Spiral.imperial.ac.uk
Myocardial infarction and ischaemic stroke following exacerbations of chronic obstructive pulmonary diseaseRunning title: Exacerbations of COPD and vascular eventsAuthors: Kieran J Rothnie1,2, Olivia Connell1, Hana Müllerová3 , LiamSmeeth2, Neil Pearce2, Ian Douglas2, Jennifer K Quint1,2 Affiliations1 Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London2 Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London3 Respiratory Epidemiology, GlaxoSmithKline R&D, UxbridgeCorresponding author Kieran J RothnieRespiratory Epidemiology, Occupational Medicine and Public HealthNational Heart and Lung InstituteEmmanuel Kaye BuildingImperial College LondonLondonSW3 6LREmail: k.rothnie@imperial.ac.ukTel: +44 20 7594 88249.6 COPD: EpidemiologyFundingThis work was funded by GSK and the MRC as part of an MRC Industry Collaboration Agreement [G0902135]. Author contributions: Conception and design: KJR, JKQ, HM, LS, ID, NP; Analysis and interpretation: KJR, OC, JKQ, HM, LS, ID, NP; Drafting the manuscript for important intellectual content: KJR, OC, JKQ, HM, LS, ID, NP. KJR is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article.AbstractRationalePrevious studies have suggested that acute exacerbations of COPD may be associated with increased risk of myocardial infarction and ischaemic stroke. ObjectiveWe aimed to quantify the increased risks of myocardial infarction and ischemic stroke risk associated with both moderate and severe acute exacerbation, and to investigate factors which may modify these risks.MethodsWe performed a self-controlled case-series to investigate the rates of myocardial infarction and ischemic stroke following acute exacerbation compared to stable time, within individuals. The participants were 5,696 adults with COPD with a first myocardial infarction (n = 2,850) or ischemic stroke (n = 3,010) and at least one acute exacerbation from the UK Clinical Practice Research Datalink with linked Hospital Episodes Statistics data. Results The risks of both myocardial infarction and ischemic stroke were increased in the 91 days following a acute exacerbation. The risks were greater following a severe exacerbation (incidence rate ratio (IRR) of 2.58 (95% CI 2.26 to 2.95) for myocardial infarction; and IRR 1.97 (95% CI 1.66-2.33) for ischemic stroke) than after a moderate exacerbation (IRR 1.58 (95% CI 1.46-1.71) for myocardial infarction; and IRR 1.45 (95% CI 1.33-1.57) for ischemic stroke. The relative risks of myocardial infarction and ischemic stroke associated with acute exacerbation were lower among those with more frequent exacerbations (IRR 1.42 (95% CI 1.24-1.62) vs 1.69 (95% CI 1.50-1.91) for myocardial infarction; and IRR 1.30 (95% CI 1.15-1.48) vs 1.68 (95% CI 1.50-1.89) for ischemic stroke). Higher GOLD stage associated with a lower rate of myocardial infarction (IRR 1.98 (95% CI 1.61-2.05) vs 1.69 (95% CI 1.45-1.98)) but not for ischemic stroke. Aspirin use at baseline was associated with a lower risk of ischemic stroke (IRR 1.28 (95% CI 1.10-1.50) vs 1.63 (95% CI 1.47-1.80)), but not with myocardial infarction. Conclusions Acute exacerbations of COPD are associated with an increased risk of myocardial infarction and ischemic stroke within 28 days of their onset. Several patient characteristics were identified which are associated with these events.IntroductionPeople with chronic obstructive pulmonary disease (COPD) are at increased risk of myocardial infarction (myocardial infarction) ADDIN EN.CITE <EndNote><Cite><Author>Rothnie</Author><Year>2015</Year><RecNum>2</RecNum><DisplayText>[1]</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rothnie, Kieran J</author><author>Yan, Ruoling</author><author>Smeeth, Liam</author><author>Quint, Jennifer K</author></authors></contributors><titles><title>Risk of myocardial infarction (MI) and death following MI in people with chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis</title><secondary-title>BMJ Open</secondary-title></titles><periodical><full-title>BMJ Open</full-title></periodical><volume>5</volume><number>9</number><dates><year>2015</year><pub-dates><date>September 1, 2015</date></pub-dates></dates><urls><related-urls><url>;[1] and stroke ADDIN EN.CITE <EndNote><Cite><Author>Morgan</Author><Year>2017</Year><RecNum>38</RecNum><DisplayText>[2]</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morgan, A. D.</author><author>Sharma, C.</author><author>Rothnie, K. J.</author><author>Potts, J.</author><author>Smeeth, L.</author><author>Quint, J. K.</author></authors></contributors><auth-address>1 Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London.
2 Faculty of Medical Sciences, University College London; and.
3 Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.</auth-address><titles><title>Chronic Obstructive Pulmonary Disease and the Risk of Stroke</title><secondary-title>Ann Am Thorac Soc</secondary-title><alt-title>Annals of the American Thoracic Society</alt-title></titles><periodical><full-title>Ann Am Thorac Soc</full-title><abbr-1>Annals of the American Thoracic Society</abbr-1></periodical><alt-periodical><full-title>Ann Am Thorac Soc</full-title><abbr-1>Annals of the American Thoracic Society</abbr-1></alt-periodical><pages>754-765</pages><volume>14</volume><number>5</number><edition>2017/05/02</edition><dates><year>2017</year><pub-dates><date>May</date></pub-dates></dates><isbn>2325-6621</isbn><accession-num>28459623</accession-num><urls></urls><custom2>Pmc5427743</custom2><electronic-resource-num>10.1513/AnnalsATS.201611-932SR</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>[2], and up to one third of COPD patients die from cardiovascular disease ADDIN EN.CITE <EndNote><Cite><Author>Sin</Author><Year>2006</Year><RecNum>18</RecNum><DisplayText>[3]</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sin, D. D.</author><author>Anthonisen, N. R.</author><author>Soriano, J. B.</author><author>Agusti, A. G.</author></authors></contributors><titles><title>Mortality in COPD: role of comorbidities</title><secondary-title>European Respiratory Journal</secondary-title></titles><periodical><full-title>European Respiratory Journal</full-title></periodical><pages>1245-1257</pages><volume>28</volume><number>6</number><dates><year>2006</year><pub-dates><date>2006-12-01 00:00:00</date></pub-dates></dates><urls><related-urls><url>;[3]. This increased risk cannot be completely explained by smoking ADDIN EN.CITE <EndNote><Cite><Author>Feary</Author><Year>2010</Year><RecNum>4</RecNum><DisplayText>[4]</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Feary, Johanna R</author><author>Rodrigues, Laura C</author><author>Smith, Christopher J</author><author>Hubbard, Richard B</author><author>Gibson, Jack E</author></authors></contributors><titles><title>Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care</title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>956-962</pages><volume>65</volume><number>11</number><dates><year>2010</year><pub-dates><date>November 1, 2010</date></pub-dates></dates><urls><related-urls><url>;[4] and has been attributed to increased systemic inflammation ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2010</Year><RecNum>5</RecNum><DisplayText>[5]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, Peter J.</author></authors></contributors><titles><title>Chronic Obstructive Pulmonary Disease: Effects beyond the Lungs</title><secondary-title>PLoS Med</secondary-title></titles><periodical><full-title>PLoS Med</full-title></periodical><pages>e1000220</pages><volume>7</volume><number>3</number><dates><year>2010</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;[5]. Acute exacerbations of COPD normally last several days; most are thought to be triggered by bacterial or viral infectionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXRoaTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [8, 9]. Previous work has shown that lower respiratory tract infections (LRTI) are associated with an increased risk of myocardial infarction in the general population ADDIN EN.CITE <EndNote><Cite><Author>Smeeth </Author><Year>2004</Year><RecNum>9</RecNum><DisplayText>[10]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smeeth , Liam</author><author>Thomas , Sara L.</author><author>Hall , Andrew J.</author><author>Hubbard , Richard</author><author>Farrington , Paddy</author><author>Vallance , Patrick</author></authors></contributors><titles><title>Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination</title><secondary-title>New England Journal of Medicine</secondary-title></titles><periodical><full-title>New England Journal of Medicine</full-title></periodical><pages>2611-2618</pages><volume>351</volume><number>25</number><dates><year>2004</year></dates><accession-num>15602021</accession-num><urls><related-urls><url>;[10](10). In addition, two small studies have suggested that there may be an increased risk of myocardial infarction following periods of acute exacerbation compared to stable periodsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25hbGRzb248L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy
