard ratio, 2.91; 95% CI, 1.20 to 6.51; P =.007), and was the only independent predictor of stroke or death. Trends toward increased risk with high plasma CRP did not reach statistical significance (P =.06 for stroke or death). CONCLUSIONS: In this pilot study, high plasma IL-6 levels were an independent predictor of stroke and the composite end point of stroke or death, suggesting that inflammation in AF may predict a poor prognosis.","author":[{"dropping-particle":"","family":"Conway","given":"Dwayne S g","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buggins","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hughes","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American heart journal","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2004","9"]]},"language":"eng","page":"462-466","publisher-place":"United States, United States","title":"Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation.","type":"article-journal","volume":"148"},"uris":[""]}],"mendeley":{"formattedCitation":"(95)","plainTextFormattedCitation":"(95)","previouslyFormattedCitation":"(95)"},"properties":{"noteIndex":0},"schema":""}(95)Prospective cohortAF, attending clinic7757;68 (62 - 75)Stroke6.3 yearsIL-6High IL-6 levels were associated with a 2.9-fold greater stroke riskCRPNo association with strokeVene, 2003 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1160/TH03-06-0363","ISSN":"0340-6245 (Print)","PMID":"14652652","abstract":"Atrial fibrillation (AF) is associated with hemostatic abnormalities and increased risk of thrombotic cardiovascular events even during oral anticoagulant therapy (OAT). The aim of our study was to evaluate the predictive value of hemostatic markers for the risk of major cardiovascular events during OAT. The study group comprised 113 patients with chronic AF (70.2 +/- 5.4 years old, 60% men), referred for OAT. Established clinical risk factors and levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) antigen and activity, before and during OAT (after 3.9 +/- 0.7 months; INR 2.57 +/- 0.57) were determined. In all patients OAT significantly suppressed levels of F1+2 by 67%,TAT by 30% and D-dimer by 48% (all p <0.001). During an average follow-up of 44 months 22/111 (20%) patients suffered a combined cardiovascular event (stroke, myocardial infarction, peripheral vascular occlusion or vascular death). Patients with cardiovascular events were significantly older, had more frequent heart failure/systolic dysfunction and had significantly increased levels of D-dimer at entry (63 vs 39 ng/mL, p = 0.005) and during OAT (33 vs 18 ng/mL, p = 0.002), and of t-PA antigen at entry (14.3 vs 10.9 ng/mL, p = 0.02) and during OAT (15.0 vs 11.2 ng/mL, p = 0.05) (all values are medians). In multivariate Cox proportional hazard models, heart failure/systolic dysfunction (hazard ratio 2.91; 95% CI 1.17-7.26; p = 0.02), high levels of D-dimer on OAT (top vs. lower two quartiles) (hazard ratio 4.78, 95% CI 1.39-16.41; p = 0.01) and t-PA antigen levels (continuous variable) (hazard ratio 1.09; 95% CI 1.01-1.17; p = 0.02) were significantly associated with combined cardiovascular events. In conclusion, high levels of D-dimer and t-PA antigen during OAT are significant predictors of combined cardiovascular events in AF patients and, on this basis, could be useful additional markers of cardiovascular risk in such patients.","author":[{"dropping-particle":"","family":"Vene","given":"Nina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mavri","given":"Alenka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kosmelj","given":"Katarina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stegnar","given":"Mojca","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thrombosis and haemostasis","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2003","12"]]},"language":"eng","page":"1163-1172","publisher-place":"Germany, Germany","title":"High D-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulant therapy.","type":"article-journal","volume":"90"},"uris":[""]}],"mendeley":{"formattedCitation":"(86)","plainTextFormattedCitation":"(86)","previouslyFormattedCitation":"(86)"},"properties":{"noteIndex":0},"schema":""}(86)Prospective cohortAF referred to clinic for initiation of OAC11360;70.2 (5.4)Composite of stroke, MI, SE, peripheral vascular occlusion and cardiovascular death44.3 monthsD-dimerHigher D-dimer levels were associated with greater risk of composite endpointtPAHigher tPA levels were associated with greater risk of composite endpointF1+2No association with composite endpointTAT complexesNo association with composite endpointPAI-1No association with composite endpointFeinberg, 1999 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/01.str.30.12.2547","ISBN":"0039-2499 (Print)\\r0039-2499 (Linking)","ISSN":"0039-2499 (Print)","PMID":"10582976","abstract":"BACKGROUND AND PURPOSE: Markers of thrombin generation and platelet activation are often elevated in patients with nonvalvular atrial fibrillation, but it is unclear whether such markers usefully predict stroke. Therefore, we undertook the present study to assess the relationship between prothrombin fragment F1.2 (F1.2), beta-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation with stroke in atrial fibrillation. METHODS: Specimens were obtained from 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. The results were correlated with patient features, antithrombotic therapy, and subsequent thromboembolism (ischemic stroke and systemic embolism) by multivariate analysis. RESULTS: Increased F1.2 levels were associated with age (P<0.001), female sex (P<0.001), systolic blood pressure (P=0.006), and heart failure (P=0.001). F1.2 were not affected by aspirin use and were not associated with thromboembolism after adjustment for age (P=0. 18). BTG levels were higher with advanced age (P=0.006), coronary artery disease (P=0.05), carotid disease (P=0.005), and heart failure (P<0.001), lower in regular alcohol users (P=0.05), and not significantly associated with thromboembolism. Fibrinogen levels were not significantly related to thromboembolism but were associated with elevated BTG levels (P<0.001). The factor V Leiden mutation was not associated with thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8). CONCLUSIONS: Elevated F1.2 levels were associated with clinical risk factors for stroke in atrial fibrillation, whereas increased BTG levels were linked to manifestations of atherosclerosis. In this large cohort of patients with atrial fibrillation who were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not independent, clinically useful predictors of stroke.","author":[{"dropping-particle":"","family":"Feinberg","given":"William M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"Lesly A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cushman","given":"Mary","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornell","given":"Elaine S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bovill","given":"Edwin G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stroke","id":"ITEM-1","issue":"12","issued":{"date-parts":[["1999","12"]]},"language":"eng","page":"2547-2553","publisher":"Lippincott Williams and Wilkins","publisher-place":"United States, United States","title":"Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study.","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(98)","plainTextFormattedCitation":"(98)","previouslyFormattedCitation":"(98)"},"properties":{"noteIndex":0},"schema":""}(98)Sub-study of prospective cohortAF with at least 1 high-risk stroke factor1,531NA;70 (NA)Ischaemic stroke or SE2 yearsF1+2No association with ischaemic stroke or SEβ-thromboglobulinNo association with ischaemic stroke or SEFibrinogenNo