Title: Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes
Abstract: HomeCirculationVol. 121, No. 24Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBAspirin for Primary Prevention of Cardiovascular Events in People With DiabetesA Position Statement of the American Diabetes Association, a Scientific Statement of the American Heart Association, and an Expert Consensus Document of the American College of Cardiology Foundation Michael Pignone, Mark J. Alberts, John A. Colwell, Mary Cushman, Silvio E. Inzucchi, Debabrata Mukherjee, Robert S. Rosenson, Craig D. Williams, Peter W. Wilson and M. Sue Kirkman Michael PignoneMichael Pignone From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). , Mark J. AlbertsMark J. Alberts From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). , John A. ColwellJohn A. Colwell From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). , Mary CushmanMary Cushman From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). , Silvio E. InzucchiSilvio E. Inzucchi From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). , Debabrata MukherjeeDebabrata Mukherjee From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). , Robert S. RosensonRobert S. Rosenson From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). , Craig D. WilliamsCraig D. Williams From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). , Peter W. WilsonPeter W. Wilson From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). and M. Sue KirkmanM. Sue Kirkman From the Department of Medicine, University of North Carolina, Chapel Hill (M.P.); the Department of Neurology, Northwestern University, Chicago, Ill (M.J.A.); the Division of Endocrinology, Diabetes, and Medical Genetics (Emeritus), Medical University of South Carolina, Charleston (J.A.C.); the Department of Medicine, University of Vermont, Burlington (M.C.); the Section of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Conn (S.E.I.); the Division of Cardiovascular Medicine, Department of Medicine, Texas Tech University, Paul Foster School of Medicine, El Paso (D.M.); Mount Sinai Heart, Mount Sinai School of Medicine, New York, NY (R.S.R.); the College of Pharmacy, Oregon State University and Oregon Health and Science University, Portland (C.D.W.); the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.W.W.); and the American Diabetes Association, Alexandria, Va (M.S.K.). Originally published27 May 2010https://doi.org/10.1161/CIR.0b013e3181e3b133Circulation. 2010;121:2694–2701Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 27, 2010: Previous Version 1 The burden of cardiovascular disease (CVD) among patients with diabetes is substantial. Individuals with diabetes are at 2- to 4-fold increased risk of cardiovascular events compared with age- and sex-matched individuals without diabetes. In diabetic patients over the age of 65 years, 68% of deaths are from coronary heart disease (CHD) and 16% are from stroke.1 A number of mechanisms for the increased cardiovascular risk with diabetes have been proposed, including increased tendency toward intracoronary thrombus formation,2 increased platelet reactivity,3 and worsened endothelial dysfunction.4The increased risk for cardiovascular events and mortality in patients with diabetes has led to considerable interest in identifying effective means for cardiovascular risk reduction. Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with myocardial infarction (MI) or stroke (secondary prevention).5 The Food and Drug Administration has not approved aspirin for use in primary prevention, and its net benefit among patients with no previous cardiovascular events is more controversial, for both patients with and without a history of diabetes.5 The U.S. Preventive Services Task Force recently updated its recommendation about aspirin use for primary prevention. The Task Force recommended encouraging aspirin use in men age 45–79 years and women age 55–79 years and not encouraging aspirin use in younger adults. They did not differentiate their recommendations based on the presence or absence of diabetes.6,7In 2007, the American Diabetes Association (ADA) and the American Heart Association (AHA) jointly recommended that aspirin therapy (75–162 mg/d) be used