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ADDIN EN.CITE.DATA [11, 12]. Frequent exacerbators (people who have two or more treated exacerbations per year), also seem to have a higher long term risk of myocardial infarction than infrequent exacerbators ADDIN EN.CITE <EndNote><Cite><Author>Donaldson</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[11]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Donaldson, Gavin C.</author><author>Hurst, John R.</author><author>Smith, Christopher J.</author><author>Hubbard, Richard B.</author><author>Wedzicha, Jadwiga A.</author></authors></contributors><titles><title>Increased Risk of Myocardial Infarction and Stroke Following Exacerbation of COPD</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1091-1097</pages><volume>137</volume><number>5</number><dates><year>2010</year><pub-dates><date>5//</date></pub-dates></dates><isbn>0012-3692</isbn><urls><related-urls><url>;[11]. The relationship between acute exacerbation and stroke is less clear. A previous study found an increased risk of stroke following acute exacerbation, but this risk was delayed until 49 days after an acute exacerbation ADDIN EN.CITE <EndNote><Cite><Author>Donaldson</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[11]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Donaldson, Gavin C.</author><author>Hurst, John R.</author><author>Smith, Christopher J.</author><author>Hubbard, Richard B.</author><author>Wedzicha, Jadwiga A.</author></authors></contributors><titles><title>Increased Risk of Myocardial Infarction and Stroke Following Exacerbation of COPD</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1091-1097</pages><volume>137</volume><number>5</number><dates><year>2010</year><pub-dates><date>5//</date></pub-dates></dates><isbn>0012-3692</isbn><urls><related-urls><url>;[11]. Another study found a slightly increased risk of stroke over a 10 year follow-up when comparing exacerbating to non-exacerbating COPD patients ADDIN EN.CITE <EndNote><Cite><Author>Lin</Author><Year>2017</Year><RecNum>40</RecNum><DisplayText>[13]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lin, Chao-Shun</author><author>Shih, Chun-Chuan</author><author>Yeh, Chun-Chieh</author><author>Hu, Chaur-Jong</author><author>Chung, Chi-Li</author><author>Chen, Ta-Liang</author><author>Liao, Chien-Chang</author></authors></contributors><titles><title>Risk of Stroke and Post-Stroke Adverse Events in Patients with Exacerbations of Chronic Obstructive Pulmonary Disease</title><secondary-title>PLOS ONE</secondary-title></titles><periodical><full-title>PLoS ONE</full-title></periodical><pages>e0169429</pages><volume>12</volume><number>1</number><dates><year>2017</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;[13]. The risk factors for myocardial infarction and ischemic stroke following acute exacerbation are not known, limiting the strategies or interventions that might mitigate this risk. Recent improvements in methods to identify acute exacerbation in electronic health records (EHR) mean that acute exacerbation can now be identified with greater sensitivity and precision ADDIN EN.CITE <EndNote><Cite><Author>Rothnie</Author><Year>2016</Year><RecNum>123</RecNum><DisplayText>[14]</DisplayText><record><rec-number>123</rec-number><foreign-keys><key app="EN" db-id="22rwes2xndfpesedpswx9dtjvtp2202rfapz">123</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rothnie, Kieran J.</author><author>Müllerová, Hana</author><author>Hurst, John R.</author><author>Smeeth, Liam</author><author>Davis, Kourtney</author><author>Thomas, Sara L.</author><author>Quint, Jennifer K.</author></authors></contributors><titles><title>Validation of the Recording of Acute Exacerbations of COPD in UK Primary Care Electronic Healthcare Records</title><secondary-title>PLOS ONE</secondary-title></titles><periodical><full-title>PLOS ONE</full-title></periodical><pages>e0151357</pages><volume>11</volume><number>3</number><dates><year>2016</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;[14]. Additionally, with linkage to secondary care records, the severity of acute exacerbations in COPD patients can be stratified using a health-care utilisation definition into moderate (general practitioner treated; primary care managed) and severe (hospitalised) events. The aims of this study were therefore to: 1) characterise the magnitude and duration of myocardial infarction and ischemic stroke risks following acute exacerbation; 2) investigate the relationship between severity of acute exacerbation and myocardial infarction and ischemic stroke risk, and; 3) investigate whether the associations between exacerbation and both myocardial infarction and ischemic stroke are modified by COPD severity, prior acute exacerbation frequency, myocardial infarction type (STEMI or non-STEMI), comorbid cardiovascular disease, use of cardiovascular medicines, use of inhaled COPD maintenance therapy, or influenza vaccination at baseline. MethodsData SourcesWe used data from the Clinical Practice Research Datalink (CPRD) linked with Hospital Episodes Statistics (HES) data. The CPRD is a large database of primary-care data. It contains details on more than 11 million patients in the UK, with over four million of these being active patients (around 7% of the UK population) ADDIN EN.CITE <EndNote><Cite><Author>Herrett</Author><Year>2015</Year><RecNum>19</RecNum><DisplayText>[15]</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Herrett, Emily</author><author>Gallagher, Arlene M</author><author>Bhaskaran, Krishnan</author><author>Forbes, Harriet</author><author>Mathur, Rohini</author><author>van Staa, Tjeerd</author><author>Smeeth, Liam</author></authors></contributors><titles><title>Data Resource Profile: Clinical Practice Research Datalink (CPRD)</title><secondary-title>International Journal of Epidemiology</secondary-title></titles><periodical><full-title>International Journal of Epidemiology</full-title></periodical><dates><year>2015</year><pub-dates><date>June 6, 2015</date></pub-dates></dates><urls><related-urls><url>;[15]. The available data includes details on symptoms, diagnoses, tests, prescriptions, details on patient demographics and health behaviours, and referrals to secondary care. The diagnostic data in CPRD are mainly recorded using a system of Read codes, which is a hierarchical classification system. HES is an administrative database containing details of all episodes of admitted patient care in England and Wales. Data are structured into episodes of care by single consultants (“finished consultant episodes”), such that each hospitalisation may be involve several finished consultant episodes. Data are recorded using ICD-10 codes. Each finished consultant episode may be associated with up to 20 ICD-10 codes, with the first code generally representing the reason for hospitalisation. The remaining codes may represent other acute problems, or co-morbidities. Data for about 60% of CPRD patients are linked to HES. CPRD-HES data were also linked to Office of National Statistics (ONS) data to determine exact date of death.Study designThe self-controlled case-series is a within-person design developed to reduce confounding in observational studies. The incidence rate of an outcome following an exposure is compared to unexposed periods of time in the same individual, using only data for those who experience the outcome ADDIN EN.CITE <EndNote><Cite><Author>Whitaker</Author><Year>2006</Year><RecNum>20</RecNum><DisplayText>[16]</DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Whitaker, Heather J.</author><author>Paddy Farrington, C.</author><author>Spiessens, Bart</author><author>Musonda, Patrick</author></authors></contributors><titles><title>Tutorial in biostatistics: the self-controlled case series method</title><secondary-title>Statistics in Medicine</secondary-title></titles><periodical><full-title>Statistics in Medicine</full-title></periodical><pages>1768-1797</pages><volume>25</volume><number>10</number><keywords><keyword>case series</keyword><keyword>conditional likelihood</keyword><keyword>control</keyword><keyword>epidemiology</keyword><keyword>modelling</keyword><keyword>proportional incidence</keyword></keywords><dates><year>2006</year></dates><publisher>John Wiley & Sons, Ltd.</publisher><isbn>1097-0258</isbn><urls><related-urls><url>;[16]. 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ADDIN EN.CITE.DATA [17, 18]. We used this design to estimate the incidences of myocardial infarction or ischemic stroke following the onset of acute exacerbation compared to stable periods. As well as being able to estimate the transient effect of an exposure, the major advantage of this design is that within-individual inferences are made since each subject acts as their own control. This means that the design implicitly controls for the effects of fixed confounders such as sex, socioeconomic status and genetic factors, as well as other unknown/unmeasured fixed confounders. Follow-up time is accumulated in various age-bands to account for confounding by age. The self-controlled case-series method relies on three assumptions: That events do not change the probability of future exposures. This assumption should be met in our analysis, as it is not likely that having an myocardial infarction or ischemic stroke changes the future risk of acute exacerbation.That recurrent events are independent. As recurrent myocardial infarctions and strokes are not likely to be independent, we restricted the analysis to first myocardial infarction or stroke only. That the occurrence of the event does not censor or alter observation periods. This assumption may not be met as myocardial infarction and ischemic stroke are associated with considerable mortality. In order to assess the impact of this assumption, we conducted a sensitivity analysis described in the statistical methods section. In addition, we also stratified the 91 day risk period into smaller time segments to address this potential issue.Following a previous study ADDIN EN.CITE <EndNote><Cite><Author>Smeeth </Author><Year>2004</Year><RecNum>9</RecNum><DisplayText>[10]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smeeth , Liam</author><author>Thomas , Sara L.</author><author>Hall , Andrew J.