association with ischaemic stroke or SEFactor V Leiden mutationNo association with ischaemic stroke or SEAF, atrial fibrillation; BNP, B-type natriuretic peptide; CrCl, creatinine clearance; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; F1+2, prothrombin fragment F1+2; hsCRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; IL-10, interleukin-10; IL-1β, interleukin-1β; IL-6, interleukin-6; IQR, interquartile range; LA, left atrial; MDRD, Modification of Diet in Renal Disease Study; MI, myocardial infarction; MMP-2, matrix metalloproteinase-2; MPV, mean platelet volume; NA, not applicable or available; NOAC, non-vitamin K oral anticoagulants; NOX2, reduced nicotinamide adenine dinucleotide phosphate oxidase 2; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OAC, oral anticoagulation; PAI-1, plasminogen activator inhibitor-1; RCT, randomised controlled trial; sCD40L, soluble CD40 ligand; SD, standard deviation; SE, systemic embolism; sVCAM-1, soluble vascular cell adhesion molecule-1; TAT, thrombin-antithrombin; TE, thromboembolism; TIA, transient ischaemic attack; TNF-α, tumour necrosis factor-alpha; tPA, tissue plasminogen activator; vWF, von Willebrand factor.Structural biomarkers for stroke risk in AFStudy, year (ref)DesignStudy populationn% male; mean (SD) age, yearsRelevant outcome measuresFollow-up durationBiomarkerFindingsDakay, 2018 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jstrokecerebrovasdis.2017.08.025","ISSN":"15328511","PMID":"28918087","abstract":"Background: Despite anticoagulation therapy, ischemic stroke risk in atrial fibrillation (AF) remains substantial. We hypothesize that left atrial enlargement (LAE) is more prevalent in AF patients admitted with ischemic stroke who are therapeutic, as opposed to nontherapeutic, on anticoagulation. Methods: We included consecutive patients with AF admitted with ischemic stroke between April 1, 2015, and December 31, 2016. Patients were divided into two groups based on whether they were therapeutic (warfarin with an international normalized ratio ≥ 2.0 or non–vitamin K oral anticoagulant with uninterrupted use in the prior 2 weeks) versus nontherapeutic on anticoagulation. Univariable and multivariable models were used to estimate associations between therapeutic anticoagulation and clinical factors, including CHADS2 score and LAE (none/mild versus moderate/severe). Results: We identified 225 patients during the study period; 52 (23.1%) were therapeutic on anticoagulation. Patients therapeutic on anticoagulation were more likely to have a larger left atrial diameter in millimeters (45.6 ± 9.2 versus 42.3 ± 8.6, P =.032) and a higher CHADS2 score (2.9 ± 1.1 versus 2.4 ± 1.1, P =.03). After adjusting for the CHADS2 score, patients who had a stroke despite therapeutic anticoagulation were more likely to have moderate to severe LAE (odds ratio, 2.05; 95% confidence interval, 1.01-4.16). Conclusion: LAE is associated with anticoagulation failure in AF patients admitted with an ischemic stroke. This provides indirect evidence that LAE may portend failure of anticoagulation therapy in patients with AF; further studies are needed to delineate the significance of this association and improve stroke prevention strategies.","author":[{"dropping-particle":"","family":"Dakay","given":"Katarina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Andrew D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hemendinger","given":"Morgan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cutting","given":"Shawna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McTaggart","given":"Ryan A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Jayaraman","given":"Mahesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chu","given":"Antony","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Panda","given":"Nikhil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merkler","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gialdini","given":"Gino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kummer","given":"Benjamin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lerario","given":"Michael P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kamel","given":"Hooman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Elkind","given":"Mitchell S.V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furie","given":"Karen L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yaghi","given":"Shadi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Stroke and Cerebrovascular Diseases","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018","1"]]},"language":"eng","page":"192-197","publisher":"Elsevier Inc.","publisher-place":"United States, United States","title":"Left Atrial Enlargement and Anticoagulation Status in Patients with Acute Ischemic Stroke and Atrial Fibrillation","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(109)","plainTextFormattedCitation":"(109)","previouslyFormattedCitation":"(109)"},"properties":{"noteIndex":0},"schema":""}(109)Prospective cohortAF hospitalised with ischaemic stroke22544.4;79.5 (10.5)Anticoagulation failureNALAEMore severe left atrial enlargement was associated with greater risk of anticoagulation failure resulting in strokeHamatani, 2016 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/srep31042","ISSN":"2045-2322 (Electronic)","PMID":"27485817","abstract":"Controversy exists regarding whether left atrial enlargement (LAE) is a predictor of stroke/systemic embolism (SE) in atrial fibrillation (AF) patients. The Fushimi AF Registry, a community-based prospective survey, enrolled all AF patients in Fushmi-ku, Japan, from March 2011. Follow-up data and baseline echocardiographic data were available for 2,713 patients by August 2015. We compared backgrounds and incidence of events over a median follow-up of 976.5 days between patients with LAE (left atrial diameter > 45 mm; LAE group) and those without in the Fushimi AF Registry. The LAE group accounted for 39% (n = 1,049) of cohort. The LAE group was older and had longer AF duration, with more prevalent non-paroxysmal AF, higher CHADS2/CHA2DS2-VASc score, and oral anticoagulant (OAC) use. A higher risk of stroke/SE during follow-up in the LAE group was found (entire cohort; hazard ratio (HR): 1.92, 95% confidence interval (CI): 1.40-2.64; p < 0.01; without OAC; HR: 1.97, 95% CI: 1.18-3.25; p < 0.01; with OAC; HR: 1.83, 95% CI: 1.21-2.82; p < 0.01). LAE was independently associated with increased risk of stroke/SE (HR: 1.74, 95% CI: 1.25-2.42; p < 0.01) after adjustment by the components of CHA2DS2-VASc score and OAC use. In conclusion, LAE was an independent predictor of stroke/SE in large community cohort of AF patients.","author":[{"dropping-particle":"","family":"Hamatani","given":"Yasuhiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogawa","given":"Hisashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takabayashi","given":"Kensuke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamashita","given":"Yugo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takagi","given":"Daisuke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Esato","given":"Masahiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chun","given":"Yeong-Hwa Hwa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsuji","given":"Hikari","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wada","given":"Hiromichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hasegawa","given":"Koji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abe","given":"Mitsuru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lip","given":"Gregory Y.H. H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akao","given":"Masaharu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific reports","id":"ITEM-1","issued":{"date-parts":[["2016","8","3"]]},"language":"eng","page":"31042","publisher":"Nature Publishing Group","publisher-place":"England, England","title":"Left atrial enlargement is an independent predictor of stroke and systemic embolism in patients with non-valvular atrial fibrillation.","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"(108)","plainTextFormattedCitation":"(108)","previouslyFormattedCitation":"(108)"},"properties":{"noteIndex":0},"schema":""}(108)Prospective registryAF2,71360.2;73.7 (NA)Ischaemic stroke or SE32.6 monthsLAELA diameter >45mm was associated with a 1.7-fold greater risk of ischaemic stroke or SEKong, 2014 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"2542-5641","PMID":"25533823","abstract":"BACKGROUND The left atrial appendage (LAA) is thought to be the main source of thrombi in patients with atrial fibrillation (AF). The purpose of this study was to describe the LAA orifice diameter, LAA length, and morphologic type of the LAA in Chinese patients with AF as well as to evaluate whether these LAA parameters are associated with a history of stroke in patients with AF from a single center in China. METHODS The study population consisted of 219 consecutive patients with drug-refractory, symptomatic paroxysmal, or persistent AF scheduled to undergo radiofrequency catheter ablation in our single center. All patients underwent extensive clinical assessment and multidetector computed tomography to fully explore the anatomy of the LAA. RESULTS Of the 219 patients who underwent catheter ablation procedures, chicken wing LAA morphology was found in 114 patients (52.2%), windsock in 52 (23.9%), cauliflower in 29 (13.0%), and cactus in 24 (10.9%). Compared with the windsock LAA morphology, cactus had a larger left atrial diameter ((42.40 ± 3.68) and (37.91 ± 4.32) mm, P = 0.005) and LAA orifice diameter ((27.38 ± 3.70) and (24.14 ± 3.58) mm, P = 0.048). The LAA length was significantly larger in the chicken wing morphology than in the windsock ((37.50 ± 6.74) and (31.33 ± 3.92) mm, P = 0.015) and cauliflower morphologies ((37.50 ± 6.74) and (31.33 ± 3.92) mm, P = 0.015). According to their medical records, 26 patients (11.9%) had suffered a prior stroke. Compared with patients who had no history of stroke, the prior-stroke patients were older (62.04 ± 8.07 and 58.24 ± 9.24, P = 0.047) and there were fewer patients with chicken wing (23.1% and 59.1%, P = 0.001) and more patients with cauliflower (26.9% and 9.8%, P = 0.046). Multivariate Logistic regression analysis demonstrated that age (odds ratio (OR) 1.26; 95% confidence interval (CI) 1.08-1.47; P = 0.003), non-chicken wing morphology (OR 5.82; 95% CI 1.61-21.03; P = 0.007), and LAA orifice diameter (OR 1.25; 95% CI 1.05-1.49; P = 0.014) were independent predictors of stroke after adjusting for all parameters that emerged as potential confounders with univariate analysis. CONCLUSION LAA analysis can potentially be used to inform guidance on the implication for stroke risk assessment.","author":[{"dropping-particle":"","family":"Kong","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"He","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Lei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fan","given":"Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mei","given":"Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Wanli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liao","given":"Jiafen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Dan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xing","given":"Dong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"He","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chinese medical journal","id":"ITEM-1","issue":"24","issued":{"date-parts":[["2014"]]},"page":"4210-4","title":"Left atrial appendage morphology in patients with atrial fibrillation in China: implications for stroke risk assessment from a single center study.","type":"article-journal","volume":"127"},"uris":[""]}],"mendeley":{"formattedCitation":"(115)","plainTextFormattedCitation":"(115)","previouslyFormattedCitation":"(115)"},"properties":{"noteIndex":0},"schema":""}(115)Prospective cohortDrug-refractory AF undergoing catheter ablation21965.3;58.1 (NA)StrokeNA(retrospective)LAA morphologyNon-chicken wing morphology was associated with 5.8-fold greater stroke riskKhurram, 2013 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.hrthm.2013.09.065","ISSN":"15475271","abstract":"Background Atrial fibrillation (AF) is an important cause of stroke. Given the morbidity and mortality associated with stroke, the risk stratification of patients based on left atrial appendage (LAA) characteristics is of great interest. Objective To explore the association between LAA morphology and LAA characteristics including the extent of trabeculations, orifice diameter, and length with prevalent stroke in a large cohort of patients with drug refractory AF who underwent AF ablation to develop mechanistic insight regarding the risk of stroke. Methods An institutional cohort of 1063 patients referred for AF ablation from 2003 to 2012 was reviewed to identify patients that underwent preprocedural cardiac computed tomography (CT). LAA morphology was characterized as chicken wing, cactus, windsock, or cauliflower by using previously reported methodology. Left atrial size and LAA trabeculations, morphology, orifice diameter, and length were compared between patients with prevalent stroke and patients without prevalent stroke. Results Of 678 patients with CT images, 65 (10%) had prior stroke or transient ischemic attack. In univariate analyses, prevalent heart failure (7.7% in cases vs 2.8% in controls; P =.033), smaller LAA orifice (2.26 ± 0.52 cm vs 2.78 ± 0.71 cm; P <.001), shorter LAA length (5.06 ± 1.17 cm vs 5.61 ± 1.17 cm; P <.001), and extensive LAA trabeculations (27.7% vs 14.4%; P =.019) were associated with stroke. LAA morphologies were unassociated with stroke risk. In multivariable analysis, smaller LAA orifice diameter and extensive LAA trabeculations remained independently associated with thromboembolic events. Conclusions The extent of LAA trabeculations and smaller LAA orifice diameter are associated with prevalent stroke and may mediate the previously described association of cauliflower LAA morphology with stroke. ? 2013 Heart Rhythm Society.","author":[{"dropping-particle":"","family":"Khurram","given":"Irfan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dewire","given":"Jane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mager","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maqbool","given":"Farhan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zimmerman","given":"Stefan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zipunnikov","given":"Vadim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beinart","given":"Roy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"E. Marine","given":"Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spragg","given":"David D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Ronald D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ashikaga","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nazarian","given":"Saman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calkins","given":"Hugh","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart Rhythm","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2013","12"]]},"page":"1843-1849","publisher":"Elsevier","title":"Relationship between left atrial appendage morphology and stroke in patients with atrial fibrillation","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(117)","plainTextFormattedCitation":"(117)","previouslyFormattedCitation":"(117)"},"properties":{"noteIndex":0},"schema":""}(117)Prospective