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Essential Evidence January 2020North Dakota Academy of Family PhysiciansBig Sky, MontanaLearning ObjectivesDiscuss recent research important to family physicians for updating their diagnostic and treatment approaches to musculoskeletal conditions, cardiovascular disease, hypertension, diabetes, Vitamin D therapy, probiotics, upper GI conditions, and pediatrics. Objectives for each presentation are listed at the beginning of each presentation. Each talk is based on a literature review of recent research studies. Evidence sources include PubMed, InfoPoems and Cochrane systematic reviews.FacultyGary Ferenchick, MD, MS. is Professor of Medicine at Michigan State University College of Human Medicine, where he practices general internal medicine and is deeply involved in MSU-CHM major curriculum renovation. He earned his master’s degree in human nutrition and medical degree from Michigan State University and completed his residency training in internal medicine at Michigan State University College of Human Medicine, where he has been a faculty member for over 25 year. Dr. Ferenchick is a Past-President of the Clerkship Directors in Internal Medicine. His research interest is the interface between medical education and information technology. He has been teaching evidence-based medicine to residents and physicians for over 20 years. John Hickner, MD, MS. is the Editor-in-Chief of the Journal of Family Practice and Professor Emeritus, Michigan State University College of Human Medicine. After receiving his medical degree from Indiana University School of Medicine, he completed a family medicine residency at the Medical University of South Carolina and received a master’s degree in Biostatistics and Research Design from the University of Michigan School of Public Health.?He was the Chair of Family Medicine at Cleveland Clinic from 2009 to 2014 and Head of Family Medicine at the University of Illinois at Chicago from 2013 to 2018. Dr. Hickner has practiced Family Medicine for over 40 years. He has been teaching evidence-based medicine courses to physicians and medical students for more than 30 years.Speaker and Faculty DisclosuresJohn Hickner disclosed no relevant financial relationship or interest with a proprietary entity producing health care goods or services.Gary Ferenchick disclosed no relevant financial relationship or interest with a proprietary entity producing health care goods or services.“Essential Evidence” and all content in this handout is copyright by John Wiley and Sons, Inc, 2014. This syllabus may not be reproduced without permission from the publisher. Evidence ScheduleThursday, January 23, 20204:30pmCV Update: Focus on Aspirin and Lipids – Gary Ferenchick, MDPage 35:00pmMusculoskeletal Update – John Hickner, MDPage 21 5:30pmHypertension Update – Gary Ferenchick, MDPage 29 6:00pmPediatric Potpourri – John Hickner, MDPage 43 6:30pmEvening Lectures EndFriday, January 24, 20207:30amDiabetes Update – Gary Ferenchick, MDPage 51 8:00amIntegrative Medicine: Focus on Probiotics – John Hickner, MDPage 62 8:30amUpper GI/ H. pylori – Gary Ferenchick, MDPage 73 9:00amVitamin D 2020– John Hickner, MDPage 83 9:30amDiscussion/Q&A – Ferenchick and Hickner9:45amSession endsCardiovascular Disease Update | 2019Gary Ferenchick MD, MSLearning objectives | Understand and apply: The USPSTF 2016 recommendation on the use of ASA for primary preventionThe recent evidence on the use of aspirin for primary prevention in light of the USPSTF recommendations focusing on the ASPREE, ASCEND and ARRIVE TrialsThat “one-size-fits-all” for the use of ASA for primary prevention may be the wrong paradigmThe 2018 ACC AHA Cholesterol Clinical Practice GuidelinesASPIRINAspirin has become one of the most popular agents used for the primary prevention of cardiovascular disease, and the past year the value of ASA for primary prevention has been called into question by several large RCTS. This story starts in 2014 when the FDA concluded that primary prevention of MI should not be an indication for aspirin. In 2016 the USPSTF published recommendations concerning the use of Low Dose Aspirin focusing on:1) ASA Use to Prevent Cardiovascular Disease2) Risk of bleeding with ASA use and3) ASA Use to Prevent Cancer My summary conclusions from these articles include:ASA Use to Prevent Cardiovascular DiseaseAbsolute risk reduction of ~ 1 per 1000 persons per year for non-fatal MIAbsolute risk reduction of ~ 1 per 2000 persons per year for non-fatal CVANo effect on CVD mortality or all-cause mortalityRisk of bleeding with ASA useAbsolute ↑ GIB risk of ~ 1 per 2000 persons per yearAbsolute ↑ ICH risk of ~ 1 per 3000 persons per yearWith a quick calculation, these statistics can be summarized as:For every 3 people avoiding an MI and 2 people avoiding a stroke, one extra patient will experience an ICH ASA Use to Prevent CancerWhat was not apparent, at least to me, was the effect of ASA on colorectal cancer Aspirin appears to reduce colorectal cancer incidence beginning 10-19 years after initiation of aspirin (RR = 0.60; CI 0.47 – 0.76)20-year colorectal cancer mortality reduced with aspirin (RR 0.67 (CI 0.52 – 0.86). USPSTF Recommendations | 2016Low Dose Aspirin Use to Prevent Cardiovascular Disease and Colorectal CancerPopulationRecommendation GradeAdults 50 - 59 ≥10% 10-year CVD riskIf not at risk of bleedingLife expectancy > 10 yearsWilling to take ASA for > 10 yrsBAdults 60 - 69 years≥10% 10-year CVD riskIf not at risk of bleedingLife expectancy > 10 yearsWilling to take ASA for > 10 yrsBAdults < 50 yearsInsufficient evidenceIAdults aged > 70 yearsInsufficient evidenceIThe first three abstracts summarize these USPSTF recommendations 1: USPSTF | Aspirin for the prevention of CV DzBACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in the United States.PURPOSE: To update a systematic review about the benefits of aspirin for the primary prevention of cardiovascular events in adults aged 40 years or older and to evaluate effect modification in subpopulations.DATA SOURCES: MEDLINE, PubMed, Cochrane Central Register of Controlled Trials (January 2008 to January 2015), and Cochrane Database of Systematic Reviews.STUDY SELECTION: Two investigators independently reviewed 3396 abstracts and 65 articles according to prespecified criteria. All included trials evaluated aspirin for the primary prevention of cardiovascular events.DATA EXTRACTION: Two investigators assessed study quality; data were abstracted by 1 reviewer and checked by a second.DATA SYNTHESIS: Two good-quality and 9 fair-quality randomized, controlled trials were identified. In analyses of all doses, aspirin reduced the risk for nonfatal myocardial infarction (MI) (relative risk [RR], 0.78 [95% CI, 0.71 to 0.87]) but not nonfatal stroke; aspirin showed little or no benefit for all-cause or cardiovascular mortality. Benefits began within the first 5 years. Older adults achieved greater relative MI reduction, but no other effect modifications were found in analyzed subpopulations. In trials with aspirin doses of 100 mg or less per day, the reduction in nonfatal MI benefit persisted (absolute risk reduction,0.15 to 1.43 events per 1000 person-years) and a 14% reduction in nonfatal stroke benefit was noted, but no benefit was found for all-cause mortality (RR, 0.95 [CI, 0.89 to 1.01]) or cardiovascular mortality (RR, 0.97 [CI, 0.85 to 1.10]).LIMITATION: Evidence for aspirin in primary prevention is heterogeneous and limited by rare events and few credible subgroup analyses.CONCLUSION: The beneficial effect of aspirin for the primary prevention of CVD is modest and occurs at doses of 100 mg or less per day. Older adults seem to achieve a greater relative MI benefit.PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.REFERENCE: Guirguis-Blake JM, et al. Aspirin for the Primary Prevention of Cardiovascular Events: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun 21;164(12):804-13.2: USPSTF | Bleeding risks with AspirinBACKGROUND: The balance between potential aspirin-related risks and benefits is critical in primary prevention.PURPOSE: To evaluate the risk for serious bleeding with regular aspirin use in cardiovascular disease (CVD) primary prevention.DATA SOURCES: PubMed, MEDLINE, Cochrane Central Register of Controlled Trials (2010 through 6 January 2015), and relevant references from other reviews.STUDY SELECTION: Randomized, controlled trials; cohort studies; and meta-analyses comparing aspirin with placebo or no treatment to prevent CVD or cancer in adults.DATA EXTRACTION: One investigator abstracted data, another checked for accuracy, and 2 assessed study quality.DATA SYNTHESIS: In CVD primary prevention studies, very-low-dose aspirin use (≤100 mg daily or every other day) increased major gastrointestinal (GI) bleeding risk by 58% (odds ratio [OR], 1.58 [95% CI, 1.29 to 1.95]) and hemorrhagic stroke risk by 27% (OR, 1.27 [CI, 0.96 to 1.68]). Projected excess bleeding events with aspirin depend on baseline assumptions. Estimated excess major bleeding events were 1.39 (CI, 0.70 to 2.28) for GI bleeding and 0.32 (CI, -0.05 to 0.82) for hemorrhagic stroke per 1000 person-years of aspirin exposure using baseline bleeding rates from a community-based observational sample. Such events could be greater among older persons, men, and those with CVD risk factors that also increase bleeding risk.LIMITATIONS: Power to detect effects on hemorrhagic stroke was limited. Harms other than serious bleeding were not examined.CONCLUSION: Consideration of the safety of primary prevention with aspirin requires an individualized assessment of aspirin's effects on bleeding risks and expected benefits because absolute bleeding risk may vary considerably by patient.PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.REFERENCE: Whitlock EP, et al. Bleeding Risks With Aspirin Use for Primary Prevention in Adults: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun 21;164(12):826-35. Comment in Ann Intern Med. 2016 Aug 16;165(4):JC17.3: USPSTF | Aspirin for the prevention of cancerBACKGROUND: Cancer is the second leading cause of death in the United States.PURPOSE: To conduct systematic reviews of aspirin and 1) total cancer mortality and incidence in persons eligible for primary prevention of cardiovascular disease (CVD) and 2) colorectal cancer (CRC) mortality and incidence in persons at average CRC risk.DATA SOURCES: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials through January 2015 and relevant references from other reviews.STUDY SELECTION: Trials comparing oral aspirin versus placebo or no treatment in adults aged 40 years or older were included. Two investigators independently reviewed abstracts and articles against inclusion and quality criteria.DATA EXTRACTION: Data from 20 good- or fair-quality trials were abstracted by one reviewer and checked by another.DATA SYNTHESIS: In CVD primary prevention trials, cancer mortality (relative risk [RR], 0.96 [95% CI, 0.87 to 1.06]) (10 trials; n?= 103?787) and incidence (RR,0.98 [CI, 0.93 to 1.04]) (6 trials; n?= 72?926) were similar in aspirin and control groups over 3.6 to 10.1 years. In CVD primary and secondary prevention trials, 20-year CRC mortality was reduced among persons assigned to aspirin therapy (RR, 0.67 [CI, 0.52 to 0.86]) (4 trials; n?= 14?033). Aspirin appeared to reduce CRC incidence beginning 10 to 19 years after initiation (RR, 0.60 [CI,0.47 to 0.76]) (3 trials; n?= 47?464).LIMITATIONS: Most data were from clinically and methodologically heterogeneous CVD prevention trials. Outcome assessment and follow-up length varied across studies. Data on non-CRC cancer types and subgroups were limited.CONCLUSION: In CVD primary prevention populations, aspirin's effect on total cancer mortality and incidence was not clearly established. Evidence from CVD primary and secondary prevention studies suggested that aspirin therapy reduces CRC incidence and perhaps mortality approximately 10 years after initiation.PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.REFERENCE: Chubak J, et al. Aspirin for the Prevention of Cancer Incidence and Mortality: Systematic Evidence Reviews for the U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun 21;164(12):814-25. Comment in Ann Intern Med. 2016 Aug 16;165(4):JC16.In mid to late 2018, there were a flurry of articles published in several highly prestigious journals all of which concluded that the risks of low dose ASA for primary prevention out weighted any benefit in patients without established CV disease (including those with DM) The primary studies were entitled: ASPREE (ASPirin in Reducing Events in the Elderly) – 3 separate studiesARRIVE (Aspirin to Reduce Risk of Initial Vascular Events)ASCEND (A Study of Cardiovascular Events iN Diabetes)JPAD (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes)4: ASPREE | Aspirin no effect on disability-free survivalClinical question: Does aspirin improve disability-free survival in an otherwise healthy older person?Study design: Randomized controlled trial (double-blinded)Setting: Population-basedSynopsis: These are the initial results of the landmark Aspirin in Reducing Events in the Elderly (ASPREE) trial. Two other reports describe the effect of aspirin on all-cause mortality and on cardiovascular disease. The authors randomized 19,114 community-dwelling adults to receive either 100 mg of enteric-coated aspirin or placebo. The study was conducted in the United States and Australia, with patients recruited between 2010 and 2014. Participants were 70 years or older (65 years or older if black or Hispanic in the United States, because of their shorter average lifespan), had no serious comorbidity that would be expected to limit their life expectancy to less than 5 years, and no known cardiovascular (CV) or cerebrovascular disease, dementia, high bleeding risk, or contraindication to aspirin. The study included a 1-month placebo run-in period to ensure at least 80% adherence to the study medication. During the run-in period, 4049 patients were excluded, 61% because they failed adherence. Included patients were contacted every 3 months to further encourage adherence and to gather interim data. Outcomes were adjudicated by a committee masked to treatment assignment. The median age of participants was 74 years, 56% were women, and 8.7% were non-white. Most of the patients were recruited in Australia (87%), 74% had hypertension, 65% had hyperlipidemia, and only 11% had diabetes. Participants were followed up for a median of 4.8 years, and only 2.2% withdrew or were lost to follow-up. The primary outcome was a composite of death, dementia, or physical disability, which occurred in 921 persons who received aspirin and 914 who received placebo (hazard ratio [HR] 1.10; 95% CI 0.92 - 1.11). All-cause mortality was slightly higher in the aspirin group (12.7 vs 11.1 events per 1000 person-years; HR 1.14, 1.01 - 1.29; number needed to treat to harm [NNTH] = 625 per year). Major hemorrhage was more common in the aspirin group (8.6 vs 6.2 events per 1000 person-years; hazard ratio 1.38; 95% CI 1.18 - 1.62; number needed to treat to harm = 417 per year).Bottom line: This landmark study found that in a contemporary population where risk factors such as hyperlipidemia and hypertension are more likely to be addressed, aspirin did not provide a benefit in terms of mortality, dementia, or disability in a largely white group of older patients.Reference: McNeil JJ, Woods RL, Nelson MR, et al, for the ASPREE Investigator Group. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med 2018;379(16):1499-1508.REFERENCE: McNeil JJ, etal for the ASPREE Investigator Group. Effect of Aspirin on Disability-free Survival in the Healthy Elderly. N Engl J Med. 2018 Oct 18;379(16):1499-1508.5: ASPREE | Aspirin may increase all-cause mortalityClinical question: Does low-dose aspirin reduce all-cause mortality in generally healthy older adults?Study design: Randomized controlled trial (double-blinded)Setting: Population-basedSynopsis: This is 1 of 3 reports of the same study in the same issue of the New England Journal of Medicine; this one focuses on all-cause mortality. The Aspirin in Reducing Events in the Elderly (ASPREE) trial randomized 19,114 community-dwelling adults to receive either 100 mg of enteric-coated aspirin or placebo. The study was conducted in the United States and Australia, with patients recruited between 2010 and 2014. Participants were 70 years or older (65 years or older if black or Hispanic in the United States, because of their shorter average lifespan), had no serious comorbidity that would be expected to limit their life expectancy to less than 5 years, and no known cardiovascular (CV) or cerebrovascular disease, dementia, high bleeding risk, or contraindication to aspirin. The study included a 1-month placebo run-in period to ensure at least 80% adherence to the study medication. During the run-in period, 4049 patients were excluded, 61% because they failed adherence. Included patients were contacted every 3 months to further encourage adherence and to gather interim data. Outcomes were adjudicated by a committee masked to treatment assignment. The median age of participants was 74 years, 56% were women, and 8.7% were non-white. Most of the patients were recruited in Australia (87%), 74% had hypertension, 65% had hyperlipidemia, and only 11% had diabetes. Participants were followed up for a median of 4.8 years, and only 2.2% withdrew or were lost to follow-up. All-cause mortality was higher in the aspirin group (5.9% vs 5.2%; hazard ratio [HR] 1.14, 95% CI 1.01 - 1.29; number needed to treat to harm [NNTH] = 143 over 4.8 years). The likelihood of cancer death was also higher in the aspirin group, with the increased risk beginning after approximately 3 years of aspirin use (3.1% vs 2.3%; HR 1.31, 1.10 - 1.56; NNTH = 125 over 4.8 years).Bottom line: These findings are completely unexpected. Although recent studies by this group and other groups of researchers have failed to find a cardiovascular benefit, likely because of better control of other cardiovascular risk factors, this study found increased all-cause mortality, primarily due to increased cancer-related mortality. Other studies, such as the individual patient meta-analysis by Rothwell and colleagues (Lancet 2011;377(9759):31-41) found the opposite. A Bayesian thinker would urge caution in interpreting these results, considering the existing body of research concluding the opposite regarding cancer-specific mortality.REFERENCE: McNeil JJ, etal for the ASPREE Investigator Group. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly HYPERLINK "(16)%3A1519-1528" . N Engl J Med. 2018 Oct 18;379(16):1519-15286: ASPREE | Aspirin no effect on CV eventsClinical question: Does low-dose aspirin prevent cardiovascular events and cardiovascular-related death in otherwise healthy older persons?Study design: Randomized controlled trial (double-blinded)Setting: Population-basedSynopsis: The Aspirin in Reducing Events in the Elderly (ASPREE) trial randomized 19,114 community-dwelling adults to receive either 100 mg of enteric-coated aspirin or placebo. The study was conducted in the United States and Australia, with patients recruited between 2010 and 2014. Participants were 70 years or older (65 years or older if black or Hispanic in the United States, because of their shorter average lifespan), had no serious comorbidity that would be expected to limit their life expectancy to less than 5 years, and no known cardiovascular (CV) or cerebrovascular disease, dementia, high bleeding risk, or contraindication to aspirin. The study included a 1-month placebo run-in period to ensure at least 80% adherence to the study medication. During the run-in period, 4049 patients were excluded, 61% because they failed adherence. Included patients were contacted every 3 months to further encourage adherence and to gather interim data. Outcomes were adjudicated by a committee masked to treatment assignment. The median age of participants was 74 years, 56% were women, and 8.7% were non-white. Most of the patients were recruited in Australia (87%), 74% had hypertension, 65% had hyperlipidemia, and only 11% had diabetes. Participants were followed up for a median of 4.8 years, and only 2.2% withdrew or were lost to follow-up. A separate report found no significant reduction in the composite of death, dementia, and disability. The current report looks at the composite outcome of fatal coronary heart disease, nonfatal myocardial infarction, stroke, and hospitalization for heart failure. This is a broad composite, so it is important to look at individual components of the outcome. In this case, there was no difference between groups regarding the composite or any of the individual components. Major hemorrhage was more common in the aspirin group (8.6 vs 6.2 events per 1000 person-years; hazard ratio 1.38; 95% CI 1.18 - 1.62; number needed to treat to harm = 417 per year).Bottom line: Low-dose aspirin does not reduce the likelihood that otherwise healthy older patients will experience a major cardiovascular event during nearly 5 years of follow-up.Reference: McNeil JJ, Wolfe R, Woods RL, et al, for the ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379(16):1509-1518.7: ARRIVE | ASA No effect on CV outcomes in patients with below average CV riskClinical question: Is low-dose aspirin effective for the primary prevention of cardiovascular disease in moderate-risk patients?Study design: Randomized controlled trial (double-blinded)Setting: Outpatient (any)Synopsis: Low-dose aspirin for secondary prevention and in the face of acute coronary events is pretty much a slam dunk. But despite of years of research, several meta-analyses, and numerous guidelines, its use for primary prevention still seems to rile people up. These researchers point out that most of the recommendations are largely for patients whose 10-year risk of a coronary event exceeds 20% and the role of aspirin in patients of intermediate risk is less clear. So, they conducted a double-blind randomized trial of 100 mg aspirin daily (n = 6270) or placebo (n = 6276) in patients at moderate risk of coronary artery disease. The study participants were men at least 55 years of age or women at least 60 years of age with a 10% to 20% 10-year risk based on age, sex, smoking status, blood pressure, lipid concentrations, and family history. They excluded patients with diabetes and those at high risk for bleeding complications. Using intention-to-treat analysis, after 5 years the rate of events (a composite of myocardial infarction, stroke, cardiovascular death, unstable angina, or transient ischemic attack) was similar between the treatment groups (4.3% vs 4.5%, respectively). The overall death rate was the same (2.6%) in each group. The aspirin-treated patients had more bleeding events (1% vs 0.5%), although very few had moderate or severe gastrointestinal bleeding. The graphs in the paper demonstrate nearly a linear relationship in outcomes over time, so the projected 10-year outcomes indicate that 9% of the placebo-treated patients would have had a coronary event. Recall last month another study that suggested aspirin's effect was potentially influenced by weight and sex (Rothwell et al. Lancet 2018;392(10145):387-399).Bottom line: In this study, after 5 years of treatment, patients at moderate risk of heart disease who took low-dose aspirin did not show a decrease in coronary events and all-cause mortality, and had slightly more, albeit minor, gastrointestinal bleeding. If you are confused by all the aspirin-related folderol of late, join the club. Using aspirin for primary prevention of cardiovascular disease is not a one-size-fits-all proposition. We need to risk-stratify patients according to benefits and harms and engage in shared decision-making with each patient.Reference: Gaziano JM, Brotons C, Coppolecchia R, et al, for the ARRIVE Executive Committee. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 2018;392(10152):1036-1046.8: ASCEND | Among patients with DM ASA CV events prevents ~ major bleeding eventsClinical question: What are the benefits and harms of low-dose aspirin in adults with diabetes mellitus?Study design: Randomized controlled trial (double-blinded)Setting: Outpatient (any)Synopsis: This British study recruited adults 40 years and older with diabetes mellitus, no known cardiovascular disease, no contraindications to aspirin, and no major comorbidity that would keep them from participating in the study for at least 5 years. After a placebo run-in period to assure adherence, 15,480 participants were randomized to receive aspirin 100 mg once daily or matching placebo. They were also randomized to receive an omega-3 fatty acid capsule or placebo; those results are reported separately. The groups were balanced at the start of the study: the patients had a mean age of 63 years, 63% were men, and 96% were white. Almost all (94%) had type 2 diabetes mellitus. A validated risk score determined that approximately 40% of participants were at low risk of vascular events (< 5% at 5 years), 40% had a 5-year risk of 5% to 10%, and the remainder were at high risk. As the trial was ongoing, the authors added TIA to the original primary composite efficacy outcome of vascular death, nonfatal MI, or nonfatal stroke (excluding intracranial hemorrhage). The primary safety outcome was a composite of intracranial hemorrhage, intra-ocular hemorrhage that threatens sight, gastrointestinal bleeding, or any other serious bleeding event. After a mean follow-up of 7.4 years, 99% of patients had complete follow-up data, with outcomes adjudicated for more than 90% by a committee masked to treatment assignment. The authors also looked at the effect of adding revascularization to the composite efficacy outcome. There was no difference between groups in the original efficacy outcome of vascular death, nonfatal MI, and nonfatal ischemic stroke (7.0% with aspirin vs 7.6% with placebo; hazard ratio [HR] 0.92, 95% CI 0.82 - 1.03). When you add TIA to the composite outcome, the difference between groups is statistically significant (8.5% vs 9.6%; HR 0.88, 0.79 – 97; number needed to treat [NNT] = 90 for 7.4 years). Adding revascularization to the original efficacy outcome had a similar result (10.8% vs 12.1%; HR 0.88, 0.80 - 0.97; NNT = 77 for 7 years). When examining results stratified by vascular risk, those at moderate and higher vascular risk also experienced more major bleeding events (8.9 - 9.6 vs 2.8 per 5000 person-years in the low-risk group). The number of serious vascular events avoided per 5000 person years was 5.7 in the low-risk group, 11.2 in the moderate-risk group, and only 4.9 in the high-risk group. For the composite harm outcome, there was a significantly increased risk of major bleeding, primarily due to more serious gastrointestinal and other bleeds (4.1% vs 3.2%; HR 1.29, 1.09 - 1.52; number needed to treat to harm = 111 over 7 years). However, there was no difference in fatal bleeding events or hemorrhagic strokes. There was no difference in the incidence of cancer (11.6% for aspirin vs 11.5% for placebo), including for gastrointestinal cancers (2.0% vs 2.0%). There was no significant differences between groups in all-cause mortality or in vascular deaths.Bottom line: The 7740 patients who took low-dose aspirin experienced 51 fewer vascular deaths, nonfatal myocardial infarctions (MIs), or nonfatal ischemic strokes; 29 fewer transient ischemic attacks (TIAs); and 44 fewer revascularizations than patients who took placebo over a mean of 7.4 years. This is balanced by an additional 69 major bleeding episodes during that period, with no effect on vascular or all-cause deaths, and no difference in the incidence of cancer.REFERENCE: The ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018;379(16):1529-1539.9. JPAD | Among patients with DM ASA CV events not prevents, ↑ major bleeding eventsBACKGROUND: The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive.METHODS: The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) was a randomized, open-label, standard care-controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity.RESULTS: The median follow-up period was 10.3 years; 1621 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91-1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83-1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P>0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82-1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group (P=0.03), and the incidence of hemorrhagic stroke was not different between groups.CONCLUSIONS: Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting.CLINICAL TRIAL REGISTRATION: URL: . Unique identifier: NCT00110448.REFERENCE: Saito Y for the JPAD Trial Investigators. Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: 10-Year Follow-Up of a Randomized Controlled Trial. Circulation. 2017 Feb 14;135(7):659-ment in Ann Transl Med. 2018 Jun;6(11):218. Ann Transl Med. 2018 Jun;6(11):219.Wow almost no discernable benefit. It makes one tempted to throw in the towel on ASA. However, “not so fast my friend”. First and importantly, these studies only looked at starting aspirin in the populations studied and none of these studies evaluated the pros and cons of stopping ASA in those who have been on it for years or even decades, the following abstract suggests that this may not be a good idea in the absence of compelling reasons. 10. Stopping long term ASA may be associated with ↑ CV risk BACKGROUND: There are increasing concerns about risks associated with aspirin discontinuation in the absence of major surgery or bleeding. We investigated whether long-term low-dose aspirin discontinuation and treatment gaps increase the risk of cardiovascular events.METHODS: We performed a cohort study of 601?527 users of low-dose aspirin for primary or secondary prevention in the Swedish prescription register between 2005 and 2009 who were >40 years of age, were free from previous cancer, and had ≥80% adherence during the first observed year of treatment. Cardiovascular events were identified with the Swedish inpatient and cause-of-death registers. The first 3 months after a major bleeding or surgical procedure were excluded from the time at risk.RESULTS: During a median of 3.0 years of follow-up, 62?690 cardiovascular events occurred. Patients who discontinued aspirin had a higher rate of cardiovascular events than those who continued (multivariable-adjusted hazard ratio, 1.37; 95% confidence interval, 1.34-1.41), corresponding to an additional cardiovascular event observed per year in 1 of every 74 patients who discontinue aspirin. The risk increased shortly after discontinuation and did not appear to diminish over time.CONCLUSIONS: In long-term users, discontinuation of low-dose aspirin in the absence of major surgery or bleeding was associated with a >30% increased risk of cardiovascular events. Adherence to low-dose aspirin treatment in the absence of major surgery or bleeding is likely an important treatment goal.REFERENCE: Sundstr?m J et al. Low-Dose Aspirin Discontinuation and Risk of Cardiovascular Events: A SwedishNationwide, Population-Based Cohort Study. Circulation. 2017 Sep 26;136(13):1183-ment in J Thorac Dis. 2018 Jan;10 (1):30-34. J Thorac Dis. 2018 Jan;10 (1):75-78.Second and importantly, it is entirely possible that we have been under dosing patients with aspirin all of these years! The following abstract makes a compelling case for this point. According to Rothwell, the purported mechanism of body weight / aspirin interaction is as follows:“Obesity and increased body-mass index (BMI) are associated with reduced inhibition of platelets by low doses of aspirin.... aspirin is rapidly de-acetylated by esterases in the intestinal wall, plasma, red blood cells, and liver, and so the proportion of a dose of aspirin that reaches the systemic circulation will depend on the mass of these tissues, which is correlated with lean body size. Thus, reduced systemic bioavailability of once-daily, low-dose aspirin at higher lean body mass could reduce clinical effectiveness, especially if doses are missed. Total bodyweight could be a particularly powerful determinant of clinical effects if obesity also increases platelet turnover.”11. Effect of aspirin mediated by bodyweightBACKGROUND: A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes.METHODS: Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (≤100 mg) and higher doses (300-325 mg or ≥500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer.RESULTS: Among ten eligible trials of aspirin in primary prevention (including 117?279 participants), bodyweight varied four-fold and trial median weight ranged from 60·0 kg to 81·2 kg (p<0·0001). The ability of 75-100 mg aspirin to reduce cardiovascular events decreased with increasing weight (p interaction=0·0072), with benefit seen in people weighing 50-69 kg (hazard ratio [HR] 0·75 [95% CI 0·65-0·85]) but not in those weighing 70 kg or more (0·95 [0·86-1·04]; 1·09 [0·93-1·29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1·33 [95% CI 1·08-1·64], p=0·0082). Higher doses of aspirin (≥325 mg) had the opposite interaction with bodyweight (difference p interaction=0·0013), reducing cardiovascular events only at higher weight (p interaction=0·017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (p interaction=0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (p interaction=0·038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (p interaction=0·0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75-100 mg aspirin (HR 1·52 [95% CI 1·04-2·21], p=0·031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1·20 [1·03-1·47], p=0·02), particularly in those weighing less than 70 kg (1·31 [1·07-1·61], p=0·009) and consequently in women (1·44 [1·11-1·87], p=0·0069).INTERPRETATION: Low doses of aspirin (75-100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required. FUNDING: Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre.REFERENCE: Rothwell PM et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet. 2018 Aug 4;392(10145):387-ment in Lancet. 2018 Aug 4;392(10145):361-362. 12. Meta-analysis: Beneficial effect of aspirin on CV outcomes ~ bleeding riskImportance The role for aspirin in cardiovascular primary prevention remains controversial, with potential benefits limited by an increased bleeding risk.Objective To assess the association of aspirin use for primary prevention with cardiovascular events and bleeding.Data Sources PubMed and Embase were searched on Cochrane Library Central Register of Controlled Trials from the earliest available date through November 1, 2018.Study Selection Randomized clinical trials enrolling at least 1000 participants with no known cardiovascular disease and a follow-up of at least 12 months were included. Included studies compared aspirin use with no aspirin (placebo or no treatment).Data Extraction and Synthesis Data were screened and extracted independently by both investigators. Bayesian and frequentist meta-analyses were performed.Main Outcomes and Measures The primary cardiovascular outcome was a composite of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. The primary bleeding outcome was any major bleeding (defined by the individual studies).Results A total of 13 trials randomizing 164?225 participants with 1?050?511 participant-years of follow-up were included. The median age of trial participants was 62 years (range, 53-74), 77?501 (47%) were men, 30?361 (19%) had diabetes, and the median baseline risk of the primary cardiovascular outcome was 9.2% (range, 2.6%-15.9%). Aspirin use was associated with significant reductions in the composite cardiovascular outcome compared with no aspirin (57.1 per 10?000 participant-years with aspirin and 61.4 per 10?000 participant-years with no aspirin) (hazard ratio [HR], 0.89 [95% credible interval, 0.84-0.95]; absolute risk reduction, 0.38% [95% CI, 0.20%-0.55%]; number needed to treat, 265). Aspirin use was associated with an increased risk of major bleeding events compared with no aspirin (23.1 per 10?000 participant-years with aspirin and 16.4 per 10?000 participant-years with no aspirin) (HR, 1.43 [95% credible interval, 1.30-1.56]; absolute risk increase, 0.47% [95% CI, 0.34%-0.62%]; number needed to harm, 210).Conclusions and Relevance The use of aspirin in individuals without cardiovascular disease was associated with a lower risk of cardiovascular events and an increased risk of major bleeding. This information may inform discussions with patients about aspirin for primary prevention of cardiovascular events and bleeding.Reference: Zheng SL, et al. Association of Aspirin Use for Primary Prevention With Cardiovascular Events and Bleeding EventsA Systematic Review and Meta-analysis. JAMA. 2019;321(3):277-287. doi:10.1001/jama.2018.20578DIETARY SUPPLEMENTSIt’s also been another disappointing year for other supplements that we previously had high hopes for regarding disease protection with minimal risk including fish oil and Vitamin D (again!)13. Fish oil has no effect on CV Dz (or cancer)BACKGROUND: Higher intake of marine n-3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n-3 fatty acids has such effects in general populations at usual risk for these end points is unclear.METHODS: We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n-3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n-3 fatty acids with placebo.RESULTS: A total of 25,871 participants, including 5106 black participants,underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed. CONCLUSIONS: Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL number, NCT01169259 .).REFERENCE: Manson JE for the VITAL Research Group. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019 Jan 3;380(1):23-3214. Vitamin D has no effect on CV Dz (or cancer)BACKGROUND: It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited.METHODS: We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes).Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo.RESULTS: A total of 25,871 participants, including 5106 black participants,underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). Noexcess risks of hypercalcemia or other adverse events were identified.CONCLUSIONS: Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo.Funded by the National Institutes of Health and others; VITAL number, NCT01169259 .).REFERENCE: Manson JE for the VITAL Research Group. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44.LIPIDSOne of the fats that we have forgotten about over the past several years as a potential therapeutic target, may be making a comeback, namely triglycerides. In the following abstract Icosapent ethyl (Vascepa ? | ~ $225/month per ). High risk patients with fasting triglyceride levels of 135 – 499 mg/dL and an LDL of 41 – 100 mg/dL and on a stable dose of a statin for at least 4 years were followed for 4.9 years and demonstrated a (NNT ~ 21) absolute risk reduction in the primary outcome of a 5 point MACE (CV death, nonfatal MI, nonfatal stroke, unstable angina or coronary revascularization) but higher rates of atrial fibrillation/flutter hospitalizations (NNH = 100) and serious bleeding events (NNT ~ 166)15. Triglycerides BACKGROUND: Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events.METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.RESULTS: A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06).CONCLUSIONS: Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo. (Funded by Amarin Pharma; REDUCE-IT number, NCT01492361 .).REFERENCE: Bhatt DL for the REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-2216. 2018 Guideline on the Management of Blood Cholesterol Reference: Grundy SM, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 Nov 8. pii: S0735-1097(18)39034-X.General comments/recommendationsTwenty-five percent of Americans >40 takes a statin. A peak effectiveness, statins produce ~ 60% reduction in LDL. Six of the 7 marketed statins are available in generic form.The following represents direct quotes or my summaries of key or interesting (at least to me) points. This document is 121 pages so I only am hitting the highlights that I think are most relevant to primary care (or quite frankly what I needed to get smarter on!)Adults > 20, order either fasting or non-fasting lipid profile (repeat fasting if initial TG’s are > 400 mg/dL)“After normal food intake, LDL-C differs minimally with time.”“Fasting and nonfasting TC and HDL-C levels appear to have fairly similar prognostic value and associations with CVD outcomes” Starting TreatmentNo need to calculate 10-year risk of ASCVD to determine candidacy for therapy for the following groups: Clinical ASCVD (hx MI or angina, revascularization (coronary or other), stroke/TIA, PAD including AAA)Use high intensity statin therapy to lower LDL-C levels by ≥50% (see table)If judged to be at “very high risk”, reasonable to add ezetimibe if LDL-C > 70 mg/dLon statin (NEW)If judged to be at “very high risk”, reasonable to add PCSK9 inhibitor if LDL-C > 70 mg/dL on statin and ezetimibe (NEW)Severe hypercholesterolemia (LDL-C > 190 mg/dL)Maximally tolerated statin therapy is recommendedIf LDL > 100 mg/dL, reasonable to add ezetimibeDiabetes Mellitus | Age 40 to 75 yearsUse moderate-intensity statin therapy (regardless of estimated 10-year risk), unless Multiple risk factors present or 50 to 75 years then use a high-intensity statin to reduce the LDL-C level by ≥50%.Calculate 10-year risk of ASCVD to determine candidacy for therapy for the following 2 groups: Primary ASCVD prevention | Age 40 to 75 years | LDL-C ≥70 mg/dL | 10-year risk > 7.5%The presence of risk-enhancing factors favor initiation or intensification of statin therapyWith uncertainty about starting a statin remains, use a CAC scoreUse moderate-intensity statin therapy to reduce LDL-C levels by ≥30% (or ≥50% if 10-year risk is ≥20%)To achieve LDL-C lowering of > 50% use high intensity statin, or moderate intensity statin and ezetimibe or bile acid sequestrantsAn upper age cutoff for moderate intensity statin therapy was not identified in patients with ASCVD in this report.“For patients >75 years of age, RCT evidence for statin therapy (for primary prevention) is not strong, so clinical assessment of risk status in a clinician–patient risk discussion is needed for deciding whether to continue or initiate statin treatment” High IntensityModerate IntensityLow IntensityLDL-C lowering> 50%30 – 49%< 30%Atorvastatin 40 - 80Rosuvastatin 20 - 40Atorvastatin 10 - 20Rosuvastatin 5 - 10Simvastatin 20 - 40Simvastatin 10Pravastatin 40 - 80Lovastatin 40 - 80Fluvastatin XL 80Fluvastatin 40 BIDPitavastatin 1 - 4Pravastatin 10 - 20Lovastatin 20Fluvastatin 20 - 40Simvastatin 80 mg not recommended by FDA due to increased risk of myopathyVery High-Risk for Future ASCVDMajor ASCVD EventsRecent ACS (within past 12 months)History of MI (other than recent ACS event listed above)History of ischemic strokeSymptomatic peripheral arterial disease (history of claudication with ABI <0.85, or previous revascularization or amputation)High-Risk ConditionsAge ≥65 yHeterozygous familial hypercholesterolemiaHistory of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s)Diabetes mellitusHypertensionCKD (eGFR 15-59 mL/min/1.73 m2) Current smokingPersistently elevated LDL-C (LDL-C ≥100 mg/dL [≥2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibeHistory of congestive HFVery high risk status = 1 major ASCVD event and multiple high-risk conditions OR Multiple major ASCVD eventsReference: Grundy SM, et al. 2018 Cholesterol Clinical Practice GuidelinesRisk-enhancing FactorsFamily history of premature ASCVD (males, age <55 y; females, age <65 y)Primary hypercholesterolemia (LDL-C, 160–189 mg/dL [4.1–4.8 mmol/L); non–HDL-C 190–219 mg/dL [4.9–5.6 mmol/L])Metabolic syndrome (increased waist circumference, elevated triglycerides [>175 mg/dL], elevated blood pressure, elevated glucose, and low HDL-C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes the diagnosis)Chronic kidney disease (eGFR 15–59 mL/min/1.73 m2 with or without albuminuria; not treated with dialysis or kidney transplantation)Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDSHistory of premature menopause (before age 40 y) and history of pregnancy-associated conditions that increase later ASCVD risk such as preeclampsiaHigh-risk race/ethnicities (e.g., South Asian ancestry)Lipid/biomarkers: Associated with increased ASCVD riskPersistently* elevated, primary hypertriglyceridemia (≥175 mg/dL);If measured:Elevated high-sensitivity C-reactive protein (≥2.0 mg/L)Elevated Lp(a): A relative indication for its measurement is family history of premature ASCVD. An Lp(a) ≥50 mg/dL or ≥125 nmol/L constitutes a risk-enhancing factor especially at higher levels of Lp(a).Elevated apoB ≥130 mg/dL: A relative indication for its measurement would be triglyceride ≥200 mg/dL. A level ≥130 mg/dL corresponds to an LDL-C >160 mg/dL and constitutes a risk-enhancing factorABI <0.9DiabetesIAAge 40 – 75 | Moderate intensity statin | Regardless of 10- year riskIIaB-RAdults | High-intensity statin to ↓ LDL-C > by 50% | If multiple ASCVD risk factorsIIbC-LDAdults | Max-tolerated statin AND ezetimibe to ↓ LDL-C by 50% | If 10-year ASCVD > 20%IIbB-NR75 years or older already on statin | Reasonable to continueIIbC-LD75 years or older NOT already on statin | Reasonable to initiate statinIIbC-LDAge 20 - 39 | Reasonable to initiate statin | DM present > 10 yr; Microvascular Dz; ABI < 0.9Primary Prevention (No DM)IAAdults | Moderate intensity statin | Intermediate-riskIAAdults | Statin to ↓ LDL-C by > 30, or > 50% | If intermediate- or high- riskIB-NRAge 40 - 75 | Estimate 10-year ASCVD risk | | If LDL 70 – 189 mg/dLIIaB-RIntermediate-risk adults | Statin initiation or intensification | Risk-enhancing factors presentIIaB-NRIntermediate-risk adults | Statin initiation uncertain | Use a CAC scoreIIbB-RIntermediate-risk adults | Statins not acceptable or tolerated | Use nonstatin drug (ezetimibe or bile acid sequestrants)17. Direct evidence for statin effectiveness for older patients is sparseBackground: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages.Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134?537) and detailed summary data from one trial (n=12?705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39?612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups.Findings: 14?483 (8%) of 186?854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (p trend=0·01), and remained non-significant for major vascular events (p trend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (pt rend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (p trend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (p trend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence.In terpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials.Reference: Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials Lancet. 2019 Feb 2;393(10170):407-415Funding: Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation.18. Statins not Effective for Older Patients OBJECTIVE: To assess whether statin treatment is associated with a reduction in atherosclerotic cardiovascular disease (CVD) and mortality in old and very old adults with and without diabetes.DESIGN: Retrospective cohort study.SETTING: Database of the Catalan primary care system (SIDIAP), Spain, 2006-15.PARTICIPANTS: 46?864 people aged 75 years or more without clinically recognised atherosclerotic CVD. Participants were stratified by presence of type 2 diabetes mellitus and as statin non-users or new users.MAIN OUTCOME MEASURES: Incidences of atherosclerotic CVD and all-cause mortality compared using Cox proportional hazards modelling, adjusted by the propensity score of statin treatment. The relation of age with the effect of statins was assessed using both a categorical approach, stratifying the analysis by old (75-84 years) and very old (≥85 years) age groups, and a continuous analysis, using an additive Cox proportional hazard model.RESULTS: The cohort included 46?864 participants (mean age 77 years; 63% women; median follow-up 5.6 years). In participants without diabetes, the hazard ratios for statin use in 75-84 year olds were 0.94 (95% confidence interval 0.86 to 1.04) for atherosclerotic CVD and 0.98 (0.91 to 1.05) for all-cause mortality, and in those aged 85 and older were 0.93 (0.82 to 1.06) and 0.97 (0.90 to 1.05), respectively. In participants with diabetes, the hazard ratio of statin use in 75-84 year olds was 0.76 (0.65 to 0.89) for atherosclerotic CVD and 0.84 (0.75 to 0.94) for all-cause mortality, and in those aged 85 and older were 0.82 (0.53 to 1.26) and 1.05 (0.86 to 1.28), respectively. Similarly, effect analysis of age in a continuous scale, using splines, corroborated the lack of beneficial statins effect for atherosclerotic CVD and all-cause mortality in participants without diabetes older than 74 years. In participants with diabetes, statins showed a protective effect against atherosclerotic CVD and all-cause mortality; this effect was substantially reduced beyond the age of 85 years and disappeared in nonagenarians.CONCLUSIONS: In participants older than 74 years without type 2 diabetes, statin treatment was not associated with a reduction in atherosclerotic CVD or in all-cause mortality, even when the incidence of atherosclerotic CVD was statistically significantly higher than the risk thresholds proposed for statin use. In the presence of diabetes, statin use was statistically significantly associated with reductions in the incidence of atherosclerotic CVD and in all-cause mortality. This effect decreased after age 85 years and disappeared in nonagenarians.REFERENCE: Ramos R et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ. 