</author><author>Hubbard , Richard</author><author>Farrington , Paddy</author><author>Vallance , Patrick</author></authors></contributors><titles><title>Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination</title><secondary-title>New England Journal of Medicine</secondary-title></titles><periodical><full-title>New England Journal of Medicine</full-title></periodical><pages>2611-2618</pages><volume>351</volume><number>25</number><dates><year>2004</year></dates><accession-num>15602021</accession-num><urls><related-urls><url>;[10] we made an a priori decision to include the maximum of 91 days following the onset of acute exacerbation as the exposure period. Additionally, we segmented this period into smaller periods of 1-3, 4-7, 8-14, 15-28, and 29-91 days, to determine how the relative risk changes over the exposure period. To reduce misclassification of acute exacerbation with myocardial infarction (or ischemic stroke), we created a 14-day window of pre-exposure time including the first day of the acute exacerbation, which was not included in either baseline or exposed time. The study design is shown in Figure 1. Study participants were followed from January 1, 2004, date of COPD diagnosis, 35th birthdate, or CPRD practice “up to standard” date, whichever was later; follow-up finished on March 31, 2015, date of death, transfer out of practice or practice last collection date, whichever was earlier; the first year of follow up served as the baseline year. Study sample, exposure, co-variates, and outcomesThe study sample was comprised of COPD patients who had at least one acute exacerbation and a first myocardial infarction or ischemic stroke during the study period. COPD patients were identified using a previously validated algorithm ADDIN EN.CITE <EndNote><Cite><Author>Quint</Author><Year>2014</Year><RecNum>122</RecNum><DisplayText>[19]</DisplayText><record><rec-number>122</rec-number><foreign-keys><key app="EN" db-id="22rwes2xndfpesedpswx9dtjvtp2202rfapz">122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Quint, Jennifer K</author><author>Müllerova, Hana</author><author>DiSantostefano, Rachael L</author><author>Forbes, Harriet</author><author>Eaton, Susan</author><author>Hurst, John R</author><author>Davis, Kourtney</author><author>Smeeth, Liam</author></authors></contributors><titles><title>Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD)</title><secondary-title>BMJ Open</secondary-title></titles><periodical><full-title>BMJ Open</full-title></periodical><volume>4</volume><number>7</number><dates><year>2014</year></dates><urls></urls><electronic-resource-num>10.1136/bmjopen-2014-005540</electronic-resource-num></record></Cite></EndNote>[19], and had a diagnostic Read code for COPD, a smoking history (ex or current smoker), and were age 35 or older. 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ADDIN EN.CITE.DATA [14, 20]. Acute exacerbations that occurred within two weeks of the onset of a previous acute exacerbation were taken to be a continuing event. Apart from age, sex, and type of myocardial infarction, all potential effect modifiers were defined during the year prior to start of follow-up using CPRD data. Cardiovascular drug use (β-blocker, aspirin, and statins), inhaled COPD therapy use (long-acting β-agonists, long-acting muscarinic antagonists, and inhaled corticosteroids), and influenza vaccination status were defined by the presence of at least one prescription during the one year period prior to the start of follow-up. Previous cardiovascular disease (stroke, heart failure, and angina for the myocardial infarction analysis; and atrial fibrillation, angina and previous myocardial infarction for the stroke analysis) was defined as any code suggesting one of these conditions was diagnosed at any time prior to follow up start. GOLD grade of airflow limitation was defined using spirometry results from the year prior to the start of follow-up. Study participants were dichotomised into exacerbation frequency phenotype categories depending on the number of exacerbations in the one year prior to follow-up start, we also expressed exacerbation frequency during this time in terms of actual number of events (0, 1, 2, ≥3). The main analyses of the associations between acute exacerbation and the risks of myocardial infarction or ischemic stroke within 91 days were stratified by potential effect modifiers. Myocardial infarction and stroke events were defined using both primary care (CPRD) and hospital data (HES). Read codes were used to define myocardial infarction and ischemic stroke in CPRD (supplementary material). In HES, myocardial infarctions and ischemic stroke were defined as an ICD-10 code for myocardial infarction or ischemic stroke in the first position of a finished consultant episode. The date of myocardial infarction or ischemic stroke was taken as the date of the start of the finished consultant episode containing the myocardial infarction or ischemic stroke code, rather than the date of admission to hospital. ICD-10 codes I21.0-I21.4 were used to identify myocardial infarction in HES. ICD-10 codes I63.0-I63.9 were used to identify ischemic stroke in HES. Statistical analysisWe used conditional Poisson regression to estimate the incidence rate ratio (IRR) of first myocardial infarction or stroke in the 91 days following acute exacerbation compared to stable periods. We adjusted for age in one year age bands. In addition, as weather may be associated with both acute exacerbation ADDIN EN.CITE <EndNote><Cite><Author>Tseng</Author><Year>2013</Year><RecNum>29</RecNum><DisplayText>[21]</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tseng, Ching-Min</author><author>Chen, Yung-Tai</author><author>Ou, Shuo-Ming</author><author>Hsiao, Yi-Han</author><author>Li, Szu-Yuan</author><author>Wang, Shuu-Jiun</author><author>Yang, Albert C.</author><author>Chen, Tzeng-Ji</author><author>Perng, Diahn-Warng</author></authors></contributors><titles><title>The Effect of Cold Temperature on Increased Exacerbation of Chronic Obstructive Pulmonary Disease: A Nationwide Study</title><secondary-title>PLoS ONE</secondary-title></titles><periodical><full-title>PLoS ONE</full-title></periodical><pages>e57066</pages><volume>8</volume><number>3</number><dates><year>2013</year><pub-dates><date>03/15
09/25/received
01/17/accepted</date></pub-dates></dates><pub-location>San Francisco, USA</pub-location><publisher>Public Library of Science</publisher><isbn>1932-6203</isbn><accession-num>PMC3598847</accession-num><urls><related-urls><url>;[21] and myocardial infarction ADDIN EN.CITE <EndNote><Cite><Author>Bhaskaran</Author><Year>2010</Year><RecNum>30</RecNum><DisplayText>[22]</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bhaskaran, Krishnan</author><author>Hajat, Shakoor</author><author>Haines, Andy</author><author>Herrett, Emily</author><author>Wilkinson, Paul</author><author>Smeeth, Liam</author></authors></contributors><titles><title>Short term effects of temperature on risk of myocardial infarction in England and Wales: time series regression analysis of the Myocardial Ischaemia National Audit Project (MINAP) registry</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>BMJ</full-title></periodical><volume>341</volume><dates><year>2010</year><pub-dates><date>2010-08-10 23:05:28</date></pub-dates></dates><urls><related-urls><url>;[22] or stroke ADDIN EN.CITE <EndNote><Cite><Author>Kyobutungi</Author><Year>2005</Year><RecNum>39</RecNum><DisplayText>[23]</DisplayText><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kyobutungi, C.</author><author>Grau, A.</author><author>Stieglbauer, G.</author><author>Becher, H.</author></authors></contributors><titles><title>Absolute Temperature, Temperature Changes and Stroke Risk: A Case-Crossover Study</title><secondary-title>European Journal of Epidemiology</secondary-title></titles><periodical><full-title>European Journal of Epidemiology</full-title></periodical><pages>693-698</pages><volume>20</volume><number>8</number><dates><year>2005</year><pub-dates><date>2005/08/01</date></pub-dates></dates><isbn>1573-7284</isbn><urls><related-urls><url>;[23], we adjusted for season (split into October-March and April-September). In addition to the main self-controlled case series analysis, we also used a non-parametric spline based self-controlled case series method ADDIN EN.CITE <EndNote><Cite><Author>Ghebremichael-Weldeselassie Y</Author><Year>2015</Year><RecNum>33</RecNum><DisplayText>[24]</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">33</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ghebremichael-Weldeselassie Y, Whitaker H, Farrington C.</author></authors></contributors><titles><title>Spline-based self-controlled case series method</title></titles><dates><year>2015</year></dates><urls><related-urls><url>(httpInfoFiles)/DE71C5F9EF48876E80257DEA0052905A/$file/non-parametric-SCCS.pdf</url></related-urls></urls></record></Cite></EndNote>[24]. The advantages of this method are that the time segments within the total risk period (91 days after an acute exacerbation) do not have to be pre-specified, and that this method allows an easier visualisation of the evolution of the relative risk across the total 91 day risk period.Secondary analysesOne of the assumptions of the self-controlled case series analysis is that the outcomes do not alter the probability of future exposure or result in censoring of the observation time. As myocardial infarction and stroke are associated with death, which would decrease the probability of further acute exacerbation and result in informative censoring, we conducted a sensitivity analysis similar to previous studies15, 16 to assess the potential impact of breaking this assumption. To do this, we repeated the main analysis in those whose follow up was not censored due to death first for at least 6 months following myocardial infarction or ischemic stroke, and also in those whose follow up was not censored due to death for at least 12 months following myocardial infarction or ischemic stroke.The analysis was conducted using Stata 14.1MP and R 3.2.4. EthicsThe protocol for this research was approved by the Independent Scientific Advisory Committee (ISAC) for the Medicines & Healthcare Products Regulatory Agency (MHRA) Database Research (protocol numbers 15_226A and 17_060). Generic ethical approval for observational research using the CPRD with approval from ISAC has been granted by a Health Research Authority (HRA) Research Ethics Committee (East Midlands – Derby, REC reference number 05/MRE04/87). The protocol is available on request. ResultsIn total, we included 5,696 participants in the study: 2,850 individuals who had a first myocardial infarction and at least one acute exacerbation, during the study period, and 3,466 with a first ischemic stroke and at least one acute exacerbation during the study period (Figure 2). 