as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are over 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria).8 These recommendations were derived from several older trials that included relatively small numbers of patients with diabetes. Results of 2 recent randomized controlled trials of aspirin performed specifically in patients with diabetes raised questions about the efficacy of aspirin for primary prevention in diabetes.9,10Because of the scope of the problem of CVD in patients with diabetes and the conflicting evidence about the efficacy of aspirin for primary prevention in people with diabetes, the ADA, AHA, and the American College of Cardiology Foundation (ACCF) convened a group of experts to review and synthesize the available evidence and use this information to create updated recommendations. The group considered and organized this report around the following questions: What is the evidence regarding aspirin to prevent initial cardiovascular events in people with diabetes?How can we reconcile the results of the different primary prevention trials?What are the risks of aspirin, and are these similar or different for people with diabetes compared to those without?What do we know about the recommended dosage or dosage range?How can we integrate potential benefits and risks of aspirin to determine which patients with diabetes should receive aspirin for the primary prevention of cardiovascular events?What are the needs for future research?1. What is the Evidence Regarding Aspirin to Prevent Initial Cardiovascular Events in People With Diabetes?Several randomized trials have examined the effect of aspirin for primary prevention of cardiovascular events and have included patients with diabetes (Table). In this section, we examine those findings with respect to the ability of aspirin to prevent cardiovascular events, which typically include ischemic or CHD events (MI, sometimes unstable angina), stroke, and vascular death (usually sudden cardiac death or death from stroke). Table. Comparison of Primary Prevention Trials of Aspirin That Enrolled Patients With Diabetes (N=11 787)Study/YearRefAspirin Dose (Study Design)Follow-Up, yNumber Enrolled With Diabetes% FemaleAge, y(Minimum/Mean) CHD End PointATT indicates Antithrombotic Trialists' (ATT) Collaboration; BMD, British Medical Doctors; BP, blood pressure; CHD, coronary heart disease; DM, diabetes mellitus; ETDRS, Early Treatment of Diabetic Retinopathy Study; HOT, Hypertension Optimal Treatment; IU, international unit; JPAD, Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; MCE, major coronary event (CHD death+nonfatal MI+sudden death); MI, myocardial infarction; NA, not available; PHS, Physicians' Health Study; POPADAD, Prevention of Progression of Arterial Disease and Diabetes; PPP, Primary Prevention Project; PT, Thrombosis Prevention Trial; RR; relative risk; WHS, Women's Health Study.*10-year extrapolated CHD event rate calculated by (10 ÷ study duration) × event rate.†Calculated based on event counts.‡Values slightly different from original PHS report based on updated ICD-9 coding information obtained by the ATT trialists.§Data used from 2003 PPP diabetic substudy16; number with diabetes is discrepant from original PPP publication15 due to continued enrollment and follow-up of diabetic patients beyond the original study period.∥Event rates slightly different than original 2005 report due to 11 extra MI/CHD deaths (6 in aspirin group and 5 in placebo) reported to the ATT study group vs. original publication.PHS DM/198912325 mg every other day(2×2 factorial design with 50 mg beta carotene)5.05330>40/NAFatal+nonfatal MIETDRS/199218650 mg daily5.0371144>18/NAFatal+nonfatal MIPPP DM/200316§100 mg daily(2×2 design with 30 mg vitamin E)3.7103152>50/64Fatal+nonfatal MIWHS DM/200517100 mg every other day(2×2 factorial design with 600 IU vitamin E every other day)10.11027100>45/55Fatal+nonfatal MI∥JPAD/20081081–100 mg daily(open label treatment assignment, blinded end-point assessment)4.4253946>30/65Fatal+nonfatal MIPOPADAD/20089100 mg daily(2×2 factorial design including antioxidants)6.7127656>40/60CHD death+nonfatal MITPT DM/1998 (data from ATT)575 mg daily6.7680>45/58MCEBMD/1988 (data from ATT)5500 