2018 Sep 5;362:k3359.Coronary Artery Calcium Scores (CACs)19. CAC Scores Predict future events in young adults in 12.5 year follow upImportance: Coronary artery calcium (CAC) is associated with coronary heart disease (CHD) and cardiovascular disease (CVD); however, prognostic data on CAC are limited in younger adults.Objective: To determine if CAC in adults aged 32 to 46 years is associated with incident clinical CHD, CVD, and all-cause mortality during 12.5 years of follow-up.Design, Setting, and Participants: The Coronary Artery Risk Development in Young Adults (CARDIA) Study is a prospective community-based study that recruited 5115 black and white participants aged 18 to 30 years from March 25, 1985, to June 7, 1986. The cohort has been under surveillance for 30 years, with CAC measured 15 (n?=?3043), 20 (n?=?3141), and 25 (n?=?3189) years after recruitment. The mean follow-up period for incident events was 12.5 years, from the year 15 computed tomographic scan through August 31, 2014.Main Outcomes and Measures: Incident CHD included fatal or nonfatal myocardial infarction, acute coronary syndrome without myocardial infarction, coronary revascularization, or CHD death. Incident CVD included CHD, stroke, heart failure, and peripheral arterial disease. Death included all causes. The probability of developing CAC by age 32 to 56 years was estimated using clinical risk factors measured 7 years apart between ages 18 and 38 years.Results: At year 15 of the study among 3043 participants (mean [SD] age, 40.3 [3.6] years; 1383 men and 1660 women), 309 individuals (10.2%) had CAC, with a geometric mean Agatston score of 21.6 (interquartile range, 17.3-26.8). Participants were followed up for 12.5 years, with 57 incident CHD events and 108 incident CVD events observed. After adjusting for demographics, risk factors, and treatments, those with any CAC experienced a 5-fold increase in CHD events (hazard ratio [HR], 5.0; 95% CI, 2.8-8.7) and 3-fold increase in CVD events (HR, 3.0; 95% CI, 1.9-4.7). Within CAC score strata of 1-19, 20-99, and 100 or more, the HRs for CHD were 2.6 (95% CI, 1.0-5.7), 5.8 (95% CI, 2.6-12.1), and 9.8 (95% CI, 4.5-20.5), respectively. A CAC score of 100 or more had an incidence of 22.4 deaths per 100 participants (HR, 3.7; 95% CI, 1.5-10.0); of the 13 deaths in participants with a CAC score of 100 or more, 10 were adjudicated as CHD events. Risk factors for CVD in early adult life identified those above the median risk for developing CAC and, if applied, in a selective CAC screening strategy could reduce the number of people screened for CAC by 50% and the number imaged needed to find 1 person with CAC from 3.5 to 2.2.Conclusions and Relevance: The presence of CAC among individuals aged between 32 and 46 years was associated with increased risk of fatal and nonfatal CHD during 12.5 years of follow-up. A CAC score of 100 or more was associated with early death. Adults younger than 50 years with any CAC, even with very low scores, identified on a computed tomographic scan are at elevated risk of clinical CHD, CVD, and death. Selective use of screening for CAC might be considered in individuals with risk factors in early adulthood to inform discussions about primary prevention.Reference: Carr JJ et al. Association of Coronary Artery Calcium in Adults Aged 32 to 46 Years With Incident Coronary Heart Disease and Death. JAMA Cardiol. 2017 Apr 1;2(4):391-399.20. CAC Scores predict future events independent of standard risk factorsAims: While coronary artery calcium (CAC) has been extensively validated for predicting clinical events, most outcome studies of CAC have evaluated coronary heart disease (CHD) rather than atherosclerotic cardiovascular disease (ASCVD) events (including stroke). Also, virtually all CAC studies are of short- or intermediate-term follow-up, so studies across multi-ethnic cohorts with long-term follow-up are warranted prior to widespread clinical use. We sought to evaluate the contribution of CAC using the population-based MESA cohort with over 10?years of follow-up for ASCVD events, and whether the association of CAC with events varied by sex, race/ethnicity, or age category.Methods and results: We utilized MESA, a prospective multi-ethnic cohort study of 6814 participants (51% women), aged 45-84?years, free of clinical CVD at baseline. We evaluated the relationship between CAC and incident ASCVD using Cox regression models adjusted for age, race/ethnicity, sex, education, income, cigarette smoking status, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, diabetes, lipid-lowering medication, systolic blood pressure, antihypertensive medication, intentional physical exercise, and body mass index. Only the first event for each individual was used in the analysis. Overall, 500 incident ASCVD (7.4%) events were observed in the total study population over a median of 11.1?years. Hard ASCVD included 217 myocardial infarction, 188 strokes (not transient ischaemic attack), 13 resuscitated cardiac arrest, and 82 CHD deaths. Event rates in those with CAC?=?0 Agatston units ranged from 1.3% to 5.6%, while for those with CAC?>?300, the 10-year event rates ranged from 13.1% to 25.6% across different age, gender, and racial subgroups. At 10?years of follow-up, all participants with CAC?>?100 were estimated to have >7.5% risk regardless of demographic subset. Ten-year ASCVD event rates increased steadily across CAC categories regardless of age, sex, or race/ethnicity. For each doubling of CAC, we estimated a 14% relative increment in ASCVD risk, holding all other risk factors constant. This association was not significantly modified by age, sex, race/ethnicity, or baseline lipid-lowering use.Conclusions: Coronary artery calcium is associated strongly and in a graded fashion with 10-year risk of incident ASCVD as it is for CHD, independent of standard risk factors, and similarly by age, gender, and ethnicity. While 10-year event rates in those with CAC?=?0 were almost exclusively below 5%, those with CAC?≥?100 were consistently above 7.5%, making these potentially valuable cutpoints for the consideration of preventive therapies. Coronary artery calcium strongly predicts risk with the same magnitude of effect in all races, age groups, and both sexes, which makes it among the most useful markers for predicting ASCVD risk.Reference: Budoff MJ et al. Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 2018 Jul 1;39(25):2401-2408.Selected Examples of Candidates for CAC Measurement Who Might Benefit From Knowing Their CAC Score Is ZeroPatients reluctant to initiate statin therapy who wish to understand their risk and potential for benefit more preciselyPatients concerned about need to reinstitute statin therapy after discontinuation for statin-associated symptomsOlder patients (men, 55-80 y of age; women, 60-80 y of age) with low burden of risk factors (S4.4.2-60) who question whether they would benefit from statin therapyMiddle-aged adults (40-55 y of age) with PCE-calculated 10-year risk of ASCVD 5% to <7.5% with factors that increase their ASCVD risk, although they are in a borderline risk groupTREAT-TO-TARGET (ish) 21. HOPE-3: Degree of LDL lowering associated with degree of CVD protection BACKGROUND: Previous trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease. Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons. It is unclear whether the benefits of statins can be extended to an intermediate-risk, ethnically diverse population without cardiovascular disease.METHODS: In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk to receive rosuvastatin at a dose of 10 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included revascularization, heart failure, and resuscitated cardiac arrest. The median follow-up was 5.6 years.RESULTS: The overall mean low-density lipoprotein cholesterol level was 26.5% lower in the rosuvastatin group than in the placebo group. The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P=0.002). The results for the second coprimary outcome were consistent with the results for the first (occurring in 277 participants [4.4%] in the rosuvastatin group and in 363 participants [5.7%] in the placebo group; hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P<0.001). The results were also consistent in subgroups defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group. In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of cataract surgery (in 3.8% of the participants, vs. 3.1% in the placebo group; P=0.02) and muscle symptoms (in 5.8%of the participants, vs. 4.7% in the placebo group; P=0.005).CONCLUSIONS: Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; HOPE- number, NCT00468923.).Reference: Yusuf et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016 May 26;374(21):2021-31.22. Meta-analysis: Degree of LDL lowering associated with degree of CVD protection IMPORTANCE: The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain.OBJECTIVE: To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies.DATA SOURCES AND STUDY SELECTION: The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included.DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression.MAIN OUTCOMES AND MEASURES: The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level.RESULTS: A total of 312?175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39?645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P?<?.001) for statins and 0.75 (95% CI, 0.66-0.86; P?=?.002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P?=?.72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P?<?.001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P?=?.24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P?=?.02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P?=?.002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P?=?.25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11?301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P?=?.008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P?<?.001).CONCLUSIONS AND RELEVANCE: In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.REFERENCE: Silverman MG et al. Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis. JAMA. 2016 Sep 27;316(12):1289-97.23. RCT: Magnitude of % reduction in LDL directly relates to efficacy AIMS: Current statin guidelines in Europe and Canada advocate achieving a fixed LDL target or the attainment of a ≥50% reduction in low-density lipoprotein cholesterol (LDLC), while current US guidelines advocate the use of statin therapies that reduce LDLC by <50% (moderate intensity) or ≥50% (high intensity). Data are limited, however, linking the achievement of these % reduction thresholds to subsequent cardiovascular outcomes particularly for contemporary high-intensity regimens.METHODS AND RESULTS: In a randomized trial of 17 082 initially healthy men and women with median baseline LDLC of 108 mg/dL (interquartile range 94-119), we (i) used waterfall plots to assess the variability in LDLC response to rosuvastatin 20 mg daily and (ii) evaluated the impact of reaching ≥50% reductions in LDLC on risk of developing the first cardiovascular events. Among rosuvastatin allocated participants, 3640 individuals (46.3%) experienced an LDLC reduction ≥50%; 3365 individuals (42.8%) experienced an LDLC reduction >0 but <50%; and 851 individuals (10.8%) experienced no reduction or an increase in LDLC compared with baseline. These % LDLC reductions directly related to the risks of first cardiovascular events; at trial completion, incidence rates for the primary endpoint were 11.2, 9.2, 6.7, and 4.8 per 1000 person-years for those in the placebo, no LDLC reduction, LDLC reduction <50%, and LDLC reduction ≥50% groups, respectively. Compared with placebo, the multivariable adjusted hazard ratios for sequentially greater on-treatment per cent reductions in LDLC were 0.91 (95%CI 0.54-1.53), 0.61 (95%CI 0.44-0.83), and 0.43 (95%CI 0.30-0.60) (P < 0.00001). Similar relationships between % reduction and clinical outcomes were observed in analyses focusing on non-HDLC or apolipoprotein B.CONCLUSIONS: As documented for low- and moderate-intensity regimens, variability in % LDLC reduction following high-intensity statin therapy is wide yet the magnitude of this % reduction directly relates to efficacy. These data support guideline approaches that incorporate % reduction targets for statin therapy as well as absolute targets, and might provide a structure for the allocation of emerging adjunctive lipid-lowering therapies such as PCSK9 inhibitors should these agents prove broadly effective for cardiovascular event reduction.REFERENCE: Ridker PM et al. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J. 2016 May 1;37(17):1373-ment in Eur Heart J. 2016 May 1;37(17 ):1380-3.24: How low can you go! An LDL of 21 appears to be achievable without ADEImportance: In the Cholesterol Treatment Trialists Collaboration (CTTC), in patients starting with low-density lipoprotein cholesterol (LDL-C) levels of approximately 3.4 mmol/L (131.5 mg/dL), there was a 22% reduction in major vascular events per 1-mmol/L (38.7-mg/dL) lowering of LDL-C. The magnitude of clinical benefit of further LDL-C lowering in patients already with very low LDL-C levels remains debated.Objective: To evaluate efficacy and safety of further lowering LDL-C levels in patient populations presenting with median LDL-C levels of 1.8 mmol/L (70 mg/dL) or less.Data Sources and Study Selection: The CTTC was used for statin data. For nonstatin therapy, Medline database was searched (2015-April 2018). Key inclusion criteria were a randomized, double-blind, controlled cardiovascular outcome trial of LDL-C lowering with data in populations starting with LDL-C levels averaging 1.8 mmol/L (70 mg/dL) or less.Data Extraction and Synthesis: Two authors independently extracted data into standardized data sheets, and data were analyzed using meta-analysis.Main Outcomes and Measures: The risk ratio (RR) of major vascular events (a composite of coronary heart death, myocardial infarction, ischemic stroke, or coronary revascularization) per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level. Results: In the subgroup of patients from the CTTC meta-analysis of statins with a mean LDL-C in the control arm of 1.7 mmol/L (65.7 mg/dL), 1922 major vascular events occurred and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.78 (95% CI, 0.65-0.94). For 3 trials of nonstatin LDL-C-lowering therapies added to statins, there were 50?627 patients, the median LDL-C in the control arms ranged from 1.6 mmol/L to 1.8 mmol/L (63 mg/dL to 70 mg/dL), and 9570 major vascular events occurred. Nonstatin therapy lowered LDL-C by 0.3 to 1.2 mmol/L (11 mg/dL to 45 mg/dL), and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.79 (95% CI, 0.70-0.88). For statins and nonstatins combined, the RR was 0.79 (95% CI, 0.71-0.87; P?<?.001). Low-density lipoprotein cholesterol lowering was not associated with an increased risk of serious adverse events, myalgias and/or myositis, elevation in the level of aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer.Conclusions and Relevance: There is a consistent relative risk reduction in major vascular events per change in LDL-C in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL), with no observed offsetting adverse effects. These data suggest further lowering of LDL-C beyond the lowest current targets would further reduce cardiovascular risk.Reference: Sabatine MS et al. Efficacy and Safety of Further Lowering of Low-Density Lipoprotein Cholesterol in Patients Starting With Very Low Levels: A Meta-analysis. JAMA Cardiol. 2018 Sep 1;3(9):823-828.25: Alirocumab IS EXPENSIVE and not cost-effective (who knew?)BACKGROUND: The ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial included participants with a recent acute coronary syndrome. Compared with participants receiving statins alone, those receiving a statin plus alirocumab had lower rates of a composite outcome including myocardial infarction (MI), stroke, and death.OBJECTIVE: To determine the cost-effectiveness of alirocumab in these circumstances.DESIGN: Decision analysis using the Cardiovascular Disease Policy Model.DATA SOURCES: Data sources representative of the United States combined with data from the ODYSSEY Outcomes trial.TARGET POPULATION: U.S. adults with a recent first MI and a baseline low-density lipoprotein cholesterol level of 1.81 mmol/L (70 mg/dL) or greater.TIME HORIZON: Lifetime.PERSPECTIVE: U.S. health system.INTERVENTION: Alirocumab or ezetimibe added to statin therapy.OUTCOME MEASURES: Incremental cost-effectiveness ratio in 2018 U.S. dollars per quality-adjusted life-year (QALY) gained.RESULTS OF BASE-CASE ANALYSIS: Compared with a statin alone, the addition of ezetimibe cost $81 000 (95% uncertainty interval [UI], $51 000 to $215 000) per QALY. Compared with a statin alone, the addition of alirocumab cost $308 000 (UI, $197 000 to $678 000) per QALY. Compared with the combination of statin and ezetimibe, replacing ezetimibe with alirocumab cost $997 000 (UI, $254 000 to dominated) per QALY.RESULTS OF SENSITIVITY ANALYSIS: The price of alirocumab would have to decrease from its original cost of $14 560 to $1974 annually to be cost-effective relative to ezetimibe.LIMITATION: Effectiveness estimates were based on a single randomized trial with a median follow-up of 2.8 years and should not be extrapolated to patients with stable coronary heart disease.CONCLUSION:The price of alirocumab would have to be reduced considerably to be cost-effective. Because substantial reductions already have occurred, we believe that timely, independent cost-effectiveness analyses can inform clinical and policy discussions of new drugs as they enter the market.PRIMARY FUNDING SOURCE: University of California, San Francisco, and Institute for Clinical and Economic Review.REFERENCE: Kazi DS et al. Cost-Effectiveness of Alirocumab: A Just-in-Time Analysis Based on the ODYSSEY Outcomes Trial. Ann Intern Med. 2019 Jan 1. doi: 10.7326/M18-1776. [Epub ahead of print]26. Statin SafetyOne in 4 Americans >40 years of age takes a statin to reduce the risk of myocardial infarction, ischemic stroke, and other complications of atherosclerotic disease. The most effective statins produce a mean reduction in low-density lipoprotein cholesterol of 55% to 60% at the maximum dosage, and 6 of the 7 marketed statins are available in generic form, which makes them affordable for most patients. Primarily using data from randomized controlled trials, supplemented with observational data where necessary, this scientific statement provides a comprehensive review of statin safety and tolerability. The review covers the general patient population, as well as demographic subgroups, including the elderly, children, pregnant women, East Asians, and patients with specific conditions such as chronic disease of the kidney and liver, human immunodeficiency viral infection, and organ transplants. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001%. The risk of statin-induced newly diagnosed diabetes mellitus is ≈0.2% per year of treatment, depending on the underlying risk of diabetes mellitus in the population studied. In patients with cerebrovascular disease, statins possibly increase the risk of hemorrhagic stroke; however, they clearly produce a greater reduction in the risk of atherothrombotic stroke and thus total stroke, as well as other cardiovascular events. There is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis. In US clinical practices, roughly 10% of patients stop taking a statin because of subjective complaints, most commonly muscle symptoms without raised creatine kinase. In contrast, in randomized clinical trials, the difference in the incidence of muscle symptoms without significantly raised creatinine kinase in statin-treated compared with placebo-treated participants is <1%, and it is even smaller (0.1%) for patients who discontinued treatment because of such muscle symptoms. This suggests that muscle symptoms are usually not caused by pharmacological effects of the statin. Restarting statin therapy in these patients can be challenging, but it is important, especially in patients at high risk of cardiovascular events, for whom prevention of these events is a priority. Overall, in patients for whom statin treatment is recommended by current guidelines, the benefits greatly outweigh the risks.Reference: Newman CB, et al for the AHA. Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association.Arterioscler Thromb Vasc Biol. 2019 Feb;39(2):e38-e81Bottom LinesDo not start low dose aspirin for primary ASCVD prevention in almost everybodyNote this does not equate to stopping ASA in those already on itWith the caveat that there might an interaction of dose of ASA and body weight – and all of the primary prevention studies need to be done again!Supplementation with n-3 fatty acids or vitamin D is not associated with improved CV outcomesIn patients with elevated triglycerides (and on a statin) ischemic events and cardiovascular death were significantly lower among those who receiving 2 g of icosapent ethyl (Vascepa?) twice dailyThe 2018 ACC AHA lipid guidelines Recommend fasting or nonfasting lipid profilesIncorporate the presence (or absence) of risk-enhancing factors and the coronary artery calcification (CAC) scores in the initiation or intensification of statin therapyHave resurrected the concept of “treating-to-target” (a concept discredited with the 2014 guidelines) which provide guidance on when to consider PCSK9 inhibitors or ezitimibeThe evidence for initiation of statin therapy in those > 75 is not strongMusculoskeletal UpdateJohn Hickner, MD, MSObjectiveReview and understand the results of recent studies on the treatment of upper extremity, lower extremity and back disorders pertinent to primary care physicians and other primary healthcare providers.Upper Extremities1. Short-term outcomes for new-onset mild carpal tunnel syndrome better with steroid injection than splintsClinical question: Is a single corticosteroid injection more effective than splinting for patients with new-onset mild carpal tunnel syndrome?Study design:?Randomized controlled trial (nonblinded)Funding source:?FoundationAllocation:?ConcealedSetting:?Outpatient (any)Synopsis: These authors randomly assigned adults with mild CTS in an unblinded manner to receive a single corticosteroid injection (n = 116) or nocturnal wrist splint (n = 118). The patients, from primary care practices and community musculoskeletal clinics, had new-onset, mild, clinically diagnosed CTS of at least 6 weeks' duration. The steroid-treated patients received a 0.5 mL single dose of 40 mg/mL?methylprednisolone?acetate injected with a 23-gauge or 25-gauge needle inserted between the proximal and distal wrist crease. The splints, worn every night for 6 weeks, held the wrist either in a neutral position or in 20 degrees of extension. The authors assessed the main outcome after 6 weeks with the Boston Carpal Tunnel Questionnaire (BCTQ), a standardized CTS symptom scale that has 2 subscales: one assesses symptom severity and the other assesses function. The author also evaluated other outcomes intermittently for up to 24 months. After 6 weeks, the corticosteroid-treated patients had statistically greater improvement of their BCTQ score than those treated with splints (standardized mean difference 0.45). After 6 months, the corticosteroid-treated patients' BCTQ scores remained stable while those using splints had improved such that there was no net difference. The authors reported that no serious adverse events occurred and that the steroid-treated patients experienced only mild local effects: thinning, lightening, or darkening of the skin, or hot flushes. Additionally, nearly half of the steroid-treated patients reported 3 days of increased pain. The night splint group had more visits with their surgeons and primary care providers and more use of physical therapy, occupational therapy, and acupuncture.Bottom line: In this unblinded study, after 6 weeks patients with mild new-onset carpal tunnel syndrome (CTS) treated with corticosteroid injections had slightly greater improvement in a composite symptom and function score than those treated with nocturnal splints. After 6 months, however, the outcomes were comparable.?(LOE = 2b)Chesterton LS, Blagojevic-Bucknall M, Burton C, et al. The clinical and cost-effectiveness of corticosteroid injection versus night splints for carpal tunnel syndrome (INSTINCTS trial): an open-label, parallel group, randomised controlled trial. Lancet 2018;392(10156):1423-1433.2. Platelet-rich plasma injection not beneficial for nonoperative treatment of rotator cuff diseaseClinical question: Are platelet-rich plasma injections beneficial in the nonoperative treatment of rotator cuff disease in adults?Study design:?Systematic reviewFunding source:?Unknown/not statedSetting:?Various (meta-analysis)Synopsis: The benefits of PRP injections in the management of various tendinopathies are inconsistent. These investigators searched MEDLINE, Embase, and the Cochrane Library for English-language-only randomized controlled trials that compared PRP injections with control treatments in adults with chronic rotator cuff disease. Two reviewers used a standard evaluation tool to independently analyze individual articles for inclusion criteria and risk of bias. Discrepancies were resolved after consensus discussion with a third reviewer. Five studies (N = 214) met inclusion criteria, with 1 considered at low risk, 3 at moderate risk, and 1 at high risk of bias. Various controls included corticosteroid injection, dry needling, saline solution injection, and formal exercise therapy. At follow-up (range = 6 to 12 months), no differences occurred between active treatment with PRP injections and any of the control interventions for pain scores, disability measures, or range of motion. In the 2 studies in which PRP injections alone were used in the treatment group, the control group receiving exercise therapy had superior clinical outcomes.Bottom line: This review found no evidence that supports any additional benefit of platelet-rich plasma (PRP) injections compared with various control interventions, including saline placebo, in the nonoperative treatment of rotator cuff disease in adults. Exercise therapy was shown to be superior to PRP injections in improving outcomes in the included studies.?(LOE = 1a)Hurley ET, Hannon CP, Pauzenberger L, Fat DL, Moran CJ, Mullett H. Nonoperative treatment of rotator cuff disease with platelet-rich plasma: A systematic review of randomized controlled trials. Arthroscopy 2019;35(5):1584-1591.3. Surgery = no surgery for patients with subacromial shoulder pain (CSAW)Clinical question:?Do patients with subacromial shoulder pain for at least 3 months who are treated surgically have better outcomes than those who are treated without surgery?Study design:?Randomized controlled trial (double-blinded)Setting:?Outpatient (specialty)Synopsis:?These authors randomized adults with subacromial pain of at least 3 months duration into 1 of 3 groups: arthroscopic decompression of the acromion (n = 106), arthroscopy without decompression (n = 103), or no additional treatment (n = 104). Before enrollment, all patients underwent physical therapy and had at least one corticosteroid injection. The authors excluded patients with complete rotator cuff tears. A healthy percentage of the patients (23%, 42%, and 12%, respectively) allocated to decompression, arthroscopy only, and no treatment did not receive their assigned treatment by 6 months because they were already better! Additionally, approximately 15% of the patients did not complete 12 months of follow up. After 6 months and 1 year, the patients treated with either surgical decompression or arthroscopy without decompression had improvements in pain and function (as measured by the Oxford Shoulder Score) compared with patients who received no treatment, but the differences were not clinically important. Additionally, there was no difference between the decompression and arthroscopy without decompression groups. Two patients in each group developed adhesive capsulitis. The authors don't report on surgical complications.Bottom line:?In patients with subacromial shoulder pain of at least 3 months duration who receive physical therapy, surgical decompression is no better than arthroscopy without decompression in improving pain or function… and neither is much better than no invasive intervention at all.Beard DJ, Rees JL, Cook JA, et al. Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial. Lancet 2018;391(10118):329-338.4. Decompression surgery no more effective than exercise for shoulder impingement syndromeClinical question: In patients with symptoms of shoulder impingement syndrome is subacromial decompression surgery more effective than sham arthroscopy or exercise therapy to decrease pain and improve function?Study design:?Randomized controlled trial (double-blinded)Funding source:?GovernmentAllocation:?ConcealedSetting:?Outpatient (specialty)Synopsis: These Finnish researchers enrolled 210 adults aged 35 to 65 years with a clinical presentation of shoulder impingement syndrome who, by magnetic resonance imaging, had no evidence of rotator cuff tear and who had not responded to 3 months of conventional treatment. The patients were first randomized to receive surgery or physical therapy using concealed allocation; patients tapped for surgery underwent diagnostic arthroscopy to rule out tears or other pathology and then, in the operating room, were randomized again to receive arthroscopic subacromial decompression or (to keep everyone unaware of treatment assignment) kept in the operating theater but without further intervention for the length of time of a typical decompression. After 2 years, patients in all 3 groups had a large decrease in reported pain, from approximately 75 to between 20 and 30 on a 100-point visual analog scale. Decompression was statistically better than exercise therapy, but the result would not be clinically relevant (a difference of at least 15 points) and was no different than diagnostic arthroscopy. There was also no difference in pain or function scores at earlier time points. The researchers did not attempt to stratify patients by degree of joint narrowing or by the presence of osteoarthritis or other morphology, and targeted therapy aimed at specific changes may have found a difference in treatment outcomes.Bottom line: Despite being one of the most common orthopedic surgeries performed, subacromial decompression is not significantly better than physical therapy to treat patients with pain and limited function due to shoulder impingement. This study is backed up by a meta-analysis that found the same results (doi:10.3109/09638288.2014.907364). Get out the stretchy bands or hand weights: another meta-analysis (doi:10.1136/bjsports-2016-096515) demonstrated the benefit of shoulder exercises over other physical therapy modalities.?(LOE = 1a)Paavola M, Malmivaara A, Taimela S, et al, for the Finnish Shoulder Impingement Arthroscopy Controlled Trial (FIMPACT) Investigators. Subacromial decompression versus diagnostic arthroscopy for shoulder impingement: randomised, placebo surgery controlled clinical trial. BMJ 2018;362:k2860.5. Subacromial decompression surgery for shoulder pain is not effectiveClinical question: Should patients be referred for subacromial decompression surgery for shoulder pain?Study design:?Practice guidelineFunding source:?FoundationSetting:?Various (guideline)Synopsis: This committee attempted to answer one question: Should patients with antero-lateral shoulder pain lasting at least 3 months, without a history of trauma, be considered for surgery aimed at decompressing the subacromial space? The guideline committee was made up of patients, clinicians, and methodologists, none of whom had financial conflicts of interest. They based their recommendations on the results of 2 systematic reviews to assess the balance of patient-oriented benefits, harms, and burdens of surgery as compared with other treatments. Based on this research, the group strongly recommends that surgery be avoided, since it does not produce important improvement in pain, function, or quality of life, and may increase the risk of frozen shoulder.Bottom line: Whatever you call it—impingement syndrome, rotator cuff disease, bursitis—surgical decompression of the subacromial space in patients with chronic shoulder pain without a history of trauma is not helpful and may be harmful. This guideline group strongly recommends against it. Stick with conservative therapy.?(LOE = 5)Vandvik PO, Lahdeoja T, Ardern C, et al. Subacromial decompression surgery for adults with shoulder pain: a clinical practice guideline. BMJ 2019;364:l294.Back PainAll of us are trying to prescribe less opioids for chronic pain. Pregabalin and gabapentin have been used for chronic pain, but the following two studies find they are not very helpful compared to placebo. An RCT at the VA showed that equivalent pain relief is possible with a non-opioid approach. 6. Pregabalin does not decrease the pain of sciaticaClinical question:?Is pregabalin an effective treatment for the pain of acute or chronic sciatica?Study design:?Randomized controlled trial (double-blinded)Setting:?Outpatient (any)Synopsis:?The closely related drugs gabapentin and pregabalin are widely used for the treatment of neuropathic pain, including sciatica. This Australian trial recruited patients with moderate to severe sciatica, defined as pain radiating below the knee and accompanied by evidence of nerve root or spinal nerve involvement such as sensory deficits, diminished reflexes, or weakness. The pain had to have been present for between 1 week and 1 year. The average age of the 207 participants was 54 years, 85% had dermatomal pain, 37% had a neurologic deficit, and 30% had a motor deficit. The patients were randomly assigned to receive either pregabalin in a dose of 75 mg twice daily, increasing to a final target dose of 300 mg twice daily at 8 weeks, or matching placebo. The primary outcome was pain on a 10-point scale, with a difference of 1.5 points considered to be the minimal clinically important difference. Patients were followed up for up to 1 year, and a variety of secondary outcomes were measured, as well. Groups were balanced at the start of the study, and analysis was by intention to treat. At both 8 weeks and 52 weeks, there was no significant difference in the primary outcome, and no difference in secondary outcomes including disability, back pain intensity, global perception of the effect, and quality of life.Bottom line:?Pregabalin does not relieve pain in patients with sciatica.Mathieson S, Maher CG, McLachlan A, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med 2017;376(12):1111-1120.7. Gabapentinoids for chronic low back pain: limited evidence, more harm than benefitClinical question:?Are gabapentinoids safe and effective in treating patients with chronic low back pain?Study design:?Meta-analysis (randomized controlled trials)Setting:?Various (meta-analysis)Synopsis:?These authors searched 2 databases and the Cochrane clinical trials register to identify randomized trials of gabapentinoids (gabapentin, pregabalin) for treating adults with back pain lasting at least 3 months. Two authors independently assessed the inclusion of articles and they resolved disagreements by consensus or through third-party adjudication. Ultimately, they included 8 small studies with 3 different comparison treatments. Most of the studies had methodologic quality issues, including selection bias and inadequate concealment of randomization. Three studies with 185 patients compared gabapentin with placebo, finding minimal improvement in pain. Three studies with 332 patients compared pregabalin with other analgesics, finding pregabalin was more effective in average pain response. The remaining studies, which assessed pregabalin as an adjunct to pain management, were heterogeneous and the authors chose not to pool the data. The largest of these studies, however, found that adding pregabalin didn't improve pain. We have commented frequently on the inconsistent reporting of treatment harms in clinical trials and these studies are no exception. However, the authors were able to pool data and estimate the number needed to treat to harm (NNTH) for several adverse effects: dizziness (NNTH = 7; 95% CI 4 - 30), fatigue (NNTH = 8; 4 - 44), altered mentation (NNTH = 6; 4 - 15), and vision disturbance (NNTH = 6; 4 - 13). The studies generally did not report on functional outcomes.Bottom line:?The existing data on gabapentinoids for chronic low back pain are limited in number and quality. The amount of pain reduction is low to moderate, while the rate of adverse effects is high. The few studies that assessed function found no improvement.Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials. PLoS Med 2017;14(8):e1002369.8. Gabapentin and pregabalin not effective for low back pain with or without radiculopathyClinical question: Are anticonvulsants an effective treatment for low back pain?Study design:?Meta-analysis (randomized controlled trials)Funding source:?Self-funded or unfundedSetting:?Various (meta-analysis)Synopsis: Particularly in this era of heightened awareness of the potential harms of opioids, anticonvulsants are often prescribed for the treatment of painful conditions. Although there is evidence of their effectiveness primarily for peripheral and diabetic neuropathy, they are increasingly prescribed for other conditions, including low back pain. This systematic review included a comprehensive search of the literature and the authors identified 9 randomized trials (3 of which were crossover studies) that compared?topiramate, pregabalin, or?gabapentin?with placebo in patients with low back pain with or without radiculopathy. They excluded studies of pregnant women; pre-operative patients; and patients with mixed conditions, such as neck and back pain. The trials were assessed for risk of bias, and only 1 was at high risk. The studies used a range of pain scales, so the standardized mean difference in pain scores between treatment and placebo groups was the primary outcome. The 9 studies reported a total of 14 comparisons, with only 2 showing a statistically significant benefit. One was a small study of high-dose?gabapentin?(3600 mg/day) in 43 patients with lumbar radicular pain, and the other was a study of 96 patients with low back pain who were given 300 mg?topiramate?300 each day. The other?topiramate?study found no benefit, as did none of the other studies of pregabalin or?gabapentin. Where results could be pooled, there was essentially no difference between groups. Where results could be pooled, there was essentially no difference between groups. There was no difference in serious adverse events: 4 in the pregabalin group, 6 in the placebo group (though these were reported in only 2 studies with a total of 423 patients). Any adverse events, however, were significantly more common with active treatment (relative risk 1.4; 95% CI 1.2 - 1.7).Bottom line: The use of anticonvulsants like?gabapentin?for painful conditions has increased greatly in recent years. This review finds good evidence that these drugs are not an effective treatment for low back pain with or without radiculopathy, and are associated with an increased risk for adverse events.?(LOE = 1a)Enke O, New HA, New CH, et al. Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis. CMAJ 2018;190(26):E786-E793.9. Nonopioids equivalent to opioids for severe chronic back, hip, or knee pain with fewer adverse outcomesClinical question:?Are opioid medications preferable for improving pain-related function in adults with severe chronic back, hip, or knee pain?Study design:?Randomized controlled trial (double-blinded)Setting:?Outpatient (primary care)Synopsis:?For decades both patients and clinicians have believed/assumed that opioids are superior for reducing pain and improving function in patients with severe chronic pain. These investigators identified adults with chronic back pain or hip or knee osteoarthritis pain that rated at least moderately severe on a standard pain rating scale and persisted every day for at least 6 months. Patients with severe depression or posttraumatic stress disorder symptoms were NOT excluded. Study participants (N = 240) randomly received assignment (concealed allocation) to either an opioid or nonopioid pain management group. Patients in the opioid group started taking immediate release (IR) oral opioids with escalation to sustained-released (SA) oral opioids and finally to transdermal fentanyl, if needed. Titration continued to a maximum daily dose of 100 morphine-equivalent milligrams. Patients in the nonopioid medication group started with acetaminophen and nonsteroidal anti-inflammatory drugs, with step-up as needed to adjuvant oral medications (eg, amitriptyline, gabapentin) and topical analgesics (eg, capsaicin, lidocaine), and finally to pregabalin, duloxetine, and/or tramadol, if needed. Medication adherence was monitored by urine drug testing and with regular checking of a state prescription monitoring program. Individuals who assessed outcomes remained masked to treatment group assignment. Follow-up rates ranged from 90% to 98% of patients at 12 months. Mean age was 58.3 years (range = 21 – 80 years) and 13% were women. Using intention-to-treat analyses, there was no significant group difference in pain-related function over 12 months based on standard rating scales. Overall, pain intensity was significantly better in the nonopioid group over 12 months. Drop-outs due to adverse medication-related symptoms were significantly higher in the opioid group than in the nonopioid group (19% vs 8%, respectively). No deaths or diversions were detected in either group. Tramadol was dispensed to 11% of patients in the nonopioid group over the 12 months of follow-up.Bottom line:?Nonopioid medications were at least as effective as opioid medications for improving pain-related function over 12 months in adults with severe chronic back pain or knee or hip osteoarthritis pain. The evidence that opioids are NOT superior to nonopioid medications for both chronic and acute pain continues to mount. The tough job will be getting patients and their clinicians to believe the evidence.Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain. The SPACE randomized clinical trial. JAMA 2018;319(9):872-882.10. Lumbar fusion of variable value based on treating diagnosis, with significant complication ratesClinical question: What are the benefits and harms of lumbar fusion for degenerative low back pain?Study design:?Meta-analysis (other)Funding source:?Unknown/not statedSetting:?Outpatient (specialty)Synopsis: Spinal fusion is an expensive procedure of uncertain value that has high cost and regional variability in annual incidence. These authors performed a careful search of the literature to identify randomized trials (n = 19), cohort studies (n = 16 prospective and 15 retrospective), and registries (n = 15) that compared the outcomes of lumbar fusion, decompression, and/or nonoperative care for degenerative spine disease. They performed a comprehensive search to identify randomized trials and cohort studies with at least 2 arms, at least 2 participants per arm, and with at least 12 months of follow-up. Studies were generally at high risk of bias because of inadequate randomization, masking, and allocation concealment; this would tend to bias the studies in favor of active therapy. I'll focus here primarily on the results from the randomized trials. Regarding the Oswestry Disability Index (a 100-point scale), there was a statistically, but not clinically, significant 5-point improvement with fusion compared with nonoperative care for patients with chronic back pain, and a statistically and clinically significant 17-point improvement for those with spondylolisthesis as the indication. Results were similar for a visual analog scale measuring leg pain, with the improvement having statistical and clinical significance for patients with spondylolisthesis (2.2 points on a 10-point scale). Leg pain was largely evaluated in registry studies, and was not more improved by fusion than by decompression in patients with any indication. Patient satisfaction was greater for fusion compared with nonoperative care among patients with spondylolisthesis, but much less so for those with low back pain. There were no significant differences in risk of death, although confidence intervals were quite broad. Based mainly on registry and cohort studies, the risk of reoperation was greater for patients undergoing fusion than decompression if the indication was spinal stenosis (relative risk [RR] 1.17; 95% CI 1.06 - 1.28), but the opposite was true if spondylolisthesis was the indication (RR 0.75; 0.68 - 0.83). Finally, based on a mix of study designs, the risk of complications was greater for patients undergoing fusion than decompression alone (RR 1.70; 1.50 - 1.92).Bottom line: Lumbar fusion for degnerative spinal disease appears to be most beneficial for patients undergoing the procedure for spondylolisthesis, but is of little clear benefit for patients with other indications, such as spinal stenosis or chronic back pain. And the risk of reoperation or complications is greater for patients with spinal stenosis who undergo fusion compared with those who have decompression alone.?(LOE = 1a-)Yavin D, Casha S, Wiebe S, et al. Lumbar fusion for degenerative disease: a systematic review and meta-analysis. Neurosurgery 2017;80(5):701-715.Knees11. Placebo more effective than glucosamine plus chondroitin sulfate for knee DJDClinical question:?How effective is glucosamine plus chondroitin sulfate in improving moderate to severe pain and function in patients with symptomatic knee degenerative joint disease?Study design:?Randomized controlled trial (double-blinded)Setting:?Outpatient (specialty)Synopsis:?In this industry-sponsored study, researchers evaluated adults with radiographically moderate to severe knee DJD and moderate to severe pain (40 mm to 80 mm on a 100-mm visual analog scale). The authors excluded patients with a body mass index greater than 35, those with concurrent arthritic conditions, and those who they thought would not be able to complete the study. They randomized patients to receive 1200 mg bovine chondroitin sulfate plus 1500 mg crustacean glucosamine (n = 81) or a "conveniently masked placebo" (n = 83). The authors evaluated pain and function using a modified intention-to-treat analysis, as well as a per-protocol approach. A worrisome matter is that by the 6-month assessment more than 20% of enrolled patients dropped out of each group. The types of analyses and the drop-out rate are both more likely to bias the results in favor of intervention. The authors report that by 6 months, regardless of analytic approach, patients treated with placebo experienced larger decreases in pain scores and function scores than patients treated with glucosamine plus chondroitin sulfate, although the differences were not statistically significant (with the exception of pain analyzed by modified intention to treat). Finally, if we estimate the proportion of patients classified as "responders" (based on the Outcome Measures in Rheumatology Osteoarthritis Research Society International 2004 response criteria and the use of rescue medication), 47% of placebo-treated patients were responders for pain or function compared with 28% of actively treated patients (number needed to treat to harm = 5). The potential biases in this study strengthen the conclusion that glucosamine plus chondroitin sulfate is ineffective. Now, do you want to hear something REALLY interesting? The data safety monitoring board, masked to interventions, stopped the study at 6 months because one intervention was clearly better than the other: placebo!Bottom line:?This is one of many studies showing that, after 6 months of treatment, glucosamine plus chondroitin sulfate is no better than placebo in improving pain and function in patients with symptomatic knee degenerative joint disease (DJD). In fact, this is one of the first studies to suggest that placebo is better.Roman-Blas JA, Castaneda S, Sanchez-Pernaute O, Largo R, Herrero-Beaumont G, CS/GS Combined Therapy Study Group. Combined treatment with chondroitin sulfate and glucosamine sulfate shows no superiority over placebo for reduction of joint pain and functional impairment in patients with knee osteoarthritis: a six-month multicenter, randomized, double-blind, placebo-controlled clinical trial. Arthritis Rheumatol 2017;69(1):77-85.12. Lateral wedge insoles not helpful for pain of knee osteoarthritisBACKGROUND: Using the lateral wedge insole is a conservative management strategy for knee?osteoarthritis. The theoretical basis for this intervention is to correct femorotibial angle, thereby reducing pain and optimising function.OBJECTIVE: This?systematic?review evaluates the evidence on the effectiveness of wedge insole compared with flat insole for the?treatment of knee?osteoarthritis.METHODS: A?systematic?review was performed, searching published (MEDLINE, EMBASE, CNKI, Cochrane Library, and Web of Science) and unpublished literature from their inception to April 2018. Randomized controlled trials (RCTs) that compared the use of wedge insole with a flat insole were included. Risk of bias and clinical relevance were assessed, and outcomes were analysed through meta-analysis.RESULT: From a total of 413 citations, 8 studies adhered to the a priori eligibility criteria. The WOMAC pain was shown to be statistically nonsignificant change with the use of wedge insole (SMD=0.07), and low heterogeneity (I2=22%) and a 95% CI that crossed zero (95% CI: -0.09 to 0.24). The 5 independent trials were not significant in improving pain score (SMD = -0.02, 95% CI: -0.19 to 0.16). This review also revealed no significance in improving Lequesne index (SMD = -0.27, 95% CI: -0.72 to 0.19). The meta-analysis from the 2 independent trials was significant in improving femorotibial angle (SMD = -0.41, 95% CI: -0.73 to -0.09). In conclusion, this meta-analysis suggested that lateral wedge insoles can improve femorotibial angle but are of no benefit with pain and functions in knee?osteoarthritis.Zhang B, Yu X, Liang L, Zhu L, Dong X, Xiong Y, Pan Q, Sun Y. Is the Wedged Insole an Effective Treatment Option When Compared with a Flat (Placebo) Insole: A Systematic Review and Meta-Analysis. Evid Based Complement Alternat Med. 2018 Dec 4;2018:8654107. 