164 COPD participants were included in both analyses. The characteristics of the study participants are summarised in Table 1. Compared to stable periods, the 91 days following the onset of acute exacerbation were associated with a 65% increased risk of myocardial infarction (IRR 1.65, 95% CI 1.50-1.81) and a 51% increased risk of ischemic stroke (IRR 1.51, 95% CI 1.39-1.65). The increased risk peaked in the first 3 days post-acute exacerbation onset for myocardial infarction and appeared to peak in the 4-7 days post onset for ischemic stroke (Figure 3). The risk gradually fell back to stable period level after 28 days for myocardial infarction, however appeared to remain elevated longer for ischemic stroke (Figure 3). The associations of acute exacerbation and both myocardial infarction and ischemic stroke were modified by the severity of acute exacerbation (p-value for interaction <0.001 for both myocardial infarction and ischemic stroke), with the risk of myocardial infarction being over 2.5 times that of stable periods in the 91 days following a severe acute exacerbation, compared to 1.6 times that of stable periods for moderate events. The risk of ischemic stroke was 1.7 times that of stable periods following severe acute exacerbation, and 1.4 times that of stable periods following moderate acute exacerbation. The results of the non-parametric self-controlled case series analysis using spline regression are displayed in Figure 4 and confirm the patterns observed in the segmented analysis (Figure 3). The association of acute exacerbation with myocardial infarction was stronger among infrequent exacerbators compared to frequent exacerbators, with infrequent exacerbators having a 69% higher rate of myocardial infarction in the 91 days following onset of acute exacerbation compared to their stable periods, and frequent exacerbators having a 42% higher rate of myocardial infarction compared to their stable periods (p=0.009); and infrequent exacerbators having a 68% higher risk of ischemic stroke following acute exacerbation compared to 30% increase for frequent exacerbators (p<0.001) (Figures 5-6). This pattern was also apparent when using number of baseline acute exacerbation rather than the dichotomous phenotype, although more so for myocardial infarction than ischemic stroke.The association of acute exacerbation with myocardial infarction was also stronger for those with severe as compared to mild-to-moderate airflow limitation (GOLD grade 1-2 IRR 1.69, 95% CI 1.45-1.98; GOLD grade 3-4 IRR 1.98, 95% CI 1.61-2.05; p=0.007). However, the association of acute exacerbation with ischaemic stroke was not modified by severity of airflow limitation (p=0.74).We found that the association of acute exacerbation with myocardial infarction in the 91 days following acute exacerbation was higher for non-STEMIs (IRR 1.80, 95% CI 1.56-2.06) than for STEMIs (IRR 1.39, 95% CI 1.16-1.68)). Those with previous heart failure had a lower relative risk of myocardial infarction associated with acute exacerbation (IRR 1.06, 95% CI 0.76-1.47, compared to IRR 1.62, 95% CI 1.48-1.78, p=0.01), and those with previous angina had a lower risk of ischaemic stroke associated with acute exacerbation (IRR 1.55, 95% CI 1.41-1.70, compared to 1.37, 95% CI 1.12-1.67, p=0.01). There was some evidence that the association between acute exacerbation and ischemic stroke was lower among those using aspirin (IRR 1.28, 95% CI 1.10-1.50) compared to non-aspirin users (IRR 1.63, 95% CI 1.47-1.80, p=0.04). There was no modification of the associations between acute exacerbation and either myocardial infarction or stroke by other previous cardiovascular disease, cardiovascular drugs, COPD medicines, or influenza vaccine in the baseline period, or by age or sex (data for age and sex not shown). In the sensitivity analysis among individuals whose observation time was not censored by death following myocardial infarction or ischemic stroke, relative risks were slightly smaller than the main analysis (supplementary material).DiscussionWe found that the increased risks of myocardial infarction and ischemic stroke in the weeks following acute exacerbation were of greater magnitude and longer duration than previously estimated ADDIN EN.CITE <EndNote><Cite><Author>Donaldson</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[11]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Donaldson, Gavin C.</author><author>Hurst, John R.</author><author>Smith, Christopher J.</author><author>Hubbard, Richard B.</author><author>Wedzicha, Jadwiga A.</author></authors></contributors><titles><title>Increased Risk of Myocardial Infarction and Stroke Following Exacerbation of COPD</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1091-1097</pages><volume>137</volume><number>5</number><dates><year>2010</year><pub-dates><date>5//</date></pub-dates></dates><isbn>0012-3692</isbn><urls><related-urls><url>;[11]. These associations were also stronger among those with a severe exacerbation requiring hospitalization. suggesting possible modifiers of the associations between acute exacerbation and both myocardial infarction and ischemic stroke risk. Our data suggest that those with a history of more frequent exacerbations may be at lower risk of myocardial infarction and ischemic stroke following an acute exacerbation, and that the association between acute exacerbation and myocardial infarction may be stronger among those with more severe airflow obstruction. The association between acute exacerbation and ischemic stroke was weaker among aspirin users compared to non-aspirin users.We found an eight-fold risk of myocardial infarction in the first three days following hospitalised acute exacerbation, compared to a two-fold risk for moderate events, suggesting a dose-response relationship by severity of acute exacerbation. Additionally, our findings suggest that risk of myocardial infarction increases again at around 8-14 days after falling for the first 7 days following moderate but not severe acute exacerbation. This could be a chance finding, but the timing may correspond to secondary bacterial infection in those with a viral exacerbation ADDIN EN.CITE <EndNote><Cite><Author>George</Author><Year>2014</Year><RecNum>23</RecNum><DisplayText>[25]</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>George, S?obhán N.</author><author>Garcha, Davinder S.</author><author>Mackay, Alexander J.</author><author>Patel, Anant R.C.</author><author>Singh, Richa</author><author>Sapsford, Raymond J.</author><author>Donaldson, Gavin C.</author><author>Wedzicha, Jadwiga A.</author></authors></contributors><titles><title>Human rhinovirus infection during naturally occurring COPD exacerbations</title><secondary-title>European Respiratory Journal</secondary-title></titles><periodical><full-title>European Respiratory Journal</full-title></periodical><pages>87-96</pages><volume>44</volume><number>1</number><dates><year>2014</year><pub-dates><date>2014-07-01 00:00:00</date></pub-dates></dates><urls><related-urls><url>;[25]. For ischemic stroke, we found a 43% increased risk of ischemic stroke in the first three days and a two-fold risk for severe acute exacerbation compared to stable periods, again suggesting a dose-response relationship. The peak risk of ischemic stroke was in the 4-7 days following acute exacerbation onset at an 80% increased risk of ischemic stroke following GP treated acute exacerbation and almost a four-fold increased risk of ischemic stroke following hospitalised acute exacerbation. Previous studies have suggested that frequent exacerbators have a higher risk of myocardial infarction ADDIN EN.CITE <EndNote><Cite><Author>Donaldson</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[11]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Donaldson, Gavin C.</author><author>Hurst, John R.</author><author>Smith, Christopher J.</author><author>Hubbard, Richard B.</author><author>Wedzicha, Jadwiga A.</author></authors></contributors><titles><title>Increased Risk of Myocardial Infarction and Stroke Following Exacerbation of COPD</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1091-1097</pages><volume>137</volume><number>5</number><dates><year>2010</year><pub-dates><date>5//</date></pub-dates></dates><isbn>0012-3692</isbn><urls><related-urls><url>;[11]. Our study found that the associations of acute exacerbation with the risks of myocardial infarction and ischemic stroke were lower for frequent exacerbators. Crucially, our study compared the relative risk of a myocardial infarction during acute exacerbation to a participant’s own stable period, not risk of myocardial infarction and ischemic stroke between individuals. One explanation could be that frequent exacerbators have a higher risk of myocardial infarction and ischemic stroke during stable periods (due to perhaps increased baseline inflammation ADDIN EN.CITE <EndNote><Cite><Author>Wedzicha</Author><Year>2013</Year><RecNum>7</RecNum><DisplayText>[26]</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wedzicha, Jadwiga A.