mg daily5.61010>50/NAMCEHOT DM/ 1998 (data from ATT)575 mg daily(co–randomized to 1 of 3 diastolic BP goals)3.8150147>50/62MCETable. ContinuedCHD End Point Event Rate(Control vs. Aspirin)10-Year Extrapolated CHD Event Rates*RR (95% CI)†Stroke Events for Aspirinvs. Control: RR (95% CI)10.5% vs. 6.2%‡ (27/258 vs. 17/275) 21% vs. 12.4%0.59 (0.33–1.06)16 vs. 10: 1.50 (0.69–3.25)15.3% vs. 13.0% (283/1855 vs. 241/1856)30.6% vs. 26.0%0.85 (0.73–1.00)92 vs. 78: 1.18 (0.88–1.58)2.0% vs. 1.0% (10/512 vs. 5/519) 5.4% vs. 2.7%0.49 (0.17–1.43)10 vs. 11: 0.90 (0.38–2.09)5.9% vs. 7.9% (29/494 vs. 42/533) 5.9% vs. 7.9%1.34 (0.85–2.12)15 vs. 31: 0.45 (0.25–0.82)1.1% vs. 1.0% (14/1277 vs. 12/1262) 2.5% vs. 2.3%0.87 (0.40–1.87)22 vs. 34: 0.65 (0.39–1.11)12.9% vs. 13.9% (82/638 vs. 89/638) 19.3% vs. 20.7%1.09 (0.82–1.44)37 vs. 50: 0.74 (0.49–1.12)15.4% vs. 13.8% (6/39 vs. 4/29)23.0% vs. 20.6%0.90 (0.28–2.89)1 vs. 2: 0.67 (0.06–7.06)18.8% vs. 18.8% (6/32 vs. 13/69)33.48% vs. 33.6%1.00 (0.42–2.40)3 vs. 1: 1.39 (0.15–12.86)3.6% vs. 2.8% (27/749 vs. 21/752) 9.5% vs 7.3%0.77 (0.44–1.36)22 vs. 24: 0.91 (0.52–1.61)Six trials—British Medical Doctors (BMD),11 Physicians' Health Study (PHS),12 Thrombosis Prevention Trial (TPT),13 Hypertension Optimal Treatment (HOT),14 Primary Prevention Project (PPP),15,16 and Women's Health Study (WHS)17—were population-based and did not focus specifically on patients with diabetes. The percentage of patients with diabetes in these studies ranged from 1–2% in TPT, BMD, and PHS to 22% in PPP. Two recent trials, the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD)9 and the Prevention of Progression of Arterial Disease and Diabetes (POPADAD),10 and 1 older trial, the Early Treatment of Diabetic Retinopathy Study (ETDRS),18 enrolled only patients with diabetes. The available trials (except ETDRS) included mainly or exclusively patients with type 2 diabetes. ETDRS enrolled patients with both type 1 and type 2 diabetes (31% type 1, 31% type 2, and 38% unclassified).Three trials (BMD, PHS, and TPT) did not include any women, and 1 (WHS) focused solely on women. The proportion of women in the remaining 5 trials varied from 44 to 56%. The dose of aspirin varied from 100 mg every other day to 650 mg daily. The 9 trials ranged from 3.7 to 10.1 years in mean duration, with most extending to 4–6 years. Each of the trials excluded potential participants at increased risk of gastrointestinal bleeding based on a history of peptic ulcer disease. Therefore, the findings of this meta-analysis, which are based on these trials, cannot be readily extended to patients with a history of gastrointestinal bleeding.Only 2 of the 9 trials reported on use of statins or other lipid-lowering therapy. In JPAD, statin use was 26%, while in PPP lipid-lowering therapy use was 13%. Three trials (BMD, PHS, and ETDRS) were conducted prior to the availability of statins, and TPT and HOT were conducted well before the widespread use of statins for primary prevention. Rates of usage in the more recent POPADAD or WHS trials were not reported.The PHS trial enrolled 533 men with diabetes and found a 41% relative risk (RR) reduction (RR 0.59, 95% CI 0.33–1.06) in fatal and nonfatal MI over 5 years for those assigned to 325 mg aspirin every other day compared with those assigned to placebo.12 The HOT trial examined the effect of 75 mg of aspirin daily versus placebo in 18,000 patients ages 50–80 years, of whom 1,501 had diabetes. Among those with diabetes, the RR reduction for CHD events was 23% (RR 0.77, 95% CI 0.44–1.36).14 The PPP trial enrolled 1031 patients with diabetes and found a nonsignificant reduction in the combined MI end point (fatal plus nonfatal MI) with 100 mg of aspirin daily compared with placebo (RR 0.50, 95% CI 0.17–1.46).15The BMD and TPT studies enrolled relatively few patients with diabetes and did not identify important reductions in CVD risk for those with diabetes, but in each case confidence intervals were quite wide.11,13 The WHS trial, the only trial that focused exclusively on women and used the lowest dose of aspirin (100 mg every other day), did not find a reduction in risk for CHD with aspirin overall or for the subset with diabetes (N=1027; RR 1.34, 95% CI 0.85–2.12). They