13. Limited evidence for benefit of stem cell injections for knee osteoarthritis: all studiesPURPOSE: To provide a?systematic?review of the clinical literature reporting the efficacy of mesenchymal stem cells (MSCs) in terms of clinical outcomes including pain and function and cartilage repair in patients with?osteoarthritis.METHODS: We systematically reviewed any studies investigating clinical outcomes and cartilage repair after the clinical application of cell populations containing MSCs in human subjects with knee?osteoarthritis?through MEDLINE, EMBASE, the Cochrane Library, CINAHL, Web of Science, and Scopus. Preferred Reporting Items for?Systematic?Reviews and Meta-Analyses guidelines were followed. Studies with a level of evidence of IV or V were excluded. Methodological quality was assessed using the Modified Coleman Methodology Score. Clinical outcomes were assessed using clinical scores, and cartilage repair was assessed using magnetic resonance imaging and second-look arthroscopy findings.RESULTS: A total of 17 studies that met the criteria of 50 full-text studies were included in this review, with 6 randomized controlled trials, 8 prospective observational studies, and 3 retrospective case-control studies. Among 17 studies, 8 studies used bone marrow-derived MSCs, 6 used adipose tissue-derived stromal vascular fraction, 2 used adipose tissue-derived MSCs, and 1 used umbilical cord blood-derived MSCs. All studies except 2 reported significantly better clinical outcomes in the MSC group or improved clinical outcomes at final follow-up. In terms of cartilage repair, 9 of 11 studies reported improvement of the cartilage state on magnetic resonance imaging, and 6 of 7 studies reported repaired tissue on second-look arthroscopy. The mean Modified Coleman Methodology Score was 55.5 ± 15.5 (range, 28-74).CONCLUSIONS: Intra-articular MSCs provide improvements in pain and function in knee?osteoarthritis?at short-term follow-up (<28?months) in many cases. Some efficacy has been shown of MSCs for cartilage repair in?osteoarthritis; however, the evidence of efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited.Ha CW, Park YB, Kim SH, Lee HJ. Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair. Arthroscopy. 2019 Jan;35(1):277-288.e2. 14. Limited evidence for effectiveness of stem cell injections for knee osteoarthritis: RCTs onlyINTRODUCTION:?Mesenchymal stem cells (MSCs) have gained popularity for articular cartilage repair. However, efficacy of intra-articular MSCs in osteoarthritis remains unclear. In the setting of a meta-analysis of randomized controlled trials (RCTs), we aimed to investigate the efficacy of intra-articular MSCs on clinical outcomes and cartilage repair in patients with knee osteoarthritis.MATERIALS AND METHODS:?PubMed, EMBASE, Cochrane Library, CINAHL, and Scopus were searched from inception to March 31, 2017. This study included RCTs using cell population containing MSCs for treatment of knee osteoarthritis. The quality was assessed by Cochrane Collaboration`s risk of bias tool. For meta-analysis, data on clinical outcomes measured by visual analog scale (VAS), Lysholm score, WOMAC and data on cartilage repair measured by MOCART and WORMS were extracted. In studies with several cell concentrations, outcomes of recommended concentration were used mainly to ensure robustness.RESULTS:?A total of five RCTs (220 patients) were included. Two studies were deemed to have low risk of bias. In pooled analysis, there was significant difference in VAS score (mean difference [MD], -?9.2; 95% CI: -?17.21, -?1.20) and Lysholm score (MD, 8.70; 95% CI 0.06, 17.34), but not WOMAC (MD, -?7.44; 95% CI -?20.38, 5.50). In cumulative functional analysis using Lysholm score and WOMAC in recommended concentration, there was a significant improvement (standard mean difference [SMD], 0.53; 95% CI 0.13, 0.94) after treatment. In cartilage repair assessed by MRI, there was no significant difference (SMD, 0.53; 95% CI-?0.28, 1.34).CONCLUSIONS:?This meta-analysis demonstrated that intra-articular MSCs have a limited evidence in pain relief and functional improvement in knee osteoarthritis. While MSCs may result in favorable clinical outcomes with a recommended concentration, use of concomitant treatment should be considered. In addition, current evidence does not support the use of intra-articular MSCs for improving cartilage repair in knee osteoarthritis.Kim SH, Ha CW, Park YB, Nam E, Lee JE, Lee HJ. Intra-articular injection of mesenchymal stem cells for clinical outcomes and cartilage repair in osteoarthritis of the knee: a meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg. 2019 Jul;139(7):971-980. PubMed PMID: 30756165.15. Platelet-rich plasma = saline for patients with patellar tendinopathyClinical question: Are platelet-rich plasma injections effective in patients with patellar tendinopathy?Study design:?Randomized controlled trial (single-blinded)Funding source:?FoundationAllocation:?ConcealedSetting:?Outpatient (specialty)Synopsis: In this multicenter (Seattle, Oslo, Bologna) trial, the authors enrolled 61 adults, 18 years to 50 years of age, with at least 6 months of clinically diagnosed patellar tendinopathy confirmed by ultrasound with persistent symptoms in spite of a minimum of 6 weeks of exercise-based rehabilitation. The authors randomized patients to receive ultrasound-guided injections of either leukocyte-rich platelet-rich plasma, leukocyte-poor platelet-rich plasma, or saline. One week later, all patients engaged in a supervised gym-based rehabilitation program 3 times weekly for 6 weeks. Using standardized scales, the researchers evaluated each patient's pain, function, and activity limitations at baseline, and at 12, 24, and 52 weeks after the injections. Additionally, they asked the patients' for their own overall rating of change at the subsequent assessments. They had nearly complete (93%) follow-up at 12 weeks, but only 79% at the end of a year. At no point in the study did the authors find any differences in the 3 groups as to any of the outcomes or patient global assessment of improvement. Six weeks after the intervention, 5 patients, none whom received saline, reported overall worsening compared with their baseline. The authors report one patient experienced localized patellar tendon pain following the injection, enough to prevent activity. No other harms are reported, possibly because of the small sample size. The study was large enough to detect clinically meaningful differences in pain and functional limitations.Bottom line: In this study, platelet-rich plasma injections were no better than saline injections in improving pain or activity in patients with patellar tendinopathy. It did not matter if the plasma was leukocyte rich or leukocyte poor. The study was too small to detect potential harms of the intervention.?(LOE = 2b)Scott A, LaPrade RF, Harmon KG, et al. Platelet-rich plasma for patellar tendinopathy: a randomized controlled trial of leukocyte-rich PRP or leukocyte-poor PRP versus saline. Am J Sports Med 2019;47(7):1654-1661.16. After 5 years, platelet-rich plasma = hyaluronic acid injections for patients with knee osteoarthritisClinical question: Are platelet-rich plasma injections as effective as hyaluronic acid injections in patients with unilateral osteoarthritis of the knee?Study design:?Randomized controlled trial (double-blinded)Funding source:?Unknown/not statedAllocation:?ConcealedSetting:?Outpatient (specialty)Synopsis: This paper provides the 5-year follow-up results of a study we reviewed in 2015. The patients had unilateral mild to moderate severe knee osteoarthritis. The researchers randomized the patients to receive 3 weekly injections of either platelet-rich plasma (n = 96) or hyaluronic acid (n = 96). At the end of 5 years, the authors only had complete follow up on 88% and 85% of the original patients, respectively, and the patients had comparable degrees of symptom and function score improvement. The paper does not report the funding source for this study, but 3 of the authors report ties to industry. Finally, this paper is one of many that highlight why treatments for painful conditions should have a placebo or sham comparator: A recent systematic review demonstrated that hyaluronic acid injections were slightly better than placebo at improving pain and function, but the improvement was not clinically important.Bottom line: After 5 years of follow-up, patients with unilateral mild to moderate knee osteoarthritis treated with either platelet-rich plasma or hyaluronic acid injections had comparable degrees of improvement. Since other studies have found viscosupplementation is minimally better than sham treatments, we can infer that neither of the tested interventions are more effective than placebo. Di Martino A, Di Matteo B, Papio T, et al. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med 2019;47(2):347-354.17. Tanezumab reduces pain of hip or knee DJD and improves function, but may increase the need for joint replacementClinical question: Is tanezumab, a monoclonal antibody inhibitor, effective and safe for the treatment of moderate to severe knee or hip degenerative joint disease?Study design:?Randomized controlled trial (double-blinded)Funding source:?IndustryAllocation:?ConcealedSetting:?Outpatient (specialty)Synopsis: Tanezumab is a monoclonal antibody that inhibits nerve growth factor binding, which, when uninhibited, enhances pain hypersensitivity. These investigators identified adults, 18 years and older, who met standard international diagnostic criteria for hip or knee osteoarthritis. Eligible patients had a documented history of insufficient pain relief from?acetaminophen?and insufficient pain relief or intolerance/contraindication to nonsteroidal anti-inflammatory drugs,?tramadol, and opioids. Additional eligibility criteria included a pain subscale score of at least 5 (on a scale where 0 = no pain and 10 = extreme pain) and a baseline physical function score of at least 5 (on a scale where 0 = no difficulty and 10 = extreme difficulty). Study participants randomly received (concealed allocation assignment) 1 of 2 subcutaneous tanezumab treatment regimens (2.5 mg at baseline and again at week 8, or 2.5 mg at baseline and 5.0 mg at week 8) or matched placebo. Individuals masked to treatment group assignment assessed all outcomes. Complete follow-up occurred for 98.8% of participants at 16 weeks. Using intention-to-treat analysis, pain scores were significantly reduced in both tanezumab groups compared with the placebo group (mean differences vs placebo of -0.60 for tanezumab 2.5 mg and -0.73 for tanezumab 2.5/5 mg). Similarly, physical function disability scores were significantly reduced in both tanezumab groups compared with the placebo group (mean differences vs placebo of -0.66 for tanezumab 2.5 mg and -0.89 for tanezumab 2.5/5 mg). Since these differences are all less than 10% (1 point or more on the 11-point scale), it remains uncertain whether these are clinically significant. The total amount of rescue medication (acetaminophen) used was not significantly different among the 3 treatment groups. Of concern: More patients from both the 2.5 mg group and the 2.5/5 mg group underwent total joint replacements than from the placebo group (3.5% and 6.9% vs 1.7%, respectively).Bottom line: Tanezumab statistically significantly reduced pain and improved function in adults with moderate to severe hip or knee degenerative joint disease (DJD). It remains uncertain whether the improvements in pain and function scores are clinically significant. This study also raises the concern that tanezumab may increase the need for total joint replacement.?(LOE = 1b)Schnitzer TJ, Easton R, Pang S, et al. Effect of tanezumab on joint pain, physical function, and patient global assessment of osteoarthritis among patients with osteoarthritis of the hip or knee. A randomized clinical trial. JAMA 2019;322(1):37-48.18. Tanezumab reduces pain of hip or knee DJD and improves function, but may increase the need for joint replacement (PubMed abstract of POEM above with more numbers in it)IMPORTANCE:?Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments.OBJECTIVE:?To assess 2 subcutaneous tanezumab dosing regimens for OA.DESIGN, SETTING, AND PARTICIPANTS:?A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit). Patients enrolled were 18 years or older with hip or knee OA, inadequate response to OA analgesics, and no radiographic evidence of prespecified joint safety conditions.INTERVENTIONS:?Patients received by subcutaneous administration either tanezumab, 2.5 mg, at day 1 and week 8 (n?=?231); tanezumab, 2.5 mg at day 1 and 5 mg at week 8 (ie, tanezumab, 2.5/5 mg; n?=?233); or placebo at day 1 and week 8 (n?=?232).MAIN OUTCOMES AND MEASURES:?Co-primary end points were change from baseline to week 16 in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain (0-10, no to extreme pain), WOMAC Physical Function (0-10, no to extreme difficulty), and patient global assessment of osteoarthritis (PGA-OA) (1-5, very good to very poor) scores.RESULTS:?Among 698 patients randomized, 696 received 1 or more treatment doses (mean [SD] age, 60.8 [9.6] years; 65.1% women), and 582 (83.6%) completed the trial. From baseline to 16 weeks, mean WOMAC Pain scores decreased from 7.1 to 3.6 in the tanezumab, 2.5 mg, group; 7.3 to 3.6 in the tanezumab, 2.5/5 mg, group; and 7.3 to 4.4 in the placebo group (least squares mean differences [95% CI] vs placebo were -0.60 [-1.07 to -0.13; P?=?.01] for tanezumab, 2.5 mg, and -0.73 [-1.20 to -0.26; P?=?.002] for tanezumab, 2.5/5 mg). Mean WOMAC Physical Function scores decreased from 7.2 to 3.7 in the 2.5-mg group, 7.4 to 3.6 in the 2.5/5-mg group, and 7.4 to 4.5 with placebo (differences vs placebo, -0.66 [-1.14 to -0.19; P?=?.007] for tanezumab, 2.5 mg, and -0.89 [-1.37 to -0.42; P?<?.001] for tanezumab, 2.5/5 mg). Mean PGA-OA scores decreased from 3.4 to 2.4 in the 2.5-mg group, 3.5 to 2.4 in the 2.5/5-mg group, and 3.5 to 2.7 with placebo (differences vs placebo, -0.22 [-0.39 to -0.05; P?=?.01] for tanezumab, 2.5 mg, and -0.25 [-0.41 to -0.08; P?=?.004] for tanezumab, 2.5/5 mg). Rapidly progressive OA occurred only in tanezumab-treated patients (2.5 mg: n?=?5, 2.2%; 2.5/5 mg: n?=?1, 0.4%). The incidence of total joint replacements was 8 (3.5%), 16 (6.9%), and 4 (1.7%) in the tanezumab, 2.5 mg; tanezumab, 2.5/5 mg; and placebo groups, respectively.CONCLUSIONS AND RELEVANCE:?Among patients with moderate to severe OA of the knee or hip and inadequate response to standard analgesics, tanezumab, compared with placebo, resulted in statistically significant improvements in scores assessing pain and physical function, and in PGA-OA, although the improvements were modest and tanezumab-treated patients had more joint safety events and total joint replacements. Further research is needed to determine the clinical importance of these efficacy and adverse event findings.Schnitzer TJ, Easton R, Pang S, Levinson DJ, Pixton G, Viktrup L, Davignon I, Brown MT, West CR, Verburg KM. Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis Among Patients With Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial. JAMA. 2019 Jul 2;322(1):37-48. PubMed PMID: 31265100.Bottom Lines1. A steroid injection gives better results than night splints alone for carpal tunnel syndrome at 6 weeks but not at 6 months.2. Platelet rich plasma injections are not effective for chronic shoulder pain, knee osteoarthritis and patellar tendonopathy. 3. Surgery is not more effective than conservative treatment for chronic shoulder pain when there is no rotator cuff tear or acute trauma.4. Gabapentinoids are minimally effective (if at all) for chronic back pain.5. Chronic back pain can be managed adequately for many patients without using opioids.6. Glucosamine/chondroitin is no better than placebo in relieving pain and improving function in patients with knee osteoarthritis.7. Lateral wedges for shoe soles are no better than regular soles for knee osteoarthritis pain.8. It is uncertain if stem cell injections improve pain and function of knee osteoarthritis.9. Tanezumab provides a small reduction in the pain of hip or knee DJD and slightly improves function, but may increase the need for joint replacement. The improvement in pain and function is less than 10% and may not be clinically meaningful for many patients. HTN | 2019 UpdateGary Ferenchick, MD, MSLearning objectives | Understand and apply: The evolution of recommendations in BP management recommendations over the past 5 yearsThe results of the ACCORD BP, the HOPE – 3 and the SPRINT trial compared to the Trial, and their relevance for cardiovascular disease prevention.AAFP and ACP guidelines on intensive BP treatment for those > 60Review the 2017 AHA ACC guideline on HTN, and why the AAFP and ACP have chosen to not endorse itThe European Society of Cardiology 2018 hypertension guidelinesIntensive BP treatment associated with lower risk of mild cognitive impairment (Sprint Mind Trial) Automated office blood pressure measurements correlate well with ambulatory blood pressure measurements.A lot has happened in the hypertension field since 2014, and honestly has become more confusing to patients and providers alike. If you feel like you have a good handle on the rapidly changing landscape of hypertension management you are doing extremely well. The ACC/AHA guidelines were released in late 2017 have the potential to radically change how we approach HTN, however as you will see the AAFP and the ACP have chosen to not endorse these guidelines. Added to the mix is the late 2018 European Guidelines, which offer their own recommendations. Let’s see if we can make sense of it all!1: JNC 8Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.REFERENCE: James PA et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311 (5):507-20.2: The SPRINT TrialBACKGROUND: The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain.METHODS: We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.RESULTS: At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group.CONCLUSIONS: Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. REFERENCE: SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16. 3: The ACCORD BP TrialBACKGROUND: There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events.METHODS: A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.RESULTS: After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001).CONCLUSIONS: In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. ( number, NCT00000620.)Reference: ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85. PMID: 202284014: The Hope-3 TrialBACKGROUND: Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear.METHODS: In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years.RESULTS: The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI,0.81 to 1.11; P=0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P=0.02 and P=0.009, respectively, for trend in the two outcomes).CONCLUSIONS: Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; number, NCT00468923.).REFERENCE: Lonn EM, et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016 May 26;374(21):2009-20.Blood pressure recommendations in the post–SPRINT eraIn January of 2017, the AAFP and the ACP jointly published a guideline based upon a systematic review of published randomized, controlled trials and observation studies (articles published through September of 2016 in Medline and January 2015 for other databases). There conclusions closely reflected the recommendations of the JNC 8. Importantly this means they has the results of the SPRINT Trial for this review.5: AAFP/ACP: Practice guideline Intensive treatment for patients > 60Description: The American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) jointly developed this guideline to present the evidence and provide clinical recommendations based on the benefits and harms of higher versus lower blood pressure targets for the treatment of hypertension in adults aged 60 years or older.Methods: This guideline is based on a systematic review of published randomized, controlled trials for primary outcomes and observational studies for harms only (identified through EMBASE, the Cochrane Database of Systematic Reviews, MEDLINE,and ), from database inception through January 2015. The MEDLINE search was updated through September2016. Evaluated outcomes included all-cause mortality, morbidity and mortality related to stroke, major cardiac events (fatal and nonfatal myocardial infarction and sudden cardiac death), and harms. This guideline grades the evidence and recommendations using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method.Target Audience and Patient Population: The target audience for this guideline includes all clinicians, and the target patient population includes all adults aged 60 years or older with hypertension.Recommendation 1: ACP and AAFP recommend that clinicians initiate treatment in adults aged 60 years or older with systolic blood pressure persistently at or above 150 mm Hg to achieve a target systolic blood pressure of less than 150 mm Hg to reduce the risk for mortality, stroke, and cardiac events. (Grade: strong recommendation, high-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient.Recommendation 2: ACP and AAFP recommend that clinicians consider initiating or intensifying pharmacologic treatment in adults aged 60 years or older with a history of stroke or transient ischemic attack to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk for recurrent stroke. (Grade: weak recommendation, moderate-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient.Recommendation 3: ACP and AAFP recommend that clinicians consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk, based on individualized assessment, to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk for stroke or cardiac events. (Grade: weak recommendation, low quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient.Reference: Qaseen A et al. Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017 Mar 21;166(6):430-437.It is now commonplace to recommend that lipid-lowering treatment be primarily based upon a patients' predicted cardiovascular disease risk rather than just the LDL cholesterol concentrations, thus essentially eliminating treatment thresholds that are based only on LDL cholesterol concentrations. This approach recognizes that the patients baseline risk "is a major determinant of the absolute benefits of statin treatment". This reflects a classic example of understanding how to apply baseline risk assessments in helping patients make treatment desicions. As a theoretical example: if a given treatment reduces the risk of an event by 50%,an individual with a low baseline risk (e.g. 2%) has almost nothing to gain (this 50% decrease translates into a post treatment risk of 1% | NNT = 100). However, an individual with a moderate-high baseline risk (e.g. 20%) has more to gain (this 50% decrease translates into a post treatment risk of 10% | NNT = 10). Also, note that in each instance the relative risk reduction is the same. Whether these levels of risk reduction are meaningful to the patient is where, of course, shared decision-making comes in. In the new AHA/ACC guidelines, we are asked to use the 10-year cohort risk calculator much like we do for determining statin eligibility, to make therapeutic decisions for primary prevention in HTN. Abstract 6 support the use of predicted baseline cardiovascular disease risk equations to inform blood pressure-lowering treatment decisions. ACC AHA Guidelines My Quick Review The following is a quick review of the ACC AHA Class of Recommendation (COR) and Level of evidence (LOE) that is now used for all ACC/AHA Guidelines. They are meant of assist us and our patients in decision-making. Note the primary differences from the previous paradigm is separating Level B and Level C evidence based upon the quality of the underlying data.Class (Strength) of Recommendation (COR) TableClass I (Benefit >>> Risk):Should be done | Is useful | (Strong)Class IIa (Benefit >> Risk):Reasonable to do | Can be useful | (Moderate)Class IIb (Benefit > Risk):May be considered | Unknown usefulness (Weak)Class III (No benefit or harm):Not helpful or harmfulLevel (Quality) of Evidence (LOE)Level A:High quality evidence from > 1 RCTMeta-analysis of high-quality RCTs> 1 RCT corroborated by high-quality registry studiesLevel B-R (Randomized):Moderate quality evidence from > 1 RCTMeta-analyses of moderate quality RCTsLevel B-NR (Non-randomized):Moderate quality evidence from > 1 high-quality nonrandomized/observational or registry studiesMeta-analyses of such studiesLevel C-LDRandomized or nonrandomized/observational or registry studies with limitations of design or executionMeta-analyses of such studiesPhysiological or mechanistic studies in humansLevel C-EOConsensus opinion based upon clinical experienceThe COR and LOE are determined independent of each other. Any COR can be paired with any LOE (notably LOE C does not imply the COR is weak2107 ACC AHA Guidelines on HTNIn November of 2017, the American College of Cardiology/American Heart Association published a new guideline on the prevention, detection, evaluation, and management of high blood pressure in adults. The article was published online and is 41 pages, 106 recommendations and 23 tables; however, the "meat" of the guideline was covered in only ~ 89 pages. Also the COI declarations covered 22 pages (on a quick review however, most authors had no COI with industry). Articles published through August of 2015 were included. This guideline was heavily influenced by results of the SPRINT study.Broad sections included the following: BP and CVD riskClassification of the BPMeasurement of BPCauses of HTNPatient EvaluationTreatment of High BPHypertension in patients with comorbiditiesSpecial patient groupsOther considerations (e.g. resistant HTN, hypertensive crises etc)I’m including my determination of the items that are most relevant for primary care providers. My Summary of key aspects of the New BP guidelines are below the numbering and emphases are mineThe New NormalBP should be categorized as normal, elevated, or stage 1 or 2 hypertension to prevent and treat high BP (Table 6) (COR I | LOE B-NR)The new normal is < 120 / < 80. In addition, a new category of “Elevated Blood Pressure” is included (i.e. 120 – 129 / < 80; and if present, non-pharmacological therapy is recommended). Hypertension is defined now as > 130 / > 80. Also returned from previous guidelines are stages of hypertension (Stage 1 and Stage 2). Note the checklist for accurate BP measurement from this guideline is in the appendixBP CategorySBPDBPNormal< 120and< 80Elevated120-129and< 80HypertensionStage 1130-139or80 - 89Stage 2> 140or> 90Out-of-office BP measurements recommendedOut-of-office BP measurements are recommended to confirm the diagnosis of hypertension and for titration of BP-lowering medication, in conjunction with telehealth counseling or clinical interventions. (COR I | LOE A)Take at least two readings 1 min apart in morning before taking medications and in evening before supper. Optimally, measure and record BP daily. Ideally, obtain weekly BP readings beginning 2 weeks after a change in the treatment regimen and during the week before a clinic visit. BP should be based on an average of readings on ≥2 occasions for clinical decision-making. Also note that the UPSTF “recommends obtaining measurements outside of the clinical setting for diagnostic confirmation before starting treatment”. “The USPSTF found convincing evidence that ABPM is the best method (i.e. reference standard) for diagnosing hypertension.” “Good-quality evidence suggests that confirmation of hypertension with HBPM (with appropriate protocols) may be acceptable.”However the evidence is not as substantial as it is for ABPMThe information above may be reinforced with videos available online: Monitoring Your Blood Pressure at Home.Treatment recommendations are a bit more nuancedUse of BP-lowering medications is recommended for secondary prevention of recurrent CVD events in patients with clinical CVD and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher, and for primary prevention in adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or higher and an average SBP 130 mm Hg or higher or an average DBP 80 mm Hg or higher. (COR I | LOE A for SBP)Use of BP-lowering medication is recommended for primary prevention of CVD in adults with no history of CVD and with an estimated 10-year ASCVD risk <10% and an SBP of 140 mm Hg or higher or a DBP of 90 mm Hg or higher. (COR I | LOE C-LD)Use the ACC/AHA Pooled Cohort Equation to estimate 10-year risk of atherosclerotic CVD.However – with one exception (as noted in the blue cell below) treatment should be initiated with a confirmed BP of > 130 / > 80. You will note that for most patients we are asked to calculated the 10-year ASCVD risk (much like we are asked to do for determining candidacy for statin therapy) to determine if the patients 10-year risk is > or < 10%Summary of BP Thresholds and Goals for Pharmacologic TreatmentClinical Condition(s)BP Threshold, mmHg BP Goal, mm HgGeneralClinical CVD or 10-year ASCVD risk ≥10%≥130/80<130/80No clinical CVD and 10-year ASCVD risk <10%≥140/90<130/80Older persons (≥65 years of age; noninstitutionalized,≥130 (SBP)<130 (SBP)Specific comorbiditiesDiabetes mellitus≥130/80<130/80Chronic kidney disease≥130/80<130/80Chronic kidney disease after renal transplantation≥130/80<130/80Heart failure≥130/80<130/80Stable ischemic heart disease≥130/80<130/80Secondary stroke prevention≥130/80<130/80Secondary stroke prevention (lacunar)≥130/80<130/80Peripheral arterial disease≥130/80<130/80For initiation of antihypertensive drug therapy, first-line agents include thiazide diuretics, CCBs, and ACE inhibitors or ARBs. (COR I | LOE A)Initiation of antihypertensive drug therapy with 2 first-line agents of different classes, either as separate agents or in a fixed-dose combination, is recommended in adults with stage 2 hypertension and an average BP more than 20/10 mm Hg above their BP target. (COR I | LOE C-EO)Special CircumstancesStable ischemic Heart Dz (SIHD)Adults with SIHD and hypertension (BP ≥130/80 mm Hg) should be treated with medications (e.g., GDMT beta blockers, ACE inhibitors, or ARBs) for compelling indications (e.g., previous MI, stable angina) as first-line therapy, with the addition of other drugs (e.g., dihydropyridine CCBs, thiazide diuretics, and/or mineralocorticoid receptor antagonists) as needed to further control hypertensionHeart Failure with Preserved Ejection Fraction Adults with HFpEF and persistent hypertension after management of volume overload should be prescribed ACE inhibitors or ARBs and beta blockers titrated to attain SBP of less than 130 mm Hg. (COR I | C-LD)Note that GDMT beta-blockers for BP control or relief of angina include carvedilol, metoprolol tartrate, metoprolol succinate, nadolol, bisoprolol, propranolol, and timolol. Avoid beta-blockers with intrinsic sympathomimetic activity (e.g. pindolol, acebutolol). The beta-blocker atenolol should not be used because it is less effective than placebo in reducing cardiovascular events.DiabetesIn adults with DM and hypertension, all first-line classes of antihypertensive agents (i.e., diuretics, ACE inhibitors, ARBs, and CCBs) are useful and effective (COR I | LOE A)In adults with DM and hypertension, ACE inhibitors or ARBs may be considered in the presence of albuminuria (COR IIb | LOE B-NR)African-AmericansIn black adults with hypertension but without HF or CKD, including those with DM, initial antihypertensive treatment should include a thiazide-type diuretic or CCB. (COR I | B-R)Two or more antihypertensive medications are recommended to achieve a BP target of less than 130/80 mm Hg in most adults with hypertension, especially in black adults with hypertension. (COR I | C-LD)Elderly (> 65)Treatment of hypertension with a SBP treatment goal of less than 130 mm Hg is recommended for noninstitutionalized ambulatory community dwelling adults (≥65 years of age) with an average SBP of 130 mm Hg or higher (COR I | LOE A)For older adults (≥65 years of age) with hypertension and a high burden of comorbidity and limited life expectancy, clinical judgment, patient preference, and a team-based approach to assess risk/benefit is reasonable for decisions regarding intensity of BP lowering and choice of antihypertensive drugs. (COR IIa | LOE C-EO)According to data from NHANEs published in the guideline, the prevalence of HTN will triple for men and double for women under the age of 45 (a group of patients not well represented in trials of aggressive BP lowering). (Ann Intern Med 2017); Recall that the average of the participants in the SPRINT trial was 50.6: 13.7% more people in the US are now classified as having HTNCONCLUSION: Compared with the JNC 7 guideline, the 2017 ACC/AHA guideline results in a substantial increase in the prevalence of hypertension but a small increase in the percentage of U.S. adults recommended antihypertensive medication. A substantial proportion of US adults taking antihypertensive medication is recommended more intensive BP lowering under the 2017 ACC/AHA guideline.REFERENCE: Muntner P et al. Potential U.S. Population Impact of the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline.J Am Coll Cardiol. 2017 Nov 6.(PMID: 29146532) AAFP does not endorse the new AHA/ACC HTN guidelines …..In Mid-December 2017, the AAFP decided to not endorse the AHA/ACC HTN guidelines, but to continue to endorse the 2014 JNC8 guideline. The AAFP was not involved in the development of the guidelines. The chair of the AAFP's Commission on Health of the Public and Science (CHPS), David O'Gurek, M.D. stated that the AAFP used the same process to review both the JNC 8 and the AHA/ACC Guidelines, and concluded that the 2017 guidelines "didn't meet the Academy's criteria for endorsement or affirmation of value," and that “JNC8 upheld the scientific rigor that provided strong recommendations to family physicians and patients on appropriate treatment of hypertension.”Reasons for non-endorsement included the contention that:The bulk of the guideline was not based on a systematic evidence reviewA systematic review was performed for 4 key questions, although the guideline provided over 100 recommendationsAssessments of the quality of individual studies or systematic reviews weren't providedSpecifically “…the guideline offered a strong recommendation (COR: I) for using the unvalidated atherosclerotic cardiovascular disease risk assessment tool previously developed by AHA and ACC to determine whether medications should be initiated for BP control. However, this recommendation wasn't based on evidence that using the tool in this way improves outcomes.”Substantial weight was given to the SPRINT trial, while other trials were minimizedThe AAFP “… commission said conflict of interest is a major concern in judging the trustworthiness of guidelines and plays a key role in the AAFP's assessment of guidelines. In the case of the AHA/ACC guideline, the guideline panel commissioned the chair of the SPRINT trial steering committee to chair its work, when, notably, the SPRINT trial served as the foundation for the guideline panel's recommendations to change BP treatment targets.”Additionally “… several other AHA/ACC guideline panel members had intellectual conflicts of interest, which were not considered in the guideline's preparation.”“The AAFP chose not to participate in this guideline development given significant concerns about the guideline methodology, including the management of intellectual conflicts of interest of guideline participants”The harms of treating patients to a lower BP were not assessed in the systematic review. "With competing guidelines and recommendations, family physicians, as bold champions of science, have an opportunity to be a guiding light in the darkness of confusion to deliver quality care that's grounded in science and is patient-centered," O'Gurek concluded.AAFP News Accessed Online February 17, 2019…… Neither does the ACP Wilt T et al, for the Clinical Guidelines Committee of the American College of Physicians. Hypertension Limbo: Balancing Benefits, Harms, and Patient Preferences Before We Lower the Bar on Blood Pressure. Ann Intern Med. 2018 Mar 6;168(5):369-370.Timothy Wilt for the Clinical Guidelines Committee of the American College of Physicians "... the (ACC/AHA) guideline falls short in weighing the potential benefits against potential harms, costs, and anticipated variation in individual patient preferences.""Are the harms, costs, and complexity of care associated with this new target justified by the presumed benefits of labeling nearly half the U.S. population as unwell and subjecting them to treatment? We think not and believe that many primary care providers and patients would agree. The ACC/AHA based the new definition primarily on selected observational studies showing an association between a BP above 130/80 mm Hg and elevated cardiovascular risk, but few empirical data show that treating to this target in the general population will improve outcomes.""It is important to consider the ramifications of labeling asymptomatic persons as unwell before expanding a disease definition""We believe that initiation of pharmacologic therapy at or above a BP of 130/80 mm Hg and treatment to targets less than 130/80 mm Hg in a broad population of older adults are not supported by evidence and may result in low-value care for several reasons.""SPRINT provides the footing for an intensive treatment target in higher-risk populations, but the lack of consistent benefit across trials underscores the uncertainty about the actual benefit of aggressive control and highlights the need for targeted application of the SPRINT findings""In addition, the assumption that data from trials in patients with established hypertension applies to newly diagnosed patients is flawed""Third, there is no evidence from randomized controlled trials to support a DBP target less than 80 mm Hg." "Clinical policy focused on lower SBP targets should permit a choice based on a patient's risk profile, susceptibility to harms, and treatment preferences."…. Neither (ish) do the European Guidelines 2018In late 2018, the European Guidelines were published (ESC/ESH Guidelines for the management of arterial hypertension). This was a very large document and without going into all of the details, I just want to show how these guidelines “stack up” against the others discussed in this chapter. Primarily their definition of hypertension is consistent with the JNC VIII and not the ACC. However, they do endorse the idea of staging of BP (a concept not mentioned in the JNC VIII guideline)REFERENCE: Williams B, Mancia et al for the ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018 Sep 1;39(33):3021-3104.REFERENCE: Whelton PK(1)(2), Williams B(3)(4). The 2018 European Society of Cardiology/European Society of Hypertension and 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines: More Similar Than Different. JAMA. 2018 Nov 6;320(17):1749-1750.JNC VIIIACC/AHAACP/AAFPEuropean Society of Cardiology/ HTNBP CategoryOptimal< 120 / <80Normal< 120 / < 80> 140 / > 90120 -129 / 80 - 84Elevated***> 120 / > 80130-139 / 85 - 89**Hypertension> 140 / > 90> 140 / > 90Stage 1> 130 / > 80140 -159 / 90 – 99Stage 2> 140 / > 90160 - 179 / 100 - 109Stage 3> 180 / > 110* > 150 / > 90 for those > 60** Consider drug treatment if CV risk is very high (i.e. CVD – including asymptomatic disease on imaging, DM, Grade 3 HTN, CKD)*** Called High Normal in ECS GuidelineThe following two observational studies essentially come to opposite conclusions (although using different study questions and different designs). With the question of intensive BP control now at the forefront for high-risk patient, Abstract # 8 using a cohort study design, demonstrated no association between treating and not treating a blood pressure of 140-159/90-99 (Stage 2 HTN according to the ACC/AHA guidelines) and CV outcomes in low risk individuals (mean age ~ 55) over ~ 6 year follow up. But anti-hypertensive treatment was associated with higher risks of syncope, electrolyte abnormalities and acute kidney injuryAbstract #9 identified participants < 40 years old with various levels of BP (normal, elevated, Stage 1, Stage 2 or taking anit-hypertensive medications) did demonstrate an association between elevated blood pressure (> 120/ >80) and subsequent adverse cardiovascular outcomes in young adults (mean age 35). Over a mean follow up of ~ 18 years, higher stages of BP were associated with heightened risk of subsequent CV disease compared with normal BP.Finally, abstract #10, a follow up to the SPRINT trial, demonstrated no improvement in dementia risk with intensive BP control but did demonstrate a decrease in mild cognitive impairment (MCI) 8: Treating patient with low risk mild HTN (untreated SBP 140 – 159 / 90 – 99) of uncertain benefit after a 6 year follow upImportance: Evidence to support initiation of pharmacologic treatment in low-risk patients with mild hypertension is inconclusive, with previous trials underpowered to demonstrate benefit. Clinical guidelines across the world are contradictory.Objective: To examine whether antihypertensive treatment is associated with a low risk of mortality and cardiovascular disease (CVD) in low-risk patients with mild hypertension.Design, Setting, and Participants: In this longitudinal cohort study, data were extracted from the Clinical Practice Research Datalink, from January 1, 1998, through September 30, 2015, for patients aged 18 to 74 years who had mild hypertension (untreated blood pressure of 140/90-159/99 mm Hg) and no previous treatment. Anyone with a history of CVD or CVD risk factors was excluded. Patients exited the cohort if follow-up records became unavailable or they experienced an outcome of interest.Exposures: Prescription of antihypertensive medication. Propensity scores for likelihood of treatment were constructed using a logistic regression model. Individuals treated within 12 months of diagnosis were matched to untreated patients by propensity score using the nearest-neighbor method.Main Outcomes and Measures: The rates of mortality, CVD, and adverse events among patients prescribed antihypertensive treatment at baseline, compared with those who were not prescribed such treatment, using Cox proportional hazards regression.Results: A total of 19?143 treated patients (mean [SD] age, 54.7?[11.8] years; 10 705 [55.9%] women; 10 629 [55.5%] white) were matched to 19?143 similar untreated patients (mean [SD] age, 54.9 [12.2] years; 10 631 [55.5%] female; 10 654 [55.7%] white). During a median follow-up period of 5.8 years (interquartile range, 2.6-9.0 years), no evidence of an association was found between antihypertensive treatment and mortality (hazard ratio [HR], 1.02; 95% CI, 0.88-1.17) or between antihypertensive treatment and CVD (HR, 1.09; 95% CI, 0.95-1.25). Treatment was associated with an increased risk of adverse events, including hypotension (HR, 1.69; 95% CI, 1.30-2.20; number needed to harm at 10 years [NNH10], 41), syncope (HR, 1.28; 95% CI, 1.10-1.50; NNH10, 35), electrolyte abnormalities (HR, 1.72; 95% CI, 1.12-2.65; NNH10, 111), and acute kidney injury (HR, 1.37; 95% CI, 1.00-1.88; NNH10, 91).Conclusions and Relevance: This prespecified analysis found no evidence to support guideline recommendations that encourage initiation of treatment in patients with low-risk mild hypertension. There was evidence of an increased risk of adverse events, which suggests that physicians should exercise caution when following guidelines that generalize findings from trials conducted in high-risk individuals to those at lower risk.REFERENCE: Sheppard JP et al. Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension. JAMA Intern Med. 2018 Oct 29. doi: 10.1001/jamainternmed.2018.4684.9: HTN (ACC criteria) in those < 40 associated with worse event rates on 18 years of follow upImportance: Little is known regarding the association between level of blood pressure (BP) in young adulthood and cardiovascular disease (CVD) events by middle age.Objective: To assess whether young adults who developed hypertension, defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline, before age 40 years have higher risk for CVD events compared with those who maintained normal BP.Design, Setting, and Participants: Analyses were conducted in the prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) study, started in March 1985. CARDIA enrolled 5115 African American and white participants aged 18 to 30 years from 4 US field centers (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California). Outcomes were available through August 2015.Exposures: Using the highest BP measured from the first examination to the examination closest to, but not after, age 40 years, each participant was categorized as having normal BP (untreated systolic BP [SBP] <120 mm Hg and diastolic BP [DBP] <80 mm Hg; n?=?2574); elevated BP (untreated SBP 120-129 mm Hg and DBP <80 mm Hg; n?=?445); stage 1 hypertension (untreated SBP 130-139 mm Hg or DBP 80-89 mm Hg; n?=?1194); or stage 2 hypertension (SBP ≥140 mm Hg, DBP ≥90 mm Hg, or taking antihypertensive medication; n?=?638). Main Outcomes and Measures: CVD events: fatal and nonfatal coronary heart disease (CHD), heart failure, stroke, transient ischemic attack, or intervention for peripheral artery disease (PAD).Results: The final cohort included 4851 adults (mean age when follow-up for outcomes began, 35.7 years [SD, 3.6]; 2657 women [55%]; 2441 African American [50%]; 206 taking antihypertensive medication [4%]). Over a median follow-up of 18.8 years, 228 incident CVD events occurred (CHD, 109; stroke, 63; heart failure, 48; PAD, 8). CVD incidence rates for normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension were 1.37 (95% CI, 1.07-1.75), 2.74 (95% CI, 1.78-4.20), 3.15 (95% CI, 2.47-4.02), and 8.04 (95% CI, 6.45-10.03) per 1000 person-years, respectively. After multivariable adjustment, hazard ratios for CVD events for elevated BP, stage 1 hypertension, and stage 2 hypertension vs normal BP were 1.67 (95% CI, 1.01-2.77), 1.75 (95% CI, 1.22-2.53), and 3.49 (95% CI, 2.42-5.05), respectively.Conclusions and Relevance: Among young adults, those with elevated blood pressure, stage 1 hypertension, and stage 2 hypertension before age 40 years, as defined by the blood pressure classification in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, had significantly higher risk for subsequent cardiovascular disease events compared with those with normal blood pressure before age 40 years. The ACC/AHA blood pressure classification system may help identify young adults at higher risk for cardiovascular disease events.Reference: Yano Y et al. Association of Blood Pressure Classification in Young Adults Using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline With Cardiovascular Events Later in Life. JAMA. 2018 Nov 6;320(17):1774-1782. Comment in JAMA. 2018 Nov 6;320(17):1760-1763.10. SPRINT Mind Trial: Intensive BP control not assoc with ↓ dementia risk, but did ↓ risk of MCIIMPORTANCE: There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia.OBJECTIVE: To evaluate the effect of intensive blood pressure control on risk of dementia.DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018.INTERVENTIONS: Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n?