</author><author>Brill, Simon E.</author><author>Allinson, James P.</author><author>Donaldson, Gavin C.</author></authors></contributors><titles><title>Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease</title><secondary-title>BMC Medicine</secondary-title></titles><periodical><full-title>BMC Medicine</full-title></periodical><pages>1-10</pages><volume>11</volume><number>1</number><dates><year>2013</year></dates><isbn>1741-7015</isbn><label>Wedzicha2013</label><work-type>journal article</work-type><urls><related-urls><url>;[26]), and thus there is less of a relative difference between stable and exacerbation periods for them. Because the self-controlled case series design includes only people who have the outcome of interest, we were not able to measure absolute rates of myocardial infarction or ischemic stroke.Others have found that increased airflow limitation is associated with increased risk of myocardial infarction. ADDIN EN.CITE <EndNote><Cite><Author>Sin</Author><Year>2005</Year><RecNum>26</RecNum><DisplayText>[27]</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sin, Don D.</author><author>Wu, LieLing</author><author>Man, S. F. Paul</author></authors></contributors><titles><title>The Relationship Between Reduced Lung Function and Cardiovascular Mortality: A Population-Based Study and a Systematic Review of the Literature</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1952-1959</pages><volume>127</volume><number>6</number><keywords><keyword>cardiovascular mortality</keyword><keyword>FEV1</keyword><keyword>lung function</keyword><keyword>metaanalysis</keyword><keyword>National Health and Nutrition Examination Survey</keyword></keywords><dates><year>2005</year><pub-dates><date>6//</date></pub-dates></dates><isbn>0012-3692</isbn><urls><related-urls><url>;[27] This is reflected in our finding that COPD patients with worse airflow limitation are more susceptible to the effects of acute exacerbation on risk of myocardial infarction than those with lesser limitation. There was no modification of the effect of acute exacerbation on risk of ischemic stroke by severity of airflow limitation, despite increased airflow limitation being associated with stroke. ADDIN EN.CITE <EndNote><Cite><Author>Truelsen</Author><Year>2001</Year><RecNum>41</RecNum><DisplayText>[28]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Truelsen, T.</author><author>Prescott, E.</author><author>Lange, P.</author><author>Schnohr, P.</author><author>Boysen, G.</author></authors></contributors><auth-address>The Danish Epidemiology Science Center at the Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark. truelsen@ipm.hosp.dk</auth-address><titles><title>Lung function and risk of fatal and non-fatal stroke. The Copenhagen City Heart Study</title><secondary-title>Int J Epidemiol</secondary-title><alt-title>International journal of epidemiology</alt-title></titles><alt-periodical><full-title>International Journal of Epidemiology</full-title></alt-periodical><pages>145-51</pages><volume>30</volume><number>1</number><edition>2001/02/15</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Confounding Factors (Epidemiology)</keyword><keyword>Denmark/epidemiology</keyword><keyword>Female</keyword><keyword>*Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Proportional Hazards Models</keyword><keyword>Stroke/*epidemiology/mortality/physiopathology</keyword></keywords><dates><year>2001</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0300-5771 (Print)
0300-5771</isbn><accession-num>11171876</accession-num><urls></urls><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>[28] Although there may be other differences between these patients, this finding points to the possibility that acutely worsening airflow limitation during acute exacerbation may be involved in the increased risk of myocardial infarction associated with acute exacerbation. This finding lends support to the idea that acute exacerbation may be a risk factor for type-2 myocardial infarction; which is the result of mismatch of myocardial supply and demand of oxygen, but not due to plaque rupture ADDIN EN.CITE <EndNote><Cite><Author>Saaby</Author><Year>2013</Year><RecNum>27</RecNum><DisplayText>[29]</DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">27</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saaby, Lotte</author><author>Poulsen, Tina Svenstrup</author><author>Hosbond, Susanne</author><author>Larsen, Torben Bjerregaard</author><author>Pyndt Diederichsen, Axel Cosmus</author><author>Hallas, Jesper</author><author>Thygesen, Kristian</author><author>Mickley, Hans</author></authors></contributors><titles><title>Classification of Myocardial Infarction: Frequency and Features of Type 2 Myocardial Infarction</title><secondary-title>The American Journal of Medicine</secondary-title></titles><periodical><full-title>The American Journal of Medicine</full-title></periodical><pages>789-797</pages><volume>126</volume><number>9</number><keywords><keyword>Troponin</keyword><keyword>Type 2 myocardial infarction</keyword><keyword>Universal definition of myocardial infarction</keyword></keywords><dates><year>2013</year><pub-dates><date>9//</date></pub-dates></dates><isbn>0002-9343</isbn><urls><related-urls><url>;[29]. Coupled with our finding that the association between acute exacerbation and ischemic stroke (but not myocardial infarction) was stronger among aspirin non-users is also suggestive of different mechanisms driving risk of ischemic stroke and myocardial infarction following acute exacerbation. We found that those with a previous heart failure diagnosis had a lower relative risk of myocardial infarction associated with acute exacerbation. However, this is based on a small number of events in the at risk period and may be due to misclassification of episodes of breathlessness due to acute heart failure being misclassified as acute exacerbation in these patients thereby misclassifying episodes of stable time as exposed time. Interestingly we also found a weaker association between acute exacerbation and ischemic stroke among those with prior angina, which is potentially due to an effect of treatment for angina.We have previously reported that people with COPD and acute myocardial infarction are more likely to have a non-STEMI than a STEMI, compared to people without COPD with acute myocardial infarction ADDIN EN.CITE <EndNote><Cite><Author>Rothnie</Author><Year>2015</Year><RecNum>24</RecNum><DisplayText>[30]</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rothnie, Kieran J</author><author>Smeeth, Liam</author><author>Herrett, Emily</author><author>Pearce, Neil</author><author>Hemingway, Harry</author><author>Wedzicha, Jadwiga</author><author>Timmis, Adam</author><author>Quint, Jennifer K</author></authors></contributors><titles><title>Closing the mortality gap after a myocardial infarction in people with and without chronic obstructive pulmonary disease</title><secondary-title>Heart</secondary-title></titles><periodical><full-title>Heart</full-title></periodical><pages>1103-1110</pages><volume>101</volume><number>14</number><dates><year>2015</year><pub-dates><date>July 15, 2015</date></pub-dates></dates><urls><related-urls><url>;[30]. Our finding that the associations of acute exacerbation with myocardial infarction was greater for non-STEMIs may help explain these excess non-STEMIs in those with COPD. Our finding that acute exacerbation is associated with a transient increased risk of myocardial infarction confirms suggestions from previous work that acute exacerbation are associated with myocardial infarctionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWxwaW48L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [11, 12] and myocardial injury ADDIN EN.CITE <EndNote><Cite><Author>McAllister</Author><Year>2012</Year><RecNum>22</RecNum><DisplayText>[31]</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">22</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McAllister, David A.</author><author>Maclay, John D.</author><author>Mills, Nicholas L.</author><author>Leitch, Andrew</author><author>Reid, Philip</author><author>Carruthers, Ross</author><author>O’Connor, Jennifer</author><author>McAlpine, Lawrence</author><author>Chalmers, George</author><author>Newby, David E.</author><author>Clark, Elaine</author><author>Macfarlane, Peter W.</author><author>MacNee, William</author></authors></contributors><titles><title>Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD</title><secondary-title>European Respiratory Journal</secondary-title></titles><periodical><full-title>European Respiratory Journal</full-title></periodical><pages>1097-1103</pages><volume>39</volume><number>5</number><dates><year>2012</year><pub-dates><date>2012-05-01 00:00:00</date></pub-dates></dates><urls><related-urls><url>;[31]. Our study also supports previous findings that exacerbating COPD patients have a higher risk of stroke compared to non-exacerbating patients over a 10 year follow up ADDIN EN.CITE <EndNote><Cite><Author>Lin</Author><Year>2017</Year><RecNum>40</RecNum><DisplayText>[13]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lin, Chao-Shun</author><author>Shih, Chun-Chuan</author><author>Yeh, Chun-Chieh</author><author>Hu, Chaur-Jong</author><author>Chung, Chi-Li</author><author>Chen, Ta-Liang</author><author>Liao, Chien-Chang</author></authors></contributors><titles><title>Risk of Stroke and Post-Stroke Adverse Events in Patients with Exacerbations of Chronic Obstructive Pulmonary Disease</title><secondary-title>PLOS ONE</secondary-title></titles><periodical><full-title>PLoS ONE</full-title></periodical><pages>e0169429</pages><volume>12</volume><number>1</number><dates><year>2017</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;[13], and our results extend these findings by precisely identifying the timing and duration of increased risk. In a within-individual analysis of 426 COPD patients and using prescription of antibiotics and oral steroids as a definition of acute exacerbation, Donaldson et al. ADDIN EN.CITE <EndNote><Cite><Author>Donaldson</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[11]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Donaldson, Gavin C.