did, however, identify a reduction in stroke with aspirin for women with diabetes (RR 0.45, 95% CI 0.25–0.82).17Three trials focused on the effect of aspirin exclusively among patients with diabetes. The ETDRS trial examined the effect of 650 mg of aspirin daily versus placebo among 3,711 patients with type 1 or type 2 diabetes between ages 18 and 70 years who had some degree of retinopathy. Approximately one-half of participants reported some history of CVD, although it should be noted that the definition of CVD included the use of antihypertensive medication. Fewer than 10% had had a previous MI or stroke, and 9% had claudication. Intervention patients experienced a decreased risk of nonfatal or fatal MI (RR 0.85, 95% CI 0.73–1.00). In contrast, stroke occurred more frequently with aspirin, although the difference was not statistically significant (RR 1.18, 99% CI 0.88–1.58). Men appeared to derive more benefit from aspirin than women for prevention of MI (RR for men 0.74, 99% CI 0.54–1.00; RR for women 0.91, 99% CI 0.65–1.28), but this difference was not statistically significant and could represent a chance finding.18The POPADAD trial studied whether aspirin and/or antioxidant therapy was more effective than placebo in reducing the incidence of cardiovascular events in patients with diabetes and asymptomatic peripheral arterial disease. This randomized, multicenter, double-blind, placebo-controlled trial involved 1276 adults over age 40 years with either type 1 or type 2 diabetes. All subjects had an ankle brachial pressure index less than 0.99 but no symptomatic CVD. They were randomized in a 2×2 factorial design to aspirin 100 mg daily, an antioxidant supplement daily, both, or neither. Two composite primary end points were 1) death from CHD or stroke, nonfatal MI or stroke, or amputation above the ankle for critical limb ischemia; and 2) death from CHD or stroke. Study medication discontinuation rates were high: 14% at 1 year and 50% at 5 years. Overall, 116 of 638 (18.2%) primary events occurred in patients assigned to aspirin therapy versus 117 of 638 (18.3%) in those on placebo (HR 0.98, 95% CI 0.76–1.26). There were 43 CHD or stroke deaths in the aspirin group and 35 in the placebo group (6.7% vs. 5.5%; HR 1.23, 95% CI 0.79–1.93). The rates of a wide variety of secondary end points and adverse events also did not differ between groups. Outcomes were also similar with or without the antioxidants; there was no interaction between the 2 active therapies.10In JPAD, investigators examined the efficacy of low-dose aspirin for primary prevention of cardiovascular events in a randomized, open-label trial conducted in 2539 Japanese patients with type 2 diabetes but no history of CVD. Patients were assigned to either aspirin (81–100 mg daily) or no aspirin and were followed for an average of 4.4 years. The primary end point was a composite of fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease. A total of 154 events occurred: 68 (5.4%) in the aspirin group and 86 (6.7%) in the nonaspirin group (HR 0.80, 95% CI 0.58–1.10). The combined secondary end point of coronary and cerebrovascular mortality occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal MIs and 5 fatal strokes) in the nonaspirin group (HR 0.10, 95% CI 0.01–0.79). Other secondary end points did not differ importantly between groups. Overall, mortality occurred in 34 patients in the aspirin group and 38 patients in the nonaspirin group (HR 0.90, 95% CI 0.57–1.14). According to prespecified subgroup analyses, however, in subjects over 65 years of age (n=1363), the incidence of the primary end point was lower with aspirin (HR 0.68, 95% CI 0.46–0.99).9In summary, the currently available evidence on aspirin for CVD prevention includes 3 trials conducted specifically in patients with diabetes and 6 other trials in which patients with diabetes constitute subgroups within broader trials of aspirin prophylaxis. No single trial provides definitive results. As such, we sought, in question 2, to use meta-analysis to try to reconcile the available data.2. How Can We Reconcile the Results of the Different Trials?In order to synthesize and reconcile the results of the available trials, we examined existing