cohortAF referred for catheter ablation67874.8;59.5 (9.7)Stroke or TIANA(retrospective)LAA morphologyNo association with stroke or TIALAA trabeculationsExtensive LAA trabeculation was associated with a greater stroke or TIA riskLAA orifice diameterSmaller LAA orifice was associated with a greater stroke or TIA riskLAA lengthShorter LAA length was associated with a greater stroke or TIA riskKimura, 2013 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.hrthm.2013.01.036","ISSN":"15563871","abstract":"BACKGROUND Strokes develop even in patients with low CHADS2 scores, and the left atrial appendage (LAA) is the embolic source 90% of the time. We focused on the LAA morphology as a new predictor of strokes. OBJECTIVE To clarify the anatomical characteristics of the LAA for risk stratification of strokes in patients with nonvalvular atrial fibrillation (AF) who have low CHADS2 scores. METHODS Among 80 patients who underwent catheter ablation of AF with contrast-enhanced computed tomography, the LAA characteristics were compared between 30 patients with histories of strokes and 50 age-matched controls. The LAA anatomy was classified into 4 types-\"cactus,\" \"cauliflower,\" \"chicken wing,\" and \"windsock\"- discriminated by the computed tomography measurements of the length, angle, and number of lobes of the LAA. RESULTS The average CHADS2 score did not differ significantly between patients with stroke and controls (0.8 ± 0.8 vs 0.6 ± 0.7; P = .277). Eight (26.7%) patients with stroke had CHA2DS2-VASc scores of 0. The left atrial size, LAA flow velocity, left ventricular function, and serum brain natriuretic peptide level were also unable to predict strokes. However, a \"cauliflower\" LAA, defined as a main lobe of less than 4 cm long without forked lobes, was significantly more common in patients with stroke (odds ratio 3.857; 95% confidence interval 1.482-10.037; P = .005). The CHA 2DS2-VASc score-adjusted logistic regression analysis revealed the cauliflower LAA as an independent predictor of a stroke (odds ratio 3.355; 95% confidence interval 1.243-9.055; P = .017). CONCLUSIONS The LAA anatomy might be useful for predicting strokes in patients with nonvalvular AF who have low CHADS2 scores. ? 2013 Heart Rhythm Society. All rights reserved.","author":[{"dropping-particle":"","family":"Kimura","given":"Takehiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takatsuki","given":"Seiji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inagawa","given":"Kohei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katsumata","given":"Yoshinori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishiyama","given":"Takahiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishiyama","given":"Nobuhiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fukumoto","given":"Kotaro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aizawa","given":"Yoshiyasu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanimoto","given":"Yoko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanimoto","given":"Kojiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jinzaki","given":"Masahiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fukuda","given":"Keiichi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart Rhythm","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2013"]]},"page":"921-925","publisher":"Elsevier","title":"Anatomical characteristics of the left atrial appendage in cardiogenic stroke with low CHADS2 scores","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(116)","plainTextFormattedCitation":"(116)","previouslyFormattedCitation":"(116)"},"properties":{"noteIndex":0},"schema":""}(116)Case-controlled studyDrug-refractory AF who underwent catheter ablation8082.5;58.6 (6.0)StrokeNA(retrospective)LAA morphologyCauliflower morphology was associated with a greater stroke riskDi Biase, 2012 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jacc.2012.04.032","ISSN":"07351097","PMID":"22858289","abstract":"Objectives: This study investigated the left atrial appendage (LAA) by computed tomography (CT) and magnetic resonance imaging (MRI) to categorize different LAA morphologies and to correlate the morphology with the history of stroke/transient ischemic attack (TIA). Background: LAA represents one of the major sources of cardiac thrombus formation responsible for TIA/stroke in patients with atrial fibrillation (AF). Methods: We studied 932 patients with drug-refractory AF who were planning to undergo catheter ablation. All patients underwent cardiac CT or MRI of the LAA and were screened for history of TIA/stroke. Four different morphologies were used to categorize LAA: Cactus, Chicken Wing, Windsock, and Cauliflower. Results: CT scans of 499 patients and MRI scans of 433 patients were analyzed (age 59 ± 10 years, 79% were male, and 14% had CHADS 2 [Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack] score <2). The distribution of different LAA morphologies was Cactus (278 [30%]), Chicken Wing (451 [48%]), Windsock (179 [19%]), and Cauliflower (24 [3%]). Of the 932 patients, 78 (8%) had a history of ischemic stroke or TIA. The prevalence of pre-procedure stroke/TIA in Cactus, Chicken Wing, Windsock, and Cauliflower morphologies was 12%, 4%, 10%, and 18%, respectively (p = 0.003). After controlling for CHADS 2 score, gender, and AF types in a multivariable logistic model, Chicken Wing morphology was found to be 79% less likely to have a stroke/TIA history (odd ratio: 0.21, 95% confidence interval: 0.05 to 0.91, p = 0.036). In a separate multivariate model, we entered Chicken Wing as the reference group and assessed the likelihood of stroke in other groups in relation to reference. Compared with Chicken Wing, Cactus was 4.08 times (p = 0.046), Windsock was 4.5 times (p = 0.038), and Cauliflower was 8.0 times (p = 0.056) more likely to have had a stroke/TIA. Conclusions: Patients with Chicken Wing LAA morphology are less likely to have an embolic event even after controlling for comorbidities and CHADS 2 score. If confirmed, these results could have a relevant impact on the anticoagulation management of patients with a low-intermediate risk for stroke/TIA. ? 2012 American College of Cardiology Foundation.","author":[{"dropping-particle":"","family":"Biase","given":"Luigi","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santangeli","given":"Pasquale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anselmino","given":"Matteo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mohanty","given":"Prasant","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salvetti","given":"Ilaria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gili","given":"Sebastiano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horton","given":"Rodney","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sanchez","given":"Javier E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bai","given":"Rong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mohanty","given":"Sanghamitra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pump","given":"Agnes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cereceda Brantes","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallinghouse","given":"G. Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burkhardt","given":"J. David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cesarani","given":"Federico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scaglione","given":"Marco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Natale","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gaita","given":"Fiorenzo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2012","8","7"]]},"language":"eng","page":"531-538","publisher-place":"United States, United States","title":"Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study","type":"article-journal","volume":"60"},"uris":[""]}],"mendeley":{"formattedCitation":"(114)","plainTextFormattedCitation":"(114)","previouslyFormattedCitation":"(114)"},"properties":{"noteIndex":0},"schema":""}(114)Prospective cohortDrug-refractory AF undergoing catheter ablation93279;59 (10)Ischaemic stroke or TIANA(retrospective)LAA morphologyChicken wing morphology was associated with lowest risk of ischaemic stroke or TIA; with chicken wing morphology as reference, cactus, windsock and cauliflower were associated with a 4.1-fold, 4.5-fold and 8.0-fold greater risks of ischaemic stroke or TIA, respectivelyBeinart, 2011 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1540-8167.2010.01854.x","ISSN":"10453873","abstract":"Risk of Stroke/TIA in Patients With Atrial Fibrillation. Introduction: Most strokes in patients with atrial fibrillation (AF) arise from thrombus formation in left atrial appendage (LAA). Our aim was to identify LAA features associated with a higher stroke risk in patients with AF using magnetic resonance imaging and angiography (MRI/MRA). Methods: The study included 144 patients with nonvalvular AF who were not receiving warfarin and who underwent MRI/MRA prior to catheter ablation for AF. LAA volume, LAA depth, short and long axes of LAA neck, and numbers of lobes were measured. Results: Of the 144 patients, 18 had a prior stroke or transient ischemic attack (TIA) (13 and 5, respectively). Compared with patients who had no history of stroke/TIA, these patients were older, had higher prevalence of hypertension and hyperlipidemia and had higher LAA volume (22.9 ± 9.6 cm 3 vs. 14.5 ± 7.1 cm 3, P < 0.001). Their LAA depth (3.76 ± 0.9 cm vs. 3.21 ± 0.8 cm, P = 0.006) and the long and short axes of the LAA neck (3.12 ± 0.7 cm vs. 2.08 ± 0.7 cm, P < 0.001; 2.06 ± 0.5 cm vs. 1.37 ± 0.4 cm, P < 0.001, respectively) were larger. Using stepwise logistic regression model, the only statistically significant multivariable predictors of events were age (OR = 1.21 per year, 95% CI 1.06-1.38, P = 0.004), aspirin use (OR = 0.039, 95% CI 0.005-0.28, P = 0.001), and LAA neck dimensions (short axis × long axis) (OR = 3.59 per cm 2, 95% CI 1.93-6.69, P < 0.001). Conclusion: LAA dimensions predict strokes/TIAs in patients with AF. LAA assessment by MRI/MRA can potentially be used as an adjunctive tool for risk stratification for embolic events in AF patients. ? 2010 Wiley Periodicals, Inc.","author":[{"dropping-particle":"","family":"Beinart","given":"Roy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heist","given":"E. Kevin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newell","given":"John B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmvang","given":"Godtfred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruskin","given":"Jeremy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mansour","given":"Moussa","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Cardiovascular Electrophysiology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2011","1"]]},"page":"10-15","title":"Left atrial appendage dimensions predict the risk of Stroke/TIA in patients with atrial fibrillation","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(118)","plainTextFormattedCitation":"(118)","previouslyFormattedCitation":"(118)"},"properties":{"noteIndex":0},"schema":""}(118)Case-controlled studyNon-anticoagulated AF 14475;54.5 (9.9)Stroke or TIANA(retrospective)LAA volumeNo association with stroke or TIALAA depthNo association with stroke or TIALAA neck dimensionsHigh LAA neck dimension was associated with greater stroke or TIA riskLAA number of lobesNo association with stroke or TIAGoldman, 1999 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0894-7317(99)70105-7","ISSN":"0894-7317 (Print)","PMID":"10588784","abstract":"Stroke associated with atrial fibrillation (AF) is mainly due to embolism of thrombus formed during stasis of blood in the left atrial appendage (LAA). Pathophysiologic correlates of appendage flow velocity as assessed by transesophageal echocardiography (TEE) in patients with AF have not been defined. To evaluate the hypothesis that reduced velocity is associated with spontaneous echocardiographic contrast and thrombus in the LAA and with clinical embolic events, we measured LAA flow velocity by TEE in 721 patients with nonvalvular AF entering the Stroke Prevention in Atrial Fibrillation (SPAF-III) study. Patient features, TEE findings, and subsequent cardioembolic events were correlated with velocity by multivariate analysis. Patients in AF during TEE displayed lower peak antegrade (emptying) flow velocity (Anu(p)) than those with intermittent AF in sinus rhythm during TEE (33 cm/s vs 61 cm/s, respectively, P <.0001). Anu(p) < 20 cm/s was associated with dense spontaneous echocardiographic contrast (P <.001), appendage thrombus (P <.01), and subsequent cardioembolic events (P <.01). Independent predictors of Anu(p) < 20 cm/s included age (P =.009), systolic blood pressure (P <.001), sustained AF (P =.01), ischemic heart disease (P =.01), and left atrial area (P =.04). Multivariate analysis found both Anu(p) <20 cm/s (relative risk 2.6, P =.02) and clinical risk factors (relative risk 3.3, P =.002) independently associated with LAA thrombus. LAA Anu(p) is reduced in AF and associated with spontaneous echocardiographic contrast, appendage thrombus, and cardioembolic stroke. Systolic hypertension and aortic atherosclerosis, independent clinical predictors of stroke in patients with AF, also correlated with LAA Anu(p). Our results support the role of reduced LAA Anu(p) in the generation of stasis, thrombus formation, and embolism in patients with AF, although other mechanisms also contribute to stroke.","author":[{"dropping-particle":"","family":"Goldman","given":"M. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"L. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"R. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zabalgoitia","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asinger","given":"R. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Safford","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"J. L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Society of Echocardiography","id":"ITEM-1","issue":"12","issued":{"date-parts":[["1999","12"]]},"language":"eng","page":"1080-1087","publisher":"Mosby Inc.","publisher-place":"United States, United States","title":"Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The stroke prevention in atrial fibrillation [SPAF-III] study)","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"(111)","plainTextFormattedCitation":"(111)","previouslyFormattedCitation":"(111)"},"properties":{"noteIndex":0},"schema":""}(111)Sub-study of prospective cohortAF with at least 1 high-risk stroke factor*72176;68 (9)Ischaemic stroke or SENALAA peak antegrade flow velocityLAA peak antegrade flow velocity <20 cm/s was associated with greater risk of ischaemic stroke or SEZabalgoitia, 1998 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/s0735-1097(98)00146-6","ISSN":"0735-1097 (Print)","PMID":"9626843","abstract":"OBJECTIVES: This study explored the mechanisms linking clinical and precordial echocardiographic predictors to thromboembolism in atrial fibrillation (AF) by assessing transesophageal echocardiographic (TEE) correlations. BACKGROUND: Clinical predictors of thromboembolism in patients with nonvalvular AF have been identified, but their mechanistic links remain unclear. TEE provides imaging of the left atrium, its appendage and the proximal thoracic aorta, potentially clarifying stroke mechanisms in patients with AF. METHODS: Cross-sectional analysis