</author><author>Hurst, John R.</author><author>Smith, Christopher J.</author><author>Hubbard, Richard B.</author><author>Wedzicha, Jadwiga A.</author></authors></contributors><titles><title>Increased Risk of Myocardial Infarction and Stroke Following Exacerbation of COPD</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1091-1097</pages><volume>137</volume><number>5</number><dates><year>2010</year><pub-dates><date>5//</date></pub-dates></dates><isbn>0012-3692</isbn><urls><related-urls><url>;[11] also found an increased risk of myocardial infarction associated with acute exacerbation, but this was limited to the first 5 days following acute exacerbation onset. Donaldson et al. also investigated the risk of stroke following acute exacerbation and found a small increase risk after 49 days following acute exacerbation. We found a significantly higher risk than that previously estimated in previous studies. Our large sample size and validated exposure measures may have allowed us to estimate a more precise effect size and duration of increased risk.Broadly, our results are comparable with those from Smeeth et al. ADDIN EN.CITE <EndNote><Cite><Author>Smeeth </Author><Year>2004</Year><RecNum>9</RecNum><DisplayText>[10]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smeeth , Liam</author><author>Thomas , Sara L.</author><author>Hall , Andrew J.</author><author>Hubbard , Richard</author><author>Farrington , Paddy</author><author>Vallance , Patrick</author></authors></contributors><titles><title>Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination</title><secondary-title>New England Journal of Medicine</secondary-title></titles><periodical><full-title>New England Journal of Medicine</full-title></periodical><pages>2611-2618</pages><volume>351</volume><number>25</number><dates><year>2004</year></dates><accession-num>15602021</accession-num><urls><related-urls><url>;[10], who investigated the relationship between lower respiratory tract infection (LRTI) and risks of myocardial infarction and stroke in 20,921 people from the general population. Smeeth et al. reported an IRR of 4.95 (95% CI 4.43-5.53) for myocardial infarction and IRR of 3.19 (95% CI 2.81-3.62) for stroke in the three days following LRTI, which declined towards baseline over time, but lasted more than 4 weeks. The higher relative risk of myocardial infarction and ischemic stroke following LRTI in the general population compared to acute exacerbation may be due to a smaller relative difference in inflammation between acute exacerbation/LRTI and stable periods for those with COPD. Alternatively, those with COPD may attend their general practitioner with milder LRTI (in terms of inflammatory burden) than would those from the general population. We did not find that beta-blockers, or statins modified the effect of acute exacerbation on risk of first myocardial infarction or ischemic stroke. These findings are is not evidence that these medicines do not prevent myocardial infarction or ischemic stroke associated with acute exacerbation, but suggest that the particular risk of myocardial infarction and ischemic stroke associated with acute exacerbation may not be mitigated by use of these medicine. Our findings do not suggest that beta blockers and statins do not attenuate risk overall, since we investigated the relative risk between periods of stability (baseline) and exacerbation. A COPD patient who has been vaccinated against influenza will have some protection from influenza, but an acute exacerbation can still occur and will still increase the risk of cardiovascular events in the short term. Similarly, while statins or aspirin will reduce the absolute risk of a cardiovascular event in an individual, they will not remove all risk, and a period of increased risk following an acute exacerbation will still occur. However, this finding might also be explained by the definition of medicine use. We defined medicine use at baseline rather than as a time-varying effect modifier as prescription of these drugs are very much more likely after acute myocardial infarction or ischemic stroke. Since we only included first myocardial infarctions in the analysis, this period would be associated with an apparent rate of myocardial infarction or ischemic stroke of zero, and as such would have resulted in bias had we used a time-varying definition of cardiovascular medicines. This approach, however, may have resulted in underestimation of any effect modification by these medicines. It is worth noting that those patients in whom primary prevention with these medicines was completely effective would have not been included in the study due to the case only nature of the design. Clinicians should be aware that their COPD patients will be at higher risk of myocardial infarction and ischemic stroke in the weeks following acute exacerbation, and that this risk is much higher for those hospitalised with acute exacerbation. Acute exacerbations are known to be associated with mortality in those with COPD, and our findings are another reason that clinicians should focus on preventing acute exacerbation. We speculate that those patients with higher exacerbation frequency are at lower risk of stroke/myocardial infarction following an exacerbation for two reasons; 1) as they have more frequent medical care and are more likely to have relevant co-morbidities diagnosed and therefore be on more robust risk reduction strategies and 2) because frequent exacerbators have a heightened inflammatory response even in the stable state, their change in inflammation is less from baseline to exacerbation. This increased response to inflammatory stimuli among infrequent exacerbators may contribute to the increased risk of myocardial infarction and stroke. Such a hypothesis would only apply to relative risk increase between baseline and exacerbation periods, but will not be associated with an overall absolute risk of myocardial infarction and stroke which is higher among frequent exacerbators. Our findings suggest that acute exacerbation may explain some of the increased cardiovascular risk in those with COPD. However, the recently reported SUMMIT trial ADDIN EN.CITE <EndNote><Cite><Author>Vestbo</Author><RecNum>31</RecNum><DisplayText>[32]</DisplayText><record><rec-number>31</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">31</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vestbo, J?rgen</author><author>Anderson, Julie A.</author><author>Brook, Robert D.</author><author>Calverley, Peter M. A.</author><author>Celli, Bartolome R.</author><author>Crim, Courtney</author><author>Martinez, Fernando</author><author>Yates, Julie</author><author>Newby, David E.</author></authors></contributors><titles><title>Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial</title><secondary-title>The Lancet</secondary-title></titles><periodical><full-title>The Lancet</full-title></periodical><pages>1817-1826</pages><volume>387</volume><number>10030</number><dates></dates><publisher>Elsevier</publisher><isbn>0140-6736</isbn><urls><related-urls><url>(16)30069-1</url></related-urls></urls><electronic-resource-num>10.1016/S0140-6736(16)30069-1</electronic-resource-num><access-date>2017/02/13</access-date></record></Cite></EndNote>[32], which investigated the effects of vilanterol and fluticasone furoate, did not find a reduction in cardiovascular events despite a reduction in acute exacerbation. However, most of the SUMMIT population had previous coronary artery disease. It is difficult to disentangle the effects of treatment of acute exacerbation on myocardial infarction from the effects of acute exacerbation itself. Our study had several strengths. Firstly, the within-individual nature of the study design minimizes confounding by factors such as sex, genetics, long term medicine use and socioeconomic status. Our study also used data from the CPRD which is broadly generalizable to the UK population. In addition, compared to previous studies, we used a validated definition of acute exacerbation in electronic health records which enabled us to accurately identify acute exacerbation and we used linked secondary care HES data to categorise them as moderate or severe. In addition, we obtained data on myocardial infarction and ischemic stroke events from both primary and linked HES data which allowed us to identify more myocardial infarction ADDIN EN.CITE <EndNote><Cite><Author>Herrett</Author><Year>2013</Year><RecNum>28</RecNum><DisplayText>[33]</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Herrett, Emily</author><author>Shah, Anoop Dinesh</author><author>Boggon, Rachael</author><author>Denaxas, Spiros</author><author>Smeeth, Liam</author><author>van Staa, Tjeerd</author><author>Timmis, Adam</author><author>Hemingway, Harry</author></authors></contributors><titles><title>Completeness and diagnostic validity of recording acute myocardial infarction events in primary care, hospital care, disease registry, and national mortality