meta-analyses of aspirin prevention trials (including those that focused on all patients and those that examined only patients with diabetes) and performed new meta-analyses with updated data.The Antithrombotic Trialists' (ATT) Collaboration recently published an individual patient-level meta-analysis of the 6 large trials of aspirin for primary prevention in the general population.5 These trials collectively enrolled over 95 000 participants, including almost 4000 with diabetes. Overall, the meta-analysis found that aspirin reduced the risk of vascular events by 12% (RR 0.88, 95% CI 0.82–0.94). The largest reduction was for nonfatal MI (RR 0.77, 95% CI 0.67–0.89). Aspirin had little effect on CHD death (RR 0.95, 95% CI 0.78–1.15) or total stroke (RR 0.95, 95% CI 0.85–1.06). The net effect on total stroke reflected a relative reduction in risk of ischemic stroke (−14%) and a relative increased risk of hemorrhagic stroke (+32%).There was some evidence of a difference in aspirin effect by sex. Aspirin reduced CHD events in men (RR 0.77, 95% CI 0.67–0.89) but not in women (RR 0.95, 95% CI 0.77–1.17). Conversely, aspirin had no effect on stroke in men (RR 1.01, 95% CI 0.74–1.39) but reduced stroke in women (RR 0.77, 95% CI 0.59–0.99). These potential differences in effect by sex were of borderline statistical significance, were affected strongly by the results of 1 trial (WHS), and cannot be considered definitive. Notably, sex differences in aspirin's effects have not been observed in studies of secondary prevention.5 The ATT collaborators did not identify other clear sources of heterogeneity of effect, although there was some suggestion that current smokers derived less benefit from aspirin than nonsmokers.In the 6 trials examined by the ATT, the effect of aspirin on major vascular events was similar for patients with and without diabetes: RR 0.88, 95% CI 0.67–1.15, and RR 0.87, 95% CI 0.79–0.96, respectively. The CI was wider for those with diabetes because of the smaller number of participants with diabetes and their smaller total numbers of CVD events.We performed a new meta-analysis that added data from 3 trials performed specifically in patients with diabetes (JPAD, POPADAD, and ETDRS)9,10,18 to the data from the subgroups of patients with diabetes from the 6 trials included in the ATT meta-analysis (Figure). Using a random-effects model, we found that aspirin was associated with a 9% decrease in risk of CHD events (nonfatal and fatal MI) that was not statistically significant (RR 0.91, 95% CI 0.79–1.05). We did not identify important heterogeneity (χ2=8.71, P=0.367, I2=8.2%), but a large portion of the summary estimate depended on the ETDRS trial. Excluding this trial, the estimate of effect for CHD events was smaller. Download figureDownload PowerPointFigure. Meta-analysis of trials examining the effects of aspirin on risk of cardiovascular disease events in patients with diabetes. A, Effect of aspirin on coronary heart disease events. Tests for heterogeneity: χ2=8.71, P=0.367, I2=8.2%. B, Effect of aspirin on risk of stroke in patients with diabetes. Tests for heterogeneity: χ2=12.48, P=0.131, I2=35.9%. BMD indicates British Medical Doctors11; CI, confidence interval; ETDRS, Early Treatment of Diabetic Retinopathy Study18; HOT, Hypertension Optimal Treatment14; JPAD, Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes9; PHS, Physicians' Health Study12; POPADAD, Prevention of Progression of Arterial Disease and Diabetes10; PPP, Primary Prevention Project15; TPT, Thrombosis Prevention Trial13; WHS, Women's Health Study.17For stroke, our random-effects meta-analysis of the 9 trials found a reduction in the risk of stroke of 15% (RR 0.85, 95% CI 0.66–1.11) that was not statistically significant. There was some heterogeneity (χ2=12.48, P=0.131, I2=35.9%). The results of these diabetes-specific analyses are consistent with the findings of the ATT meta-analysis and suggest that aspirin likely produces a modest reduction in CVD risk, but limitations in the amount of available data preclude a precise estimate of effect. We also do not have access to sufficient patient-level data in patients with diabetes to consider whether the effect of aspirin on CHD events and stro