of TEE features correlated with low, moderate and high thromboembolic risk during aspirin therapy among 786 participants undergoing TEE on entry into the Stroke Prevention in Atrial Fibrillation III trial. RESULTS: TEE features independently associated with increased thromboembolic risk were appendage thrombi (relative risk [RR] 2.5, p = 0.04), dense spontaneous echo contrast (RR 3.7, p < 0.001), left atrial appendage peak flow velocities < or = 20 cm/s (RR 1.7, p = 0.008) and complex aortic plaque (RR 2.1, p < 0.001). Patients with AF with a history of hypertension (conferring moderate risk) more frequently had atrial appendage thrombi (RR 2.6, p < 0.001) and reduced flow velocity (RR 1.8, p = 0.003) than low risk patients. Among low risk patients, those with intermittent AF had similar TEE features to those with constant AF. CONCLUSIONS: TEE findings indicative of atrial stasis or thrombosis and of aortic atheroma were independently associated with high thromboembolic risk in patients with AF. The increased stroke risk associated with a history of hypertension in AF appears to be mediated primarily through left atrial stasis and thrombi. The presence of complex aortic plaque distinguished patients with AF at high risk from those at moderate risk of thromboembolism.","author":[{"dropping-particle":"","family":"Zabalgoitia","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halperin","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pearce","given":"L A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blackshear","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asinger","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"R G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["1998","6"]]},"language":"eng","page":"1622-1626","publisher-place":"United States, United States","title":"Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators.","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"(113)","plainTextFormattedCitation":"(113)","previouslyFormattedCitation":"(113)"},"properties":{"noteIndex":0},"schema":""}(113)Sub-study of prospective cohortAF with at least 1 high-risk stroke factor*78676;69 (9)Ischaemic stroke or SENALAA thrombusPresence of LAA thrombus was associated with a 2.5-fold greater risk of ischaemic stroke or SESECPresence of SEC was associated with a 3.7-fold greater risk of ischaemic stroke or SELAA peak antegrade flow velocityLAA peak antegrade flow velocity <20 cm/s was associated with a 1.7-fold greater risk of ischaemic stroke or SEComplex aortic plaquePresence of complex aortic plaque was associated with a 2.1-fold greater risk of ischaemic stroke or SELeung, 1994 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/0735-1097(94)90025-6","ISSN":"0735-1097 (Print)","PMID":"8077549","abstract":"OBJECTIVES: This study examined the influence of left atrial spontaneous echo contrast on the subsequent stroke or embolic event rate and on survival in patients with nonvalvular atrial fibrillation. BACKGROUND: Left atrial spontaneous echo contrast is associated with atrial fibrillation and a history of previous stroke or other embolic events. However, the prognostic implications of spontaneous contrast in patients with nonvalvular atrial fibrillation are unknown. METHOD: The study group comprised 272 consecutive patients with nonvalvular atrial fibrillation undergoing transesophageal echocardiography. Clinical and echocardiographic data were collected at baseline, and patients were prospectively followed up, and all strokes, other embolic events and deaths were documented. The relation between spontaneous contrast at baseline and subsequent stroke, other embolic events and survival was analyzed. RESULTS: Left atrial spontaneous echo contrast was detected at baseline in 161 patients (59%). The mean follow-up was 17.5 months. The stroke or other embolic event rate was 12%/year (15 strokes, 3 transient ischemic attacks, 2 peripheral embolisms) in patients with, compared with 3%/year (5 strokes) in patients without, baseline spontaneous contrast (p = 0.002). In 149 patients without previous thromboembolism, the event rate was 9.5%/year in patients with and 2.2%/year in patients without spontaneous contrast (p = 0.003). There were 25 deaths in patients with and 11 deaths in patients without spontaneous contrast. Patients with spontaneous contrast had significantly reduced survival (p = 0.025). On multivariate analysis, spontaneous contrast was the only positive predictor (odds ratio 3.5, p = 0.03) and warfarin therapy on follow-up the only negative predictor (odds ratio 0.23, p = 0.02) of subsequent stroke or other embolic events. CONCLUSIONS: Transesophageal echocardiography can risk stratify patients with nonvalvular atrial fibrillation by identifying left atrial spontaneous echo contrast. These patients have both a significantly higher risk of developing stroke or other embolic events and a reduced survival, and they may represent a subgroup in whom the risk/benefit ratio of anticoagulation may be most favorable.","author":[{"dropping-particle":"","family":"Leung","given":"Dominic Y C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Black","given":"Ian W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cranney","given":"Gregory B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hopkins","given":"Andrew P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walsh","given":"Warren F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["1994","9"]]},"language":"eng","page":"755-762","publisher-place":"United States, United States","title":"Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation.","type":"article-journal","volume":"24"},"uris":[""]}],"mendeley":{"formattedCitation":"(112)","plainTextFormattedCitation":"(112)","previouslyFormattedCitation":"(112)"},"properties":{"noteIndex":0},"schema":""}(112)Prospective cohortAF undergoing TOE27268;68 (11)Stroke or SE17.5 monthsLA SECPresence of LA SEC was associated with a 3.5-fold greater risk of stroke or SESPAF, 1992 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.7326/0003-4819-116-1-6","ISSN":"0003-4819 (Print)","PMID":"1727097","abstract":"OBJECTIVE: To identify echocardiographic predictors of arterial thromboembolism in patients with nonrheumatic atrial fibrillation and to determine whether these add to clinical variables for risk stratification. DESIGN: Cohort study of patients assigned to placebo in a randomized clinical trial. SETTING: Five hundred sixty-eight inpatients and outpatients with nonrheumatic atrial fibrillation assigned to placebo therapy at 15 U.S. medical centers from 1987 to 1989 in the Stroke Prevention in Atrial Fibrillation study. Patients were followed for a mean of 1.3 years. MEASUREMENTS: M-mode and two-dimensional (2-D) echocardiograms performed at study entry and interpreted by local cardiologists. The predictive value of 14 echocardiographic variables for later ischemic stroke or systemic embolism was assessed by multivariate analysis. MAIN RESULTS: Left ventricular dysfunction from 2-D echocardiograms (P = 0.003) and the size of the left atrium from M-mode echocardiograms (P = 0.02) were the strongest independent predictors of later thromboembolism. Multivariate analysis of these two independent echocardiographic predictors with the three independent clinical predictors of thromboembolism (history of hypertension, recent congestive heart failure, previous thromboembolism) identified 26% of the cohort with a low risk for thromboembolism (1.0% per year; 95% Cl, 0.2% to 4.0%). Compared with risk stratification using clinical variables alone, echocardiographic results altered thromboembolic risk stratification in 18% of the entire cohort and in 38% of those without clinical risk factors. CONCLUSIONS: Both left ventricular and left atrial variables are significant predictors of thromboembolism in patients with nonvalvular atrial fibrillation. Our results challenge traditional views of the pathogenesis of ischemic stroke in patients with atrial fibrillation and suggest that standard echocardiography contributes to risk stratification, differentiating the one third of patients without clinical risk factors who are at increased risk for stroke from the remainder who may not need antithrombotic prophylaxis.","container-title":"Annals of internal medicine","id":"ITEM-1","issue":"1","issued":{"date-parts":[["1992","1"]]},"language":"eng","page":"6-12","publisher-place":"United States, United States","title":"Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators.","type":"article-journal","volume":"116"},"uris":[""]}],"mendeley":{"formattedCitation":"(107)","plainTextFormattedCitation":"(107)","previouslyFormattedCitation":"(107)"},"properties":{"noteIndex":0},"schema":""}(107)Sub-study of RCTAF56870;67 (12)Ischaemic stroke or SE1.3 years14 echocardiographic parametersLV dysfunction and higher LA size were the associated with greater risk of ischaemic stroke or SEAF, atrial fibrillation; IQR, interquartile range; LA, left atrial; LAA, left atrial appendage; LAE, left atrial enlargement; LV, left ventricular; NA, not applicable or available; RCT, randomised controlled trial; SD, standard deviation; SE, systemic embolism; SEC, spontaneous echo contrast; TIA, transient ischaemic attack; TOE, trans-oesophageal echocardiography.* Similar study cohortRisk factors for anticoagulation-related bleeding Risk factorPossible risk factorClinical markersHistory of bleedingAntiplatelets or NSAID useExcess alcoholUncontrolled hypertensionIncreasing ageMalignancyPrior strokeVascular diseaseRace/ethnicity (non-white)Choice of anticoagulantDiabetes mellitusFemale sexPrior fallsThyroid diseasePrior MI or known IHDBiological markersPoor anticoagulation control(high INR or reduced TTR)Liver dysfunctionRenal dysfunctionAnaemiaReduced platelet count or functionInterleukin-6von Willebrand factorGrowth differentiation factor-15TroponinsGenetic markerCYP 2C9 polymorphismCYP, cytochrome P450; IHD, ischaemic heart disease; INR, international normalised ratio; MI, myocardial infarction; NSAID, non-steroidal anti-inflammatory drug; TTR, time-in-therapeutic range.Bleeding risk scores in AFRisk factorsABC-bleeding ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0140-6736(16)00741-8","ISSN":"1474-547X (Electronic)","PMID":"27056738","abstract":"BACKGROUND: The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischaemic stroke and increase in major bleeding. We aimed to develop and validate a new biomarker-based risk score to improve the prognostication of major bleeding in patients with atrial fibrillation. METHODS: We developed and internally validated a new biomarker-based risk score for major bleeding in 14,537 patients with atrial fibrillation randomised to apixaban versus warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomised to dabigatran versus warfarin in the RE-LY trial. Plasma samples for determination of candidate biomarker concentrations were obtained at randomisation. Major bleeding events were centrally adjudicated. The predictive values of biomarkers and clinical variables were assessed with Cox regression models. The most important variables were included in the score with weights proportional to the model coefficients. The ARISTOTLE and RE-LY trials are registered with , numbers NCT00412984 and NCT00262600, respectively. FINDINGS: The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0.68 [95% CI 0.66-0.70] vs 0.61 [0.59-0.63] vs 0.65 [0.62-0.67], respectively; ABC-bleeding vs HAS-BLED p<0.0001 and ABC-bleeding vs ORBIT p=0.0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0.71 [95% CI 0.68-0.73] vs 0.62 [0.59-0.64] for HAS-BLED vs 0.68 [0.65-0.70] for ORBIT; ABC-bleeding vs HAS-BLED p<0.0001 and ABC-bleeding vs ORBIT p=0.0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores. INTERPRETATION: The ABC-bleeding score, using age, history of bleeding, and three biomarkers (haemoglobin, cTn-hs, and GDF-15 or cystatin C/CKD-EPI) was internally and externally validated and calibrated in large cohorts of patients with atrial fibrillation receiving anticoagulation therapy. The …","author":[{"dropping-particle":"","family":"Hijazi","given":"Ziad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldgren","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindback","given":"Johan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alexander","given":"John H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connolly","given":"Stuart J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelboom","given":"John W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael 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J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelboom","given":"John W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ezekowitz","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Held","given":"Claes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hylek","given":"Elaine M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lopes","given":"Renato D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegbahn","given":"Agneta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yusuf","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granger","given":"Christopher 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warfarin-associated hemorrhage. Optimal decision making regarding warfarin use for atrial fibrillation requires estimation of hemorrhage risk. We followed up 9,186 patients with atrial fibrillation contributing 32,888 person-years of follow-up on warfarin, obtaining data from clinical databases and validating hemorrhage events using medical record review. We used Cox regression models to develop a hemorrhage risk stratification score, selecting candidate variables using bootstrapping approaches. The final model was internally validated by split-sample testing and compared with 6 published hemorrhage risk schemes. We observed 461 first major hemorrhages during follow-up (1.4% annually). Five independent variables were included in the final model and weighted by regression coefficients: anemia (3 points), severe renal disease (e.g., glomerular filtration rate <30 ml/min or dialysis-dependent, 3 points), age ≥75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Major hemorrhage rates ranged from 0.4% (0 points) to 17.3% per year (10 points). Collapsed into a 3-category risk score, major hemorrhage rates were 0.8% for low risk (0 to 3 points), 2.6% for intermediate risk (4 points), and 5.8% for high risk (5 to 10 points). The c-index for the continuous risk score was 0.74 and 0.69 for the 3-category score, higher than in the other risk schemes. There was net reclassification improvement versus all 6 comparators (from 27% to 56%). A simple 5-variable risk score was effective in quantifying the risk of warfarin-associated hemorrhage in a large community-based cohort of patients with atrial fibrillation. Copyright ? 