=?4678) or less than 140 mm Hg (standard treatment group; n?=?4683).MAIN OUTCOMES AND MEASURES: The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia.RESULTS: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97).CONCLUSIONS AND RELEVANCE: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point.REFERENCE: Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019 Jan 28. doi: 10.1001/jama.2018.21442As part of the systematic review supporting the 2015 USPSTF updated BP guidelines, AHRQ concluded that “evidence supports ambulatory blood-pressure monitoring as the reference standard for confirming elevated office blood pressure …?to avoid misdiagnosis and overtreatment,” particularly for persons who have elevated blood pressure as measured in the office but normal ambulatory pressure (“white-coat” hypertension). (Ann Intern Med. 2015 Feb 3;162(3):192-204). Abstract 11 confirms this conclusion and abstract 12 adds a new twist, namely that Automated in Office Blood Pressures (AOBPs) are as accurate as ambulatory measured BPs.Concerning ambulatory blood pressure monitoring (ABPM), and home blood pressure monitoring (HBPM)The USPSTF found convincing evidence that ABPM is the best method for diagnosing hypertension; the USPSTF recommends ABPM as the reference standard for confirming the diagnosis of hypertension.Good-quality evidence suggests that confirmation of hypertension with HBPM may be acceptable. The USPSTF considers ABPM to be the reference standard for confirming the diagnosis of hypertension. However, the USPSTF acknowledges that the use of ABPM may be problematic in some situations. Home blood pressure monitoring using appropriate protocols is an alternative method of confirmation if ABPM is not available.11. Ambulatory BP stronger predictor of adverse outcomes than clinic BP measurementsBACKGROUND: Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population-based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24-hour ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of patients in primary care.METHODS: We analyzed data from a registry-based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24-hour ambulatory blood-pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24-hour ambulatory blood pressure), "white-coat" hypertension (elevated clinic and normal 24-hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24-hour ambulatory blood pressure), and normotension (normal clinic and normal 24-hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24-hour ambulatory blood pressures and for confounders.RESULTS: During a median follow-up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24-hour and clinic measurements, 24-hour systolic pressure was more strongly associated with all-cause mortality (hazard ratio, 1.58 per 1-SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to 1.04, after adjustment for 24-hour blood pressure). Corresponding hazard ratios per 1-SD increase in pressure were 1.55 (95% CI, 1.53 to 1.57, after adjustment for clinic and daytime blood pressures) for nighttime ambulatory systolic pressure and 1.54 (95% CI, 1.52 to 1.56, after adjustment for clinic and nighttime blood pressures) for daytime ambulatory systolic pressure. These relationships were consistent across subgroups of age, sex, and status with respect to obesity, diabetes, cardiovascular disease, and antihypertensive treatment. Masked hypertension was more strongly associated with all-cause mortality (hazard ratio, 2.83; 95% CI, 2.12 to 3.79) than sustained hypertension (hazard ratio, 1.80; 95% CI, 1.41 to 2.31) or white-coat hypertension (hazard ratio, 1.79; 95% CI, 1.38 to 2.32). Results for cardiovascular mortality were similar to those for all-cause mortality.CONCLUSIONS: Ambulatory blood-pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood-pressure measurements. White-coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension. (Funded by the Spanish Society of Hypertension and others.).REFERENCE: Banegas JR et al. Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality. N Engl J Med. 2018 Apr 19;378(16):1509-1520. Comment in: N Engl J Med. 2018 Apr 19;378(16):1555-1556.12. Automated office blood pressure measurements similar to ambulatory BPsIMPORTANCE: Automated office blood pressure (AOBP) measurement involves recording several blood pressure (BP) readings using a fully automated oscillometric sphygmomanometer with the patient resting alone in a quiet place. Although several studies have shown AOBP measurement to be more accurate than routine office BP measurement and not subject to a "white coat effect," the cumulative evidence has not yet been systematically reviewed.OBJECTIVE: To perform a systematic review and meta-analysis to examine the association between AOBP and office BP readings measured in routine clinical practice and in research studies, and ambulatory BP recorded during awake hours, as the latter is a standard for predicting future cardiovascular events.DATA SOURCES: The MEDLINE, Embase, and Cochrane Library were searched from 2003 to April 25, 2018.STUDY SELECTION: Studies on systolic and diastolic BP measurement by AOBP in comparison with awake ambulatory BP, routine office BP, and research BP measurements were included if they contained 30 patients or more.DATA EXTRACTION AND SYNTHESIS: Study characteristics were abstracted independently and random effects meta-analyses and meta-regressions were conducted.MAIN OUTCOMES AND MEASURES: Pooled mean differences (95% CI) of systolic and diastolic BP between types of BP measurement.RESULTS: Data were compiled from 31 articles comprising 9279 participants (4736 men and 4543 women). In samples with systolic AOBP of 130 mm Hg or more, routine office and research systolic BP readings were substantially higher than AOBP readings, with a pooled mean difference of 14.5 mm Hg (95% CI, 11.8-17.2 mm Hg; n=9; I2=94.3%; P<.001) for routine office systolic BP readings and 7.0 mm Hg (95% CI, 4.9-9.1 mm Hg; n=?9; I2=85.7%; P<?.001) for research systolic BP readings. Systolic awake ambulatory BP and AOBP readings were similar, with a pooled mean difference of 0.3 mm Hg (95% CI, -1.1 to 1.7 mm Hg; n=19; I2=90%; P<.001).CONCLUSIONS AND RELEVANCE: Automated office blood pressure readings, only when recorded properly with the patient sitting alone in a quiet place, are more accurate than office BP readings in routine clinical practice and are similar to awake ambulatory BP readings, with mean AOBP being devoid of any white coat effect. There has been some reluctance among physicians to adopt this technique because of uncertainty about its advantages compared with more traditional methods of recording BP during an office visit. Based on the evidence, AOBP should now be the preferred method for recording BP in routine clinical practice.REFERENCE: Roerecke M, et al. Comparing Automated Office Blood Pressure Readings With Other Methods of Blood Pressure Measurement for Identifying Patients With Possible Hypertension: A Systematic Review and Meta-analysis. JAMA Intern Med. 2019 Feb 4An obvious area we can make an impact is de-escalating anti-hypertensive therapy where appropriate. Once area is to review any pharmaceutical changes when patients are discharged from hospital13. Inappropriate intensification of BP treatment upon discharge from the hospitalOBJECTIVES: To assess how often older adults admitted to hospital for common non-cardiac conditions were discharged with intensified antihypertensive treatment, and to identify markers of appropriateness for these intensifications.DESIGN: Retrospective cohort study.SETTING: US Veterans Administration Health System.PARTICIPANTS: Patients aged 65 years or over with hypertension admitted to hospital with non-cardiac conditions between 2011 and 2013.MAIN OUTCOME MEASURES: Intensification of antihypertensive treatment, defined as receiving a new or higher dose antihypertensive agent at discharge compared with drugs used before admission. Hierarchical logistic regression analyses were used to control for characteristics of patients and hospitals.RESULTS: Among 14?915 older adults (median age 76, interquartile range 69-84), 9636 (65%) had well controlled outpatient blood pressure before hospital admission. Overall, 2074 (14%) patients were discharged with intensified antihypertensive treatment, more than half of whom (1082) had well controlled blood pressure before admission. After adjustment for potential confounders, elevated inpatient blood pressure was strongly associated with being discharged on intensified antihypertensive regimens. Among patients with previously well controlled outpatient blood pressure, 8% (95% confidence interval 7% to 9%) of patients without elevated inpatient blood pressure, 24% (21% to 26%) of patients with moderately elevated inpatient blood pressure, and 40% (34% to 46%) of patients with severely elevated inpatient blood pressure were discharged with intensified antihypertensive regimens. No differences were seen in rates of intensification among patients least likely to benefit from tight blood pressure control (limited life expectancy, dementia, or metastatic malignancy), nor in those most likely to benefit (history of myocardial infarction, cerebrovascular disease, or renal disease).CONCLUSIONS: One in seven older adults admitted to hospital for common non-cardiac conditions were discharged with intensified antihypertensive treatment. More than half of intensifications occurred in patients with previously well-controlled outpatient blood pressure. More attention is needed to reduce potentially harmful overtreatment of blood pressure as older adults transition from hospital to home.REFERENCE: TS et al. Intensification of older adults' outpatient blood pressure treatment at hospital discharge: national retrospective cohort study. BMJ. 2018 Sep 12;362:k3503.Bottom LinesThe JNC 8 (published in 2014) recommends treatment for BP when it is > 140/>90 in patients < 60 and>150/>90 in patients over 60.The SPRNT trial demonstrated that in a select group of high-risk hypertensive patients, treating to a BP target of ~ 120/80 is associated with fewer adverse CV event and mortality (NNT ~ 90) but more harm (NNH -=45) and higher medication burden, but did not include diabetics or patients with cerebrovascular diseaseThe AAFP and ACP jointly published a guideline in 2017 essentially endorsing the JNC 8 recommendations of treating a blood pressure of >150/>90 for those over the age of 60The AHA ACC guideline published in late 2017 recommended treatment at a threshold of 130/80 for almost all adult patients (the exception is a treatment threshold of 140/90for lower risk patientsThe AAFP and the ACP have not endorsed the AHA ACC guidelineNeither has the201 European GuidelinesTreating low risk patients with blood pressures of 140-159/90-99 is of uncertain benefitThe SPRINT Mind Trial demonstrated less mild cognitive impairment with intensive BP treatment with no change in dementia riskAutomated office blood pressure measurements correlate well with ambulatory blood pressure measurementsAbout 14% of elderly patients admitted to hospital are discharged with more intensive anti-hypertensive therapyPediatric PotpourriJohn Hickner, MD, MSObjectives1. Describe recent trends in childhood morbidity and mortality 2. Present new evidence regarding of ADHD3. Describe the results of recent studies of various pediatric infections4. Provide an update on recent USPSTF recommendations regarding screening in children and adolescentsWhat are some recent trends in childhood and adolescent mortality and morbidity?After an overall decline in the total death rate for children and adolescents from 1999-2013, we have started to see a reversal of this trend from 2013 onwards. This was due to a rise in injury deaths due to unintentional injuries, suicide and homicide.1. Childhood and adolescent firearm injuriesObjectives: Examine fatal and nonfatal firearm injuries among children aged 0 to 17 in the United States, including intent, demographic characteristics, trends, state-level patterns, and circumstances.Methods: Fatal injuries were examined by using data from the National Vital Statistics System and nonfatal injuries by using data from the National Electronic Injury Surveillance System. Trends from 2002 to 2014 were tested using joinpoint regression analyses. Incident characteristics and circumstances were examined by using data from the National Violent Death Reporting System.Results: Nearly 1300 children die and 5790 are treated for gunshot wounds each year. Boys, older children, and minorities are disproportionately affected. Although unintentional firearm deaths among children declined from 2002 to 2014 and firearm homicides declined from 2007 to 2014, firearm suicides decreased between 2002 and 2007 and then showed a significant upward trend from 2007 to 2014. Rates of firearm homicide among children are higher in many Southern states and parts of the Midwest relative to other parts of the country. Firearm suicides are more dispersed across the United States with some of the highest rates occurring in Western states. Firearm homicides of younger children often occurred in multi-victim events and involved intimate partner or family conflict; older children more often died in the context of crime and violence. Firearm suicides were often precipitated by situational and relationship problems. The shooter playing with a gun was the most common circumstance surrounding unintentional firearm deaths of both younger and older children.Conclusions: Firearm injuries are an important public health problem, contributing substantially to premature death and disability of children. Understanding their nature and impact is a first step toward prevention.Katherine A. Fowler, Linda L. Dahlberg, Tadesse Haileyesus, Carmen Gutierrez, Sarah Bacon, Childhood Firearm Injuries in the United States Pediatrics, June 2017, Vol 140 #4, Pediatrics. 2017 Jul;140(1). pii: e20163486. doi: 10.1542/peds.2016-3486. Epub 2017 Jun 19.From the AAP Policy statement on firearm injuries in children:“The absence of guns from children’s homes and communities is the most reliable and effective measure to prevent firearm-related injuries in children and adolescents. Adolescent suicide risk is strongly associated with firearm availability. Safe gun storage (guns unloaded and locked, ammunition locked separately) reduces children’s risk of injury. Physician counseling of parents about firearm safety appears to be effective, but firearm safety education programs directed at children are ineffective.”2. Childhood secondhand smoke exposure increase the risk of chronic obstructive pulmonary disease death Introduction: Secondhand smoke is known to have adverse effects on the lung and vascular systems in both children and adults. It is unknown if childhood exposure to secondhand smoke is associated with adult mortality.Methods: The authors examined associations of childhood and adult secondhand smoke exposure with death from all causes, ischemic heart disease, stroke, and chronic obstructive pulmonary disease among 70,900 never smoking men and women, predominantly aged ≥50 years, from the Cancer Prevention Study–II Nutrition Cohort in 1992–1993. There were 25,899 participant deaths during follow-up through 2014. During 2016–2017, Cox proportional hazards regression models were used to calculate multivariable-adjusted hazard ratios and 95% CIs.Results: Childhood secondhand smoke exposure was not associated with all-cause mortality. However, childhood secondhand smoke (living with a smoker for 16–18 years during childhood) was associated with higher mortality from chronic obstructive pulmonary disease (hazard ratio=1.31, 95% CI=1.05, 1.65). Adult secondhand smoke exposure of ≥10 hours/week at enrollment was associated with a higher risk of all-cause (hazard ratio=1.09, 95% CI=1.04, 1.14); ischemic heart disease (hazard ratio=1.27, 95% CI=1.14, 1.42); stroke (hazard ratio=1.23, 95% CI=1.04, 1.45); and chronic obstructive pulmonary disease (hazard ratio=1.42, 95% CI=0.97, 2.09) mortality.Conclusions: These results suggest that childhood secondhand smoke exposure, as well as adult secondhand smoke exposure, increase the risk of chronic obstructive pulmonary disease death in adulthood. Consistent with previous studies, the results also show that adult secondhand smoke is meaningfully associated with higher mortality from vascular disease and all causes. Overall, these findings provide further evidence for reducing secondhand smoke exposure throughout life.Diver R, Jacobs EJ, Gapstur SM. Secondhand smoke exposure in childhood and adulthood in relation to adult mortality among never smokers. Am J Prev Med. 2018;55(3):345-352 doi:10.1016/j.amepre.2018.05.005.3. Most children born prematurely survive to early- to mid-adulthood without major comorbiditiesClinical question: Among children born prematurely, what is the prevalence of survival without major comorbidities to adulthood?Study design:?Cohort (retrospective)Funding source:?GovernmentSetting:?Population-basedSynopsis: The prevalence of good health among adults born prematurely is uncertain. These investigators analyzed data obtained from multiple registries in Sweden that record births, deaths, outpatient and inpatient diagnoses, and pharmaceutical prescriptions. The information obtained for all live births (N = 2,574,537) occurring from 1973 to 1997 included gestational age at birth, survival without any major comorbidities (ie, asthma, hypertension, diabetes, kidney disease, mental disorders, cerebral palsy, and epilepsy), birth year, sex, fetal growth, multiple birth, maternal age at delivery, maternal education level, maternal smoking, and hypertensive disorders and diabetes during pregnancy. A total of 149,065 persons (5.8%) were born preterm of whom 94.2% survived to at least 18 years of age. Of the entire cohort, 62.1% were still alive without major comorbidities. Corresponding prevalence by gestational age at birth were 54.6% for all preterm, 22.3% for extremely preterm (22 - 27 weeks'), 48.5% for very preterm (28 - 33 weeks'), 58.0% for late preterm (34 - 36 weeks'), 61.2% for early term (37 - 38), and 63% for full-term. The most common comorbidity in the entire cohort was asthma. A co-sibling analysis to control for unmeasured shared familial factors did not change the results. Similarly, adjustments for other comorbidities had little effect on the reported findings.Bottom line: This study found that children born prematurely (see Synopsis) between 1973 and 1997 survived to early- to mid-adulthood without major comorbidities at nearly similar rates to those born near-term and full-term. Outcomes were worse, however, for those born extremely preterm (22 to 27 weeks' gestation).?(LOE = 1b)Crump C, Winkleby MA, Sundquist J, Sundquist K. Prevalence of survival without major comorbidities among adults born prematurely. JAMA 2019;322(16):1580-1588.ADD/ADHDADHD is the most common neurobehavioral condition in children and among the most prevalent chronic health conditions that affect school-aged children.4. Increasing digital media use is associated with ADHDClinical question: Is frequent use of digital media associated with the development of attention-deficit/hyperactivity disorder symptoms in high school students?Study design: Cohort (prospective)Funding source: GovernmentSetting: Population-basedSynopsis: These investigators analyzed data obtained from a longitudinal cohort survey of adolescents enrolled in 10 high schools in the Los Angeles, California, area. Beginning in the fall of 10th grade, eligible students (n = 2587) initially classified as not having ADHD symptoms based on a previously validated evaluation tool, provided follow-up self-reported symptom scores at 6, 18, and 24 months. At baseline and at 12 and 24 months students also indicated how frequently they engaged in various digital media activities in the past week (0, 1 - 2 times per week, 1 - 2 times per day, or many times per day). The authors performed various analyses to address potential confounders, including age, sex, family income, history of delinquent behavior, race/ethnicity, depressive symptoms, substance use, and family history of substance use. More than half (54.1%) of the students reported high frequency of checking social media, which was the most common media activity. High frequency engagement in digital media activity at baseline was significantly associated with a higher odds of reporting symptoms of ADHD at follow-up (odds ratio 1.10; 95% CI 1.05 - 1.15). In addition, the mean rate of having ADHD symptoms at follow-up was significantly increased among the 51 students who reported 14 high-frequency media use activities and the 114 students who reported 7 high-frequency media use activities at baseline compared with the 495 students who reported no high-frequency media use over the preceding week (10.5% and 9.5% vs 4.6%, respectively).Bottom line: High school students who reported a high frequency (many times per day) of digital media use (eg, social networking, streaming movies or music, texting) were significantly more likely to self-report symptoms of attention-deficit/hyperactivity disorder (ADHD) over 2 years of follow-up (10% higher symptom reporting rate). It remains uncertain whether the association is causal and whether efforts to reduce exposure can result in less symptom development. (LOE = 1b)Ra CK, Cho J, Stone MD, et al. Association of digital media use with subsequent symptoms of attention-deficit/hyperactivity disorder among adolescents. JAMA 2018;320(3):255-263.5. The Mediterranean diet may play a role in managing ADHDObjectives: Although attention-deficit/hyperactivity disorder (ADHD) has been related to nutrient deficiencies and “unhealthy” diets, to date there are no studies that examined the relationship between the Mediterranean diet and ADHD. We hypothesized that a low adherence to a Mediterranean diet would be positively associated with an increase in ADHD diagnosis. Methods: A total of 120 children and adolescents (60 with newly diagnosed ADHD and 60 controls) were studied in a sex- and age-matched case-control study. ADHD diagnosis was made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Energy, dietary intake, adherence to a Mediterranean diet, and familial background were measured. Logistic regression was used to determine associations between the adherence to a Mediterranean diet and ADHD. Results: Lower adherence to a Mediterranean diet was associated with ADHD diagnosis (odds ratio: 7.07; 95% confidence interval: 2.65–18.84; relative risk: 2.80; 95% confidence interval: 1.54–5.25). Both remained significant after adjusting for potential confounders. The lower frequency of consuming fruit, vegetables, pasta, and rice and higher frequency of skipping breakfast and eating at fast-food restaurants were associated with ADHD diagnosis (P < .05). High consumption of sugar, candy, cola beverages, and noncola soft drinks (P < .01) and low consumption of fatty fish (P < .05) were also associated with a higher prevalence of ADHD diagnosis. Conclusions: Although these cross-sectional associations do not establish causality, they raise the question of whether low adherence to a Mediterranean diet might play a role in ADHD development. Our data support the notion that not only “specific nutrients” but also the “whole diet” should be considered in ADHD.Alejandra Ríos-Hernández, José A. Alda, Andreu Farran-Codina, Estrella Ferreira-García, Maria Izquierdo-Pulido, The Mediterranean Diet and ADHD in Children and Adolescents, Pediatrics, January 20176. 2019 guidelines for ADHD: structure plus medicationClinical question: What are the recommendations from the American Academy of Pediatrics for the evaluation and treatment of attention-deficit/hyperactivity disorder?Study design:?Practice guidelineFunding source:?FoundationSetting:?Various (guideline)Synopsis: The AAP's 2019 guideline for the evaluation and treatment of attention-deficit/hyperactivity disorder is largely the same as previous versions of the guideline. Evaluation can begin as early as age 4 years in children who present with inattention, hyperactivity, or impulsivity resulting in behavioral or academic problems. Diagnosis should take into account symptoms, along with evidence of social, academic, or occupational impairment, and other causes should be excluded. Preschool children should be treated with parent training in behavior management (strong recommendation); treatment with?methylphenidate should be considered if training is not effective or is unavailable, weighing harms with benefits. Medication along with classroom interventions and parent training should be used for elementary school children. Adolescents should also be treated with a stimulant, behavior interventions, and school-based individualized education plans. The authors cite too little evidence to recommend mindfulness, cognitive training, diet modification, electroencephalogram biofeedback, supportive counseling, or cannabidiol oil. They do not provide guidance regarding what stimulant or nonstimulant medication to use first, though they cite evidence to suggest that stimulants may be more effective. An extensive list of medications is at . These guidelines were developed by an expert group composed of pediatricians, pediatric psychologists, pediatric psychiatrists, a family physician, and epidemiologists, with feedback from a patient group. The recommendations seem to be based on a systematic review, with the evidence graded and the recommendations ranked by strength. The guideline developers compared benefits and harms of treatments when making their recommendations. A number of the developers, including the workgroup chair, have financial conflicts of interests.Bottom line: The American Academy of Pediatrics (AAP) continues to recommend evaluation and treatment of children between the ages of 4 years and 18 years with inattention, hyperactivity, or impulsivity resulting in behavioral or academic problems. Specific parent training in behavior management is first-line treatment for preschoolers, but medication along with modifications at home and at school (see synopsis) are crucial. The AAP does not recommend diet modification, cognitive training, or the new kid on the block, cannabidiol oil.?(LOE = 5)Wolraich ML, Hagan JF, Allan C, et al, for the Subcommittee on Children and Adolescents with Attention-Deficit/Hyperactive Disorder. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics 2019;144(4):e20192528.Pediatric ENT and Infections7. Clinical suspicion is not an effective way to diagnose Lyme DiseaseClinical question: In children, how accurate is the clinical suspicion for Lyme disease in areas of high prevalence?Study design: Cohort (prospective)Funding source: FoundationSetting: Emergency departmentSynopsis: The researchers assembled a convenience sample of children, 1 year and older, who underwent evaluation for Lyme disease at 1 of 5 hospital emergency departments in endemic areas, mostly on the east coast of the United States (one site was in Wisconsin). The children were evaluated by clinicians who had received training on the diagnosis of Lyme disease. The diagnostic criterion was a single characteristic lesion of at least 5 cm in diameter with or without central clearing, or a single smaller but enlarging lesion associated with a known or suspected tick bite with a known interval between the bite and the onset of the lesion. Lyme disease was confirmed in was 23% of the 1021 children via either a positive 2-tiered serology result within 30 days of presentation (82.4% of diagnoses) or a physician-diagnosed erythema migrans lesion at the time of presentation. Clinician suspicion in cases without clear erythema migrans was "minimally accurate" in either ruling in or ruling out Lyme disease (concordance statistic = .75; 95% CI .71 to .79). Of the 554 (54%) thought to be unlikely to have Lyme disease, 12% had a positive laboratory diagnosis, and 39 (31%) of the 127 children deemed to be very likely to have Lyme disease by clinicians did not have Lyme disease.Bottom line: For children with suspected Lyme disease but without a classic bull's-eye lesion (erythema migrans of at least 5 cm), check serology rather than rely on your clinical impression. In this study, 12% of the children not suspected of having Lyme disease did have Lyme, and 31% of children thought to have Lyme disease did not have serologic findings either at that time or within 30 days. Nigrovic LE, Bennett JE, Balamuth F, et al, for Pedi Lyme Net. Accuracy of clinician suspicion of Lyme disease in the emergency department. Pediatrics 2017;140(6):e20171975.8. Use narrow spectrum antibiotics to treat children with acute respiratory tract infections rather than broad spectrum antibiotics; they have less adverse eventsClinical question: Are broad-spectrum antibiotics the preferred treatment in children with acute respiratory tract infections?Study design: Cohort (retrospective)Funding source: GovernmentSetting: Population-basedSynopsis: These investigators collected data both retrospectively and prospectively from a network of pediatric primary care practices on outcomes of infants and children, aged 6 months to 12 years, who met international standards for the diagnosis of acute respiratory tract infection, including otitis media, group A streptococcal pharyngitis, and sinusitis. Exclusion criteria included not receiving a prescription for an oral antibiotic, antibiotic use in the last 30 days, and being younger than 3 years with a diagnosis of group A streptococcal pharyngitis. The children who were prescribed broad-spectrum antibiotics, including amoxicillin-clavulanate, cephalosporins, and macrolides, were defined as exposed; children who were prescribed narrow-spectrum antibiotics, including penicillin and amoxicillin, were defined as unexposed. The authors do not specifically state whether the individuals who assessed outcomes remained masked to group assignments. Of the 30,159 children in the retrospective cohort that met inclusion criteria with complete data, 4307 (14%) were prescribed broad-spectrum antibiotics. Broad-spectrum antibiotic use was not significantly associated with a lower rate of treatment failure compared with narrow-spectrum antibiotics (3.4% vs 3.1%, respectively). Similarly broad-spectrum antibiotics were not associated with a clinically significant difference in quality of life scores compared with narrow-spectrum antibiotics. However, broad-spectrum antibiotics were significantly associated with a higher risk of reported adverse events compared with narrow-spectrum antibiotics (3.7% vs 2.7%, respectively, as documented by clinicians, and 35.6% vs 25.1%, respectively, as documented by the parents and/or patients). Adverse events included diarrhea, candidiasis, rash, other unspecified allergic reactions, and vomiting.Bottom line: Broad-spectrum antibiotics are no more effective than narrow-spectrum antibiotics for treating acute respiratory tract infections in infants and children, and adverse events are significantly more common in children treated with broad-spectrum antibiotics.Gerber JS, Ross RK, Bryan M, et al. Association of broad- vs narrow-spectrum antibiotics with treatment failure, adverse events, and quality of life in children with acute respiratory tract infections. JAMA 2017;318(23):2325-2336.9. Surgical removal of tonsils and adenoids was associated with increased risk of respiratory, infectious and allergic diseasesQuestion: Are there long-term health risks after having adenoids or tonsils removed in childhood?Findings: In this population-based cohort study of almost 1.2 million children, removal of adenoids or tonsils in childhood was associated with significantly increased relative risk of later respiratory, allergic, and infectious diseases. Increases in long-term absolute disease risks were considerably larger than changes in risk for the disorders these surgeries aim to treat.Meaning: The long-term risks of these surgeries deserve careful consideration.Importance: Surgical removal of adenoids and tonsils to treat obstructed breathing or recurrent middle-ear infections remain common pediatric procedures; however, little is known about their long-term health consequences despite the fact that these lymphatic organs play important roles in the development and function of the immune system.Objective: To estimate long-term disease risks associated with adenoidectomy, tonsillectomy, and adenotonsillectomy in childhood.Design, Setting, and Participants: A population-based cohort study of up to 1?189?061 children born in Denmark between 1979 and 1999 and evaluated in linked national registers up to 2009, covering at least the first 10 and up to 30 years of their life, was carried out. Participants in the case and control groups were selected such that their health did not differ significantly prior to surgery.Exposures: Participants were classified as exposed if adenoids or tonsils were removed within the first 9 years of life.Main Outcomes and Measures: The incidence of disease (defined by International Classification of Diseases, Eighth Revision [ICD-8] and Tenth Revision [ICD-10] diagnoses) up to age 30 years was examined using stratified Cox proportional hazard regressions that adjusted for 18 covariates, including parental disease history, pregnancy complications, birth weight, Apgar score, sex, socioeconomic markers, and region of Denmark born.Results: A total of up to 1?189?061 children were included in this study (48% female); 17?460 underwent adenoidectomy, 11?830 tonsillectomy, and 31?377 adenotonsillectomy; 1?157?684 were in the control group. Adenoidectomy and tonsillectomy were associated with a 2- to 3-fold increase in diseases of the upper respiratory tract (relative risk [RR], 1.99; 95% CI, 1.51-2.63 and RR, 2.72; 95% CI, 1.54-4.80; respectively). Smaller increases in risks for infectious and allergic diseases were also found: adenotonsillectomy was associated with a 17% increased risk of infectious diseases (RR, 1.17; 95% CI, 1.10-1.25) corresponding to an absolute risk increase of 2.14% because these diseases are relatively common (12%) in the population. In contrast, the long-term risks for conditions that these surgeries aim to treat often did not differ significantly and were sometimes lower or higher.Conclusions and Relevance: In this study of almost 1.2 million children, of whom 17?460 had adenoidectomy, 11?830 tonsillectomy, and 31?377 adenotonsillectomy, surgeries were associated with increased long-term risks of respiratory, infectious, and allergic diseases. Although rigorous controls for confounding were used where such data were available, it is possible these effects could not be fully accounted for. Our results suggest it is important to consider long-term risks when making decisions to perform tonsillectomy or adenoidectomy.Byars SG, Stearns SC, Boomsma JJ. Association of Long-Term Risk of Respiratory, Allergic, and Infectious Diseases with Removal of Adenoids and Tonsils in Childhood. JAMA Otolaryngol Head Neck Surg 2018; 144:594.10. Tubes ineffective in treating otitis media in childrenClinical question: In children with recurrent otitis media or chronic effusion, do tympanostomy tubes decrease further episodes, improve hearing, or improve language acquisition?Study design: Meta-analysis (other)Funding source: GovernmentSetting: Various (meta-analysis)Synopsis: These researchers searched 4 databases, including Cochrane CENTRAL, to find randomized controlled trials and other comparative research studies that evaluated the effectiveness of tympanostomy tubes. They included research written in any language. Citations were selected by 2 independent researchers. Study details were abstracted by one researcher and checked by a second researcher. In 16 randomized controlled trials of treating children with otitis media with effusion, the insertion of tubes with or without adenoidectomy decreased (improved) hearing threshold within the first 1 month to 3 months by an average 9.1 dB to 10.0 dB as compared with no treatment. However, there was no effect on hearing thresholds at 12 months to 24 months for tympanostomy alone or combined with adenoidectomy, prophylactic antibiotic treatment, or myringotomy as compared with no treatment. Overall, there was no effect on cognitive, language, and behavioral outcomes. In 3 small studies of children with recurrent acute otitis media the effect of tympanostomy tubes was inconsistent regarding recurrences. This analysis was a Bayesian network analysis, a statistical approach that still has some kinks in it, and the study report itself was somewhat incomplete, as is the evidence base for this common intervention.Bottom line: Tympanostomy tubes, with or without other interventions, do not produce sustained improved hearing as compared with no treatment, and has not been shown to improve language acquisition, cognitive development, or behavior measures. There might be a small reduction in the recurrence of acute otitis media, but there is little research in this area. Another study of tubes found no long-term (6 years to 9 years) benefit on development (N Engl J Med 2007;356:248-261). (LOE = 1a-)Steele DW, Adam GP, Di M, Halladay CW, Balk EM, Trikalinos TA. Effectiveness of tympanostomy tubes for otitis media: a meta-analysis. Pediatrics 2017;139(6):e2017012511. Oral prednisolone = placebo in children with otitis media with effusion (OSTRICH)Clinical question: Are corticosteroids more effective than placebo in the resolution of otitis media with effusion (OME) and in restoring hearing in children with OME with hearing loss?Study design:?Randomized controlled trial (double-blinded)Funding source:?GovernmentAllocation:?ConcealedSetting:?Outpatient (specialty)Synopsis: These authors randomized children with OME and hearing loss for at least 3 months to receive 7 days of oral?prednisolone?(20 mg/day for children 2 to 5 years of age; 30 mg/day for children 6 to 8 years of age; n = 193) or matching placebo (n = 187). The children had at least 20 dB loss in any of the typical speech frequencies (0.5 - 4 KHz). The researchers reassessed the children's hearing 4 weeks after completing treatment, and then again at 6 months and 12 months. Although more than one-third of the children had meaningful improvement in hearing, at the end of each follow-up interval, the researchers found no statistically significant differences between the treatment groups. There was also no difference in the use of tympanostomy tubes. Approximately 1 in 8 of the children in each group did not complete the 1-year follow up. Only one child experienced an adverse event related to treatment.Bottom line: In this study, children with OME and hearing loss treated with steroids experienced no significant improvement in hearing compared with placebo-treated children.?(LOE = 1b)Francis NA, Cannings-John R, Waldron CA, et al. Oral steroids for resolution of otitis media with effusion in children (OSTRICH): a double-blinded, placebo-controlled randomised trial. Lancet 2018;392(10147):557-568.12. Optimum time for probing lacrimal ductsClinical question: When is the optimal time to intervene with probing for unresolved congenital nasolacrimal duct obstruction?Study design:?Cohort (prospective)Funding source:?FoundationSetting:?Outpatient (specialty)Synopsis: CNLDO is common, occurring in approximately 1 in 9 newborns. These investigators reviewed medical records of 1998 consecutive children, younger than 5 years, who were given a diagnosis of CNLDO while residing in Olmsted County, Minnesota, from January 1, 1995, through December 31, 2004. Among these children, CNLDO spontaneously resolved in 83.5%, with 14.5% requiring surgical treatment and 2.0% lost to follow-up. The median age at resolution was 2.4 months, with the rate of spontaneous resolution highest in the first few months of life and declining until age 9 months when the rate of resolution reached a plateau. Of the patients who underwent surgical intervention with probing, children aged 15 months or older had a decreased odds of resolution compared with children aged 12 to 14 months (odds ratio 0.11; 95% CI 0.01 - 0.89). No difference in probing success rate occurred, however, when patients younger than 9 months and aged 9 to 11 months were compared with patients aged 12 to 14 months.Bottom line: The rate of spontaneous resolution of congenital nasolacrimal duct obstruction (CNLDO) is highest in the first 4 months to 6 months of age, with plateauing of resolution after 9 months of age. Surgical probing appears to be optimal at approximately 12 months of age, after the CNLDO has had time to resolve on its own but before surgical success rates begin to decline (after age 15 months).?(LOE = 1b)Sathiamoorthi S, Frank RD, Mohney BG. Spontaneous resolution and timing of intervention in congenital nasolacrimal duct obstruction. JAMA Ophthalmol 2018;136(11):1281-1286.13. It takes up to 3 weeks for 90% of respiratory infections to resolve in kidsClinical question: How long do colds last in children?Study design:?Cohort (prospective)Funding source:?GovernmentSetting:?Population-basedSynopsis: These researchers from the United Kingdom enrolled a cohort of 485 generally healthy children aged between 3 months and 15 years from February to July 2016. They recruited patients from the enrollment lists of practices located within 10 miles of Bristol. They excluded immunocompromised children and those with terminal illnesses. If the child had a respiratory illness, the researchers asked the parents to start the cohort once the symptoms resolved. Each week, the researchers sent an e-mail or text message asking whether the child had specific respiratory tract symptoms, such as rhinorrhea, earache, sore throat, or cough. If the child had any of these symptoms, the researchers asked the parent to provide daily online updates. They also asked the parents about missed school, medication use, consultations, and so forth. Based on the patient lists from the participating practices, participating children tended to be 2 years younger and less socioeconomically deprived than the nonparticipating children. During 5 months of follow up, parents reported 346 new respiratory infections in 259 children—53% of children had at least one new respiratory infection; the attack rate was 71% and afflicted kids averaged 1.3 infections during this short interval. The researchers report on 197 children's first illness. The median duration of illness was 9 days, but this is a skewed distribution with a long tail: It took 23 days for 90% of the children to recover. Approximately half the parents reported symptoms associated with lower respiratory infections and the presence of these symptoms was associated with longer duration. Sniffles tended to last, while earaches were of the shortest duration. Dry cough was most severe for the first 10 days, but also persisted for about 3 weeks. The parents had primary care consultations (office or telephone encounters) only 8% of the time, and only 9% of infections caused a missed day of school. As one might expect, the severity of symptoms was worse among those kids. Since a healthy chunk of the study period occurred in spring and summer, these numbers might be worse during fall and winter months.Bottom line: Most respiratory illnesses in children are mild and don't result in seeking medical care or missing school, but they can last as long as 3 weeks.?(LOE = 1b-)Hay AD, Anderson E, Ingle S, Beck C, Hollingworth W. Respiratory tract infections in children in the community: prospective online inception cohort study. Ann Fam Med 2019;17(1):14-22.Screening14. Screening for child abuse gets an “I” rating from the USPSTFClinical question: Should primary care clinicians screen for child maltreatment in otherwise healthy-appearing children and adolescents?Study design:?Practice guidelineFunding source:?GovernmentSetting:?Population-basedSynopsis: In this 2018 update, the task force found insufficient evidence to support the use of an assessment instrument for identifying children at risk of maltreatment. In addition, the task force found limited and inconsistent evidence of the benefits of interventions to prevent child maltreatment, including reports to child protective services and removal of the child from the home. No studies showed evidence of any harms associated with interventions to prevent child maltreatment. The American Academy of Family Physicians and the American Academy of Pediatrics do not specifically recommend primary interventions to prevent child maltreatment.Bottom line: In this updated 2018 review, the US Preventive Services Task Force (USPSTF) concludes there is insufficient evidence to assess the balance of benefits and harms of screening for child maltreatment (abuse and neglect) in otherwise healthy-appearing children and adolescents (I statement). These recommendations are essentially unchanged from the 2013 USPSTF recommendations.?(LOE = 2c)US Preventive Services Task Force. Interventions to prevent child maltreatment. US Preventive Services Task Force recommendation statement. JAMA 2018;320(20):2122-2128.15. “I” recommendation for scoliosis screening from USPSTFClinical question: Should primary care clinicians screen for adolescent idiopathic scoliosis in children and adolescents aged 10 years to 18 years?Study design:?Practice guidelineFunding source:?GovernmentSetting:?Population-basedSynopsis: In this updated review the USPSTF evaluated current evidence assessing the accuracy of screening tests, and the benefits and harms of screening and treatment for asymptomatic AIS in children and adolescents aged 10 to 18 years. The prevalence of AIS in this age group is 1% to 3%. No eligible randomized clinical trials directly compared screening with no screening. Currently available screening tests can accurately detect AIS. The task force found adequate evidence that treatment with bracing may decrease curvature progression, but no high-quality studies of bracing have evaluated long-term patient-oriented outcomes such as back pain, pulmonary disorders, or quality of life. Inadequate evidence found minimal, if any, benefit to exercise. No studies that evaluated surgery were found. Potential harms of screening include psychosocial issues due to labeling and anxiety (eg, overtreatment with bracing), unnecessary referrals due to false-positive results, and the potential risk of radiation exposure. Overall, the task force considered the potential harms of screening and subsequent treatment as minimal. The American Academy of Pediatrics and the American Academy of Orthopedic Surgeons recommend screening for scoliosis twice in girls, at 10 years and 12 years of age, and once in boys at 13 or 14 years of age.Bottom line: The United States Preventive Services Task Force (USPSTF) concludes that current evidence is insufficient to recommend for or against screening for adolescent idiopathic scoliosis (AIS) in asymptomatic children and adolescents aged 10 years to 18 years (I recommendation). This updated recommendation is a change from the previous recommendation in 2004 (D recommendation).?(LOE = 2b)US Preventive Services Task Force, Grossman DC, Curry SJ, et al. Screening for adolescent idiopathic scoliosis. US Preventive Services Task Force recommendation statement. JAMA 2018;319(2):165-172.16. Most infants with hip clicks do not have hip dysplasiaClinical question: How common is hip dysplasia in infants who are referred for the evaluation of clicky hips?Study design:?Cross-sectionalFunding source:?Unknown/not statedSetting:?Outpatient (specialty)Synopsis: These authors from the United Kingdom report the outcomes of 362 infants referred over a 20-year period for the evaluation of "clicky" hips (I love this expression—it could have come from an episode of Doctor Who). Each infant underwent clinical and sonographic assessments. The authors don't describe any paired independent assessments or other measures that would give me great trust in their methodology. The infants were 14 weeks of age on average and two thirds were female. Nearly all (97%) of the infants had normal hips. A few children had mild abnormalities that resolved spontaneously on follow up. Only 2 children had moderate dysplasia or an irreducible dislocation. Finally, the few children with true dysplasia had unilateral limited abduction.Bottom line: Most infants with a hip click but normal results on the Ortolani test and Barlow maneuver do not have hip dysplasia.?