records: cohort study</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>BMJ</full-title></periodical><volume>346</volume><dates><year>2013</year><pub-dates><date>2013-05-21 22:56:30</date></pub-dates></dates><urls><related-urls><url>;[33] and ischemic stroke. Another strength of our study was that, compared to previous work in similar populations, our sample size was significantly larger. Our study also has some weaknesses. In order to deal with time-varying confounders, we split time up into one year age bands and adjusted for these. In addition, we specifically adjusted for the effects of season. However, our study could still be susceptible to time-varying confounders if these correlated very closely in time with acute exacerbation, such as the use of treatments for acute exacerbation. Additionally, our study may have been susceptible to misclassification of acute exacerbation and myocardial infarction. We have previously demonstrated that people with COPD have delayed diagnosis of myocardial infarction ADDIN EN.CITE <EndNote><Cite><Author>Rothnie</Author><Year>2015</Year><RecNum>24</RecNum><DisplayText>[30]</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="2eezwwezba0wpiefwtnvwsvle0a5pa5erwet">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rothnie, Kieran J</author><author>Smeeth, Liam</author><author>Herrett, Emily</author><author>Pearce, Neil</author><author>Hemingway, Harry</author><author>Wedzicha, Jadwiga</author><author>Timmis, Adam</author><author>Quint, Jennifer K</author></authors></contributors><titles><title>Closing the mortality gap after a myocardial infarction in people with and without chronic obstructive pulmonary disease</title><secondary-title>Heart</secondary-title></titles><periodical><full-title>Heart</full-title></periodical><pages>1103-1110</pages><volume>101</volume><number>14</number><dates><year>2015</year><pub-dates><date>July 15, 2015</date></pub-dates></dates><urls><related-urls><url>;[30], if these events are originally diagnosed as acute exacerbation, this may result in a spurious association between acute exacerbation and myocardial infarction. However, to reduce the impact of this bias we excluded the first day of acute exacerbation from the analysis, and used a validated algorithm for identifying acute exacerbation ADDIN EN.CITE <EndNote><Cite><Author>Rothnie</Author><Year>2016</Year><RecNum>123</RecNum><DisplayText>[14]</DisplayText><record><rec-number>123</rec-number><foreign-keys><key app="EN" db-id="22rwes2xndfpesedpswx9dtjvtp2202rfapz">123</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rothnie, Kieran J.</author><author>Müllerová, Hana</author><author>Hurst, John R.</author><author>Smeeth, Liam</author><author>Davis, Kourtney</author><author>Thomas, Sara L.</author><author>Quint, Jennifer K.</author></authors></contributors><titles><title>Validation of the Recording of Acute Exacerbations of COPD in UK Primary Care Electronic Healthcare Records</title><secondary-title>PLOS ONE</secondary-title></titles><periodical><full-title>PLOS ONE</full-title></periodical><pages>e0151357</pages><volume>11</volume><number>3</number><dates><year>2016</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;[14]. We are aware we may not have eliminated this bias completely, however; such a bias is very unlikely to explain a substantial proportion of the effect however, as the effect of acute exacerbation in the risk of myocardial infarction lasted for several weeks. We find it unlikely that stroke would be misclassified as acute exacerbation. Whilst there is evidence that troponin may rise at the time of an acute exacerbation, we are also aware that people with COPD do not have as great a troponin rise at myocardial infarction as people without COPD. Thus, the misclassification may occur in both directions. We have used validated definitions for acute exacerbation and validated myocardial infarction codes based on the work of others and so what we have defined as “events” are likely to be true exacerbations or myocardial infarction/stroke events. ConclusionsCompared to stable periods, we found associations between acute exacerbation and increased risks of myocardial infarction and ischemic stroke in the four weeks following the exacerbation. The increased risk of acute vascular events following acute exacerbation was significantly higher for severe compared to moderate acute exacerbation. The association of acute exacerbation with myocardial infarction risk was higher for infrequent exacerbators, and for those with more severe airflow limitation, and was more strongly associated with non-STEMIs. The association of acute exacerbation with ischemic stroke risk was higher for infrequent exacerbators and weaker among aspirin non-users.References ADDIN EN.REFLIST 1Rothnie KJ, Yan R, Smeeth L, et al. Risk of myocardial infarction (MI) and death following MI in people with chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis. BMJ Open 2015;5.2Morgan AD, Sharma C, Rothnie KJ, et al. Chronic Obstructive Pulmonary Disease and the Risk of Stroke. Annals of the American Thoracic Society 2017;14:754-65.3Sin DD, Anthonisen NR, Soriano JB, et al. Mortality in COPD: role of comorbidities. European Respiratory Journal 2006;28:1245-57.4Feary JR, Rodrigues LC, Smith CJ, et al. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax 2010;65:956-62.5Barnes PJ. Chronic Obstructive Pulmonary Disease: Effects beyond the Lungs. PLoS Med 2010;7:e1000220.6Sethi S. Bacteria in Exacerbations of Chronic Obstructive Pulmonary Disease. Proceedings of the American Thoracic Society 2004;1:109-14.7Wedzicha JA. Role of Viruses in Exacerbations of Chronic Obstructive Pulmonary Disease. Proceedings of the American Thoracic Society 2004;1:115-20.8Wedzicha JA, Seemungal TAR, MacCallum PK, et al. Acute Exacerbations of Chronic Obstructive Pulmonary Disease Are Accompanied by Elevations of Plasma Fibrinogen and Serum IL-6 Levels. Thrombosis and Haemostasis 2000;84:210-5.9Dev D, Wallace E, Sankaran R, et al. Value of C-reactive protein measurements in exacerbations of chronic obstructive pulmonary disease. Respiratory Medicine 1998;92:664-7.10Smeeth L, Thomas SL, Hall AJ, et al. Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination. New England Journal of Medicine 2004;351:2611-8.11Donaldson GC, Hurst JR, Smith CJ, et al. Increased Risk of Myocardial Infarction and Stroke Following Exacerbation of COPD. Chest 2010;137:1091-7.12Halpin DMG, Decramer M, Celli B, et al. Risk of Nonlower Respiratory Serious Adverse Events Following COPD Exacerbations in the 4-year UPLIFT(?) Trial. Lung 2011;189:261-8.13Lin C-S, Shih C-C, Yeh C-C, et al. Risk of Stroke and Post-Stroke Adverse Events in Patients with Exacerbations of Chronic Obstructive Pulmonary Disease. PLOS ONE 2017;12:e0169429.14Rothnie KJ, Müllerová H, Hurst JR, et al. Validation of the Recording of Acute Exacerbations of COPD in UK Primary Care Electronic Healthcare Records. PLOS ONE 2016;11:e0151357.15Herrett E, Gallagher AM, Bhaskaran K, et al. Data Resource Profile: Clinical Practice Research Datalink (CPRD). International Journal of Epidemiology 2015.16Whitaker HJ, Paddy Farrington C, Spiessens B, et al. Tutorial in biostatistics: the self-controlled case series method. Statistics in Medicine 2006;25:1768-97.17Minassian C, Thomas SL, Smeeth L, et al. Acute Cardiovascular Events after Herpes Zoster: A Self-Controlled Case Series Analysis in Vaccinated and Unvaccinated Older Residents of the United States. PLOS Medicine 2015;12:e1001919.18Thomas SL, Minassian C, Ganesan V, et al. Chickenpox and Risk of Stroke: A Self-controlled Case Series Analysis. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 2014;58:61-8.19Quint JK, Müllerova H, DiSantostefano RL, et al. Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD). BMJ Open 2014;4.20Rothnie KJ, Müllerová H, Thomas SL, et al. Recording of hospitalizations for acute exacerbations of COPD in UK electronic health care records. Clinical Epidemiology 2016;8:771-82.21Tseng C-M, Chen Y-T, Ou S-M, et al. The Effect of Cold Temperature on Increased Exacerbation of Chronic Obstructive Pulmonary Disease: A Nationwide Study. PLoS ONE 2013;8:e57066.22Bhaskaran K, Hajat S, Haines A, et al. Short term effects of temperature on risk of myocardial infarction in England and Wales: time series regression analysis of the Myocardial Ischaemia National Audit Project (MINAP) registry. BMJ 2010;341.23Kyobutungi C, Grau A, Stieglbauer G, et al. Absolute Temperature, Temperature Changes and Stroke Risk: A Case-Crossover Study. European Journal of Epidemiology 2005;20:693-8.24Ghebremichael-Weldeselassie Y WH, Farrington C. Spline-based self-controlled case series method. 2015.25George SN, Garcha DS, Mackay AJ, et al. Human rhinovirus infection during naturally occurring COPD exacerbations. European Respiratory Journal 2014;44:87-96.26Wedzicha JA, Brill SE, Allinson JP, et al. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Medicine 2013;11:1-10.27Sin DD, Wu L, Man SFP. The Relationship Between Reduced Lung Function and Cardiovascular Mortality: A Population-Based Study and a Systematic Review of the Literature. Chest 2005;127:1952-9.28Truelsen T, Prescott E, Lange P, et al. Lung function and risk of fatal and non-fatal stroke. The Copenhagen City Heart Study. Int J Epidemiol 2001;30:145-51.29Saaby L, Poulsen TS, Hosbond S, et al. Classification of Myocardial Infarction: Frequency and Features of Type 2 Myocardial Infarction. The American Journal of Medicine 2013;126:789-97.30Rothnie KJ, Smeeth L, Herrett E, et al. Closing the mortality gap after a myocardial infarction in people with and without chronic obstructive pulmonary disease. Heart 2015;101:1103-10.31McAllister DA, Maclay JD, Mills NL, et al. Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD. European Respiratory Journal 2012;39:1097-103.32Vestbo J, Anderson JA, Brook RD, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. The Lancet;387:1817-26.33Herrett E, Shah AD, Boggon R, et al. Completeness and diagnostic validity of recording acute myocardial infarction events in primary care, hospital care, disease registry, and national mortality records: cohort study. BMJ 2013;346.Figure 1. Diagram representing the study design. In this hypothetical example the patient has two exposed periods (acute exacerbation) during follow up and a first myocardial infarction within 91 days of the start of the second exposed period (acute exacerbation). Figure 2. Patient flow in the study.Figure 3. Incidence rate ratios of first myocardial infarction or ischaemic stroke in risk periods after an acute exacerbation of COPD relative to stable periods and stratified by acute exacerbation severityp-value for interaction between moderate and severe acute exacerbation for risk of myocardial infarction <0.001p-value for interaction between moderate and severe acute exacerbation for risk of ischemic stroke <0.001IRR – incidence rate ratio.Figure 4. A Risk of myocardial infarction associated with moderate (general practitioner treated) acute exacerbation; B Risk of myocardial infarction associated with severe (hospitalized) acute exacerbation; C Risk of ischaemic stroke associated with moderate (general practitioner treated) acute exacerbation; and D Risk of ischaemic stroke associated with severe (hospitalized) acute exacerbationFigure 5: Incidence rate ratios of first myocardial infarction in risk period (91 days) after an acute exacerbation of COPD relative to stable periods stratified by COPD patient characteristicsFigure 6: Incidence rate ratios of first ischaemic stroke in risk period (91 days) after an acute exacerbation of COPD (relative to stable periods stratified by COPD patient characteristics Table 1. Characteristics of study participants with myocardial infarction or ischemic stroke and acute exacerbation of COPD during the study period CharacteristicMyocardial infarction Ischaemic stroke No. of participants2,8503,466Age at index myocardial infarction/ischemic stroke, years73.3 (66.0-80.3)75.8 (68.8-81.8)Average observation time from follow-up start, years8.2 (6.0-10.3)6.3 (3.9-9.0)Male sex59.5%55.1%Number with at least one severe event (acute exacerbation requiring hospitalisation)51.0%36.1%Frequent exacerbators, 12mo prior to follow-up start42.9%39.5%Cardiovascular comorbid disease at any time prior to the start of follow upAngina17.9%17.2%Heart failure7.7%-Stroke5.7%-Atrial fibrillation-19.0%Myocardial infarction-7.2%Prescribed cardiovascular drug within 12 months prior to the start of follow-upStatin29.4%30.5%Aspirin28.6%30.6%Beta-blocker20.7%23.7%GOLD stage of airflow limitation at start of follow-up (N=1476)Grade 1-2, n (%)976 (64.1)978 (65.3)Grade 3-4, n (%)547 (35.9)519 (34.7)Missing, n1,3741,513Prescribed respiratory drug, 12 months prior to the start of follow upICS users 60.8%42.1%Concomitant LABA79.8%72.4%Concomitant LAMA34.5%29.0%Non ICS users 39.2%57.9%LABA14.1%34.8%LAMA16.0%22.8%Baseline influenza vaccination status69.3%72.6%Type of myocardial infarction (N=1872)STEMI, n (%)734 (37.2)-Non-STEMI, n (%)1,242 (62.9)-Missing, n978-Data are median (interquartile range) or percentageSupplementary online material Table S1 Medical codes used to identify myocardial infarction in CPRD.Table S2. Medical codes used to identify ischaemic stroke in CPRD.Table S3. Incidence rate ratios of first myocardial infarction in risk periods after an acute exacerbation of COPD relative to stable periods sensitivity analysis censoring within 6 months of myocardial infarctionTable S4 Incidence rate ratios of first myocardial infarction in risk periods after an acute exacerbation of COPD relative to stable periods sensitivity analysis censoring within 12 months of myocardial infarctionTable S5. Incidence rate ratios of first myocardial infarction in risk periods after an acute exacerbation of COPD relative to stable periods sensitivity analysis censoring within 6 months of ischemic strokeTable S6 Incidence rate ratios of first myocardial infarction in risk periods after an acute exacerbation of COPD relative to stable periods sensitivity analysis censoring within 12 months of ischemic strokeTable S1 Medical codes used to identify myocardial infarction in CPRD.Medical codeRead term241acute myocardial infarction1204heart attack1677mi - acute myocardial infarction1678inferior myocardial infarction nos5387other specified anterior myocardial infarction10562acute non-st segment elevation myocardial infarction12229acute st segment elevation myocardial infarction14658acute myocardial infarction nos14897anterior myocardial infarction nos14898lateral myocardial infarction nos23892posterior myocardial infarction nos29758acute transmural myocardial infarction of unspecif site32854acute posterolateral myocardial infarction34803other acute myocardial infarction46017other acute myocardial infarction nos63467true posterior myocardial infarction96838[x]acute transmural myocardial infarction of unspecif siteTable S2 Medical codes used to identify ischaemic stroke in CPRD.Medical codeRead term94482[x]cereb infarct due unsp occlus/stenos precerebr arteries91627[x]cerebrl infarctn due/unspcf occlusn or sten/cerebrl artrs92036[x]occlusion and stenosis of other cerebral arteries90572[x]occlusion and stenosis of other precerebral arteries53745[x]other cerebral infarction19280anterior cerebral artery syndrome32447basilar artery occlusion8443brain stem stroke syndrome25615brainstem infarction15252brainstem infarction nos4240carotid artery occlusion39344cereb infarct due cerebral venous thrombosis, nonpyogenic40758cereb infarct due unsp occlus/stenos precerebr arteries5602cerebellar infarction17322cerebellar stroke syndrome8837cerebral arterial occlusion15019cerebral embolism34758cerebral embolus23671cerebral infarct due to thrombosis of precerebral arteries27975cerebral infarction due to embolism of cerebral arteries24446cerebral infarction due to embolism of precerebral arteries36717cerebral infarction due to thrombosis of cerebral arteries3149cerebral infarction nos16517cerebral thrombosis33543cerebrl infarctn due/unspcf occlusn or sten/cerebrl artrs5363cva - cerebral artery occlusion40053generalised ischaemic cerebrovascular disease nos12555generalised ischaemic cerebrovascular disease nos569infarction - cerebral57495infarction - precerebral26424infarction of basal ganglia9985left sided cerebral infarction18689middle cerebral artery syndrome98642multiple and bilateral precerebral arterial occlusion57527occlusion and stenosis of anterior cerebral artery55602occlusion and stenosis of cerebellar arteries51759occlusion and stenosis of middle cerebral artery65770occlusion and stenosis of posterior cerebral artery71274occlusion+stenosis of multiple and bilat cerebral arteries51326other precerebral artery occlusion19260posterior cerebral artery syndrome45781precerebral arterial occlusion71585precerebral artery occlusion nos33499pure motor lacunar syndrome51767pure sensory lacunar syndrome10504right sided cerebral infarction6155stroke due to cerebral arterial occlusion4152thrombosis, carotid artery40847vertebral artery occlusion73901[x]cerebrovascular diseases70536acute cerebrovascular insufficiency nos10062cerebrovascular disease nos47607cva - cerebrovascular accident in the puerperium6116cva - cerebrovascular accident unspecified1298cva unspecified7780left sided cva37493other cerebrovascular disease nos34117other cerebrovascular disease os51311other specified cerebrovascular disease12833right sided cva98188small vessel cerebrovascular disease1469stroke and cerebrovascular accident unspecified56279stroke in the puerperium6253stroke unspecifiedTable S3 Incidence rate ratios of first myocardial infarction in risk periods after an acute exacerbation of COPD relative to stable periods sensitivity analysis censoring within six months of myocardial infarctionRisk periodN outcome events (myocardial infarction)IRR (95% CI)Total risk period (91 days)6951.53 (1.38-1.68)1-3 days732.68 (2.11-3.41)4-7 days661.91 (1.48-2.45)8-14 days1212.11 (1.74-2.56)15-28 days1721.80 (1.52-2.12)29-91 days2631.12 (0.97-1.29)Table S4 Incidence rate ratios of first myocardial infarction in risk periods after an acute exacerbation of COPD relative to stable periods sensitivity analysis censoring within 12 months of myocardial infarctionRisk periodN outcome events (myocardial infarction)IRR (95% CI)Total risk period (91 days)5861.49 (1.34-1.67)1-3 days592.48 (1.90-3.25)4-7 days561.85 (1.41-2.44)8-14 days1042.08 (1.69-2.56)15-28 days1381.67 (1.39-2.01)29-91 days2291.14 (0.98-1.32)Table S5. Incidence rate ratios of first ischaemic stroke in risk periods after an acute exacerbation of COPD relative to stable periods sensitivity analysis censoring within 6 months of ischemic strokeRisk periodN outcome events (myocardial infarction)IRR (95% CI)Total risk period (91 days)8041. (1.-1.)1-3 days471.54 (1.15-2.07)4-7 days701.79 (1.40-2.28)8-14 days1191.80 (1.40-2.28)15-28 days1851.65 (1.41-1.93)29-91 days3831.35 (1.20-1.52)Table S6. Incidence rate ratios of first ischaemic stroke in risk periods after an acute exacerbation of COPD relative to stable periods sensitivity analysis censoring within 12 months of ischemic strokeRisk periodN outcome events (myocardial infarction)IRR (95% CI)Total risk period (91 days)7491.52 (1.38-1.68)1-3 days431.53 (1.13-2.08)4-7 days611.69 (1.31-2.20)8-14 days1121.84 (1.51-2.24)15-28 days1701.64 (1.39-1.94)29-91 days3631.39 (1.24-1.57) ................
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