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Fang","given":"Margaret C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Go","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Yuchiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borowsky","given":"Leila H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pomernacki","given":"Niela K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Udaltsova","given":"Natalia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singer","given":"Daniel E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American College of Cardiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2011","7"]]},"language":"eng","page":"395-401","publisher-place":"United States, United States","title":"A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.","type":"article-journal","volume":"58"},"uris":[""]}],"mendeley":{"formattedCitation":"(177)","plainTextFormattedCitation":"(177)","previouslyFormattedCitation":"(177)"},"properties":{"noteIndex":0},"schema":""}(177)HAS-BLED ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1378/chest.09-1584","ISSN":"19313543","PMID":"19762550","abstract":"BACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism (TE) in patients with atrial fibrillation (AF) are largely derived from risk factors identified from trial cohorts. Thus, many potential risk factors have not been included. METHODS: We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF. RESULTS: Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003). CONCLUSIONS: Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. 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fibrillation.","type":"article-journal","volume":"137"},"uris":[""]}],"mendeley":{"formattedCitation":"(18)","plainTextFormattedCitation":"(18)","previouslyFormattedCitation":"(18)"},"properties":{"noteIndex":0},"schema":""}(18)HEMORR?HAGES ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ahj.2005.04.017","ISSN":"00028703","PMID":"16504638","abstract":"Background: Although warfarin and other anticoagulants can prevent ischemic events, they can cause hemorrhage. Quantifying the rate of hemorrhage is crucial for determining the risks and net benefits of prescribing antithrombotic therapy. Our objective was to find a bleeding classification scheme that could quantify the risk of hemorrhage in elderly patients with atrial fibrillation. Methods: We combined bleeding risk factors from existing classification schemes into a new scheme, HEMORR2HAGES, and validated all bleeding classification schemes. We scored HEMORR2HAGES by adding 2 points for a prior bleed and 1 point for each of the other risk factors: hepatic or renal disease, ethanol abuse, malignancy, older (age > 75 years), reduced platelet count or function, hypertension (uncontrolled), anemia, genetic factors, excessive fall risk, and stroke. We used data from quality improvement organizations representing 7 states to assemble a registry of 3791 Medicare beneficiaries with atrial fibrillation. Results: There were 162 hospital admissions with an International Classification of Diseases, Ninth Revision, Clinical Modification code for hemorrhage. With each additional point, the rate of bleeding per 100 patient-years of warfarin increased: 1.9 for 0, 2.5 for 1, 5.3 for 2, 8.4 for 3, 10.4 for 4, and 12.3 for ≥5 points. In patients prescribed warfarin, HEMORR2HAGES had greater predictive accuracy (c statistic 0.67) than other bleed prediction schemes (P < .001). Conclusions: Adaptations of existing classification schemes, especially a new bleeding risk scheme, HEMORR2HAGES, can quantify the risk of hemorrhage and aid in the management of antithrombotic therapy. ? 2006, Mosby, Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Gage","given":"Brian F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yan","given":"Yan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milligan","given":"Paul E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waterman","given":"Amy D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Culverhouse","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rich","given":"Michael W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Radford","given":"Martha J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Heart Journal","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2006","3"]]},"language":"eng","page":"713-719","publisher-place":"United States, United States","title":"Clinical classification schemes for predicting hemorrhage: Results from the National Registry of Atrial Fibrillation (NRAF)","type":"article-journal","volume":"151"},"uris":[""]}],"mendeley":{"formattedCitation":"(178)","plainTextFormattedCitation":"(178)","previouslyFormattedCitation":"(178)"},"properties":{"noteIndex":0},"schema":""}(178)ORBIT ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ahj.2005.04.017","ISSN":"00028703","PMID":"16504638","abstract":"Background: Although warfarin and other anticoagulants can prevent ischemic events, they can cause hemorrhage. Quantifying the rate of hemorrhage is crucial for determining the risks and net benefits of prescribing antithrombotic therapy. Our objective was to find a bleeding classification scheme that could quantify the risk of hemorrhage in elderly patients with atrial fibrillation. Methods: We combined bleeding risk factors from existing classification schemes into a new scheme, HEMORR2HAGES, and validated all bleeding classification schemes. We scored HEMORR2HAGES by adding 2 points for a prior bleed and 1 point for each of the other risk factors: hepatic or renal disease, ethanol abuse, malignancy, older (age > 75 years), reduced platelet count or function, hypertension (uncontrolled), anemia, genetic factors, excessive fall risk, and stroke. We used data from quality improvement organizations representing 7 states to assemble a registry of 3791 Medicare beneficiaries with atrial fibrillation. Results: There were 162 hospital admissions with an International Classification of Diseases, Ninth Revision, Clinical Modification code for hemorrhage. With each additional point, the rate of bleeding per 100 patient-years of warfarin increased: 1.9 for 0, 2.5 for 1, 5.3 for 2, 8.4 for 3, 10.4 for 4, and 12.3 for ≥5 points. In patients prescribed warfarin, HEMORR2HAGES had greater predictive accuracy (c statistic 0.67) than other bleed prediction schemes (P < .001). Conclusions: Adaptations of existing classification schemes, especially a new bleeding risk scheme, HEMORR2HAGES, can quantify the risk of hemorrhage and aid in the management of antithrombotic therapy. ? 2006, Mosby, Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Gage","given":"Brian F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yan","given":"Yan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milligan","given":"Paul E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waterman","given":"Amy D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Culverhouse","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rich","given":"Michael W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Radford","given":"Martha J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Heart Journal","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2006","3"]]},"language":"eng","page":"713-719","publisher-place":"United States, United States","title":"Clinical classification schemes for predicting hemorrhage: Results from the National Registry of Atrial Fibrillation (NRAF)","type":"article-journal","volume":"151"},"uris":[""]}],"mendeley":{"formattedCitation":"(178)","plainTextFormattedCitation":"(178)","previouslyFormattedCitation":"(178)"},"properties":{"noteIndex":0},"schema":""}(178)Antiplatelets or NSAID usexxDiabetes mellitusExcess alcoholxxExcessive falls riskxFemalesxHistory of bleedingxxxxxHypertensionxxxElderly patientsxxxxxMalignancyxPrevious strokexxAbnormal liver functionxxAbnormal renal functionxxxxAnaemiaxxxxLabile INR (TTR <60%)xRaised GDF-15xRaised hsTropxReduced platelet count or functionxCYP 2C9 polymorphismxTotal score45109127CYP, cytochrome P450; GDF-15, growth differentiation factor-15; hsTrop, high-sensitivity troponin; INR, international normalised ratio; NSAID, non-steroidal anti-inflammatory drug; TTR, time-in-therapeutic range. ................
................

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