(LOE = 3b)Nie K, Rymaruk S, Paton RW. Clicky hip alone is not a true risk factor for developmental dysplasia of the hip. Bone Joint J 2017;99-B(11):1533-1536.17. Brief alcohol interventions for adolescents in primary care settings can result in clinically important changes in alcohol-related outcomesObjective: To systematically describe when and how brief alcohol interventions delivered to adolescents in primary care settings reduce alcohol use and alcohol-related consequences among adolescents, using realist review methodology.Study Design: Eleven electronic databases, gray literature, and reference screening were searched up to June 2016; 11 brief interventions published in 13 studies met inclusion criteria. Intervention design components (delivery context and intervention mechanisms) underlying brief alcohol interventions for adolescents were extracted and linked to alcohol use and related consequences.Results: Brief interventions had either an indicated context of delivery (provided to adolescent patients with low-to-moderate risk for alcohol problems) or universal context of delivery (provided to general adolescent patient population). Interventions that used motivational interviewing in an indicated delivery context had 2 potential mechanisms-eliciting and strengthening motivation to change and providing direction through interpretation. These interventions resulted in clinically significant reductions in alcohol use and associated consequences. Peer risk also was identified among universal and indicated brief interventions as a potential mechanism for changing alcohol-related outcomes among adolescents who received the intervention. None of the studies tested the processes by which interventions were expected to work.Conclusions: The current evidence base suggests that both indicated and universal delivery of brief alcohol interventions to adolescents in primary care settings can result in clinically important changes in alcohol-related outcomes. Studies that test brief intervention processes are now necessary to better understand how brief interventions work with adolescents in primary care settings.Newton AS, Mushquash C, Krank M, Wild TC, Dyson MP, Hartling L, & Stewart SH. (2018). When and how do brief alcohol interventions in primary care reduce alcohol use and alcohol-related consequences among adolescents? Journal of Pediatrics. J Pediatr. 2018 Jun;197:221-232.e2. doi: 10.1016/j.jpeds.2018.02.002. Epub 2018 Apr 12.Refer to the NIH-Alcohol screening and brief intervention for youth at the end of this chapter, a practical guide for two questions that a practitioner should ask to address alcohol usage in children.Bottom LinesAsk about alcohol use, second hand smoke exposure, and firearms in the house during routine well-child visits. Get specific and provide counseling.Use a behavioral approach (structured environment) and medication when needed for childhood ADHD.Limiting screen time in adolescents may reduce ADHD prevalence.Choose narrow spectrum antibiotics for acute respiratory tract infections.Don’t use prednisone for otitis media with effusion.Exhaust non-surgical options before considering tonsillectomy/adenoidectomy and PE tubes.12 months of age is the optimal time for probing blocked nasolacrimal ducts.Most infants with hip clicks do not have hip dysplasia.It can take a long time for acute respiratory infection symptoms to resolve. Brief Screening instrument for youth alcohol use Ferenchick, MD, MSLearning objectives: Understand and apply:The emerging data on SGLT2 inhibitors and GLP-1 receptor agonists.2019 ADA and AHA/ACC guidelines emphasizing their enhanced role in managing diabetics with established vascular disease, renal disease and heart failure Other 2019 ADA Standards Certain sodium-glucose cotransporter 2 inhibitors (SGLTi's) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) have shown significant reductions in the risk of major adverse cardiovascular events (MACE) ...unrelated to the direct glucose-lowering effects of these agents. (ACC AHA)SGLT2 receptor exists in the proximal tubule of the kidney and is responsible for ~ 90% of urinary glucose reabsorption. Inhibiting SGLT2 produces a glycosuria → plasma glucose loweringGLP-1 is a GI hormone released after oral nutrient intake → enhanced insulin secretion and decreased glucagon secretion. GLP-1 receptor agonists represent incretin-based therapy (Intestinal Secretion of Insulin). DPP-IV inhibitors are also incretin-based therapies Sodium-glucose cotransporter 2 inhibitors (SGLTi's) & glucagon-like peptide 1 receptor agonists (GLP-1RAs)# 1: RCT | Empagliflozin (Jardiance?) is associated with ↓ CV events & all-cause mortality in DM-IIBACKGROUND: The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.METHODS: We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina.RESULTS: A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.CONCLUSIONS: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME number, NCT01131676.).REFERENCE: Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17. PMID: 26378978 [PubMed - indexed for MEDLINE]# 2: RCT | Canaglofozin (Invokana?)) is associated with ↓ CV events & higher risk of amputationBackground Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R numbers, NCT01032629 and NCT01989754, respectively.).Reference: Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657.#3: Systematic Review | SGLT2i decrease ASCVD events in pts with preexisting ASCVDBACKGROUND: The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined.METHODS: We did a systematic review and meta-analysis of randomised,placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function.FINDINGS: We included data from three identified trials and 34?322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisations for heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83-0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80-0·93]) and not in those without (1·00 [0·87-1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71-0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48-0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline.INTERPRETATION: SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.REFERENCE: Zelniker TA et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2018 Nov 9. pii: S0140-6736(18)32590-X.#4: International registry | SGLT-2i associated with a lower risk of CV eventsBACKGROUND: Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe.OBJECTIVES: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions.METHODS: New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis.RESULTS: After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ～27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95%?confidence interval [CI]: 0.37 to 0.70; p?< 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p?=?0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p?< 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p?< 0.001), and stroke (HR: 0.68; 95%?CI: 0.55 to 0.84; p?< 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease.CONCLUSIONS: In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614).REFERENCE: Kosiborod M et al for the CVD-REAL Investigators and Study Group.Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018 Jun 12;71(23):2628-2639.According to the ACC/AHA "To date, empagliflozin is the only SGLT2 inhibitor specifically approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of CV death in adults with T2D and established CV disease"#5: RCT | Liraglutide (Victoza?) decreases cardiovascular events and all-cause mortality in DM-IIBACKGROUND: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.METHODS: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes.RESULTS: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER number, NCT01179048.).REFERENCE: Marso SP, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. Comment in: N Engl J Med. 2016 Jul 28;375(4):380-2. #6: RCT | Semaglutide decreases cardiovascular death, MI and CVA in DM-IIBackground Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. Methods We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. Results At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.Conclusions In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 number,NCT01720446 .).Reference: Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844.According to the ACC/AHA “Of the 6 FDA-approved GLP-1RAs, to date only liraglutide has been definitively demonstrated to significantly reduce CV events”#7: Network Meta-analysis| SGLT-2i or GLP-1 agonists associated with lower mortalityImportance: The comparative clinical efficacy of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors for treatment of type 2 diabetes is unknown.Objective: To compare the efficacies of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors on mortality and cardiovascular end points using network meta-analysis.Data Sources: MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, and published meta-analyses from inception through October 11, 2017.Study Selection: Randomized clinical trials enrolling participants with type 2 diabetes and a follow-up of at least 12 weeks were included, for which SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors were compared with either each other or placebo or no treatment.Data Extraction and Synthesis: Data were screened by 1 investigator and extracted in duplicate by 2 investigators. A Bayesian hierarchical network meta-analysis was performed.Main Outcomes and Measures: The primary outcome: all-cause mortality; secondary outcomes: cardiovascular (CV) mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke; safety end points: adverse events and hypoglycemia.Results: This network meta-analysis of 236 trials randomizing 176?310 participants found SGLT-2 inhibitors (absolute risk difference [RD], -1.0%; hazard ratio [HR], 0.80 [95% credible interval {CrI}, 0.71 to 0.89]) and GLP-1 agonists (absolute RD, -0.6%; HR, 0.88 [95% CrI, 0.81 to 0.94]) were associated with significantly lower all-cause mortality than the control groups. SGLT-2 inhibitors (absolute RD, -0.9%; HR, 0.78 [95% CrI, 0.68 to 0.90]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.86 [95% CrI, 0.77 to 0.96]) were associated with lower mortality than were DPP-4 inhibitors. DPP-4 inhibitors were not significantly associated with lower all-cause mortality (absolute RD, 0.1%; HR, 1.02 [95% CrI, 0.94 to 1.11]) than were the control groups. SGLT-2 inhibitors (absolute RD, -0.8%; HR, 0.79 [95% CrI, 0.69 to 0.91]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.85 [95% CrI, 0.77 to 0.94]) were significantlyassociated with lower CV mortality than were the control groups. SGLT-2 inhibitors were significantly associated with lower rates of HF events (absolute RD, -1.1%; HR, 0.62 [95% CrI, 0.54 to 0.72]) and MI (absolute RD, -0.6%; HR, 0.86 [95% CrI, 0.77 to 0.97]) than were the control groups. GLP-1 agonists were associated with a higher risk of adverse events leading to trial withdrawal than were SGLT-2 inhibitors (absolute RD, 5.8%; HR, 1.80 [95% CrI, 1.44 to 2.25]) and DPP-4 inhibitors (absolute RD, 3.1%; HR, 1.93 [95% CrI, 1.59 to 2.35]).Conclusions and Relevance: In this network meta-analysis, the use of SGLT-2 inhibitors or GLP-1 agonists was associated with lower mortality than DPP-4 inhibitors or placebo or no treatment. Use of DPP-4 inhibitors was not associated with lower mortality than placebo or no treatment.REFERENCE: Zheng SL et al. Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA. 2018 Apr 17;319(15):1580-1591.ADA Standards 2019Given all of this, there have been some relatively substantial changes in the 2019 ADA Standard of Care in Diabetes. These are summarized in the following section.#8: ADA | 2019 Standards on the pharmacological approaches to treatmentThe American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction Readers who wish to comment on the Standards of Care are invited to do so at professional.SOC.REFERENCE: American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care 2019 Jan; 42(Supplement 1): S90-S102My key take away points (directly quoted) from the 219 ADA Standards of Medical Care in Diabetes – 2019” Metformin“Metformin should be started at the time type 2 diabetes is diagnosed unless there are contraindications, for most patients this will be monotherapy in combination with lifestyle modifications”“The FDA has revised the label for metformin to reflect its safety in patients with eGFR > 30 mL/min/1.73 m2.”"... metformin use is associated with vitamin B12 deficiency" ..."biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin treated patients"Combo TherapyInsulin “Insulin should be considered as part of any combination regimen when hyperglycemia is severe.”“Consider initiating insulin therapy when blood glucose is >300 mg/dL or A1C is >10% or if the patient has symptoms of hyperglycemia (i.e., polyuria or polydipsia), even at diagnosis or early in the course of treatment.“As glucose toxicity resolves, simplifying the regimen and/or changing to oral agents is often possible.”Non-insulin therapies | No ASCVD, CKD or HF"Each new class of noninsulin agents added to initial therapy generally lowers A1C approximately 0.7–1.0%.""...after approximately 3 months … consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, dipeptidyl peptidase 4 (DPP-4) inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin;""The choice of a second agent to add to metformin is not yet guided by empiric evidence. Rather, drug choice is based on avoidance of side effects, particularly hypoglycemia and weight gain, cost, and patient preferences"Non-insulin therapies | AND ASCVD, CKD or HFClinically evident atherosclerotic CVD is defined as history of an acute coronary syndrome or myocardial infarction; stable or unstable angina; coronary heart disease with or without revascularization; and other arterial revascularization, stroke, or peripheral artery disease assumed to be atherosclerotic in origin.""For patients in whom ASCVD, HF, or CKD predominates, the best choice for a second agent is a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular risk reduction""There are now multiple large randomized controlled trials reporting statistically significant reductions in cardiovascular events in patients with type 2 diabetes treated with an SGLT2 inhibitor (empagliflozin, canagliflozin) or GLP-1 receptor agonist (liraglutide, semaglutide).""The subjects enrolled in the cardiovascular outcomes trials using empagliflozin, canagliflozin, liraglutide, and semaglutide had A1C >7%, and more than 70% were taking metformin at baseline.""Thus, extension of these results to practice is most appropriate for people with type 2 diabetes and established ASCVD who require additional glucose-lowering treatment beyond metformin and lifestyle management."Insulin vs GLP-1 Agonists (No ASCVD)"The eventual need for the greater potency of injectable medications is common, particularly in people with a longer duration of diabetes.""In trials comparing the addition of GLP-1 receptor agonists or insulin in patients needing further glucose lowering, the efficacy of the two treatments was similar""...trial results support a GLP-1 receptor agonist as the preferred option for patients requiring the potency of an injectable therapy for glucose control""GLP-1 receptor agonists had a lower risk of hypoglycemia and beneficial effects on body weight compared with insulin, albeit with greater gastrointestinal side effects” “In most patients who need the greater glucose-lowering effect of an injectable medication, glucagon-like peptide 1 receptor agonists are preferred to insulin.” ADA: Algorithm for pharmacological treatment in DM-II (figure)One big change that bears repeating is the preferred option for the use of GLP-1 RAs over insulin when choosing an injection therapy. The following abstract shows that these agents produce a similar effect on glycemic control as does insulin #9. The effect of GLP-1 agonists and insulin on A1c is similarAIMS: To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM).METHODS: Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared.RESULTS: Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P < .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ -1.8 mmol/L, P < .0001). GLP-1 RAs reduced bodyweight more effectively (Δ -3.71 kg; P < .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP-1 RAs ( P < .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better thanshort-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similarregarding bodyweight.CONCLUSIONS: Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs.REFERENCE: Abd El Aziz MS et al. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients.Diabetes Obes Metab. 2017 Feb;19(2):216-227.The monthly average wholesale price of:SGLT2 inhibitors is about $550GLP-1 Receptor agonist ~ $850 - 1000ACC/AHA Expert Consensus Pathway on Novel Therapies and CV Risk Reduction in DM The ACC/AHA in late 2018 endorsed the preferential use of SGLT2i’s and GLP-1 RA’s in patients with type II DM and established ASCVD#10: ACC AHA paper on novel therapies for CV risk reduction in DM-IIReference: Das SR, et al. 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018 Dec 18;72(24):3200-3223.Opportunities to initiate one of these therapies In patients with DM-II and ASCVDAt the time of diagnosis of clinical ASCVD in a patient with DMII on a drug regimen, that does not include a GLP1-RA or SGLT2 inhibitorAt the time of diagnosis of DM-II in a patient with clinical ASCVDAs mentioned, the ACC AHA are only specifically endorsing empagliflozin and liraglutide Important practical points (from the ACC AHA recommendations): Data supporting the use of a GLP1-RA or SGLT2 inhibitor in patients with an A1C < 7% are limitedThere is no evidence of a graded dose response regarding CV disease outcomes, SGLT2 inhibitors with demonstrated CV benefit should be initiated at the lowest available dose (e.g., 10 mg for empagliflozin, 100 mg for canagliflozin, and so on). No further uptitration is needed for CV risk reduction, although dose may be increased by the doctor managing the patient’s glucose, and cardiologists should make patients aware that this may happen for non-CVD risk reduction reasonsLiraglutide should be initiated at the lowest dose and up-titrated slowly to the maximal tolerated dose, noting that the goal dose for liraglutide is 1.8 mg daily for CVD reduction.Patients with T2D and clinical ASCVD treated with metformin should have an SGLT2 inhibitor or GLP-1 RA with proven CV benefit added to their treatment regimenNo definitive clinical trial data exists (yet) that provide evidence of benefit to the approach of using an SGLT2 inhibitor or GLP-1RA for the reduction of cardiovascular risk in patients not already on metformin.It appears reasonable to use both an SGLT2 inhibitor and a GLP-1RA with demonstrated CV benefit concomitantly if clinically indicated, even though such combination therapy has not been studied for CVD risk reduction.Until further data from ongoing clinical trials become available, patients at high risk for HF (and possibly those with established HF) may derive more benefit from an SGLT2 inhibitor with demonstrated CV benefit, whereas those with osteoporosis, prior amputations, severe peripheral artery disease, peripheral neuropathy, or active lower extremity soft tissue ulcers or infections may have a more favorable benefit/risk balance if initially treated with a GLP-1RALike everything in medicine, these recommendations are not all “upside”Amputation risk with certain SGLT2 inhibitorsFDA Warnings concerning SGLT2 inhibitorsAmputation risk with canagliflozin | FDA Boxed WarningHealth care professionals should, before starting canagliflozin, consider factors that may predispose patients to the need for amputations. These factors include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Monitor patients receiving canagliflozin for the signs and symptoms described above and discontinue canagliflozin if these complications occur. (May 2017)Necrotizing fasciitis of the perineum (Fournier’s gangrene) | FDA Warning“From 2013 to 2018, the FDA has identified 12 cases of Fournier's gangrene among patients using SGLT2 inhibitors, seven were men and five were women. Fournier's gangrene is usually diagnosed in men. All of the cases had recently started an SGLT2 inhibitor. All patients were hospitalized and had surgery. One patient died.” According to the ACC AHA these cases occurred over 5 years and 1.7 million patients were Rx’s an DGLT2 inhibitor in 2107)Case reports have pointed to an increased risk of diabetic ketoacidosis with SGLT2 inhibitors in the absence of significant hyperglycemia, often called “euglycemic diabetic ketoacidosis,” although moderate hyperglycemia is common. This risk has been shown to be very low in the large randomized controlled trials of patients with T2D, particularly in those not requiring insulin therapy Treating-to-target 2019#11: ACP: HBA1c targets of 7 – 8% recommended for “most patients with type 2 diabetes”Description: The American College of Physicians developed this guidance statement to guide clinicians in selecting targets for pharmacologic treatment of type 2 diabetes.Methods: The National Guideline Clearinghouse and the Guidelines International Network library were searched (May 2017) for national guidelines, published in English, that addressed hemoglobin A1c (HbA1c) targets for treating type 2 diabetes in nonpregnant outpatient adults. The authors identified guidelines from the National Institute for Health and Care Excellence and the Institute for Clinical Systems Improvement. In addition, 4 commonly used guidelines were reviewed, from the American Association of Clinical Endocrinologists and American College of Endocrinology, the American Diabetes Association, the Scottish Intercollegiate Guidelines Network, and the U.S. Department of Veterans Affairs and Department of Defense. The AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument was used to evaluate the guidelines.Guidance Statement 1: Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients' preferences, patients' general health and life expectancy, treatment burden, and costs of care.Guidance Statement 2: Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes.Guidance Statement 3: Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%.Guidance Statement 4: Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population.REFERENCE: Qaseem A for the Clinical Guidelines Committee of the American College of Physicians. Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the American College of Physicians. Ann Intern Med. 2018 Apr 17;168(8):569-576.#12: However, in newly diagnosed diabetics a “legacy effect” of tighter control may be associated with better outcomesOBJECTIVE: To examine for a legacy effect of early glycemic control on diabetic complications and death.RESEARCH DESIGN AND METHODS: This cohort study of managed care patients with newly diagnosed type 2 diabetes and 10 years of survival (1997-2013, average follow-up 13.0 years, N = 34,737) examined associations between HbA1c <6.5% (<48 mmol/mol), 6.5% to <7.0% (48 to <53 mmol/mol), 7.0% to <8.0% (53 to <64 mmol/mol), 8.0% to <9.0% (64 to <75 mmol/mol), or ≥9.0% (≥75 mmol/mol) for various periods of early exposure (0-1, 0-2, 0-3, 0-4, 0-5, 0-6, and 0-7 years) and incident future microvascular (end-stage renal disease, advanced eye disease, amputation) and macrovascular (stroke, heart disease/failure, vascular disease) events and death, adjusting for demographics, risk factors, comorbidities, and later HbA1c.RESULTS: Compared with HbA1c <6.5% (<48 mmol/mol) for the 0-1-year early exposure period, HbA1c levels ≥6.5% (≥48 mmol/mol) were associated with increased microvascular and macrovascular events (e.g., HbA1c 6.5% to <7.0% [48 to <53 mmol/mol] microvascular: hazard ratio 1.204 [95% CI 1.063-1.365]), and HbA1c levels ≥7.0% (≥53 mmol/mol) were associated with increased mortality (e.g., HbA1c 7.0% to <8.0% [53 to <64 mmol/mol]: 1.290 [1.104-1.507]). Longer periods of exposure to HbA1c levels ≥8.0% (≥64 mmol/mol) were associated with increasing microvascular event and mortality risk.CONCLUSIONS: Among patients with newly diagnosed diabetes and 10 years of survival, HbA1c levels ≥6.5% (≥48 mmol/mol) for the 1st year after diagnosis were associated with worse outcomes. Immediate, intensive treatment for newly diagnosed patients may be necessary to avoid irremediable long-term risk for diabetic complications and mortality.REFERENCE: Laiteerapong N et al. The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (the Diabetes & Aging Study). Diabetes Care. 2018 Aug 13. pii: dc171144.Glycemic Targets | the following is taken verbatim from the ADA Standards of CareADA GLYCEMIC TargetsA reasonable A1C goal for many nonpregnant adults is <7% (A)Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment (i.e., polypharmacy). Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, or no significant cardiovascular disease (C)Less stringent A1C goals (such as <8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the goal is difficult to achieve despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin (B)Miscellaneous interesting articles (at least to me) on DM published in the last year #13: Vitamin C (1000 mg daily in divided doses) improves glycemic controlAIM: The primary aim of this study was to investigate whether ascorbic acid (AA) supplementation improves postprandial glucose responses under free-living conditions in individuals with type 2 diabetes. A secondary aim was to investigate the effect of AA supplementation on blood pressure.MATERIALS AND METHODS: A total of 31 individuals with type 2 diabetes (26 males and 5 females; aged 61.8 ± 6.8 years; duration of diabetes, 5.6 ± 4.6 years; HbA1c, 7.6% ± 0.7% [mean ± SD]) were enrolled in a randomized cross-over study involving 4 months of supplementation with oral AA (2 × 500 mg/d) or placebo. Participants wore continuous glucose monitors for 48 hours and consumed standardized meals pre- and post-supplementation. Measurements included postprandial glucose incremental areas under the curve (iAUC), duration of day in hyper- and hypo-glycaemia status, average 24-hour and daily postprandial glucose concentrations, HbA1c, insulin, blood pressure (BP) and oxidative stress (F2 -isoprostanes).RESULTS: Following AA supplementation, significant decreases were observed in daily postprandial glucose iAUC (-36%), in duration of day with hyperglycaemia (-2.8 h/d) and postprandial hyperglycaemia (-1.7 h/d), in average 24-hour glucose (-0.8 mmol/L) and daily postprandial glucose (-1.1 mmol/L) concentrations, in systolic (-7 mm Hg) and diastolic (-5 mm Hg) blood pressures and in a specific fraction of free plasma F2 -isoprostanes (-47 pg/mL) as compared to placebo.CONCLUSIONS: Individuals with type 2 diabetes experienced improved postprandial and 24-hour glycaemia and decreased BP after 4 months of AA supplementation as compared to placebo. These findings offer evidence for the proposed use of AA as an adjunct therapy to improve glycaemic and BP control in individuals with type 2 diabetes.REFERENCE: Mason SA, Rasmussen B, van Loon LJC, et al. Ascorbic acid supplementation improves postprandial glycaemic control and blood pressure in people with type 2 diabetes: Findings of a randomized cross-over trial. Diabetes Obes Metab. 2018 Nov 4#14. Weight gain with smoking cessation associated with DM-II risk but lower mortalityBACKGROUND: Whether weight gain after smoking cessation attenuates the health benefits of quitting is unclear.METHODS: In three cohort studies involving men and women in the United States, we identified those who had reported quitting smoking and we prospectively assessed changes in smoking status and body weight. We estimated risks of type 2 diabetes, death from cardiovascular disease, and death from any cause among those who had reported quitting smoking, according to weight changes after smoking cessation.RESULTS: The risk of type 2 diabetes was higher among recent quitters (2 to 6 years since smoking cessation) than among current smokers (hazard ratio, 1.22; 95% confidence interval [CI], 1.12 to 1.32). The risk peaked 5 to 7 years after quitting and then gradually decreased. The temporary increase in the risk of type 2 diabetes was directly proportional to weight gain, and the risk was not increased among quitters without weight gain (P<0.001 for interaction). In contrast, quitters did not have a temporary increase in mortality, regardless of weight change after quitting. As compared with current smokers, the hazard ratios for death from cardiovascular disease were 0.69 (95% CI, 0.54 to 0.88) among recent quitters without weight gain, 0.47 (95% CI, 0.35 to 0.63) among those with weight gain of 0.1 to 5.0 kg, 0.25 (95% CI, 0.15 to 0.42) among those with weight gain of 5.1 to 10.0 kg, 0.33 (95% CI, 0.18 to 0.60) among those with weight gain of more than 10.0 kg, and 0.50 (95% CI, 0.46 to 0.55) among longer-term quitters (>6 years since smoking cessation). Similar associations were observed for death from any cause.CONCLUSIONS: Smoking cessation that was accompanied by substantial weight gain was associated with an increased short-term risk of type 2 diabetes but did not mitigate the benefits of quitting smoking on reducing cardiovascular and all-cause mortality. (Funded by the National Institutes of Health.).REFERENCE: Hu Y et al. Smoking Cessation, Weight Change, Type 2 Diabetes, and Mortality. N Engl J Med. 2018 Aug 16;379(7):623-632. Comment in N Engl J Med. 2018 Aug 16;379(7):684-685.#15. In DM-II the risk of death, MI or CVA = the general population if risk factors in target rangeBACKGROUND: Patients with diabetes are at higher risk for death and cardiovascular outcomes than the general population. We investigated whether the excess risk of death and cardiovascular events among patients with type 2 diabetes could be reduced or eliminated.METHODS: In a cohort study, we included 271,174 patients with type 2 diabetes who were registered in the Swedish National Diabetes Register and matched them with 1,355,870 controls on the basis of age, sex, and county. We assessed patients with diabetes according to age categories and according to the presence of five risk factors (elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure). Cox regression was used to study the excess risk of outcomes (death, acute myocardial infarction, stroke, and hospitalization for heart failure) associated with smoking and the number of variables outside target ranges. We also examined the relationship between various risk factors and cardiovascular outcomes.RESULTS: The median follow-up among all the study participants was 5.7 years, during which 175,345 deaths occurred. Among patients with type 2 diabetes, the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range. Among patients with diabetes who had all five variables within target ranges, the hazard ratio for death from any cause, as compared with controls, was 1.06 (95% confidence interval [CI], 1.00 to 1.12), the hazard ratio for acute myocardial infarction was 0.84 (95% CI, 0.75 to 0.93), and the hazard ratio for stroke was 0.95 (95% CI, 0.84 to 1.07). The risk of hospitalization for heart failure was consistently higher among patients with diabetes than among controls (hazard ratio, 1.45; 95% CI, 1.34 to 1.57). In patients with type 2 diabetes, a glycated hemoglobin level outside the target range was the strongest predictor of stroke and acute myocardial infarction; smoking was the strongest predictor of death.CONCLUSIONS: Patients with type 2 diabetes who had five risk-factor variables within the target ranges appeared to have little or no excess risk of death, myocardial infarction, or stroke, as compared with the general population.REFERENCE: Rawshani A et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2018 Aug 16;379(7):633-644. Comment in N Engl J Med. 2018 Aug 16;379(7):684-685.#16: A single blood sample using both fasting glucose and HbA1c is sufficient to diagnose DM Background: Current clinical definitions of diabetes require repeated blood work to confirm elevated levels of glucose or hemoglobin A1c (HbA1c) to reduce the possibility of a false-positive diagnosis. Whether 2 different tests from a single blood sample provide adequate confirmation is uncertain.Objective: To examine the prognostic performance of a single-sample confirmatory definition of undiagnosed diabetes.Design: Prospective cohort study.Setting: The ARIC (Atherosclerosis Risk in Communities) study.Participants: 13 346 ARIC participants (12 268 without diagnosed diabetes) with 25 years of follow-up for incident diabetes, cardiovascular outcomes, kidney disease, and mortality.Measurements: Confirmed undiagnosed diabetes was defined as elevated levels of fasting glucose (=7.0 mmol/L [=126 mg/dL]) and HbA1c (=6.5%) from a single blood sample.Results: Among 12 268 participants without diagnosed diabetes, 978 had elevated levels of fasting glucose or HbA1c at baseline (1990 to 1992). Among these, 39% had both (confirmed undiagnosed diabetes), whereas 61% had only 1 elevated measure (unconfirmed undiagnosed diabetes). The confirmatory definition had moderate sensitivity (54.9%) but high specificity (98.1%) for identification of diabetes cases diagnosed during the first 5 years of follow-up, with specificity increasing to 99.6% by 15 years. The 15-year positive predictive value was 88.7% compared with 71.1% for unconfirmed cases. Confirmed undiagnosed diabetes was significantly associated with cardiovascular and kidney disease and mortality, with stronger associations than unconfirmed diabetes.Limitation: Lack of repeated measurements of fasting glucose and HbA1c.Conclusion: A single-sample confirmatory definition of diabetes had a high positive predictive value for subsequent diagnosis and was strongly associated with clinical end points. Our results support the clinical utility of using a combination of elevated fasting glucose and HbA1c levels from a single blood sample to identify undiagnosed diabetes in the population.Reference: Prognostic Implications of Single-Sample Confirmatory Testing for Undiagnosed Diabetes: A Prospective Cohort Study Ann Intern Med. 2018;169(3):156-164.#17: Bariatric surgery associated with lower microvascular complications vs usual care Background: Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes.Objective: To investigate the relationship between bariatric surgery and incident microvascular complications of T2DM.Design: Retrospective matched cohort study from 2005 to 2011 with follow-up through September 2015.Setting: 4 integrated health systems in the United States.Participants: Patients aged 19 to 79 years with T2DM who had bariatric surgery (n = 4024) were matched on age, sex, body mass index, hemoglobin A1c level, insulin use, diabetes duration, and intensity of health care use up to 3 nonsurgical participants (n = 11 059).Intervention: Bariatric procedures (76% gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) compared with usual care.Measurements: Adjusted Cox regression analysis investigated time to incident microvascular disease, defined as first occurrence of diabetic retinopathy, neuropathy, or nephropathy.Results: Median follow-up was 4.3 years for both surgical and nonsurgical patients. Bariatric surgery was associated with significantly lower risk for incident microvascular disease at 5 years (16.9% for surgical vs. 34.7% for nonsurgical patients; adjusted hazard ratio [HR], 0.41 [95% CI, 0.34 to 0.48]). Bariatric surgery was associated with lower cumulative incidence at 5 years of diabetic neuropathy (7.2% for surgical vs. 21.4% for nonsurgical patients; HR, 0.37 [CI, 0.30 to 0.47]), nephropathy (4.9% for surgical vs. 10.0% for nonsurgical patients; HR, 0.41 [CI, 0.29 to 0.58]), and retinopathy (7.2% for surgical vs. 11.2% for nonsurgical patients; HR, 0.55 [CI, 0.42 to 0.73]).Limitation: Electronic health record databases could misclassify microvascular disease status for some patients.Conclusion: In this large, multicenter study of adults with T2DM, bariatric surgery was associated with lower overall incidence of microvascular disease (including lower risk for neuropathy, nephropathy, and retinopathy) than usual care.Reference: O’Brien R et al. Microvascular Outcomes in Patients With Diabetes After Bariatric Surgery Versus Usual Care: A Matched Cohort Study. Ann Intern Med. 2018;169(5):300-310.Bottom – LinesSGLT2 inhibitors and GLP-1 receptor agonists may be taking a more prominent role in the management of diabetics with macrovascular disease (and chronic renal failure)The ACC and AHA endorse empagliflozin and liraglutide as the preferred agents in such patients. The ADA also implicitly endorses these 2 medications. Therefore as of yet one cannot be confident that there is a class effect with these drugsThe ADA has recommended that to use of GLP-1 RAs over insulin when choosing an injection therapy.Although an A1c target of 7 – 8% is appropriate for most patients with DM-II under most circumstances, a lower A1c target (< 6.5%) within the first year of diagnosis may be associated with a legacy effect and better long-term outcomesVitamin C intake may be associated with improved glycemic controlSmoking cessation is associated with a short-term increased risk of DM-II, but (no big surprise!) in spite of this quitters live longer Diabetics with optimal levels of A1c, LDL, BP, and no albuminuria or smoking have mortality and macrovascular event rates equal to that of non-diabeticsA single blood sample is sufficient to diagnose DM (also BTW endorsed this year by the ADA)Bariatric surgery is associated with less microvascular complications than usual careIntegrative Medicine: Focus on ProbioticsJohn Hickner, MD, MSObjectives1. review and understand results of recently published studies of probiotic therapies2. understand the evolving evidence for effectiveness of probiotics for a variety of conditionsA PubMed search using the search terms “probiotics” and “therapy” in January, 2019 yielded 10,797 references and 463 clinical reviews. This is an area of intensive investigation with conflicting results in some areas of study. The following abstracts summarize recent studies and systematic reviews of probiotics that are pertinent to primary care physicians, nurse practitioners and physician assistants. Childhood EczemaThe following 4 abstracts give conflicting evidence regarding the effectiveness of probiotics in preventing eczema in infants and children. Lactobacillus rhamnosus HN001 has a significant positive effect on reducing eczema and allergy when give to infants and their moms during pregnancy and breastfeeding.1. Probiotics may reduce the incidence of eczema in infants BACKGROUND: Allergic diseases are considered a health burden because of their high and constantly increasing prevalence, high direct and indirect costs, and undesirable effects on quality of life.?Probiotics?have been suggested as an intervention to prevent allergic diseases.OBJECTIVE: We sought to synthesize the evidence supporting use of?probiotics?for the prevention of allergies and inform World Allergy Organization guidelines on probiotic use.METHODS: We performed a systematic review of randomized trials assessing the effects of any probiotic administered to pregnant women, breast-feeding mothers, and/or infants.RESULTS: Of 2403 articles published until December 2014 identified in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, 29 studies fulfilled a priori specified inclusion criteria for the analyses.?Probiotics?reduced the risk of?eczema?when used by women during the last trimester of pregnancy (relative risk [RR], 0.71; 95% CI, 0.60-0.84), when used by breast-feeding mothers (RR, 0.57; 95% CI, 0.47-0.69), or when given to infants (RR, 0.80; 95% CI, 0.68-0.94). Evidence did not support an effect on other allergies, nutrition status, or incidence of adverse effects. The certainty in the evidence according to the Grading of Recommendation Assessment Development and Evaluation approach is low or very low because of the risk of bias, inconsistency and imprecision of results, and indirectness of available research.CONCLUSION: Probiotics?used by pregnant women or breast-feeding mothers and/or given to infants reduced the risk of?eczema?in infants; however, the certainty in the evidence is low. No effect was observed for the prevention of other allergic conditions.Cuello-Garcia CA, Bro?ek JL, Fiocchi A, Pawankar R, Yepes-Nu?ez JJ, Terracciano L, Gandhi S, Agarwal A, Zhang Y, Schünemann HJ. Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol. 2015 Oct;136(4):952-61.2. Lactobacillus rhamnosus?GG did not reduce infant eczema or asthma at 2 years of ageOBJECTIVES: To determine if probiotic administration during the first 6 months of life decreases childhood asthma and?eczema.METHODS: We conducted a randomized, double-blind controlled trial of?Lactobacillus rhamnosus?GG (LGG) supplementation on the cumulative incidence of?eczema?(primary end point) and asthma and rhinitis (secondary end points) in high-risk infants. For the first 6 months of life, intervention infants (n?= 92) received a daily dose of 10 billion colony-forming units of LGG and 225 mg of inulin (Amerifit Brands, Cromwell, CT), and control infants (n?= 92) received 325 mg of inulin alone. We used survival analysis methods to estimate disease incidences in the presence or absence of LGG and to estimate the efficacy of LGG in delaying or preventing these diseases.RESULTS: Infants were accrued over a 6-year period (median follow-up: 4.6 years; 95% retention rate at 2 years). At 2 years of age, the estimated cumulative incidence of?eczema?was 30.9% (95% confidence interval [CI], 21.4%-40.4%) in the control arm and 28.7% (95% CI, 19.4%-38.0%) in the LGG arm, for a hazard ratio of 0.95 (95% CI, 0.59-1.53) (log-rank?P?= .83). At 5 years of age, the cumulative incidence of asthma was 17.4% (95% CI, 7.6%-27.1%) in the control arm and 9.7% (95% CI, 2.7%-16.6%) in the LGG arm, for a hazard ratio of 0.88 (95% CI, 0.41-1.87) (log-rank?P?= .25).CONCLUSIONS: For high-risk infants, early LGG supplementation for the first 6 months of life does not appear to prevent the development of?eczema?or asthma at 2 years of age.Cabana MD, McKean M, Caughey AB, Fong L, Lynch S, Wong A, Leong R, Boushey HA, Hilton JF. Early Probiotic Supplementation for Eczema and Asthma Prevention: A Randomized Controlled Trial. Pediatrics. 2017 Sep;140(3).3. Lactobacillus rhamnosus HN001 but not Bifidobacterium lactis NH019 reduced eczema in children at 11 year follow upBACKGROUND: In a two-centre randomized placebo-controlled trial of Lactobacillus rhamnosus HN001 (HN001) (6?×?109?colony-forming units [cfu]) or Bifidobacterium lactis HN019 (HN019) (9?×?109?cfu) taken daily from 35-week gestation to 6?months' post-partum in mothers while breastfeeding and from birth to age 2?years in infants, we showed that HN001 significantly protected against?eczema?development at 2, 4 and 6?years and atopic sensitization at 6?years. There was no effect of HN019. We report here the findings for 11-year outcomes.METHODS: At age 11?years,?eczema?was defined as previously using the UK Working Party's Diagnostic Criteria. Asthma, wheeze, hay fever and rhinitis were defined based on the International Study of Asthma and Allergies in Childhood (ISAAC) questions. Atopic sensitization was defined as one or more positive responses (mean wheal diameter ≥3?mm) to a panel of food and aeroallergens. Analysis was intention-to-treat using hazard ratios to assess probiotic effects on the 11-year lifetime prevalence and relative risks for point or 12-month prevalence at 11?years.RESULTS: Early childhood HN001 supplementation was associated with significant reductions in the 12-month prevalence of?eczema?at age 11?years (relative risk [RR]?=?0.46, 95% CI 0.25-0.86, P?=?0.015) and hay fever (RR?=?0.73, 95% CI 0.53-1.00, P?=?0.047). For the lifetime prevalence, HN001 was associated with a significant reduction in atopic sensitization (hazard ratio [HR]?=?0.71, 95% CI 0.51-1.00, P?=?0.048),?eczema?(HR?=?0.58, 95% CI 0.41-0.82, P?=?0.002) and wheeze (HR?=?0.76, 95% CI 0.57-0.99, P?=?0.046). HN019 had no significant effect on these outcomes.CONCLUSION: This is the first early probiotic intervention to show positive outcomes for at least the first decade of life across the spectrum of allergic disease.Wickens K, Barthow C, Mitchell EA, Kang J, van Zyl N, Purdie G, Stanley T, Fitzharris P, Murphy R, Crane J. Effects of Lactobacillus rhamnosus HN001 in early life on the cumulative prevalence of allergic disease to 11?years. Pediatr Allergy Immunol. 2018 Dec;29(8):808-814.4. Lactobacillus rhamnosus did not prevent infant eczema when give to pregnant women: RCTBACKGROUND: In a randomized placebo-controlled trial, we previously found that the probiotic Lactobacillus rhamnosus HN001 (HN001) taken by mothers from 35?weeks of gestation until 6?months post-partum if breastfeeding and their child from birth to age 2?years halved the risk of?eczema?during the first 2?years of life. We aimed to test whether maternal supplementation alone is sufficient to reduce?eczema?and compare this to our previous study when both the mother and their child were supplemented.METHODS: In this 2-centre, parallel double-blind, randomized placebo-controlled trial, the same probiotic as in our previous study (HN001, 6?×?109?colony-forming units) was taken daily by mothers from 14-16?weeks of gestation till 6?months post-partum if breastfeeding, but was not given directly to the child. Women were recruited from the same study population as the first study, where they or their partner had a history of treated asthma,?eczema?or hay fever.RESULTS: Women were randomized to HN001 (N?=?212) or placebo (N?=?211). Maternal-only HN001 supplementation did not significantly reduce the prevalence of?eczema, SCORAD?≥?10, wheeze or atopic sensitization in the infant by 12?months. This contrasts with the mother and child intervention study, where HN001 was associated with reductions in?eczema?(hazard ratio (HR): 0.39, 95% CI 0.19-0.79, P?=?.009) and SCORAD (HR?=?0.61, 95% 0.37-1.02). However, differences in the HN001 effect between studies were not significant. HN001 could not be detected in breastmilk from supplemented mothers, and breastmilk TGF-β/IgA profiles were unchanged.CONCLUSION: Maternal probiotic supplementation without infant supplementation may not be effective for preventing infant?eczema.Wickens K, Barthow C, Mitchell EA, Stanley TV, et. al. Maternal supplementation alone with Lactobacillus rhamnosus HN001 during pregnancy and breastfeeding does not reduce infant eczema. Pediatr Allergy Immunol. 2018 May;29(3):296-302.Infant ColicA 2014 meta-analysis and a 2018 randomized trial both demonstrate reduced crying and fussing in breast-fed colicky infants given probiotics.5. L reuteri?DSM17938 reduces colic in breast-fed infants; uncertain in formula-fed infants CONTEXT: Lactobacillus reuteri?DSM17938 has shown promise in managing colic, but conflicting study results have prevented a consensus on whether it is truly effective.OBJECTIVE: Through an individual participant data meta-analysis, we sought to definitively determine if?L reuteri?DSM17938 effectively reduces crying and/or fussing time in infants with colic and whether effects vary by feeding type.DATA SOURCES: We searched online databases (PubMed, Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Database of Abstracts of Reviews of Effects, and Cochrane), e-abstracts, and clinical trial registries.STUDY SELECTION: These were double-blind randomized controlled trials (published by June 2017) of?L reuteri?DSM17398 versus a placebo, delivered orally to infants with colic, with outcomes of infant crying and/or fussing duration and treatment success at 21 days.DATA EXTRACTION: We collected individual participant raw data from included studies modeled simultaneously in multilevel generalized linear mixed-effects regression models.RESULTS: Four double-blind trials involving 345 infants with colic (174 probiotic and 171 placebo) were included. The probiotic group averaged less crying and/or fussing time than the placebo group at all time points (day 21 adjusted mean difference in change from baseline [minutes] -25.4 [95% confidence interval (CI): -47.3 to -3.5]). The probiotic group was almost twice as likely as the placebo group to experience treatment success at all time points (day 21 adjusted incidence ratio 1.7 [95% CI: 1.4 to 2.2]). Intervention effects were dramatic in breastfed infants (number needed to treat for day 21 success 2.6 [95% CI: 2.0 to 3.6]) but were insignificant in formula-fed infants.LIMITATIONS: There were insufficient data to make conclusions for formula-fed infants with colic.CONCLUSIONS: L reuteri?DSM17938 is effective and can be recommended for breastfed infants with colic. Its role in formula-fed infants with colic needs further research.Sung V, D'Amico F, Cabana MD, Chau K, Koren G, Savino F, Szajewska H, Deshpande G, Dupont C, Indrio F, Mentula S, Partty A, Tancredi D. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics. 2018 Jan;141(1).6. Two lactobacillus strain probiotic decreased mean crying time more than placebo in infants with colicBackground: Infant colic is a common condition of unknown pathogenesis that brings frustration to families seeking for effective management. Accumulating evidence suggests that some single strains of lactobacilli may play a positive dietary role in attenuation of colic in exclusively breastfed infants. Methods: The objective of this study was to evaluate a mixture of two?Lactobacillus?strains in decreasing infant cry and fuss in this population. Infants aged 4?12 weeks received?L. rhamnosus?19070-2 and?L. reuteri?12246 in a daily dose of 250 × 10? CFU, 3.33 mg of fructooligosaccharide, and 200 IU of vitamin D? (84 infants, probiotic group) or just vitamin D? (84 infants, control group) for 28 days. Cry and fuss time were measured with validated Baby's Day Diary on days 0 and 28. Results: At baseline, mean (SD) duration of cry and fuss time was comparable in the probiotic and control groups: 305 (81) vs. 315 (90) min., respectively (p?=?0.450). On day 28, mean cry and fuss time became statistically different: 142 (89) vs. 199 (72), respectively (p?<?0.05). Mean change in cry and fuss time from day 0 through day 28 was -163 (99) minutes in the probiotic and -116 (94) minutes in the control group (p?=?0.019). Conclusion: Our findings confirm that lactobacilli decrease cry and fuss time and provide a dietary support in exclusively breastfed infants with colic, decreasing mean cry and fuss time 47 minutes more than placebo at 28 days.Gerasimov S, Gantzel J, Dementieva N, Schevchenko O, Tsitsura O, Guta N, Bobyk V, Kaprus V. Role of Lactobacillus rhamnosus (FloraActive?) 19070-2 and Lactobacillus reuteri (FloraActive?) 12246 in Infant Colic: A Randomized Dietary Study. Nutrients. 2018 Dec 13;10(12).Diarrhea in childrenTwo recently published large trials did NOT show effectiveness of probiotics in reducing diarrhea in children with gastroenteritis, despite prior smaller trials and meta-analyses of small trials showing a positive effect. Lactobacillus rhamnosus, however, does reduce antibiotic associated diarrhea in children, and probiotics help reduce symptoms of travelers’ diarrhea and clostridium difficile diarrhea. 7. Two strain lactobacillus did not prevent moderate to severe diarrhea in children with gastroenteritisBACKGROUND: Gastroenteritis accounts for approximately 1.7 million visits to the emergency department (ED) by children in the United States every year. Data to determine whether the use of?probiotics?improves outcomes in these children are lacking.METHODS: We conducted a randomized, double-blind trial involving 886 children 3 to 48 months of age with gastroenteritis who presented to six pediatric EDs in Canada. Participants received a 5-day course of a combination probiotic product containing Lactobacillus rhamnosus R0011 and L. helveticus R0052, at a dose of 4.0×109?colony-forming units twice daily or placebo. The primary outcome was moderate-to-severe gastroenteritis, which was defined according to a post-enrollment modified Vesikari scale symptom score of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease). Secondary outcomes included the duration of diarrhea and vomiting, the percentage of children who had unscheduled physician visits, and the presence or absence of adverse events.RESULTS: Moderate-to-severe gastroenteritis within 14 days after enrollment occurred in 108 of 414 participants (26.1%) who were assigned to?probiotics?and 102 of 413 participants (24.7%) who were assigned to placebo (odds ratio, 1.06; 95% confidence interval [CI], 0.77 to 1.46; P=0.72). After adjustment for trial site, age, detection of rotavirus in stool, and frequency of diarrhea and vomiting before enrollment, trial-group assignment did not predict moderate-to-severe gastroenteritis (odds ratio, 1.06; 95% CI, 0.76 to 1.49; P=0.74). There were no significant differences between the probiotic group and the placebo group in the median duration of diarrhea (52.5 hours [interquartile range, 18.3 to 95.8] and 55.5 hours [interquartile range, 20.2 to 102.3], respectively; P=0.31) or vomiting (17.7 hours [interquartile range, 0 to 58.6] and 18.7 hours [interquartile range, 0 to 51.6], P=0.18), the percentages of participants with unscheduled visits to a health care provider (30.2% and 26.6%; odds ratio, 1.19; 95% CI, 0.87 to 1.62; P=0.27), and the percentage of participants who reported an adverse event (34.8% and 38.7%; odds ratio, 0.83; 95% CI, 0.62 to 1.11; P=0.21).CONCLUSIONS: In children who presented to the emergency department with gastroenteritis, twice-daily administration of a combined L. rhamnosus-L. helveticus probiotic did not prevent the development of moderate-to-severe gastroenteritis within 14 days after enrollment.?Collaborators: Johnson D, Sweeney J, Rumatir M, Plint A, Dalgleish D, Auclair MC, Black K, Fitzpatrick E. Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis. Freedman SB, Williamson-Urquhart S, Farion KJ, Gouin S, et. al.;PERC PROGUT Trial Group. N Engl J Med. 2018 Nov 22;379(21):2015-2026. 8. Lactobacillus rhamnosus GG did not improve symptoms in preschoolers with acute diarrheaBACKGROUND: Acute gastroenteritis develops in millions of children in the United States every year, and treatment with?probiotics?is common. However, data to support the use of?probiotics?in this population are limited.METHODS: We conducted a prospective, randomized, double-blind trial involving children 3 months to 4 years of age with acute gastroenteritis who presented to one of 10 U.S. pediatric emergency departments. Participants received a 5-day course of Lactobacillus rhamnosus GG at a dose of 1×1010?colony-forming units twice daily or matching placebo. Follow-up surveys were conducted daily for 5 days and again 14 days after enrollment and 1 month after enrollment. The primary outcome was moderate-to-severe gastroenteritis, which was defined as an illness episode with a total score on the modified Vesikari scale of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease), within 14 days after enrollment. Secondary outcomes included the duration and frequency of diarrhea and vomiting, the duration of day-care absenteeism, and the rate of household transmission (defined as the development of symptoms of gastroenteritis in previously asymptomatic household contacts).RESULTS: Among the 971 participants, 943 (97.1%) completed the trial. The median age was 1.4 years (interquartile range, 0.9 to 2.3), and 513 participants (52.9%) were male. The modified Vesikari scale score for the 14-day period after enrollment was 9 or higher in 55 of 468 participants (11.8%) in the L. rhamnosus GG group and in 60 of 475 participants (12.6%) in the placebo group (relative risk, 0.96; 95% confidence interval, 0.68 to 1.35; P=0.83). There were no significant differences between the L. rhamnosus GG group and the placebo group in the duration of diarrhea (median, 49.7 hours in the L. rhamnosus GG group and 50.9 hours in the placebo group; P=0.26), duration of vomiting (median, 0 hours in both groups; P=0.17), or day-care absenteeism (median, 2 days in both groups; P=0.67) or in the rate of household transmission (10.6% and 14.1% in the two groups, respectively; P=0.16).CONCLUSIONS: Among preschool children with acute gastroenteritis, those who received a 5-day course of L. rhamnosus GG did not have better outcomes than those who received placebo.Schnadower D, Tarr PI, Casper TC, Gorelick MH, et. al. Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children. N Engl J Med. 2018 Nov 22;379(21):2002-2014.9. Lactobacillus reuteri DSM 17938 may reduce duration of acute gastroenteritis in childrenThe effectiveness of?Lactobacillus reuteri?DSM 17938 (L. reuteri) for the management of acute gastroenteritis (AGE) has been recently questioned. We performed a systematic review to update evidence on?L. reuteri?for treating AGE in children. We searched MEDLINE, EMBASE, the Cochrane Library databases, and additional data sources from January 2016 (end of search for our 2016 systematic review) to August 2019. The primary outcomes were stool volume and duration of diarrhea. Four RCTs were included. None of them evaluated stool volume. Compared with placebo or no treatment,?L. reuteri?reduced diarrhea duration (four RCTs,?n?= 347, mean difference, MD -0.87 days, 95% CI [-1.43, -0.31]).?L. reuteri?use was also associated with a reduced duration of hospitalization (three RCTs,?n?= 284, MD -0.54 days, 95% CI [-1.09, 0.0]). The small effect sizes of limited clinical relevance and methodological limitations of the included trials should be noted when interpreting these findings.Patro-Go??b B, Szajewska H. Systematic Review with Meta-Analysis: Lactobacillus reuteri DSM 17938 for Treating Acute Gastroenteritis in Children. An Update. Nutrients. 2019 Nov 14;11(11). pii: E2762. doi: 10.3390/nu11112762. Review. PubMed PMID: 31739457.10. S. boulardii CNCM I-745 reduced duration of diarrhea in children with acute gastroenteritisEvidence from the literature has shown that Saccharomyces boulardii provides a clinically significant benefit in the treatment of acute infectious?diarrhoea?in children. In this multicentre, randomised, prospective, controlled, single blind clinical trial performed in children with acute watery?diarrhoea, we aimed to evaluate the impact of S. boulardii CNCM I-745 in hospitalised children, in children requiring emergency care unit (ECU) stay and in outpatient settings. The primary endpoint was the duration of?diarrhoea?(in hours). Secondary outcome measures were duration of hospitalisation and?diarrhoea?at the 3(rd) day of intervention. In the whole study group (363 children), the duration of?diarrhoea?was approximately 24 h shorter in the S. boulardii group (75.4±33.1 vs 99.8±32.5 h, P<0.001). The effect of S. boulardii (diarrhoea-free children) was observed starting at 48 h. After 72 h, only 27.3% of the children receiving probiotic still had watery?diarrhoea, in contrast to 48.5% in the control group (P<0.001). The duration of?diarrhoea?was significantly reduced in the probiotic group in hospital, ECU and outpatient settings (P<0.001, P<0.01 and P<0.001, respectively). The percentage of?diarrhoea-free children was significantly larger after 48 and 72 h in all settings. The mean length of hospital stay was shorter with more than 36 h difference in the S. boulardii group (4.60±1.72 vs 6.12±1.71 days, P<0.001). The mean length of ECU stay was shorter with more than 19 h difference in the probiotic group (1.20±0.4 vs 2.0±0.3 days, P<0.001). No adverse effects related to the probiotic were noted. Because treatment can shorten the duration of?diarrhoea?and reduce the length of ECU and hospital stay, there is likely a social and economic benefit of S. boulardii CNCM I-745 in adjunction to oral rehydration solution in acute infectious gastroenteritis in children.Dinleyici EC, Kara A, Dalgic N, et. al. Saccharomyces boulardii CNCM I-745 reduces the duration of diarrhoea, length of emergency care and hospital stay in children with acute diarrhoea. Benef Microbes. 2015;6(4):415-21. PubMed PMID: 25653151.Other types of diarrhea11. Lactobacillus rhamnosus?GG best for antibiotic associated diarrheaBACKGROUND: Probiotics?are commonly used for the prevention of antibiotic-associated diarrhea (AAD). However, the optimum regimen remains controversial.OBJECTIVE: The objective of this article is to compare and rank the relative efficacy and tolerability among all available probiotic agents for AAD through a network meta-analysis.METHODS: Eligible studies were identified by searching PubMed, Embase, Medline, Cochrane library and Web of Science for randomized controlled trials (RCTs) that examined the efficacy of probiotic therapy for AAD. A random-effects model was applied within a frequentist framework. Quality of evidence was performed by the GRADE approach. The project was prospectively registered with PROSPERO (CRD 42016050776).RESULTS: Fifty-one articles (60 comparisons, 9569 participants), including 10 probiotic interventions, were identified.?Lactobacillus rhamnosus?GG (LGG) had the highest probability of being ranked best both in effectiveness (odds ratio (OR), 95% confidence interval (CI) = 0.28 (0.17, 0.47)) and tolerance (0.44 (0.23, 0.84)) on prevention of AAD. With regard to reducing?Clostridium difficile?infection rate,?Lactobacillus casei?(L. casei) was considered better efficacy (0.04 (0.00, 0.77)) and medium tolerance (0.56 (0.19, 1.66)). Strain combination reported no superiority over single strain in either efficacy or tolerability.CONCLUSIONS: LGG is probably the best option to consider when AAD is indicated.?L. casei?appears to be the most efficacious choice when associated with severe?C. difficile-related cases.Cai J, Zhao C, Du Y, Zhang Y, Zhao M, Zhao Q. Comparative efficacy and tolerability of probiotics for antibiotic-associated diarrhea: Systematic review with network meta-analysis. United European Gastroenterol J. 2018 Mar;6(2):169-180.12. Travelers’ diarrheaBACKGROUND: Travellers' diarrhea (TD) impacts annually over 20 million tourists, business travellers and military troops on a worldwide basis. Reliance on antibiotic prophylaxis and educational programs has not led to a significant reduction in TD rates. Previous reviews of?probiotics?for TD have not accounted for the strain-specificity of probiotic efficacy nor have investigated prebiotics for the prevention of TD.METHODS: Standard literature databases were searched from 1977 to June 2018 unrestricted by language. Inclusion criteria included: Probiotic, probiotic or symbiotic interventions, randomized, controlled clinical trials (RCTs) and ≥2 RCTs with the same probiotic strain or mixture.RESULTS: Of 158 screened articles, 12 RCT were included in the?systematic?review and 6 RCTs (with nine treatment different arms) were included in the meta-analysis. Saccharomyces boulardii CNCM I-745 showed a significant reduction in TD incidence (RR?=?0.79, 95% C.I. 0.72-0.87, p?<?0.001), while L. rhamnosus GG showed a trend (p?=?0.08) and L. acidophilus showed no significant (p?=?0.16) reduction of TD.CONCLUSIONS: The number of trials using?probiotics?or prebiotics for the prevention of TD continues to be limited in number. Only one of three?probiotics?showed significant efficacy for the prevention of TD. More research is needed for other?probiotics?strains and prebiotics to determine if they could also prevent TD.McFarland LV, Goh S.Are probiotics and prebiotics effective in the prevention of travellers' diarrhea: A systematic review and meta-analysis. Travel Med Infect Dis. 2019 Jan - Feb;27:11-19.13. Probiotics reduce the incidence of clostridium difficile diarrhea in higher risk patientsBACKGROUND: Antibiotics can disturb gastrointestinal microbiota which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile).?Probiotics?are live microbial preparations that, when administered in adequate amounts, may confer a health benefit to the host, and are a potential C. difficile prevention strategy. Recent clinical practice guidelines do not recommend probiotic prophylaxis, even though?probiotics?have the highest quality evidence among cited prophylactic therapies.OBJECTIVES: To assess the efficacy and safety of?probiotics?for preventing C.difficile-associated diarrhea (CDAD) in adults and children.SEARCH METHODS: We searched PubMed, EMBASE, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 21 March 2017. Additionally, we conducted an extensive grey literature search.SELECTION CRITERIA: Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating?probiotics?(any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion.DATA COLLECTION AND ANALYSIS: Two authors (independently and in duplicate) extracted data and assessed risk of bias. The primary outcome was the incidence of CDAD. Secondary outcomes included detection of C. difficile infection in stool, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. The overall quality of the evidence supporting each outcome was independently assessed using the GRADE criteria.MAIN RESULTS: Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that?probiotics?reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of?probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the?probiotics?group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates?probiotics?reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. AUTHORS' CONCLUSIONS: Based on this?systematic?review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that?probiotics?are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that?probiotics?are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk ≤5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of?probiotics?appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of?probiotics.Goldenberg JZ, Yap C, Lytvyn L, Lo CK, Beardsley J, Mertz D, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017 Dec 19;12:CD006095.Childhood functional abdominal pain and constipationAlthough lactobacillus rhanmosus somewhat reduces symptoms of irritable bowel syndrome in children, overall, they do not appear to be effective for functional abdominal pain or constipation in children.14. Probiotics not effective for children with functional abdominal pain or constipationOBJECTIVE:?The objective of this study was to investigate the effect of probiotics on functional abdominal pain disorders (FAPD) and functional constipation (FC).METHODS:?A systematic review was conducted, searching PubMed and Cochrane databases from inception to January 2018 for randomized controlled trials (RCTs) investigating the efficacy of probiotics in children aged 4 to 18 years with FAPD or children aged 0 to 18 years with FC.RESULTS:?A total of 657 citations were identified. Finally, 11 RCTs for FAPD and 6 RCTs for FC were included. Some evidence exists for Lactobacillus rhamnosus GG (n=3) in reducing frequency and intensity of abdominal pain in children with irritable bowel syndrome. There is no evidence to recommend L. reuteri DSM 17938 (n=5), a mix of Bifidobacterium infantis, Bifidobacterium breve and Bifidobacterium longum (n=1), Bifidobacterium lactis (n=1) or VSL#3 (n=1) for children with FAPD. No evidence exists to support the use of Lactobacillus casei rhamnosus LCR35 (n=1), B. lactis DN173 010 (n=1), B. longum (n=1), L. reuteri DSM 17938 (n=1), a mix of B. infantis, B. breve and B. longum (n=1), or Protexin mix (n=1) for children with FC. In general, studies had an unclear or high risk of bias.CONCLUSIONS:?Insufficient evidence exists for the use of probiotics in FAPD and FC, only L. rhamnosus GG seems to reduce frequency and intensity of abdominal pain but only in children with irritable bowel syndrome. A better understanding of differences in gut microbiota in health and disease might lead to better probiotic strategies to treat disease.Carrie A M Wegh, Marc A Benninga, Merit M Tabbers. Effectiveness of Probiotics in Children With Functional Abdominal Pain Disorders and Functional Constipation: A Systematic Review. Journal of Clinical Gastroenterology 2018, 52 Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition & Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12, 2017: S10-S26And from another systematic review: “Limited evidence does not support the use of any of currently evaluated probiotics in the treatment of functional constipation in children. Probiotics are ineffective for the management of functional constipation in children in terms of treatment success, frequency of fecal incontinence, and frequency of abdominal pain.” Systematic review: probiotics for functional constipation in children. European Journal of Pediatrics 176(10):1-8 · August 2017Two studies have shown some effectiveness for constipation in adults, but the evidence is not strong. Effect of the probiotic strain Bifidobacterium animalis subsp. lactis, BB-12(R), on defecation frequency in healthy subjects with low defecation frequency and abdominal discomfort: a randomised, double-blind, placebo-controlled, parallel-group trial. The British journal of nutrition. 2015;114(10):1638-1646. Effect of a fermented milk containing Bifidobacterium lactis DN-173010 on Chinese constipated women. World journal of gastroenterology. 2008;14(40):6237-6243.Diabetes mellitusProbiotics appear to have some positive effects on metabolic parameters of patients with type 2 diabetes, thought the clinical importance is not known. Probiotics did not prevent gestational diabetes in one recent randomized trial. 15. 7-strain probiotic mix reduced fasting blood sugar, increased HDL cholesterol and did not affect insulin level, total cholesterol and insulin resistanceAIMS: The role of gut microbiota in the pathogenesis of diabetes is increasing; this study investigates the effect of multi-strain?probiotics?on fasting plasma glucose (FPG), plasma insulin and lipid profile among patients.METHODS: This randomized double-blind controlled trial was performed among 60 patients; individuals were randomly assigned into 2 groups of 30 participants in order to take either probiotic supplements or placebo for 6 weeks. The probiotic supplement consisted of 7 viable strains Lactobacillus, Bifidobacterium and Streptococcus. Nutrient intakes were estimated using a 3-day and 24 hour-dietary recall at the beginning and end of study. Fasting blood samples were taken before and after intervention to measure the levels of FPG, plasma insulin and lipid profiles.RESULTS: Within group comparisons showed significant decrease and increase in the levels of FPG (P?=?0.001) and HDL-C (P?=?0.002) in probiotic group, respectively. No significant alterations were observed for within and between group comparisons in the levels of insulin, triglycerides, total cholesterol, insulin resistance and anthropometric measurements, including weight, waist circumference and body mass index (all P?>?0.05).CONCLUSIONS: This study showed a significant decrease in FPG level by multi-strain probiotic supplements in within group comparison; though, further studies are needed to confirm results.Razmpoosh E, Javadi A, Ejtahed HS, Mirmiran P, Javadi M, Yousefinejad A.The effect of probiotic supplementation on glycemic control and lipid profile in patients with type 2 diabetes: A randomized placebo controlled trial. Diabetes Metab Syndr. 2019 Jan - Feb;13(1):175-182.16. Probiotics and synbiotics improve metabolic parameters in people with type 2 diabetes mellitusPurpose:?Diabetes Mellitus (T2DM) as a chronic disease, is on rise in parallel with other non-communicable diseases. Several studies have shown that?probiotics?and prebiotics might exert beneficial effects in chronic diseases including diabetes. Because of controversial results from different trials, the present study aims to assess the effects of prebiotic/synbiotic consumption on metabolic parameters in patients with type2 diabetes.?Methods:?A systematic literature search was performed on randomized controlled trial published in PubMed/Medline, SciVerse Scopus, Google scholar, SID and Magiran up to March 2018. Of a total number of 255 studies found in initial literature search, ten randomized controlled trials were included in the meta-analysis. The pooled mean net change were calculated in fasting blood-glucose [FBG], Hemoglobin A1c [HbA1c] and lipid markers (total cholesterol [TC], triglyceride [TG], low-density lipoprotein cholesterol [LDL-C], high density lipoprotein cholesterol [HDL-C]). The meta-analyses was conducted using Revman Software (v5.3).?Results:?The pooled estimate indicated a significant difference for the mean change in FBG, HbA1c and HDL in treatment group in comparison with control group. Subgroup analysis by intervention showed a significant difference in TG, LDL and HDL (synbiotic group) and in TG, TC, FBG, HDL and HbA1c (prebiotic group) compared with placebo. In another subgroup analysis, high quality studies showed significant reductions in TG, TC, FBG and HbA1c in intervention group compared with placebo group.?Conclusion:?In summary, diets supplemented with either prebiotics or synbiotics can result in improvements in lipid metabolism and glucose homeostasis in type 2 diabetic patients.Mahboobi S, Rahimi F, Jafarnejad S. Effects of Prebiotic and Synbiotic Supplementation on Glycaemia and Lipid Profile in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Adv Pharm Bull. 2018 Nov;8(4):565-574.17. Probiotics do not prevent gestational diabetesOBJECTIVE: Given the role of gut microbiota in regulating metabolism,?probiotics?administered during pregnancy might prevent gestational diabetes mellitus (GDM). This question has not previously been studied in high-risk overweight and obese pregnant women. We aimed to determine whether?probiotics?(Lactobacillus rhamnosus?and?Bifidobacterium animalis?subspecies?lactis?[BB-12]) administered from the second trimester in overweight and obese women prevent GDM as assessed by an oral glucose tolerance test (OGTT) at 28 weeks' gestation. Secondary outcomes included maternal and neonatal complications, maternal blood pressure and BMI, and infant body composition.RESEARCH DESIGN AND METHODS: This was a double-blind randomized controlled trial of probiotic versus placebo in overweight and obese pregnant women in Brisbane, Australia.RESULTS: The study was completed in 411 women. GDM occurred in 12.3% (25 of 204) in the placebo arm and 18.4% (38 of 207) in the?probiotics?arm (P?= 0.10). At OGTT, mean fasting glucose was higher in women randomized to?probiotics?(79.3 mg/dL) compared with placebo (77.5 mg/dL) (P?= 0.049). One- and two-hour glucose measures were similar. Preeclampsia occurred in 9.2% of women randomized to?probiotics?compared with 4.9% in the placebo arm (P?= 0.09). Excessive weight gain occurred in 32.5% of women in the?probiotics?arm (55 of 169) compared with 46% in the placebo arm (81 of 176) (P?= 0.01). Rates of small for gestational age (<10th percentile) were 2.4% in the?probiotics?arm (5 of 205) and 6.5% in the placebo arm (13 of 199) (P?= 0.042). There were no differences in other secondary outcomes.CONCLUSIONS: The?probiotics?used in this study did not prevent GDM in overweight and obese pregnant women.Callaway LK, McIntyre HD, Barrett HL, et. al. Probiotics for the Prevention of Gestational Diabetes Mellitus in Overweight and Obese Women: Findings From the SPRING Double-blind Randomized Controlled Trial. Diabetes Care. 2019 Jan 18. 18. Choosing the appropriate probioticINTRODUCTION: Clinicians and patients face a daunting task when choosing the most appropriate probiotic for their specific needs. Available preparations encompass a diverse and continuously expanding product base, with most available products lacking evidence-based trials that support their use. Even when evidence exists, not all probiotic products are equally effective for all disease prevention or treatment indications. At this point in time, drug regulatory agencies offer limited assistance with regard to guidance and oversight in most countries, including the U.S.METHODS: We reviewed the current medical literature and sources on the internet to survey the types of available probiotic products and to determine which?probiotics?had evidence-based efficacy data. Standard medical databases from inception to June 2018 were searched and discussions with experts in the field were conducted. We graded the strength of the evidence for?probiotics?having multiple, randomized controlled trials and developed a guide for the practical selection of current probiotic products for specific uses.RESULTS: We found the efficacy of probiotic products is both strain-specific and disease-specific. Important factors involved in choosing the appropriate probiotic include matching the strain(s) with the targeted disease or condition, type of formulation, dose used and the source (manufacturing quality control and shelf-life). While we found many probiotic products lacked confirmatory trials, we found sufficient evidence for 22 different types of?probiotics?from 249 trials to be included. For example, several types of?probiotics?had strong evidence for the prevention of antibiotic-associated diarrhea [Saccharomyces boulardii I-745, a three-strain mixture (Lactobacillus acidophilus CL1285, L. casei Lbc80r, L. rhamnosus CLR2) and L. casei DN114001]. Strong evidence was also found for four types of?probiotics?for the prevention of a variety of other diseases/conditions (enteral-feed associated diarrhea, travellers' diarrhea, necrotizing enterocolits and side-effects associated with H. pylori treatments. The evidence was most robust for the treatment of pediatric acute diarrhea based on 59 trials (7 types of?probiotics?have strong efficacy), while an eight-strain multi-strain mixture showed strong efficacy for inflammatory bowel disease and two types of?probiotics?had strong efficacy for irritable bowel disease. Of the 22 types of?probiotics?reviewed, 15 (68%) had strong-moderate evidence for efficacy for at least one type of disease.CONCLUSION: The choice of an appropriate probiotic is multi-factored, based on the mode and type of disease indication and the specific efficacy of probiotic strain(s), as well as product quality and formulation.Sniffen JC, McFarland LV, Evans CT, Goldstein EJC. Choosing an appropriate probiotic product for your patient: An evidence-based practical guide. PLoS One. 2018 Dec 26;13(12):e0209205. Although probiotics may help prevent eczema in children, they do not help established eczema. Probiotics for treating eczema. Cochrane Database Syst Rev. 2018 Nov 21;11:CD006135. Probiotics do not help chronic kidney disease. Prebiotic, Probiotic, and Synbiotic Supplementation in Chronic Kidney Disease: A Systematic Review and Meta-analysis. J Ren Nutr. 2018 Oct 23. pii: S1051-2276(18)30191-2.Probiotics may be helpful for cystic fibrosis. Systematic Review of Probiotics for Cystic Fibrosis Patients: Moving Forward. J Pediatr Gastroenterol Nutr. 2018 Oct 24.Probiotics may be helpful for IBS, but evidence is weak and what formula is best is unclear. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome.Aliment Pharmacol Ther. 2018 Nov;48(10):1044-1060.Probiotics may reduce antibiotic use in infants and children. Does probiotic consumption reduce antibiotic utilization for common acute infections? A systematic review and meta-analysis. Eur J Public Health. 2018 Sep 14.There is no evidence of benefit of probiotics for treating childhood asthma. Probiotics supplementation in children with asthma: A systematic review and meta-analysis. J Paediatr Child Health. 2018 Sep;54(9):953-961.Probiotics are not effective for fibromyalgia. Benef Microbes. 2018 Jun 15;9(4):603-611. Are probiotic treatments useful on fibromyalgia syndrome or chronic fatigue syndrome patients? A systematic review.Probiotics provide minimal relief for symptoms of vaginal yeast infections. Probiotics for vulvovaginal candidiasis in non-pregnant women. Cochrane Database Syst Rev. 2017 Nov 23;11:CD010496. Not so much for halitosis. The Effect of Probiotics on Halitosis: a Systematic Review and Meta-analysis. Probiotics Antimicrob Proteins. 2017 Nov 22.Not for obesity. Effects of probiotics on body weight, body mass index, fat mass and fat percentage in subjects with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials. Obes Rev. 2018 Feb;19(2):219-232.Bottom LinesLactobacillus rhamnosus HN001 appears effective in preventing childhood eczema, but other probiotics do not.L. rhamnosus?and?L. reuteri?reduce crying time in colicky, breast-fed infants. It is uncertain if they are effective for bottle-fed infants.Lactobacillus rhamnosus does not reduce diarrhea in children with acute gastroenteritis, but Lactobacillus reuteri DSM 17938 and S. boulardii CNCM I-745 may reduce duration of diarrhea by about 1 day.Saccharomyces boulardii CNCM I-745 significantly reduced travelers’ diarrhea, but L. rhamnosus GG and L. acidophilus did not. Probiotics reduce the incidence of Clostridium difficile diarrhea in high risk patients.Probiotics improve metabolic parameters for patients with type 2 diabetes, but the clinical significance is not known. All probiotics are not equally effective. When recommending probiotics, consult a reference and use the ones with evidence to support effectiveness. AppendixRecommendations for specific probiotic strains (products) and dosages for specific indications are provided in the following table. (from Merenstein, Journal of Family Practice. accepted for publication)Selecting a probioticCommonly used probiotics with good evidence (either SORT Grade A/Level 1 or evidence that has been systematically reviewed by select expert panels who offered a recommendation for use). All products are dietary supplements unless otherwise indicated. NNT, number needed to treat; AAD, antibiotic-associated diarrhea; CFU, colony forming units; CDI, Clostridium difficile infection; CDAD, Clostridium difficile-associated diarrhea; B., Bifidobacterium; L., Lactobacillus; S., Saccharomyces; C., Clostridium; RCT, randomized, controlled trial; ESPGHAN, European Society for Paediatric Gastroenterology, Hepatology and Nutrition; GRADE, Grading of Recommendations Assessment, Development and Evaluation.Endpoint, Study EffectProbiotic Strain(s)Examples of Product Brand NamesDosage (in CFU/d, unless Otherwise specified)Estimated NNT (95% CI) or effect sizeAntibiotic associated diarrhea, reduced incidenceL. rhamnosus GGCulturelle1-40 billion 6.6 [4.5, 12.0]S. boulardii CNCM I-745 Florastor226 – 1000 mg/d10 [9, 13] L. casei DN-114 001, S. thermophilus + L. bulgaricus Actimel/DanActive (fermented milk product from Danone)20 billion L. casei DN-114 001 & S. thermophilus; 2 billion L bulgaricus 5 [3, 15] L. acidophilus CL1285, L. casei LBC80R, + L. rhamnosus CLR2fBio K+ or Bio K+ CL128550 billion to 100 billion CFU/day9.0 [5.6, 21.9] for 50 billion CFU / day3.5 [2.4, 6.3] for 100 billion CFU / dayimproved therapeutic efficacy of antibiotic treatment of bacterial vaginosisL. rhamnosus GR-1 +L. reuteri RC-14 Fem-DophilusRePhresh ProB4 billion3.7 [2.5, 6.6] Colic in breast fed infants, reduced symptoms and crying timeL. reuteri DSM17938 BioGaia ProTectis100 million 2.6 [2.0, 3.6] Clostridium difficile diarrhea, reduced incidenceS. boulardii CNCM I-745Florastord10 to 30 billion CFU/day41.2 [25.2, 108.1] L. acidophilus CL1285, L. casei, +L. rhamnosus CLR2fBio K+ or Bio K+ CL128550 billion to 100 billion CFU/day30.3 [16.3, 211.5] for 50 billion CFU/day4.3 [3.0, 7.1] for 100 billion CFU/dayL. casei DN-114 001, L. bulgaricus + S. thermophilusDanActive (fermented milk)20 billion L. casei DN-114 001 & 20 billion S. thermophilus; 2 billion L. bulgaricus 5[3, 15]PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaWNrc29uPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48

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ADDIN EN.CITE.DATA 36Constipation, management of symptomsB. lactis BB-12See footnotei1 billion – 10 billionjRisk difference (95% CI) of 10.4 (4.7, 16.0) percentage points a NNT (95%) of 9.6 (6.2, 21.2).B. lactis DN-173010, L. bulgaricus, S. thermophilus + Lactococcus lactis Activia12 billion B. lactis DN-1730101 billion L. bulgaricus, S. thermophilus + Lactococcus lactis 40% increase in stool frequency by week one and 58% by week twoAcute pediatric diarrhea, treatmentS. boulardii CNCM I-745Florastord10 billion CFUReduced duration of diarrhea, mean 19.7 hoursL. reuteri DSM 17938 BioGaia ProTectis100 million - 400 millionNNT (95% CI): Day 1 Cure = 8.0 (5.5, 14.8); Mean difference in diarrhea duration, -24.82 h (95% CI: -38.8 to -10.8 h)GI And Liver Update | 2019 Ferenchick, MD, MSLearning objectives: Understand:1. Highlights from recent consensus documents on H pylori 2. H pylori is the major risk factor for gastric cancer (GC)3. Eradication of HP is associated with less risk for GC4. PPI AND ASA for 9 years improves outcomes in patients with Barrett’s Esophagus (BE)5. AGA and CAG clinical guideline on dyspepsia 6. Diet quality is associated with hepatic steatosisIn the past four years, two major consensus reports and one guideline on H pylori infection have been published. Highlights from each of these three documents are outlined belowBottom line: All H pylori infections should be considered pathogenic and should be eradicatedKyoto global consensus report (2015)"H. pylori causes a chronic infection, similar to asymptomatic syphilis or tuberculosis; and the final outcome for any individual cannot be predicted. “H. pylori gastritis may remain clinically unapparent or evolve into severe complications.HP leads to chronic active gastritis of varying severity in virtually all infected subjects and causes progressive damage to the gastric mucosa, leading to: peptic ulcer disease (gastric and duodenal), gastric adenocarcinoma and gastric MALT (mucosa-associated lymphoid tissue) lymphoma “The rate of progression is unpredictable and "... most patients with chronic gastritis may remain asymptomatic until the appearance of severe complications."Importantly not all patients with dyspeptic symptoms are infected with HP, and not all HP infected patients are symptomaticMaastricht V/Florence Consensus Report (2017)“H. pylori infection is accepted as the major etiological factor for gastric cancer.”“…it is acknowledged that at least 90% of (gastric) cancers are related to H. pylori infection.”“…the International Agency for Research on Cancer (IARC) monographs classify H. pylori as a group 1 carcinogen that causes NCGC (non-cardia gastric cancer re: distal CA)”“H. pylori eradication reduces the risk of gastric cancer development”“There is evidence linking H. pylori to unexplained iron deficiency anaemia (IDA), idiopathic thrombocytopenic purpura (ITP), and vitamin B12 deficiency. In these disorders, H. pylori should be sought and eradicated”“The use of aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) increases the risk of ulcer disease in H. pylori infected subjects. H. pylori ‘test-and-treat’ strategiesUninvestigated dyspepsia (in absence of alarm symptoms)Iron deficiency anemiaITPB12 deficiencyH. pylori ‘screen-and-treat’ strategiesRecommended in communities at high risk of gastric cancerShould be considered in communities with intermediate to low risk for gastric cancerIndividuals at high risk of gastric cancer (positive family history)Long-term ASA or NSAID use (with a history of PUD) – use PPI alsoThe economic benefit of H. pylori eradication is greater if reductions on dyspepsia and peptic ulcer disease are consideredTesting optionsUrea breath test (UBT) is the most investigated and best recommended non-invasive test in the context of a ‘test-and-treat strategy’.Stool antigen tests (SATs) may less acceptable but has high sensitivity and specificityPPIs should be discontinued for 2 weeks prior to testing (UBT AND SAT) as PPIs have anti-H. pylori activity leading to false negative tests.No need to discontinue H2 blockers or antacids (aside from bismuth)Locally validated serological testsUnder certain clinical circumstances, there are important local changes that may lead to a low bacterial load in the stomach and to a decreased sensitivity of all diagnostic methods except serology. These clinical situations include GI bleeding, atrophic gastritis, gastric MALT lymphoma, and gastric carcinoma.Because serology is able to detect past infection with H. pylori it should not be used as a method to monitor effectiveness of eradication.Confirmation of eradicationUBT is the best option for confirmation of H. pylori eradication and monoclonal SAT is an alternative. It should be performed at least 4 weeks after completion of therapy. (Same PPI recommendations as above)American College of Gastroenterology | 2107“All patients with a positive test of active infection with H. pylori should be offered treatment;”The critical issue is which patients should be tested for the infection. The AGA recommends All patients with PUD (active or past hx)Hx of MALT Lymphoma | Hx endoscopic resection of gastric CAPts < 60 with uninvestigated dyspepsia (pain or discomfort centered in the upper abdomen) without alarm features – “consider” non-endoscopic testingPatients taking long-term, low-dose aspirin or NSAIDs to reduce risk of bleeding ulcer“Eradication of H. pylori infection before starting NSAID therapy may be the single most cost-effective strategy for the primary prevention of NSAID-associated ulcers in adult patients”“The benefit of H. pylori eradication in patients already taking NSAIDs is less clear”Pts with unexplained iron deficiency anemia despite an appropriate evaluationAdults with idiopathic thrombocytopenic purpura (ITP)“A systematic review of 25 studies (1555 adult patients), all of which included at least 15 patients, found that platelet counts in ITP patients tended to increase after H. pylori eradication”Whenever H. pylori infection is identified and treated, testing to prove eradication should be performed using a urea breath test, fecal antigen test or biopsy-based testing at least 4 weeks after the completion of antibiotic therapy and after PPI therapy has been withheld for 1–2 weeks“When conducted properly, the urea breath test, fecal antigen test, and endoscopic tests all are highly sensitive and specific at detecting persistent H. pylori infection.”NO TestingPatients with typical symptoms of (GERD) who do not have a history of PUD need not be tested for H. pylori infection.#1: PubMed: Kyoto global consensus report on Helicobacter pylori gastritis OBJECTIVE: To present results of the Kyoto Global Consensus Meeting, which was convened to develop global consensus on (1) classification of chronic gastritis and duodenitis, (2) clinical distinction of dyspepsia caused by Helicobacter pylori from functional dyspepsia, (3) appropriate diagnostic assessment of gastritis and (4) when, whom and how to treat H. pylori gastritis.DESIGN: Twenty-three clinical questions addressing the above-mentioned four domains were drafted for which expert panels were asked to formulate relevant statements. A Delphi method using an anonymous electronic system was adopted to develop the consensus, the level of which was predefined as ≥80%. Final modifications of clinical questions and consensus were achieved at the face-to-face meeting in Kyoto.RESULTS: All 24 statements for 22 clinical questions after extensive modifications and omission of one clinical question were achieved with a consensus level of >80%. To better organize classification of gastritis and duodenitis based on aetiology, a new classification of gastritis and duodenitis is recommended for the 11th international classification. A new category of H.pylori-associated dyspepsia together with a diagnostic algorithm was proposed. The adoption of grading systems for gastric cancer risk stratification, and modern image-enhancing endoscopy for the diagnosis of gastritis, were recommended. Treatment to eradicate H. pylori infection before preneoplastic changes develop, if feasible, was recommended to minimize the risk of more serious complications of the infection.CONCLUSIONS: A global consensus for gastritis was developed for the first time, which will be the basis for an international classification system and for further research on the subject.REFERENCES: Sugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut. 2015 Sep;64(9):1353-67.#2 Maastricht V/Florence Report: Management of Helicobacter pylori InfectionImportant progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.Reference: Malfertheiner P et al for the European Helicobacter and Microbiota Study Group and Consensus panel.Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut. 2017 Jan;66(1):6-30.#3 ACG Clinical Guideline: Treatment of Helicobacter pylori InfectionHelicobacter pylori (H. pylori) infection is a common worldwide infection that is an important cause of peptic ulcer disease and gastric cancer. H. pylori may also have a role in uninvestigated and functional dyspepsia, ulcer risk in patients taking low-dose aspirin or starting therapy with a non-steroidal anti-inflammatory medication, unexplained iron deficiency anemia, and idiopathic thrombocytopenic purpura. While choosing a treatment regimen for H. pylori, patients should be asked about previous antibiotic exposure and this information should be incorporated into the decision-making process. For first-line treatment, clarithromycin triple therapy should be confined to patients with no previous history of macrolide exposure who reside in areas where clarithromycin resistance amongst H. pylori isolates is known to be low. Most patients will be better served by first-line treatment with bismuth quadruple therapy or concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and metronidazole. When first-line therapy fails, a salvage regimen should avoid antibiotics that were previously used. If a patient received a first-line treatment containing clarithromycin, bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options. If a patient received first-line bismuth quadruple therapy, clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options. Details regarding the drugs, doses and durations of the recommended and suggested first-line and salvage regimens can be found in the guideline.Reference: Chey WD et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017 Feb;112(2):212-239.#4 The overall prevalence of H Pylori worldwide is 44%BACKGROUND: The epidemiology of Helicobacter pylori infection is poorly understood.AIM: To establish the reported regional and national prevalence of H. pylori infection, stratified by age and gender.METHODS: All relevant English publications from 2000 to 2017 cited by PubMed and Scopus were retrieved using comprehensive combinations of keywords. The overall prevalence of H. pylori was estimated using both random effect and fixed effect meta-analyses, and presented as prevalence rate (% and 95% CI). The analyses were extended by separation into gender and age groups.RESULTS: A total of 14?056 records were obtained initially. After applying exclusion criteria in several steps, 183 studies were selected. Analysis of 410?879 participants from 73 countries in six continents revealed an overall prevalence of 44.3% (95% CI: 40.9-47.7) worldwide. This rate ranged from 50.8% (95% CI: 46.8-54.7) in developing countries compared with 34.7% (95% CI: 30.2-39.3) in developed countries. The global H. pylori infection rate was 42.7% (95% CI: 39-46.5) in females compared to 46.3% (95% CI: 42.1-50.5) in males. The prevalence in adults (≥18?years) was significantly higher than in children (48.6% [95% CI: 43.8-53.5] vs 32.6% [95% CI: 28.4-36.8], respectively). There was a statistically nonsignificant decrease in the prevalence in 2009-2016 compared with the 2000-2009 period.CONCLUSIONS: The observed differences between countries appear to be due to economic and social conditions. H. pylori infection can be a benchmark for the socioeconomic and health status of a country. Further studies are suggested to investigate the natural history of the acquisition of H. pylori infection from childhood into adult life.REFERENCE: Zamani M et al. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Aliment Pharmacol Ther. 2018 Apr;47(7):868-876. H Pylori and Gastric CancerGastric cancer is preventable through the eradication of H pylori. The following studies all demonstrate that GC risk reduction is greatest many years after H pylori treatment. #5 Cohort Study: Treating H Pylori associated with lower gastric cancer risk in older patientsBACKGROUND & AIMS: Eradication of Helicobacter pylori infection has been reported to reduce the risk of gastric cancer among asymptomatic individuals in high-risk areas. The magnitude of benefit of H pylori eradication in populations with different levels of gastric cancer risk and in different clinical scenarios is unclear. We performed a systematic review and meta-analysis of randomized controlled trials and observational studies to investigate the effects of H pylori eradication on the incidence of gastric cancer.METHODS: We searched PubMed, Cochrane Library, and , reviewing titles and abstracts of studies of the effects of eradication of H pylori infection on risk of gastric cancer, through May 2015. We also searched bibliographies of included studies, related reviews, and abstracts presented at Digestive Disease Week. Twenty-four eligible studies (22 research manuscripts and 2 abstracts) were included in our meta-analysis (715 incident gastric cancers among a total of 48,064 individuals/340,255 person-years). We assessed the effects, as well as their modification by baseline gastric cancer incidence, study design (randomized trial vs observational study), clinical scenario (asymptomatic infected individuals vs individuals after endoscopic resection of early gastric cancer), demographic characteristics of patients (age and sex), and duration of follow-up.RESULTS: After adjustment for baseline gastric cancer incidence, individuals with eradication of H pylori infection had a lower incidence of gastric cancer than those who did not receive eradication therapy (pooled incidence rate ratio = 0.53; 95% confidence interval: 0.44-0.64). There was little heterogeneity among studies. Baseline gastric cancer incidence modified the benefit of H pylori eradication (P = .037 for interaction); the incidence rate ratio of gastric cancer decreased in a nonlinear fashion with increasing baseline incidence of gastric cancer (P = .018, in comparison with the linear model). The benefit also modestly increased with age (P = .023 for interaction), but this might be due to correlation between age and baseline gastric cancer incidence. Eradication provided significant benefit for asymptomatic infected individuals (pooled incidence rate ratio, 0.62; 95% CI: 0.49-0.79) and individuals after endoscopic resection of gastric cancers (pooled incidence rate ratio, 0.46; 95% CI: 0.35-0.60). The benefits of H pylori eradication did not differ with study design, sex, or follow-up period.CONCLUSIONS: In a systematic review and meta-analysis, we associated eradication of H pylori infection with a reduced incidence of gastric cancer. The benefits of eradication vary with baseline gastric cancer incidence, but apply to all levels of baseline risk.REFERENCE: Lee YC et al. Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: A Systematic Review and Meta-analysis. Gastroenterology. 2016 May;150(5):1113-1124.e5.#6 Cohort Study: Treating H Pylori associated with lower gastric cancer risk in older patientsBACKGROUND & AIMS: Although eradication of Helicobacter pylori infection reduces the risk of gastric cancer, few data are available on its effects in older subjects. We compared the age-specific risk of gastric cancer in a large cohort of subjects who received H pylori eradication therapy vs a matched general population.METHODS: We searched the Hospital Authority database of Hong Kong to identify individuals with H pylori infection who had received a course of clarithromycin-containing eradication therapy from January 2003 through December 2012. We compared the gastric cancer incidence in this cohort with the expected incidence for the local general population by retrieving the gastric cancer incidence of the age- and sex-matched population from 2003 through 2014 (the latest available year) from the Hong Kong Cancer Registry. The primary outcome was the incidence of gastric cancer development in the cohort treated for H?pylori infection vs the expected number of gastric cancer cases in the general population. Analyses were conducted by a priori age groups of less than 40 years,40-59 years, and 60 years or older.RESULTS: Among 73,237 subjects infected with H pylori who received eradication therapy, 200 (0.27%) developed gastric cancer during a median follow-up time of 7.6 years. Compared with the matched general population, the gastric cancer risk was significantly lower in subjects 60 years or older who had received H pylori treatment (standardized incidence ratio [SIR], 0.82; 95% confidence interval [CI], 0.69-0.97; P?= .02) but not in younger groups. When data were stratified based on time from H pylori treatment (less than 5 years, 5-9 years, and 10 or more years), the risk of gastric cancer was significantly lower than the general population 10 or more years after eradication in the group 40-59 years old (SIR 0.32; 95% CI, 0.08-0.88; P?= .04) and the group 60?years or older (SIR, 0.42; 95% CI, 0.42-0.84; P?= .02) than the other age groups.CONCLUSIONS: In an analysis of data from a public hospital database on Hong Kong, we associated treatment of H pylori infection with a lower risk of gastric cancer, particularly in older subjects, 10 or more years after treatment.REFERENCE: Leung WK et al. Effects of Helicobacter pylori Treatment on Incidence of Gastric Cancer in Older Individuals. Gastroenterology. 2018 Jul;155(1):67-75. #7 Cohort Study: Treating H Pylori associated with lower gastric cancer risk OBJECTIVE: Gastric infection with Helicobacter pylori is a strong risk factor for non-cardia gastric adenocarcinoma. The aim of this study was to assess whether the risk of gastric adenocarcinoma and non-cardia gastric adenocarcinoma decreases after eradication treatment for H. pylori in a Western population.DESIGN: This was a nationwide, population-based cohort study in Sweden in 2005-2012. Data from the Swedish Prescribed Drug Registry provided information on H. pylori eradication treatment, whereas information concerning newly developed gastric adenocarcinoma was retrieved from the Swedish Cancer Registry. The risk of gastric adenocarcinoma and non-cardia gastric adenocarcinoma in individuals who had received H. pylori eradication treatment was compared with the background population of the corresponding age, sex and calendar year distribution, yielding standardised incidence ratios (SIRs) with 95% CIs.RESULTS: During the follow-up of 95?176 individuals who had received eradication treatment (351?018 person-years at risk), 75 (0.1%) developed gastric adenocarcinoma and 69 (0.1%) developed non-cardia gastric adenocarcinoma. The risk of gastric adenocarcinoma decreased over time after eradication treatment to levels below that of the corresponding background population. The SIRs were 8.65 (95% CI 6.37 to 11.46) for 1-3 years, 2.02 (95% CI 1.25 to 3.09) for 3-5 years and 0.31 (95% CI 0.11 to 0.67) for 5-7.5 years after eradication treatment. When restricted to non-cardia adenocarcinoma, the corresponding SIRs were 10.74 (95% CI 7.77 to 14.46), 2.67 (95% CI 1.63 to 4.13) and 0.43 (95% CI 0.16 to 0.93).CONCLUSION: Eradication treatment for H. pylori seems to counteract the development of gastric adenocarcinoma and non-cardia gastric adenocarcinoma in this Western population.REFERENCE: Doorakkers E et al. Helicobacter pylori eradication treatment and the risk of gastric adenocarcinoma in a Western population. Gut. 2018 Dec;67(12):2092-2096. #8 Cohort Study: Treating H Pylori associated with lower gastric cancer risk BACKGROUND: Helicobacter pylori (H. pylori) is considered to be the most important risk factor for gastric cancer (GC). The International Agency for Research on Cancer reported that H. pylori eradication could reduce the risk of developing GC. Several clinical studies have investigated this relationship as well; however, their results are inconsistent owing to the varied inclusion criteria. To address the effect of H. pylori eradication on GC incidence, we conducted a comprehensive meta-analysis with several subgroup analyses to resolve these inconsistencies.METHODS: We searched MEDLINE and Ichushi-Web to identify randomized control trial and cohort study articles (English or Japanese) through December 2016. Manual searches were also conducted to identify unlisted references in these databases. Eligible studies reported GC incidence as an outcome, with comparisons between H.pylori eradication and control groups. Subgroup analyses were conducted by country, conditions at baseline, and follow-up periods.RESULTS: We selected 28 studies among 1583 references in the databases and 4 studies by manual searches. The H. pylori eradication group showed significantly lower risk of GC [odds ratio (OR) 0.46; 95% confidence interval 0.39-0.55]. The subgroup analyses indicated that the beneficial effect of eradication was greater in Japan (OR 0.39; 95% CI 0.31-0.49), particularly among those with benign conditions (OR 0.32; 95% CI 0.19-0.54), although none of them was statistically significant. However, reduction of gastric cancer after eradication was significantly greater (p?=?0.01) in the groups with long-term (5?years or longer) follow-up (OR 0.32; 95% CI 0.24-0.43) as compared to those with shorter follow-up (less than 5?years) (OR 0.55; 95% CI 0.41-0.72).CONCLUSION: Real world data showed that large-scale eradication therapy has been performed mostly for benign conditions in Japan. Since eradication effects in preventing gastric cancer are conceivably greater there, GC incidence may decline faster in Japan than expected from the previous meta-analyses data which were based on multi-national, mixed populations with differing screening quality and disease progression.REFERENCE: Sugano K. Effect of Helicobacter pylori eradication on the incidence of gastric cancer: a systematic review and meta-analysis. Gastric Cancer. 2018 Sep 11. doi: 10.1007/s10120-018-0876-0Endoscopic removal of early gastric cancer or high-grade adenomas still “leaves the stomach largely conserved but with the atrophic gastric mucosa remaining in a preneoplastic “alarm state” according to Malfertheiner (N Engl J Med 2018; 378:1154-1156). In the following RCT, H pylori eradication decreased subsequent development of GA by 50% vs no treatment. #9 RCT: Treating H Pylori lowers gastric cancer recurrence risk BACKGROUND: Patients with early gastric cancers that are limited to gastric mucosa or submucosa usually have an advanced loss of mucosal glandular tissue (glandular atrophy) and are at high risk for subsequent (metachronous) development of new gastric cancer. The long-term effects of treatment to eradicate Helicobacter pylori on histologic improvement and the prevention of metachronous gastric cancer remain unclear.METHODS: In this prospective, double-blind, placebo-controlled, randomized trial, we assigned 470 patients who had undergone endoscopic resection of early gastric cancer or high-grade adenoma to receive either H. pylori eradication therapy with antibiotics or placebo. Two primary outcomes were the incidence of metachronous gastric cancer detected on endoscopy performed at the 1-year follow-up or later and improvement from baseline in the grade of glandular atrophy in the gastric corpus lesser curvature at the 3-year follow-up.RESULTS: A total of 396 patients were included in the modified intention-to-treat analysis population (194 in the treatment group and 202 in placebo group). During a median follow-up of 5.9 years, metachronous gastric cancer developed in 14 patients (7.2%) in the treatment group and in 27 patients (13.4%) in the placebo group (hazard ratio in the treatment group, 0.50; 95% confidence interval, 0.26 to 0.94; P=0.03). Among the 327 patients in the subgroup that underwent histologic analysis, improvement from baseline in the atrophy grade at the gastric corpus lesser curvature was observed in 48.4% of the patients in the treatment group and in 15.0% of those in the placebo group (P<0.001). There were no serious adverse events; mild adverse events were more common in the treatment group (42.0% vs. 10.2%, P<0.001).CONCLUSIONS: Patients with early gastric cancer who received H. pylori treatment had lower rates of metachronous gastric cancer and more improvement from baseline in the grade of gastric corpus atrophy than patients who received placebo.(Funded by the National Cancer Center, South Korea; number,NCT02407119 .).REFERENCE: Choi IJ et al. Helicobacter pylori Therapy for the Prevention of Metachronous Gastric Cancer. N Engl J Med. 2018 Mar 22;378(12):1085-1095. Comment in: N Engl J Med. 2018 Mar 22;378(12 ):1154-1156."No institutionalized screening programs exist for gastric cancer prevention in Western countries. According to data from ... trials, 125 persons would need to be treated to prevent one case of gastric cancer, so such a strategy is cost-effective in countries with a high incidence of the disease. The number of persons who would need to be treated would be much higher in countries with a low or intermediate incidence of gastric cancer, a factor that has been used to argue against preventive strategies in these populations. However, modeling studies that include economic considerations and additional clinical benefits beyond gastric cancer prevention (e.g., the prevention of ulcers and gastric lymphoma) suggest that H. pylori screen-and-treat strategies also merit consideration in communities at low or intermediate risk. The first approach to prevention should be noninvasive (i.e., serologic analysis), which can be followed by endoscopy in patients at risk. Such an approach should be encouraged in combination with screening for colorectal cancer in patients older than 50 years of age in Western societies that have a low or intermediate risk of gastric cancer" (N Engl J Med 2018; 378:1154-1156) According to the AGA "it is often difficult to know what the H. pylori prevalence is in the local population"Barrett’s esophagusThe following study demonstrates that laboratories’ differ in their evaluation of BE and this plays a role in the quality of the diagnosis of low-grade dysplasia10: Pathologists differ in BE risk stratification | Pathologists agreement on reading Barrett’s BACKGROUND AND AIMS: The diagnosis of low-grade dysplasia (LGD) in Barrett's esophagus (BE) is subject to substantial interobserver variation. Our central aim in this study is to compare independent pathology practices using objective measures of BE risk stratification proficiency, including frequency of diagnosis and rate of progression, with high-grade dysplasia (HGD) or adenocarcinoma (EAC) after the first diagnosis of LGD.METHODS: We retrospectively evaluated over 29,000 endoscopic biopsy cases to identify 4734 patients under endoscopic biopsy surveillance for BE in a healthcare system with multiple independent pathology practices: a subspecialized GI pathology group (SSGI; 162 BE cases per pathologist annually), 3 high BE volume general surgical pathology practices (GSPs; >50 BE cases per pathologist annually), and multiple low BE volume GSPs (10.6 BE cases per pathologist annually). We measured LGD diagnosis frequencies and rates of diagnostic progression to HGD or EAC in patients diagnosed with LGD.RESULTS: The proportion of all BE cases diagnosed as LGD (LGD/BE diagnosis ratio) ranged from 1.1% to 6.8% in the different hospital settings (P?< .001). The cumulative proportion of patients with HGD or EAC within 2 years of the first diagnosis of LGD was 35.3% in the SSGI and ranged from 1.4% to 14.3% in the GSPs (P?< .001). LGD diagnosed by the GSP with the lowest LGD/BE diagnosis ratio had an adjusted risk of progression similar to LGD diagnosed by subspecialists (hazard ratio, .42; 95% CI, .06-3.03). However, when LGD was diagnosed by other generalists, the adjusted risk of progression was 79% to 91% lower than subspecialists (P?< .001). When LGD was diagnosed in a low-volume GSP practice, the risk of progression was not significantly increased relative to patients with nondysplastic BE (hazard ratio, 1.3; 95% CI, .4-3.9).CONCLUSIONS: General surgical pathologists and subspecialists show highly significant differences with respect to LGD/BE ratio, risk of progression relative to nondysplastic BE, crude annual progression rates, and the cumulative 2-year progression rate after LGD. These metrics can be used to assess proficiency in BE risk stratification in historical cases. Some general practitioners were able to achieve results similar to subspecialists. General surgical pathologists with little annual experience evaluating BE biopsy specimens did not successfully risk stratify patients with BE.REFERENCE: Davison JM Low-grade dysplasia diagnosis ratio and progression metrics identify variable Barrett's esophagus risk stratification proficiency in independent pathology practices. Gastrointest Endosc. 2018 Nov;88(5):807-815.e2. Comment in Gastrointest Endosc. 2018 Nov;88(5):816-817.The following demonstrated that high-dose proton-pump inhibitor plus daily full-dose aspirin improved outcomes in patients with BE vs use in patients with well-established Barrett esophagus. As a reminder I put in the appendix the AGA recommendation for screening for Barrett’s from their 2015 guideline11. PPI AND ASA for 9 years improves outcomes in patients with Barrett’sBACKGROUND: Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus.METHODS: The Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2×2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77.FINDINGS: Between March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2-9·8), and we collected 20,095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01-1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98-1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01-1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14-2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events.INTERPRETATION: High-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus.FUNDING: Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.REFFERENCE: Jankowski JAZ, de Caestecker J, Love SB, et al. Esomeprazole and aspirin in Barrett's oesophagus (AspECT): a randomised factorial trial. Lancet. 2018 Aug 4;392(10145):400-408. doi: 10.1016/S0140-6736(18)31388-6. Epub 2018 Jul 26. Management of DyspepsiaAccording to Feld, “Dyspepsia is epigastric pain that does not have predominant reflux symptoms. Dyspepsia is common, affecting approximately 20% of the global population, and is frequently encountered in primary care“. For purposes of this guideline dyspepsia is defined as “Predominately epigastric pain lasting at least one month” The following are the key recommendations for managing dyspepsia from the American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) Clinical Guideline. The guideline developers are clear that “clinical decisions should be based on symptoms, patient concerns, physical examination findings, laboratory and radiologic studies, and data from the literature, when available.” Note these are synthesis of the 14 specific recommendations, I include “ “ when I have directly quoted the guideline:Patients with dyspepsia who are > 60 years should have an EGD to exclude upper GI neoplasia (conditional recommendation; very low-quality evidence).Note that the risk of malignancy is related to age Patients younger than 60 years with dyspepsia should not routinely (e.g. automatically) have an upper GI tract endoscopy to evaluate their symptoms, even if alarm features are present (conditional recommendation; moderate-quality evidence).Alarm symptoms included in this recommendation are weight loss, anemia, dysphagia and persistent vomiting. They note that, "A systematic review of .... over 46,000 dyspepsia patients undergoing upper GI endoscopy found that alarm features had limited value" (risk < 1% for GI malignancy)Note some patients younger than 60 with dyspepsia should have EGD (e.g. those residing during childhood in high risk gastric cancer countries in locations in SE Asia or S America, family hx of GI malignancy, severe symptoms or combinations of symptoms)Patients younger than 60 years with dyspepsia should be tested for Helicobacter pylori infection and treated for the infection if the test result is positive (strong recommendation; high-quality evidence)."Clinicians should allow at least 4 weeks before reassessing symptomatic response to H. pylori eradication therapy."Patients younger than 60 years with dyspepsia should be treated with proton pump inhibitor (PPI) therapy if they are H pylori negative or it they remain symptomatic after H pylori eradication therapy (strong recommendation; high-quality evidence).Patients younger than 60 years with dyspepsia not responding to PPI or H pylori eradication should be offered tricyclic antidepressant therapy (conditional recommendation; low-quality evidence).“A systematic review identified 13 trials involving 1,241 patients with FD that evaluated psychotropic drugs compared to placebo. The review identified three trials that evaluated TCA therapy and these drugs had a significant effect in reducing dyspepsia symptoms (RR=0.74; 95% CI=0.61–0.91). No effect was seen with serotonin reuptake inhibitor therapy.”12. ACG/CAG Dyspepsia GuidelineBACKGROUND: Dyspepsia, or epigastric pain without predominant reflux symptoms, affects about 20% of the global population and is associated with a low prevalence of serious underlying disease.METHODS: The authors, from the University of Chicago, report the recommendations of a 2017 guideline update from the American College of Gastroenterology and the Canadian Association of Gastroenterology on the treatment of dyspepsia persisting for at least one month in adults.RESULTS: Upper GI endoscopy to evaluate for neoplasia is conditionally recommended for patients aged 60 or older based on very low-quality evidence. Among patients below age 60 with dyspepsia, routine upper GI endoscopy is not recommended, even in those with alarm symptoms (e.g., weight loss, anemia, dysphagia); this is a conditional recommendation based on moderate-quality evidence (the very low rate of malignancy in these patients in the absence of alarm symptoms and the limited predictive utility of alarm symptoms). In patients below the age of 60, recommendations include noninvasive testing for H. pylori with appropriate treatment if test results are positive (strong recommendation based on high-quality evidence), and treatment with proton pump inhibitors if H. pylori test results are negative or if symptoms persist after treatment to eradicate the infection when H. pylori testing is positive (strong recommendation based on high-quality evidence); absolute rates of symptom reduction after four weeks of PPI therapy have been reported to be 15.5% in comparisons with histamine blockers and 27.8% in comparisons with placebo. The updated guideline places emphasis on management of symptoms and reducing the use of procedures, with an anticipated cost savings. Potential harms of the guideline involve those associated with delayed diagnosis. 9 references (adamcifu@uchicago.edu - no reprints)REFERENCE: Feld L et al. Management of Dyspepsia. JAMA. 2018 May 1;319(17):1816-1817.NASH And Diet Quality13. Framingham heart Study | Mediterranean diet associated with lower liver fatBACKGROUND & AIMS: Dietary modification has been recommended for treatment of nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent its development. We performed a prospective study to examine the association between diet quality change and change in liver fat. We also examined the association between genetic risk score and liver fat change in individuals with different levels of diet quality change.METHODS: Our study included 1521 participants who attended the seventh and eighth examinations (1998-2001 and 2005-2008) of the second-generation cohort or attended the first and second examinations (2002-2005 and 2008-2011) of the third-generation cohort in the Framingham Heart Study. The self-administered semiquantitative 126-item Harvard food frequency questionnaire was used to determine dietary intake in the year leading up to an examination. We assessed levels of liver fat using liver-phantom ratio (LPR) on computed tomography images from 2002 through 2005 and again from 2008 through 2011. LPR values are inversely related to liver fat: increased LPR indicates decreased liver fat. We examined associations of changes in 2 diet scores, the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI), with changes in liver fat and new-onset fatty liver. We evaluated interactions between diet score change and a weighted genetic risk score for NAFLD, determined based on multiple single-nucleotide polymorphisms identified in genome-wide association studies of NAFLD. The primary outcome was change in LPR between baseline and follow-up measurement.RESULTS: For each 1 standard deviation increase in MDS, the LPR increased (meaning liver fat decreased) by 0.57 (95% confidence interval [CI] 0.27-0.86; P?<?.001) and the odds for incident fatty liver decreased by 26% (95% CI 10%-39%; P?= .002). For each 1 standard deviation increase in AHEI, LPR increased by 0.56 (95% CI 0.29-0.84; P?<?.001) and the odds for incident fatty liver decreased by 21% (95% CI 5%-35%; P?= .02). Increased diet scores were also associated with reduced odds of developing more-advanced fatty liver. Higher genetic risk scores were associated with increased liver fat accumulation in participants who had decreased MDS (P < .001) or AHEI scores (P?= .001), but not in those with stable or improved diet scores (P for gene-diet interaction <.001).CONCLUSIONS: In an analysis of participants in the Framingham Heart Study, increasing diet quality, determined based on MDS and AHEI scores, is associated with less liver fat accumulation and reduced risk for new-onset fatty liver. An improved diet is particularly important for individuals with a high genetic risk for NAFLD.REFERENCE: Ma J et al. Improved Diet Quality Associates With Reduction in Liver Fat, Particularly in Individuals With High Genetic Risk Scores for Nonalcoholic Fatty Liver Disease. Gastroenterology. 2018 Jul;155(1):107-117.14. Reducing free sugar to < 3% of daily calories assoc with less hepatic steatosisIMPORTANCE: Pediatric guidelines for the management of nonalcoholic fatty liver disease (NAFLD) recommend a healthy diet as treatment. Reduction of sugary foods and beverages is a plausible but unproven treatment.OBJECTIVE: To determine the effects of a diet low in free sugars (those sugars added to foods and beverages and occurring naturally in fruit juices) in adolescent boys with NAFLD.DESIGN, SETTING, AND PARTICIPANTS: An open-label, 8-week randomized clinical trial of adolescent boys aged 11 to 16 years with histologically diagnosed NAFLD and evidence of active disease (hepatic steatosis >10% and alanine aminotransferase level ≥45 U/L) randomized 1:1 to an intervention diet group or usual diet group at 2 US academic clinical research centers from August 2015 to July 2017; final date of follow-up was September 2017.INTERVENTIONS: The intervention diet consisted of individualized menu planning and provision of study meals for the entire household to restrict free sugar intake to less than 3% of daily calories for 8 weeks. Twice-weekly telephone calls assessed diet adherence. Usual diet participants consumed their regular diet.MAIN OUTCOMES AND MEASURES: The primary outcome was change in hepatic steatosis estimated by magnetic resonance imaging proton density fat fraction measurement between baseline and 8 weeks. The minimal clinically important difference was assumed to be 4%. There were 12 secondary outcomes, including change in alanine aminotransferase level and diet adherence.RESULTS: Forty adolescent boys were randomly assigned to either the intervention diet group or the usual diet group (20 per group; mean [SD] age, 13.0 [1.9] years; most were Hispanic [95%]) and all completed the trial. The mean decrease in hepatic steatosis from baseline to week 8 was significantly greater for the intervention diet group (25% to 17%) vs the usual diet group (21% to 20%) and the adjusted week 8 mean difference was -6.23% (95% CI, -9.45% to -3.02%; P?<?.001). Of the 12 prespecified secondary outcomes, 7 were null and 5 were statistically significant including alanine aminotransferase level and diet adherence. The geometric mean decrease in alanine aminotransferase level from baseline to 8 weeks was significantly greater for the intervention diet group (103 U/L to 61 U/L) vs the usual diet group (82 U/L to 75 U/L) and the adjusted ratio of the geometric means at week 8 was 0.65 U/L (95% CI, 0.53 to 0.81 U/L; P?<?.001). Adherence to the diet was high in the intervention diet group (18 of 20 reported intake of <3% of calories from free sugar during the intervention). There were no adverse events related to participation in the study.CONCLUSIONS AND RELEVANCE: In this study of adolescent boys with NAFLD, 8 weeks of provision of a diet low in free sugar content compared with usual diet resulted in significant improvement in hepatic steatosis. However, these findings should be considered preliminary and further research is required to assess long-term and clinical outcomes.REFERENCE: Schwimmer JB, et al. Effect of a Low Free Sugar Diet vs Usual Diet on Nonalcoholic Fatty Liver Disease in Adolescent Boys: A Randomized Clinical Trial. JAMA. 2019 Jan 22;321(3):256-265. doi: 10.1001/jama.2018.20579.15. Ideal CV health associated with less hepatic steatosisBACKGROUND: Cardiovascular health has been proven to be associated with major cardiometabolic diseases. However, little is known of associations between cardiovascular health and nonalcoholic fatty liver disease.METHODS: This study included 3424 adults aged ≥40 years who were free of nonalcoholic fatty liver disease at baseline from a community cohort followed for up to 5 years. Liver ultrasonography was conducted at baseline and at follow-up to diagnose incident nonalcoholic fatty liver disease. Six metrics including smoking, physical activity, body mass index, total cholesterol, blood pressure, and fasting glucose were used to define cardiovascular health status. Associations of individual cardiovascular health metrics, number of cardiovascular health metrics, and overall cardiovascular health status at baseline, as well as changes in cardiovascular health during follow-up with risks of developing nonalcoholic fatty liver disease, were examined. RESULTS: A total of 649 participants developed nonalcoholic fatty liver disease during follow-up. Risks of nonalcoholic fatty liver disease reduced in a dose-response manner in participants with 3-4 ideal cardiovascular health metrics (odds ratio 0.50; 95% confidence interval, 0.41-0.61) and in participants with 5-6 ideal metrics (odds ratio 0.34; 95% confidence interval 0.22-0.51) compared with participants with 0-2 ideal metrics. An overall ideal or intermediate cardiovascular health was associated with 37% reduction in developing nonalcoholic fatty liver disease compared with poor cardiovascular health. In addition, improving cardiovascular health during follow-up reduced the risk by 71% compared with deteriorating cardiovascular health. Furthermore, an overall ideal or intermediate cardiovascular health was significantly associated with alower fibrosis score in nonalcoholic fatty liver disease patients compared with an overall poor cardiovascular health.CONCLUSIONS: Ideal cardiovascular health was inversely associated with risks of nonalcoholic fatty liver disease. Although treatment of nonalcoholic fatty liver disease and subsequent inflammation and fibrosis remains a challenge, cardiovascular health goals should be advocated for nonalcoholic fatty liver disease prevention.REFERENCE: Wang L et al. Ideal Cardiovascular Health Is Inversely Associated with Nonalcoholic Fatty Liver Disease: A Prospective Analysis. Am J Med. 2018 Dec;131(12):1515.e1-1515.e10. GI Bleed with NOACs16. GI bleeding with NOACs lowest with apixabanImportance: Anticoagulant choice and proton pump inhibitor (PPI) cotherapy could affect the risk of upper gastrointestinal tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment.Objectives: To compare the incidence of hospitalization for upper gastrointestinal tract bleeding in patients using individual anticoagulants with and without PPI cotherapy, and to determine variation according to underlying gastrointestinal bleeding risk.Design, Setting, and Participants: Retrospective cohort study in Medicare beneficiaries between January 1, 2011, and September 30, 2015.Exposures: Apixaban, dabigatran, rivaroxaban, or warfarin with or without PPI cotherapy.Main Outcomes and Measures: Hospitalizations for upper gastrointestinal tract bleeding: adjusted incidence and risk difference (RD) per 10?000 person-years of anticoagulant treatment, incidence rate ratios (IRRs).Results: There were 1,643,123 patients with 1,713,183 new episodes of oral anticoagulant treatment included in the cohort (mean [SD] age, 76.4 [2.4] years, 651,427 person-years of follow-up [56.1%] were for women, and the indication was atrial fibrillation for 870?330 person-years [74.9%]). During 754,389 treatment person-years without PPI cotherapy, the adjusted incidence of hospitalization for upper gastrointestinal tract bleeding (n?=?7119) was 115 per 10?000 person-years (95% CI, 112-118). The incidence for rivaroxaban (n?=?1278) was 144 per 10?000 person-years (95% CI, 136-152), which was significantly greater than the incidence of hospitalizations for apixaban (n?=?279; 73 per 10?000 person-years; IRR, 1.97 [95% CI, 1.73-2.25]; RD, 70.9 [95% CI, 59.1-82.7]), dabigatran (n?=?629; 120 per 10?000 person-years; IRR, 1.19 [95% CI, 1.08-1.32]; RD, 23.4 [95% CI, 10.6-36.2]), and warfarin (n?=?4933; 113 per 10?000 person-years; IRR, 1.27 [95% CI, 1.19-1.35]; RD, 30.4 [95% CI, 20.3-40.6]). The incidence for apixaban was significantly lower than that for dabigatran (IRR, 0.61 [95% CI, 0.52-0.70]; RD, -47.5 [95% CI,-60.6 to -34.3]) and warfarin (IRR, 0.64 [95% CI, 0.57-0.73]; RD, -40.5 [95% CI, -50.0 to -31.0]). When anticoagulant treatment with PPI cotherapy (264?447 person-years; 76 per 10?000 person-years) was compared with treatment without PPI cotherapy, risk of upper gastrointestinal tract bleeding hospitalizations (n?=?2245) was lower overall (IRR, 0.66 [95% CI, 0.62-0.69]) and for apixaban (IRR, 0.66 [95% CI, 0.52-0.85]; RD, -24 [95% CI, -38 to -11]), dabigatran (IRR, 0.49 [95% CI, 0.41-0.59]; RD, -61.1 [95% CI, -74.8 to -47.4]), rivaroxaban (IRR, 0.75 [95% CI, 0.68-0.84]; RD, -35.5 [95% CI, -48.6 to -22.4]), and warfarin (IRR, 0.65 [95% CI, 0.62-0.69]; RD, -39.3 [95% CI, -44.5 to -34.2]).Conclusions and Relevance: Among patients initiating oral anticoagulant treatment, incidence of hospitalization for upper gastrointestinal tract bleeding was the highest in patients prescribed rivaroxaban, and the lowest for patients prescribed apixaban. For each anticoagulant, the incidence of hospitalization for upper gastrointestinal tract bleeding was lower among patients who were receiving PPI cotherapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.Reference: Ray WA et al. Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. JAMA. 2018 Dec 4;320(21):2221-2230.Bottom LinesH pylori is the major risk factor for gastric cancerAll H pylori infections should be considered pathogenic and should be eradicatedAlthough no screening programs exist in the US for H pylori, a good case can be made that perhaps there should be.High-dose PPI and aspirin chemoprevention therapy reduced morbidity associated with Barrett’s For dyspeptic patients in general offer EGD for those > 60, and test and treat for H pylori for those < 60. Those testing negative offer PPI therapy.Mediterranean diet and diets with restricted free sugar are associated with less hepatic steatosis.Certain NOACs have a higher risk of GI bleed hospitalization, PPIs are protective regardless of which NOAC is usedVitamin D update 2019John Hickner, MD, MScObjectives1. Review the evidence that Vitamin D supplementation is effective for some conditions2. Review the evidence that Vitamin D is not effective for some conditions3. Review the evidence that Vitamin D may or may not be effective for some conditionsTo prepare this talk, I reviewed all 283 abstracts of systematic reviews and meta-analyses of “Vitamin D Supplementation” AND “therapy” in PubMed Clinical Queries in November 2019. The systematic reviews dated back to 1981. There were also 5117 original clinical studies as well. I reviewed titles and some abstracts from original RCTs published in 2018 and 2019. I choose representative meta-analyses and randomized trials for this presentation. There are about 80 conditions for which Vitamin D has been tested as therapy in randomized trials. I have briefly summarized the results under 3 categories: 1) strong evidence of effectiveness, 2) weak evidence of effectiveness, and 3) probably not effective. After the brief summary, I present 20 abstracts of individual studies and meta-analyses as examples of the current state of Vitamin D supplementation research. I will end with three important references that cast considerable doubt on the “normal” values for Vitamin D in humans, which in turn casts considerable doubt on the results of most research on Vitamin D supplementation to date.1) Conditions for which Vitamin D supplementation has a positive effect (though the effect size is usually small)prevention of steroid requiring asthma exacerbationsprevention of upper respiratory infections, but not monthly dosesImproving metabolic parameters for patients with type 2 diabetesreducing the number of moderate or severe COPD exacerbations in those Vit D deficientmortality from cancerall-cause mortality: it might! NNT between 200 and 5002) Conditions for which Vitamin D supplementation may (or may not) have a positive effect but evidence is weak ADHD: maybe; some small RCTs; inconclusivebirth size: increase of about 2 to 3 ounces; decrease SGApremature birth: yes, but data weakpre-eclampsia, hypertensive disorder of pregnancy: maybe, but weak dataperiodontal disease; weak evidence it might be beneficialpulmonary tuberculosis: slight improvement in response rate in one meta-analysis, not in anotherpolycystic ovarian syndrome: biomarkers only, mixed results physical performance in older adults: probably not, but some weak evidence to supportThyroiditis: biomarker study only; some positive effectsirritable bowel syndrome: maybe; insufficient evidence; one recent small positive studycongestive heart failure: some improvement in biomarkers but not clinical outcomespain from sickle cell crises: only one RCT; less painchronic widespread pain syndrome (fibromyalgia): slight improvement but very limited datapain in general: mixed results; a recent meta-analysis is equivocalatopic dermatitis: maybe; weak and conflicting evidenceinfant wheezing: yes, but no difference in wheezing at 6 years age Parkinson’s Disease: only 1 RCT; maybefalls: maybe, in nursing home patients onlypost CABG atrial fibrillation: one positive study cut incidence in halfdepression: insufficient data, mixed results in RCT headachefatigue: one negative RCT (spun as positive, but small difference was not clinically significant)3) Conditions for which Vitamin D supplementation has been studied and has no conclusive evidence of effectivenessheart and vascular diseasehypertensionmultiple sclerosis: no improvement in RCTs; data limitedrenal function and chronic kidney disease: negative except proteinuriaHIV: no RCTs; some immune biomarker improvement inflammatory bowel disease: some RCTs with weak design, maybe in adolescents (one trial)musculoskeletal health: good evidence for no improvementlow back pain: no RCTsfoot and ankle fracture healing: insufficient dataknee osteoarthritisosteoporosisrheumatic diseasespsoriasis and psoriatic arthritis; one small trial in Thailand positive; otherwise negativesystemic inflammationautoimmune disease: no RCT; not likely due to lack of effects on inflammatory biomarkersSLE: no RCTs statin associated myalgias: association; no RCT of therapy cancer in generalhematological malignancies: no associationprostate cancer treatment: 1 positive RCT; 3 neg RCT; probably no benefitcolorectal cancer treatment: association, 2 RCTs in NEJM; no statistically significant differencegestational diabetescommunity dwelling elderly adultschronic liver diseasechildren overall health: no data for supplementation above recommended requirement of 400 IU/daychildhood pneumonia: negative but insufficient quality dataautism spectrum disorder: insufficient evidence; see trial retractionallergy prevention and treatment in childrenrecurrent UTI in childreninfections on children under 5: no for diarrhea and pneumoniaperinatal depression: no dataassisted reproduction: insufficient datacystic fibrosiscritical care neuro patientsrestless legs syndromepremenstrual disorderAlzheimer’scognitive impairment: some RCTs; no improvementhealth related quality of lifeMeta-analyses of Vitamin D and non-skeletal conditions1. Effect of vitamin D supplementation on non-skeletal disorders Background: Randomised trials reported up to Dec 31, 2012, did not confirm that vitamin D supplementation could protect from non-skeletal health conditions affecting adults, as was expected on the basis of data from observational studies. Methods: To examine whether the more recently published meta-analyses and trials would change past conclusions, we systematically reviewed meta-analyses of vitamin D supplementation and non-skeletal disorders published between Jan 1, 2013, and May 31, 2017, that included study participants of all ages, including pregnant women. We also searched for randomised trials not included in meta-analyses. Results: We identified 87 meta-analyses, of which 52 were excluded because they contained less recent literature or were of suboptimal quality. We retrieved 202 articles on trials that were not included in meta-analyses. Recent meta-analyses reinforce the finding that 10-20 μg per day of vitamin D can reduce all-cause mortality and cancer mortality in middle-aged and older people. Although vitamin D doses were greater than those assessed in the past, we found no new evidence that supplementation could have an effect on most non-skeletal conditions, including cardiovascular disease, adiposity, glucose metabolism, mood disorders, muscular function, tuberculosis, and colorectal adenomas, or on maternal and perinatal conditions. New data on cancer outcomes were scarce. The compilation of results from 83 trials showed that vitamin D supplementation had no significant effect on biomarkers of systemic inflammation. The main new finding highlighted by this systematic review is that vitamin D supplementation might help to prevent common upper respiratory tract infections and asthma exacerbations. Conclusions: There remains little evidence to suggest that vitamin D supplementation has an effect on most conditions, including chronic inflammation, despite use of increased doses of vitamin D, strengthening the hypothesis that low vitamin D status is a consequence of ill health, rather than its cause. We further hypothesise that vitamin D supplementation could exert immunomodulatory effects that strengthen resistance to acute infections, which would reduce the risk of death in debilitated individuals. We identified many meta-analyses of suboptimal quality, which is of concern. Future systematic reviews on vitamin D should be based on data sharing so that data for participants with the same outcomes measured in the same way can be pooled to generate stronger evidence.Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, Pizot C, Boniol M. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017 Dec;5(12):986-1004.2. Non-skeletal health effects of vitamin D supplementation BACKGROUND:? A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a?systematic?quantitative review on characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of?vitamin D?supplementation.METHODS AND FINDINGS:? We identified?systematic?reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of?vitamin D supplementation?was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses.CONCLUSIONS:?Published RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels.Rejnmark L, Bislev LS, Cashman KD, Eiríksdottir G, Gaksch M, Grübler M, Grimnes G, Gudnason V, Lips P, Pilz S, van Schoor NM, Kiely M, Jorde R. Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data. PLoS One. 2017 Jul 7;12(7):e0180512.Cardiovascular disease, cancer, mortality3. High dose bolus vitamin D does NOT prevent cardiovascular diseaseIMPORTANCE: Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low?vitamin D status. To date, randomized clinical trials of?vitamin D?supplementation?have not found an effect, possibly because of using too low a dose of?vitamin D.OBJECTIVE: To examine whether monthly high-dose?vitamin D?supplementation?prevents CVD in the general population.DESIGN, SETTING, AND PARTICIPANTS: The?Vitamin D?Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47?905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n?=?2558) or placebo (n?=?2552). Two participants retracted consent, and all others (n?=?5108) were included in the primary analysis.INTERVENTIONS: Oral vitamin D3 in an initial dose of 200?000 IU, followed a month later by monthly doses of 100?000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years).MAIN OUTCOMES AND MEASURES: The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with?vitamin D?deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis.RESULTS: Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being?vitamin D?deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the?vitamin D?group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the?vitamin D?group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline?vitamin D?deficiency and for secondary outcomes.CONCLUSIONS AND RELEVANCE: Monthly high-dose?vitamin D?supplementation?does not prevent CVD. This result does not support the use of monthly?vitamin D?supplementation?for this purpose. The effects of daily or weekly dosing require further study.Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J, Murphy J, Khaw KT, Camargo CA Jr. Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study : A Randomized Clinical Trial. JAMA Cardiol. 2017 Jun 1;2(6):608-616. 4. Vitamin D does not reduce the incidence of cancer or cardiovascular disease: RCTBACKGROUND:?It is unclear whether?supplementation?with?vitamin D?reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited.METHODS:?We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of?vitamin D3(cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of?vitamin D?with placebo.RESULTS:?A total of 25,871 participants, including 5106 black participants, underwent randomization.?Supplementation?with?vitamin D?was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the?vitamin D?group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the?vitamin D 5 group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified.CONCLUSIONS:?Supplementation?with?vitamin D?did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL number,?NCT01169259?.).Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44. PubMed PMID: 30415629.5. Vitamin D may reduce cancer mortality but not incidenceBACKGROUND:?Previous meta-analyses of randomized controlled trials (RCTs) of?vitamin D?supplementation?and total cancer incidence and mortality found inconsistent results, and most included trials administered generally low doses of?vitamin D(≤1100?IU/day). We updated the meta-analysis by incorporating recent RCTs that have tested higher doses of?vitamin Dsupplements.MATERIALS AND METHODS:?PubMed and Embase were searched from the inception to November 2018. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effects model.RESULTS:?For total cancer incidence, 10 trials were included [6537 cases; 3-10?years of follow-up; 54-135?nmol/l of attained levels of circulating 25(OH)?vitamin D?[25(OH)D] in the intervention group]. The summary RR was 0.98 (95% CI, 0.93-1.03; P = 0.42; I2 = 0%). The results remained null across subgroups tested, including even when attained 25(OH)D levels exceeded 100?nmol/l (RR, 0.95; 95% CI, 0.83-1.09; P = 0.48; I2 = 26%). For total cancer mortality, five trials were included [1591 deaths; 3-10?years of follow-up; 54-135?nmol/l of attained levels of circulating 25(OH)D in the intervention group]. The summary RR was 0.87 (95% CI, 0.79-0.96; P = 0.005; I2 = 0%), which was largely attributable to interventions with daily dosing (as opposed to infrequent bolus dosing). No statistically significant heterogeneity was observed by attained levels of circulating 25(OH)D (Pheterogeneity = 0.83), with RR being 0.88 (95% CI, 0.78-0.98; P = 0.02; I2 = 0%) for ≤100?nmol/l and 0.85 (95% CI, 0.70-1.03; P = 0.11; I2 = 0%) for >100?nmol/l.CONCLUSIONS:?In an updated meta-analysis of RCTs,?vitamin D?supplementation?significantly reduced total cancer mortality but did not reduce total cancer incidence.Keum N, Lee DH, Greenwood DC, Manson JE, Giovannucci E. Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. Ann Oncol. 2019 May 1;30(5):733-743. doi:10.1093/annonc/mdz059. PubMed PMID: 30796437.Respiratory Tract Infections, Asthma, Allergic Rhinitis6. Bolus dosing of Vitamin D does not prevent ARTI or asthma exacerbation in vitamin D–deficient patientsClinical question: Does vitamin D supplementation improve asthma symptoms?Study design: Randomized controlled trial (double-blinded)Setting: Outpatient (any)Synopsis: Ah, vitamin D. You are such a good marker of bad health, yet supplementing you seems to have so little effect. For example, lots of observational studies have found an association between low vitamin D levels and a high rate of acute respiratory tract infections (ARTI). This is the first randomized trial to test the hypothesis that vitamin D supplementation would reduce the likelihood of ARTI or asthma exacerbation in adults with corticosteroid-treated asthma. The authors identified 590 patients with asthma: 297 were then screened for inclusion and 250 met the inclusion criteria. All were between the ages of 16 and 80 years, had smoked less than 15 pack-years, were using an inhaled corticosteroid, and had evidence of reversible airway obstruction. The 250 participants were randomized to receive either 120,000 IU vitamin D every 2 months for 1 year, or matching placebo. The mean age of participants was 48 years, 44% were male, most had received a flu vaccine, and most had moderately severe asthma. Most (82%) had a low vitamin D level at enrollment (serum 25(OH)D level < 75 nmol/L [30 ng/mL]). Unfortunately, the intervention had no effect. The intervention group experienced a significant increase in vitamin D levels (23 nmol/L [10 ng/mL]), but there was no difference between groups in the time to first exacerbation or time to first ARTI. The study was powered to detect a 60-day difference in the time to event.Bottom line: Vitamin D supplementation does nothing to prevent exacerbations or improve clinical outcomes in a group of adults with asthma, most of whom were also vitamin D deficient.Martineau AR, MacLaughlin BD, Hooper RL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax 2015;70(5): 451-457.7. High-dose vitamin D does not reduce wintertime URIs in healthy children ages 1 to 5Clinical question: Does high-dose vitamin D reduce the incidence of wintertime upper respiratory infections in otherwise healthy children?Study design: Randomized controlled trial (double-blinded)Setting: Outpatient (primary care)Synopsis: Vitamin D increases the synthesis of antimicrobial peptides in respiratory epithelium and may thus reduce viral replication and subsequent URIs. These investigators enrolled 703 healthy children, 1 year to 5 years old, who presented for a scheduled well-child visit prior to the wintertime viral season in Toronto, Ontario, Canada. Eligible children randomly received (concealed allocation assignment) liquid vitamin D in a standard dose (400 IU daily) or a high-dose (2000 IU daily). Drops were identical in taste, volume, and color. Throughout the winter months parents completed a symptom checklist and collected viral nasal swabs for suspected URIs. The individuals who assessed outcomes remained masked to treatment group assignment. Follow-up occurred for 99.4% of participants for approximately 6 months (winter lasts a LONG time up there). Mean baseline serum 25-hydroxyvitamin D levels were comparable in the standard-dose and high-dose groups (36.9 ng/mL and 35.9 ng/mL, respectively). Using intention-to-treat analysis, no significant differences occurred between the 2 groups in the mean number of infections per child based on both parent-reported URIs and laboratory confirmed upper respiratory virus infections from nasal smears. There was a statistically significant difference in serum 25-hydroxyvitamin D levels between the standard-dose and high-dose groups after treatment (36.8 ng/mL vs 48.7 ng/mL, respectively). The study was 90% powered to detect a reduction of at least 1 URI per winter season between the 2 treatment groups.Bottom line: Daily administration of high-dose vitamin D (2000 IU) did not reduce the incidence of wintertime upper respiratory infections (URIs) compared with standard dose vitamin D (400 IU) in otherwise healthy children residing in Toronto, Canada.Aglipay M, Birken CS, Parkin PC, et al, for the TARGet Kids! Collaboration. Effect of high-dose vs standard-dose wintertime vitamin D supplementation on viral upper respiratory tract infections in young healthy children. JAMA 2017;318(3):245-255.8. No effect of vitamin D3 supplementation on respiratory tract infections in healthy individualsOBJECTIVE: Vitamin D supplementation may be a simple preventive measure against respiratory tract infections (RTIs) but evidence from randomized controlled trials is inconclusive. We aimed to systematically summarize results from interventions studying the protective effect of vitamin D supplementation on clinical and laboratory confirmed RTIs in healthy adults and children.METHODS: Medline, EMBASE, CENTRAL, and CINAHL were screened from inception until present (last updated in January 2016) completed by a search of the grey literature, clinical trial registers and conference abstracts. We included randomized trials comparing vitamin D versus placebo or no treatment. Two independent reviewers were responsible for study selection and data extraction. Cochrane's risk of bias tool and the GRADE approach were used for quality assessment. Estimates were pooled with random-effects models. Heterogeneity was explored by sub-group and meta-regression analyses.RESULTS: Of 2627 original hits, 15 trials including 7053 individuals were ultimately eligible. All used oral cholecalciferol. We found a 6% risk reduction with vitamin D3 supplementation on clinical RTIs, but the result was not statistically significant (RR 0.94; 95% CI 0.88 to 1.00). Heterogeneity was large (I-square 57%) and overall study quality was low. There were too few studies to reliably assess a potential risk reduction of laboratory confirmed RTI. Evidence was insufficient to demonstrate an association between vitamin D supplementation and risk of clinical RTI in sub-groups with vitamin D deficiency.CONCLUSIONS: In previously healthy individuals vitamin D supplementation does not reduce the risk of clinical RTIs. However, this conclusion is based on a meta-analysis where the included studies differed with respect to population, baseline vitamin D levels and study length. This needs to be considered when interpreting the results. Future trials should focus on vitamin D deficient individuals and apply more objective and standardized outcome measurements.Vuichard Gysin D, Dao D, Gysin CM, Lytvyn L, Loeb M. Effect of Vitamin D3 Supplementation on Respiratory Tract Infections in Healthy Individuals: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS One. 2016 Sep 15;11(9):e0162996. 9. Vitamin D reduces the frequency of respiratory tract infectionsObjectives?To assess the overall effect of?vitamin D?supplementation?on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design?Systematic?review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources?Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, , and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection?Randomised, double blind, placebo controlled trials of?supplementation?with?vitamin D3?or?vitamin D2?of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results?25 eligible randomised controlled trials (total 11?321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10?933 (96.6%) participants.?Vitamin D?supplementation?reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly?vitamin D?without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly?vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006).?Vitamin D?did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions?Vitamin D?supplementation?was safe and it protected against acute respiratory tract infection overall. Patients who were very?vitamin D?deficient and those not receiving bolus doses experienced the most benefit.Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Griffiths CJ, Janssens W, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S Jr, Stelmach I, Kumar GT, Urashima M, Camargo CA Jr. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017 Feb 15;356:i6583. 10. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhoodBACKGROUND: We recently published two independent randomized controlled trials of?vitamin D?supplementation?during pregnancy, both indicating a >20% reduced risk of asthma/recurrent wheeze in the offspring by 3 years of age. However, neither reached statistical significance.OBJECTIVE: To perform a combined analysis of the two trials and investigate whether maternal 25-hydroxy-vitamin D?(25(OH)D) level at trial entry modified the intervention effect.METHODS: VDAART (N = 806) and COPSAC2010. (N = 581) randomized pregnant women to daily high-dose vitamin D3 (4,000 IU/d and 2,400 IU/d, respectively) or placebo. All women also received a prenatal vitamin containing 400 IU/d vitamin D3. The primary outcome was asthma/recurrent wheeze from 0-3yrs. Secondary end-points were specific IgE, total IgE, eczema and lower respiratory tract infections (LRTI). We conducted random effects combined analyses of the treatment effect, individual patient data (IPD) meta-analyses, and analyses stratified by 25(OH)D level at study entry.RESULTS: The analysis showed a 25% reduced risk of asthma/recurrent wheeze at 0-3yrs: adjusted odds ratio (aOR) = 0.74 (95% CI, 0.57-0.96), p = 0.02. The effect was strongest among women with 25(OH)D level ≥30ng/ml at study entry: aOR = 0.54 (0.33-0.88), p = 0.01, whereas no significant effect was observed among women with 25(OH)D level <30ng/ml at study entry: aOR = 0.84 (0.62-1.15), p = 0.25. The IPD meta-analyses showed similar results. There was no effect on the secondary end-points.CONCLUSIONS: This combined analysis shows that?vitamin D?supplementation?during pregnancy results in a significant reduced risk of asthma/recurrent wheeze in the offspring, especially among women with 25(OH)D level ≥ 30 ng/ml at randomization, where the risk was almost halved. Future studies should examine the possibility of raising 25(OH)D levels to at least 30 ng/ml early in pregnancy or using higher doses than used in our studies.Wolsk HM, Chawes BL, Litonjua AA, Hollis BW, Waage J, Stokholm J, B?nnelykke K, Bisgaard H, Weiss ST. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials. PLoS One. 2017 Oct 27;12(10):e0186657. The reduction in wheezing from Vitamin D supplementation disappeared by age 6. Brustad N, Eliasen AU, et. al. High-Dose Vitamin D Supplementation During Pregnancy and Asthma in Offspring atthe Age of 6 Years. JAMA. 2019 Mar 12;321(10):1003-1005. 11. Vitamin D reduces the risk of asthma exacerbations requiring steroidsBACKGROUND: A previous aggregate data meta-analysis of randomised controlled trials showed that?vitamin D?supplementation?reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline?vitamin D?status is unknown.METHODS: For this?systematic?review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of?vitamin D3?or?vitamin D2?supplementation?in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of?vitamin D?on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index,?vitamin D?dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953.FINDINGS: Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants).?Vitamin D?supplementation?reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between?vitamin D?and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I2=0·0, p=0·56).INTERPRETATION: Vitamin D?supplementation?reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients.Jolliffe DA, Greenberg L, Hooper RL, Griffiths CJ, Camargo CA Jr, Kerley CP, Jensen ME, Mauger D, Stelmach I, Urashima M, Martineau AR. Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med. 2017 Nov;5(11):881-890.12. Vitamin D reduces the incidence of COPD exacerbations in those with low Vit D levels: meta-analysisBACKGROUND:?Randomised controlled trials (RCTs) of vitamin D to prevent COPD exacerbations have yielded conflicting results. Individual participant data meta-analysis could identify factors that explain this variation.METHODS:?PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched from inception up to and including 5 October 2017 to identify RCTs of vitamin D supplementation in patients with COPD that reported incidence of acute exacerbations. Individual participant data meta-analysis was performed using fixed effects models adjusting for age, sex, Global Initiative for Chronic Obstructive Lung Disease spirometric grade and trial.RESULTS:?Four eligible RCTs (total 560 participants) were identified; individual participant data were obtained for 469/472 (99.4%) participants in three RCTs. Supplementation did not influence overall rate of moderate/severe COPD exacerbations (adjusted incidence rate ratio (aIRR) 0.94, 95% CI 0.78 to 1.13). Prespecified subgroup analysis revealed that protective effects were seen in participants with baseline 25-hydroxyvitamin D levels <25?nmol/L (aIRR 0.55, 95% CI 0.36 to 0.84) but not in those with baseline 25-hydroxyvitamin D levels ≥25?nmol/L (aIRR 1.04, 95% CI 0.85 to 1.27; p for interaction=0.015). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted OR 1.16, 95% CI 0.76 to 1.75).CONCLUSIONS:?Vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D levels <25?nmol/L but not in those with higher levels.Jolliffe DA, Greenberg L, Hooper RL, Mathyssen C, Rafiq R, de Jongh RT, Camargo CA, Griffiths CJ, Janssens W, Martineau AR. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax. 2019 Apr;74(4):337-345. PubMed PMID: 30630893.13. Vitamin D reduced allergic rhinitis symptoms after 8 weeksPURPOSE:?In this study, we aimed to determine whether short-term (2?months)?vitamin D?supplementation?could improve the allergic symptoms in AR patients.METHODS:?A randomized double-blind placebo-controlled clinical trial was performed on allergic rhinitis patients with?vitamin D deficiency from Nov. 2017-2018. 80 cases with allergic rhinitis and?vitamin D?deficiency were divided into two groups and?vitamin D?plus routine antihistamine medication (cetirizine) was prescribed for the study group, whereas the control group received cetirizine plus placebo. The clinical symptoms questionnaire was completed at baseline and after 4 and 8?weeks of treatment initiation.?Vitamin D?levels were re-measured at the end of the 8-week treatment course.RESULTS:?In total, 80 patients with allergic rhinitis and?vitamin D?deficiency were enrolled. Among them, 35 cases and 33 controls visited the clinic after 8?weeks; the mean age in the aforementioned groups was 29.68?years and 29.13?years demonstrating no meaningful difference (P?>?0.05). At study initiation, the mean?vitamin D?level was 14?ng/ml and 14.67?ng/ml in the study and control groups, respectively, indicating no significant difference (P?=?0.189). The mean serum?vitamin D?level at 8?weeks of treatment in the study group (24.08?ng/ml) indicated a statistically meaningful difference with the mean?vitamin D level at baseline (P?<?0.001). Comparison of the mean scores of symptoms severity showed no significant difference between the two groups at study initiation and 4?weeks later (P?=?0.073), whereas a significant difference was obtained between baseline and 8?weeks of treatment initiation (P?=?0.007).CONCLUSION:?Based on the findings of the present study, it can be concluded that?vitamin D?supplementation?along with antihistamines can result in relative symptoms improvement in AR patients with?vitamin D?deficiency.Bakhshaee M, Sharifian M, Esmatinia F, Rasoulian B, Mohebbi M. Therapeutic effect of vitamin D supplementation on allergic rhinitis. Eur Arch Otorhinolaryngol. 2019 Oct;276(10):2797-2801. PubMed PMID: 31332549.Another recent randomized trial was negative for atopic dermatitis in children. Vitamin D Level and Supplementation in Pediatric Atopic Dermatitis: A Randomized Controlled Trial. J Cutan Med Surg. 2018 Oct Pain14. Vitamin D for the treatment of chronic painful conditions in adultsBackground: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 1, 2010) on 'Vitamin D for the treatment of chronic painful conditions in adults'. Vitamin D is produced in the skin after exposure to sunlight and can be obtained through food. Vitamin D deficiency has been linked with a range of conditions, including chronic pain. Observational and circumstantial evidence suggests that there may be a role for vitamin D deficiency in the aetiology of chronic painful conditions.Objectives: To assess the efficacy and safety of vitamin D supplementation in chronic painful conditions when tested against placebo or against active comparators.Search methods: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE to February 2015. This was supplemented by searching the reference lists of retrieved articles, reviews in the field, and online trial registries.Selection criteria: We included studies if they were randomised double-blind trials of vitamin D supplementation compared with placebo or with active comparators for the treatment of chronic painful conditions in adults.Data collection and analysis: Two review authors independently selected the studies for inclusion, assessed methodological quality, and extracted data. We did not undertake pooled analysis due to the heterogeneity of the data. Primary outcomes of interest were pain responder outcomes, and secondary outcomes were treatment group average pain outcomes and adverse events.Main results: We included six new studies (517 participants) in this review update, bringing the total of included studies to 10 (811 participants). The studies were heterogeneous with regard to study quality, the chronic painful conditions that were investigated, the dose of vitamin D given, co-interventions, and the outcome measures reported. Only two studies reported responder pain outcomes; the other studies reported treatment group average outcomes only. Overall, there was no consistent pattern that vitamin D treatment was associated with greater efficacy than placebo in any chronic painful condition (low quality evidence). Adverse events and withdrawals were comparatively infrequent, with no consistent difference between vitamin D and placebo (good quality evidence).Authors' conclusions: The evidence addressing the use of vitamin D for chronic pain now contains more than twice as many studies and participants than were included in the original version of this review. Based on this evidence, a large beneficial effect of vitamin D across different chronic painful conditions is unlikely. Whether vitamin D can have beneficial effects in specific chronic painful conditions needs further investigation.Straube S, Derry S, Straube C, Moore RA. Vitamin D for the treatment of chronic painful conditions in adults. Cochrane Database of Systematic Reviews 2015, Issue 5. Art. No.: CD007771. DOI: 10.1002/14651858.CD007771.pub3.15. Effect of Vitamin D supplementation on chronic pain is equivocal BACKGROUND:?There is conflicting evidence from previous qualitative reviews on the effect of?vitamin D?supplementation?on pain.OBJECTIVE:?To determine with quantitative methods if?vitamin D?supplementation?lowers pain levels.STUDY DESIGN:?Quantitative meta-analysis of published randomized controlled trials (RCTs).SETTING:?This meta-analysis examined all studies involving the effect of?vitamin D?supplementation?on pain score.METHOD:?Electronic sources (Medline, Embase, Cochrane Central Register of Controlled Trials, clinical trials website, and Google scholar) were systematically searched for RCTs of?vitamin D?supplementation?and pain from inception of each database to October 2015.RESULTS:?Nineteen RCTs with 3,436 participants (1,780 on?vitamin D?supplementation?and 1,656 on placebo) were included in the meta-analysis. For the primary outcome (mean change in pain score from baseline to final follow-up), 8 trials with 1,222 participants on?vitamin D?and 1,235 on placebo reported a significantly greater mean decrease in pain score for the?vitamin D?group compared to placebo (mean difference -0.57, 95% CI: -1.00 to -0.15, P = 0.007). The effect from?vitamin D?was greater in patients recruited with pre-existing pain (P-value for interaction = 0.03). Fourteen studies (1,548 on?vitamin D, 1,430 on placebo) reported the mean pain score at final follow-up outcome, and no statistical difference was observed (mean difference -0.06, 95%CI: -0.44 to 0.33, P = 0.78). In 4 studies which reported pain improvement (209 on?vitamin D, 146 on placebo), the effect size although not significant, shows participants in the?vitamin D?supplementation?group were more likely to report pain improvement compared with the placebo group (relative risk 1.38, 95%CI: 0.93 to 2.05, P = 0.11).LIMITATIONS:?Only a few studies reported the mean score change from baseline to final follow-up, and we do not have enough data to determine any modifying effect of baseline?vitamin D?status and different doses of?vitamin D?supplementation?on pain.CONCLUSION:?A significantly greater mean decrease in pain score (primary outcome) was observed with?vitamin D?supplementation compared with placebo in people with chronic pain. These results suggest that?vitamin D?supplementation?could have a role in the management of chronic pain.Wu Z, Malihi Z, Stewart AW, Lawes CM, Scragg R. Effect of Vitamin D Supplementation on Pain: A Systematic Review and Meta-analysis. Pain Physician. 2016 Sep-Oct;19(7):415-27.16. Vitamin D does not reduce pain in adults with symptomatic knee osteoarthritisClinical question: Does vitamin D supplementation reduce pain in adults with symptomatic knee osteoarthritis and low vitamin D levels?Study design: Randomized controlled trial (double-blinded)Setting: Outpatient (primary care)Synopsis: These investigators identified adults, aged 50 to 79 years, in otherwise good health with at least 6 months of symptomatic knee osteoarthritis (based on standard diagnostic criteria) and a pain score of 20 mm to 80 mm on a 100-mm visual analog scale. Eligibility criteria also included a low serum 25-hydroxyvitamin D level (12.5 nmol/L to 60 nmol/L). Study patients randomly received (concealed allocation assignment) a monthly capsule of 50,000 IU vitamin D3 or identical placebo for 24 months. The primary outcomes of knee pain and tibial cartilage volume were assessed using standard evaluation tools by individuals masked to treatment group assignment. Complete follow-up occurred for 82.4% of participants at 24 months. Serum 25-hydroxyvitamin D levels increased significantly more in the vitamin D group than in the placebo group, with 79% versus 43% of patients, respectively, who reached a 25-hydroxyvitamin D level of greater than 60 nmol/L at month 3. Although pain scores significantly decreased from baseline over 24 months in both groups, there was no difference in change of pain scores from baseline to 24 months between the 2 groups using intention-to-treat and per-protocol analyses. Tibial cartilage volume loss also occurred similarly between both groups. The study was 80% powered to detect predetermined clinically significant differences in pain scores and cartilage loss.Bottom line: Vitamin D supplementation did not significantly reduce pain or prevent cartilage loss compared with placebo in adults with symptomatic knee osteoarthritis and low vitamin D levels over 2 years.Jin X, Jones G, Cicuttini F, et al. Effect of vitamin D supplementation on tibial cartilage volume and knee pain among patients with symptomatic knee osteoarthritis. A randomized clinical trial. JAMA 2016;315(10):1005-1013.17. Maintaining Vitamin D sufficiency is associated with improved structural and symptomatic outcomes in knee osteoarthritisBACKGROUND: The aim of this study was to describe whether maintaining sufficient serum vitamin D levels in people with knee osteoarthritis and baseline vitamin D insufficiency has an association with change in knee structures and symptoms over 2 years.METHODS: Participants (n = 413, mean age 63.2 years) with symptomatic knee osteoarthritis and vitamin D insufficiency were enrolled in a clinical trial. In all, 340 participants (82.3%) completed the study, with 25-hydroxyvitamin D [25(OH)D] measurements at baseline and months 3 and 24. Participants were classified as consistently insufficient [serum 25(OH)D ≤50 nmol/L at months 3 and 24, n = 45], fluctuating [25(OH)D >50 nmol/L at either point, n = 68), and consistently sufficient [25(OH)D >50 nmol/L at months 3 and 24, n = 226] groups. Knee cartilage volume, cartilage defects, bone marrow lesions, and effusion-synovitis volume were assessed using MRI at baseline and month 24. Knee symptoms were assessed at baseline and months 3, 6, 12, and 24 using the Western Ontario and McMaster Universities Arthritis Index.RESULTS: The consistently sufficient group had significantly less loss of tibial cartilage volume (β 2.1%; 95% confidence interval [CI], 0.3%, 3.9%), less increase in effusion-synovitis volume (β -2.5 mL; 95 CI%, -4.7, -0.2 mL), and less loss of Western Ontario and McMaster Universities Arthritis Index physical function (β -94.2; 95% CI, -183.8, -4.5) compared with the consistently insufficient group in multivariable analyses. In contrast, there were no significant differences in these outcomes between the fluctuating and consistently insufficient groups. Changes in cartilage defects, bone marrow lesions, and knee pain were similar between groups.CONCLUSION: This post hoc analysis suggests beneficial effects of maintaining vitamin D sufficiency on cartilage loss, effusion-synovitis, and physical function in people with knee osteoarthritis. Am J Med. Zheng S1, Jin X1, Cicuttini F2, Wang X1, Zhu Z1, Wluka A2, Han W3, Winzenberg T4, Antony B1, Aitken D1, Blizzard L1, Jones G1, Ding C5. Maintaining Vitamin D Sufficiency Is Associated with Improved Structural and Symptomatic Outcomes in Knee Osteoarthritis. 2017 Oct;130(10):1211-1218. doi: 10.1016/j.amjmed.2017.04.038. Epub 2017 May 24.18. Vitamin D supplementation improves pain symptoms in patients with chronic widespread pain (aka fibromyalgia)Chronic non-specific widespread pain (CWP) including fibromyalgia (FMS) is characterized by widespread pain, reduced pain threshold, and multiple tender points on examination, causing disability and decreased quality of life. Vitamin D has been proposed as an associated factor in CWP. This meta-analysis aimed to explore the benefit of vitamin D supplementation in the management of CWP. A comprehensive search of the CENTRAL, MEDLINE, and Embase databases was performed from inception through January 2017. The inclusion criterion was the randomized clinical trials' evaluating the effects of vitamin D treatment in adult subjects with CWP or FMS. CWP was defined as chronic recurrent musculoskeletal pain without secondary causes; FMS patients met the American College of Rheumatology criteria for FMS. Study outcome was assessed using visual analog scale (VAS) of pain intensity. Pooled mean difference (MD) of VAS and 95% confidence interval (CI) were calculated using a random-effect meta-analysis. Meta-regression analysis using a random-effects model was performed to explore the effects of change in vitamin D in the treatment group on difference in the mean of VAS. Sensitivity analysis was performed to evaluate the robustness of results. The between-study heterogeneity of effect size was quantified using the Q statistic and I 2. Data were extracted from four randomized controlled trials involving 287 subjects. Pooled result demonstrated a significantly lower VAS in CWP patients who received vitamin D treatment compared with those who received placebo (MD = 0.46; 95% CI 0.09-0.89, I 2 = 48%). Meta-regression analysis revealed no significant relationship between the changes of vitamin D and VAS (coefficient = 0.04 (95% CI -0.01 to 0.08), p = 0.10). In this meta-analysis, we conclude that vitamin D supplementation is able to decrease pain scores and improve pain despite no significant change in VAS after increasing serum vitamin D level. Further studies need to be conducted in order to explore the improvement of functional status, quality of life, and the pathophysiological change that improves chronic widespread pain.Yong WC, Sanguankeo A, Upala S. Effect of vitamin D supplementation in chronic widespread pain: a systematic review and meta-analysis. Clin Rheumatol. 2017 Dec;36(12):2825-2833. 19. Vitamin D decreased migraine frequency but not intensityBACKGROUND: Vitamin D levels have been linked to certain pain states, including migraine. This study investigated whether vitamin D supplementation would be beneficial for adult patients with migraine.METHODS: A randomized, double-blinded, placebo-controlled parallel trial was conducted in migraine patients (36 women and 12 men, 18-65 years of age). A 4-week baseline period was conducted before randomization to 24 weeks of treatment. Participants were assigned to receive D3-Vitamin (n?=?24, 18 women and 6 men, 100?μg/day D3-Vitamin) or placebo (n?=?24,?18 women and 6 men). Migraine attacks and related symptoms were assessed by self-reported diaries. The response rate (i.e. experiencing a 50% or greater reduction in migraine frequency from baseline to week 24), change in migraine severity, and number of migraine days were recorded. Changes in migraine-related symptoms, HIT-6TM scores, and pain sensitivity tests (pressure pain threshold and temporal summation) were also evaluated. Serum levels of both 25 (OH)D and 1,25 (OH)2D were assessed from baseline to week 24.RESULTS: The number of headache days changed from 6.14?±?3.60 in the treatment group and 5.72?±?4.52 in the placebo group at baseline to 3.28?±?3.24 and 4.93?±?3.24 by the end of the trial, respectively. Migraine patients on D3-Vitamin demonstrated a significant decrease (p?<?.001) in migraine frequency from baseline to week 24 compared with placebo. However, migraine severity, pressure pain thresholds, or temporal summation did not show a significant change. 25(OH)D levels increased significantly for the D3-Vitamin group during the first 12 weeks of treatment. There was no significant change in 1,25(OH)2D. No side-effects were reported or noted.CONCLUSIONS: D3-Vitamin was superior to placebo in reducing migraine days in migraine patients. Larger studies are required to confirm that vitamin D3 might be one of the prophylactic options for adult patients with migraine.Gazerani P, Fuglsang R, Pedersen JG, S?rensen J, Kjeldsen JL, Yassin H, Nedergaard BS. A randomized, double-blinded, placebo-controlled, parallel trial of vitamin D3 supplementation in adult patients with migraine. Curr Med Res Opin. 2018 Sep 28:1-9Diabetes20. The effect of improved serum 25-hydroxyvitamin D status on glycemic control in diabetic patients: A meta-analysisBackground: Type 2 diabetes is a global health concern, with an increased prevalence and high cost of treatment.Objective: The aim of this systematic review and meta-analysis was to determine the effect of vitamin D supplementation and improved vitamin D status on glycemia and insulin resistance in type 2 diabetic patients.Data Source: We searched PUBMED/Medline, Cumulative Index to Nursing and Allied Health, and Cochrane Library (until January 2017).Study Selection: Prospective clinical trials were selected evaluating the impact of vitamin D supplementation on glycosylated hemoglobin (HbA1c), serum fasting plasma glucose (FPG), and homeostatic model assessment of insulin resistance (HOMA-IR) in diabetic patients. Data Extraction and Synthesis: We used a random-effects model to synthesize quantitative data, followed by a leave-one-out method for sensitivity analysis. The systematic review registration was CRD42017059555. From a total of 844 entries identified via literature search, 24 controlled trials (1528 individuals diagnosed with type 2 diabetes) were included. The meta-analysis indicated a significant reduction in HbA1c [mean difference: -0.30%; 95% confidence interval (CI): -0.45 to -0.15, P < 0.001], FPG [mean difference: -4.9 mg/dL (-0.27 mmol/L); 95% CI: -8.1 to -1.6 (-0.45 to -0.09 mmol/L), P = 0.003], and HOMA-IR (mean difference: -0.66; 95% CI: -1.06 to -0.26, P = 0.001) following vitamin D supplementation and significant increase in serum 25-hydroxyvitamin D levels [overall increase of 17 ± 2.4 ng/mL (42 ± 6 nmol/L)].Conclusions: Vitamin D supplementation, a minimum dose of 100 ?g/d (4000 IU/d), may significantly reduce serum FPG, HbA1c, and HOMA-IR index, and helps to control glycemic response and improve insulin sensitivity in type 2 diabetic patients.Mirhosseini N1, Vatanparast H2, Mazidi M3,4, Kimball SM1,5. The Effect of Improved Serum 25-Hydroxyvitamin D Status on Glycemic Control in Diabetic Patients: A Meta-Analysis. J Clin Endocrinol Metab. 2017 Sep 1;102(9):3097-3110. doi: 10.1210/jc.2017-01024. 21. Vitamin D supplementation does not prevent type 2 diabetesBACKGROUND:?Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether?vitamin D?supplementation?lowers the risk of diabetes is unknown.METHODS:?We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of?vitamin D3?or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508.RESULTS:?A total of 2423 participants underwent randomization (1211 to the?vitamin D?group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the?vitamin D?group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the?vitamin D?group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for?vitamin D?as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P?=?0.12). The incidence of adverse events did not differ significantly between the two groups.CONCLUSIONS:?Among persons at high risk for type 2 diabetes not selected for?vitamin D?insufficiency,?vitamin D3?supplementation?at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d number,?NCT01942694.).Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, et. al; D2d Research Group. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019 Aug 8;381(6):520-530.22. Vitamin D and Omega-3 fatty acid supplementation does not improve kidney function in type 2 diabetesImportance:??Chronic kidney disease (CKD) is a common complication of type 2 diabetes that can lead to end-stage kidney disease and is associated with high cardiovascular risk. Few treatments are available to prevent CKD in type 2 diabetes.Objective:??To test whether supplementation with vitamin D3?or omega-3 fatty acids prevents development or progression of CKD in type 2 diabetes.Design, Setting, and Participants:?Randomized clinical trial with a 2?×?2 factorial design conducted among 1312 adults with type 2 diabetes recruited between November 2011 and March 2014 from all 50 US states as an ancillary study to the Vitamin D and Omega-3 Trial (VITAL), coordinated by a single center in Massachusetts. Follow-up was completed in December 2017.Interventions:??Participants were randomized to receive vitamin D3(2000 IU/d) and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/d) (n?=?370), vitamin D3?and placebo (n?=?333), placebo and omega-3 fatty acids (n?=?289), or 2 placebos (n?=?320) for 5 years.Main Outcomes and Measures:?The primary outcome was change in glomerular filtration rate estimated from serum creatinine and cystatin C (eGFR) from baseline to year 5.Results:??Among 1312 participants randomized (mean age, 67.6 years; 46% women; 31% of racial or ethnic minority), 934 (71%) completed the study. Baseline mean eGFR was 85.8 (SD, 22.1) mL/min/1.73 m2. Mean change in eGFR from baseline to year 5 was ?12.3 (95% CI, ?13.4 to ?11.2) mL/min/1.73 m2?with vitamin D3?vs ?13.1 (95% CI, ?14.2 to ?11.9) mL/min/1.73 m2?with placebo (difference, 0.9 [95% CI, ?0.7 to 2.5] mL/min/1.73 m2). Mean change in eGFR was ?12.2 (95% CI, ?13.3 to ?11.1) mL/min/1.73 m2?with omega-3 fatty acids vs ?13.1 (95% CI, ?14.2 to ?12.0) mL/min/1.73 m2?with placebo (difference, 0.9 [95% CI, ?0.7 to 2.6] mL/min/1.73 m2). There was no significant interaction between the 2 interventions. Kidney stones occurred among 58 participants (n?=?32 receiving vitamin D3?and n?=?26 receiving placebo) and gastrointestinal bleeding among 45 (n?=?28 receiving omega-3 fatty acids and n?=?17 receiving placebo).Conclusions and Relevance:??Among adults with type 2 diabetes, supplementation with vitamin D3?or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes.Boer IH, Zelnick LR, Ruzinski J.et al. Effect of Vitamin D and Omega-3 Fatty Acid Supplementation on Kidney Function in Patients With Type 2 Diabetes A Randomized Clinical Trial. JAMA. 2019;322(19):1899-1909. November 8, 2019.Miscellaneous23. Vitamin D does not improve fatigue significantly in healthy volunteers with fatigueBACKGROUND:?Vitamin D?deficiency is frequent and has been associated with?fatigue?in uncontrolled trials.METHODS:?This is the first double-blind placebo-controlled clinical trial to investigate the efficacy of oral vitamin D3 (cholecalciferol) in treating?fatigue?among otherwise healthy persons with low serum 25-hydroxyvitamin D (25(OH)D) levels. We enrolled 120 individuals (mean age 29?±?6 years, 53% women) presenting with?fatigue?and?vitamin D?deficiency (serum 25(OH)D?<?20?μg/L). Participants were randomized to a single oral dose of 100,000 units of?vitamin D?or placebo. The primary endpoint was intra-individual change in the?fatigue?assessment scale (FAS) at 4 weeks after treatment.RESULT:?The mean age of the participants was 29?±?6 years, 53% were women. Mean FAS decreased significantly more in the?vitamin Dgroup (-3.3?±?5.3; 95% confidence interval [CI] for change -14.1 to 4.1) compared with placebo (-0.8?±?5.3; 95% CI for change -9.0 to 8.7); (P?=?0.01). Amelioration of?fatigue?was reported more frequently in?vitamin D?than in placebo group (42 [72%] vs. 31 [50%]; P?=?0.01; odds ratio [OR] 2.63, 95% CI for OR 1.23-5.62). Among all participants, improvement in?fatigue?score correlated with the rise in 25(OH)D level (R?=?-0.22, P?=?0.02).CONCLUSION:?Vitamin D?treatment significantly improved?fatigue?in otherwise healthy persons with?vitamin D?deficiency.Nowak A, Boesch L, Andres E, Battegay E, Hornemann T, Schmid C, Bischoff-Ferrari HA, Suter PM, Krayenbuehl PA. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore). 2016 Dec;95(52):e5353. PubMed PMID: 28033244;24. Vitamin D improved IBS symptoms in Vitamin D deficient adolescentsBACKGROUND/AIM:?Vitamin D?deficiency is common in irritable bowel syndrome (IBS). There is growing interest in the role of?vitamin D?in pediatric IBS. We aimed to evaluate the effect of?vitamin D?supplementation?in adolescents with IBS and?vitamin Ddeficiency.PATIENTS AND METHODS:?One hundred and twelve adolescents with IBS and?vitamin D?deficiency were randomly divided into two groups of matched age and sex. The first group received oral?vitamin D3?2000IU/day for 6 months and the second group received placebo for 6 months.?Vitamin D?status as well as different IBS score systems (IBS-SSS, IBS-QoL, and total score) were evaluated before and 6 months after treatment.RESULTS:?IBS patients who received?vitamin D?supplementation?for 6 months showed significant improvement in IBS-SSS (P < 0.001), IBS-QoL (P < 0.001), and total score (P = 0.02) compared to IBS placebo group. IBS patients treated with?vitamin D showed two folds increase in their serum?vitamin D?levels (from 17.2 ± 1.3 to 39 ± 3.3) ng/ml with P < 0.001. While in the placebo group, their serum?vitamin D?levels were not significantly changed (P = 0.66).?Vitamin D?was tolerated well without any recorded adverse effects during the study period.CONCLUSION:?Vitamin D?supplementation?can be effective in treating adolescents with IBS and?vitamin D?deficiency.El Amrousy D, Hassan S, El Ashry H, Yousef M, Hodeib H. Vitamin D supplementation in adolescents with irritable bowel syndrome: Is it useful? A randomized controlled trial. Saudi J Gastroenterol. 2018 Mar-Apr;24(2):109-114. PubMed PMID: 29637918.25. High dose Vitamin D (10,000 IU/day) decreases bone mineral densityIMPORTANCE:?Few studies have assessed the effects of daily?vitamin D?doses at or above the tolerable upper intake level for 12 months or greater, yet 3% of US adults report?vitamin D?intakes of at least 4000 IU per day.OBJECTIVE:?To assess the dose-dependent effect of?vitamin D?supplementation?on volumetric bone mineral density (BMD) and strength.DESIGN, SETTING, AND PARTICIPANTS:?Three-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017, including 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L.INTERVENTIONS:?Daily doses of vitamin D3 for 3 years at 400 IU (n?=?109), 4000 IU (n?=?100), or 10?000 IU (n?=?102). Calcium?supplementation?was provided to participants with dietary intake of less than 1200 mg per day.MAIN OUTCOMES AND MEASURES:?Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis.RESULTS:?Of 311 participants who were randomized (53% men; mean [SD] age, 62.2 [4.2] years), 287 (92%) completed the study. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10?000-IU group. There were significant group?×?time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (-3.9 mg HA/cm3 [95% CI, -6.5 to -1.3]) and 10?000 IU group (-7.5 mg HA/cm3 [95% CI, -10.1 to -5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of -1.2% (400 IU group), -2.4% (4000 IU group), and -3.5% (10?000 IU group). Tibial volumetric BMD differences from the 400 IU group were -1.8 mg HA/cm3 (95% CI, -3.7 to 0.1) in the 4000 IU group and -4.1 mg HA/cm3 in the 10?000 IU group (95% CI, -6.0 to -2.2), with mean percent change values of -0.4% (400 IU), -1.0% (4000 IU), and -1.7% (10?000 IU). There were no significant differences for changes in failure load (radius, P?=?.06; tibia, P?=?.12).CONCLUSIONS AND RELEVANCE:?Among healthy adults, treatment with?vitamin D?for 3 years at a dose of 4000 IU per day or 10?000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10?000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose?vitamin D?supplementation?for bone health; further research would be needed to determine whether it is harmful.Burt LA, Billington EO, Rose MS, Raymond DA, Hanley DA, Boyd SK. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA. 2019 Aug 27;322(8):736-745. PubMed PMID: 31454046.26. Retraction of Vitamin D autism randomized trialThe above article, published in print in the Jan 2018 issue of the Journal of Child Psychology & Psychiatry and online in Wiley Online Library (), has been retracted by the JCPP Editor-in-Chief, Edmund Sonuga-Barke, and John Wiley & Sons. Following a series of communications from readers highlighting concerns about the paper (now published on the journal website), the journal editors requested that the authors send them the raw data from the trial. In response the authors informed the editors that; (i) the electronic data base had been lost following a computer outage and (ii) that they could send only 95 out of 120 hard-copy participant data sheets as one site had closed and was no longer contactable. The substantial data loss in and of itself posed a serious difficulty in verifying the correctness of the data presented in the paper. The JCPP then analysed the data from the 95 cases itself. A number of significant discrepancies emerged between the re-analysis and the findings reported in the paper both in terms of means and standard deviations of key outcome variables across the trial. These involved very substantial differences that we judged to be extremely unlikely to have arisen due to variations in composition of the original and re-analysed samples. We also discovered previously unidentified/reported problems with missing data and recording irregularities regarding changes in treatment regimen and subject identifiers. As a result of these issues the Editors no longer have confidence in the findings reported in the original paper. Based on all these matters combined and following published guidance from the Committee on Publishing Ethics (COPE) and Wiley's Best Practice Guidelines on Publishing Ethics, we have decided that the only course of action available to us is to retract the paper.Saad K, Abdel-Rahman A, Elserogy Y, Al-Atram A, El-Houfey A, Othman H,Bj?rklund G, Jia F, Urbina M, Abo-Elela M, Ahmad F, Abd El-Baseer A, Ahmed A, Abdel-Salam A. Retraction: Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. J Child Psychol Psychiatry. 2019 Jun;60(6):711. PubMed PMID: 31087556.The correct cut-off for Vitamin D deficiency is probably 12 ng/ml rather than 20 ng/mlDebate about the proper normal range for serum Vitamin D started back in 2012. Here is an excerpt from the Institute of Medicine’s rebuttal of the Endocrine Society vitamin D guidelines: “For the IOM, the 20-ng/ml level is the upper range of human requirements, and therefore, on a population basis, 20 ng/ml reflects a level that more than meets the needs of almost all of the general population. The guideline's use of 20 ng/ml as the point for defining deficiency in the general population is inconsistent with the data and inflates the number of persons deemed to be vitamin D deficient. Less than 3% of the general population is likely to have vitamin D needs that require levels to be higher than 20 ng/ml; more than 97% are adequate in vitamin D with serum levels of 20 ng/ml and 50% are adequate at levels of 16 ng/ml.1?These delineations were defined for the general population for the United States and Canada. Although more study is necessary to clarify the nature of the serum response to dietary vitamin D, it would appear that intakes between 400 and 800 IU/d are likely to increase serum levels to at least 20 ng/ml and probably higher, depending on a variety of factors.” Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Manson JE, Mayne ST, Ross AC, Shapses SA, Taylor CL. IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab. 2012 Apr;97(4):1146-52. doi:10.1210/jc.2011-2218. Epub 2012 Mar 22. PubMed PMID: 22442278; PubMed CentralPMCID: PMC5393439.Read this editorial to better understand what a normal Vitamin D level should be. Manson JE, Brannon PM, Rosen CJ, Taylor CL. Vitamin D Deficiency - Is There Really a Pandemic? N Engl J Med. 2016 Nov 10;375(19):1817-1820. PubMed PMID: 27959647.This study from Australia suggests that a lower limit of 12 ng/ml is the right threshold, at least for bone health.27. Serum 25-hydroxyvitamin D insufficiency in search of a bone diseaseCONTEXT: Vitamin D "insufficiency" and "deficiency" are defined as serum 25-hydroxyvitamin D [25(OH)D] levels <75 and <30 nmol/L, respectively. We aimed to determine whether these values signal hypocalcemia and hypophosphatemia, secondary hyperparathyroidism, high bone remodeling, low areal bone mineral density (aBMD), microstructural deterioration, or reduced matrix mineralization density (MMD) and so suggest whether bone fragility is present.METHODS: Concentrations of 25(OH)D, calcium, phosphate, creatinine, and parathyroid hormone (PTH) were measured in 11,855 participants. Serum C-terminal telopeptide of type 1 collagen, procollagen type 1 N-terminal propeptide (P1NP), aBMD, and distal radius microstructure and MMD were measured in a second subset of 150 participants.RESULTS: A breakpoint for calcium, PTH, and alkaline phosphatase was identified at a threshold 25(OH)D level <30 nmol/L. There was no plateau beyond 75 nmol/L. In the subgroup with measurements of bone morphology, no associations were detectable between serum 25(OH)D concentration, aBMD, trabecular density, cortical porosity, or MMD. Among 1439 participants with serum 25(OH)D <30 nmol/L, 6.1% had low serum calcium, 3.4% had low serum phosphate, 6.1% had high alkaline phosphatase, and 34.2% had elevated PTH. Most participants did not have any abnormalities.CONCLUSION: At a 25(OH)D threshold of ≤30 nmol/L(12 ng/ml), abnormalities in biochemical features support the notion of a "deficiency" state predisposing to bone disease. However, no deleterious effects were found in participants within an insufficiency threshold of a 25(OH)D level of 30 (12 ng/ml) to 75 nmol/L (30 ng/ml), which challenges the rationale justifying vitamin D supplementation in these individuals.Shah S,?Chiang C,?Sikaris K,?Lu Z,?Bui M,?Zebaze R,?Seeman E. Serum 25-Hydroxyvitamin D Insufficiency in Search of a Bone Disease. J Clin Endocrinol Metab.?2017 Jul 1;102(7):2321-2328. 28. Most vitamin D research does not study patients with Vitamin D deficiency BACKGROUND: Research waste can occur when trials are conducted in the wrong populations. Vitamin D deficient populations are most likely to benefit from vitamin D supplementation. We investigated waste attributable to randomized controlled trials (RCTs) of supplementation in populations that were not vitamin D deficient.METHODS: In December 2015, we searched Pubmed, recent systematic reviews, and three trial registries for RCTs of vitamin D with clinical endpoints in adults, and 25-hydroxvitamin D (25OHD) survey data relevant to large (N?≥?1000) RCTs. We investigated the proportion of RCTs that studied vitamin D deficient populations, temporal trends in baseline 25OHD, and whether investigators in large RCTs considered relevant 25OHD survey data or systematic reviews in their trial justifications.RESULTS: Of 137 RCTs of vitamin D with clinical endpoints, 118 (86%) reported baseline mean/median 25OHD, which was <?25, 25-49, 50-74, and?≥?75?nmol/L in 12 (10%), 62 (53%), 36 (31%), and 8 (7%) RCTs, respectively. In 70% of RCTs, baseline 25OHD was >?40?nmol/L. Baseline 25OHD increased over time. Before 2006, 38%, 62%, 0% and 0% of RCTs had baseline 25OHD <?25, 25-49, 50-74, and?≥?75?nmol/L respectively; in 2011-15, the respective proportions were 9%, 49%, 37%, and 6%. Of 12 RCTs with baseline 25OHD <?25?nmol/L, 8 had neutral findings. Of 25 large RCTs (18 completed, 7 ongoing), 1 was undertaken in a vitamin D deficient population, 3 in vitamin D insufficient populations, and 17 had, or probably will have, baseline 25OHD >?40?nmol/L. 44% (8/18) of largecompleted RCTs cited relevant prior population 25OHD data, and only 3/10 (30%) relevant prior systematic reviews.CONCLUSIONS: Up to 70% of RCTs of vitamin D with clinical endpoints, 71% of large completed RCTs, and 100% of ongoing large RCTs could be considered research waste because they studied cohorts that were not vitamin D deficient.Bolland MJ, Grey A, Avenell A. Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation. BMC Med Res Methodol. 2018 Oct 3;18(1):101.Bottom Lines1. Vitamin D supplementation does not appear to prevent cancer, but may have a small positive effect on cancer survival.2. Vitamin D supplementation does not appear to prevent or improve cardiovascular conditions.3. There may be a small effect of Vitamin D on chronic pain, but larger and better studies are needed.4. Vitamin D does not improve pain associated with knee osteoarthritis.5. Vitamin D decreases the frequency of acute respiratory infections.6. Vitamin D decreases asthma exacerbations requiring steroids, but not the rate of exacerbations. 7. Vitamin D reduces the frequency of mod/severe COPD exacerbations in those Vitamin D deficient.8. Vitamin D decreases A1C slightly in type 2 diabetes; the clinical significance is unknown.9. Vitamin D does not prevent type 2 diabetes or improve kidney function.10. We have much to learn about Vitamin D supplementation to improve health. We need better studies of patients who are truly vitamin D deficient. ................
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