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Effect of Aspirin on Mortality in the Primary Prevention of Cardiovascular Disease

      Abstract

      Objective

      The lack of a mortality benefit of aspirin in prior meta-analyses of primary prevention trials of cardiovascular disease has contributed to uncertainty about the balance of benefits and risks of aspirin in primary prevention. We performed an updated meta-analysis of randomized controlled trials of aspirin to obtain best estimates of the effect of aspirin on mortality in primary prevention.

      Methods

      Eligible articles were identified by searches of electronic databases and reference lists. Outcomes of interest were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and bleeding. Data were pooled from individual trials using the DerSimonian-Laird random-effects model, and results are presented as relative risk (RR) and 95% confidence intervals (CIs).

      Results

      Nine randomized controlled trials enrolling 100,076 participants were included. Aspirin reduced all-cause mortality (RR 0.94; 95% CI, 0.88-1.00), myocardial infarction (RR 0.83; 95% CI, 0.69-1.00), ischemic stroke (RR 0.86; 95% CI, 0.75-0.98), and the composite of myocardial infarction, stroke, or cardiovascular death (RR 0.88; 95% CI, 0.83-0.94), but did not reduce cardiovascular mortality (RR 0.96; 95% CI, 0.84-1.09). Aspirin increased the risk of hemorrhagic stroke (RR 1.36; 95% CI, 1.01-1.82), major bleeding (RR 1.66; 95% CI, 1.41-1.95), and gastrointestinal bleeding (RR 1.37; 95% CI, 1.15-1.62). A lack of availability of patient-level data precluded exploration of benefits and risks of aspirin in key subgroups.

      Conclusion

      Aspirin prevents deaths, myocardial infarction, and ischemic stroke, and increases hemorrhagic stroke and major bleeding when used in the primary prevention of cardiovascular disease.

      Keywords

      Aspirin reduces nonfatal and fatal cardiovascular events in patients with a history of symptomatic cardiovascular disease, and it is widely accepted that the benefits of aspirin outweigh the increased risk of bleeding in this setting.
      • Yusuf S.
      • Reddy S.
      • Ounpuu S.
      • Anand S.
      Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization.
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      In patients without a history of cardiovascular disease, aspirin has not been shown to reduce mortality,
      • Hart R.G.
      • Halperin J.L.
      • McBride R.
      • Benavente O.
      • Man-Son-Hing M.
      • Kronmal R.A.
      Aspirin for the primary prevention of stroke and other major vascular events: meta-analysis and hypotheses.
      • Sanmuganathan P.S.
      • Ghahramani P.
      • Jackson P.R.
      • Wallis E.J.
      • Ramsay L.E.
      Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials.
      • Hayden M.
      • Pignone M.
      • Phillips C.
      • Mulrow C.
      Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force.
      • Bredie S.J.
      • Wollersheim H.
      • Verheugt F.W.
      • Thien T.
      Low-dose aspirin for primary prevention of cardiovascular disease.
      • Eidelman R.S.
      • Hebert P.R.
      • Weisman S.M.
      • Hennekens C.H.
      An update on aspirin in the primary prevention of cardiovascular disease.
      • Bartolucci A.A.
      • Howard G.
      Meta-analysis of data from the six primary prevention trials of cardiovascular events using aspirin.
      • Berger J.S.
      • Roncaglioni M.C.
      • Avanzini F.
      • Pangrazzi I.
      • Tognoni G.
      • Brown D.L.
      Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      and it is uncertain whether the reduction in myocardial infarction and ischemic stroke outweighs the increased risk of bleeding.
      • In patients without a history of cardiovascular disease, long-term treatment with aspirin reduces all-cause mortality, myocardial infarction, and ischemic stroke, and increases hemorrhagic stroke and major bleeding.
      • The reduction in all-cause mortality should be taken into account by clinicians and guideline panels when making recommendations about the use of aspirin for primary prevention of cardiovascular disease.
      Uncertainty about the balance between the risks and the benefits of aspirin in the primary prevention of cardiovascular disease is reflected in conflicting recommendations by guideline panels.
      • Pearson T.A.
      • Blair S.N.
      • Daniels S.R.
      • et al.
      AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases American Heart Association Science Advisory and Coordinating Committee.
      • Buse J.B.
      • Ginsberg H.N.
      • Bakris G.L.
      • et al.
      Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association.
      • Graham I.
      • Atar D.
      • Borch-Johnsen K.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice: executive summary Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts).
      • Patrono C.
      • Baigent C.
      • Hirsh J.
      • Roth G.
      Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      Aspirin for the prevention of cardiovascular disease U.S. Preventive Services Task Force recommendation statement.
      The 2002 and 2007 American Heart Association guidelines and the 2008 American College of Chest Physicians' guidelines recommend aspirin for primary prevention of cardiovascular disease in patients with a 10-year risk of coronary heart disease of 10%,
      • Pearson T.A.
      • Blair S.N.
      • Daniels S.R.
      • et al.
      AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases American Heart Association Science Advisory and Coordinating Committee.
      • Buse J.B.
      • Ginsberg H.N.
      • Bakris G.L.
      • et al.
      Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association.
      • Patrono C.
      • Baigent C.
      • Hirsh J.
      • Roth G.
      Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      the 2005 Joint British Societies' guidelines recommend aspirin for patients with a 10-year risk of cardiovascular events of20%,
      JBS 2 Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice.
      and the 2007 European Society of Cardiology guidelines recommend aspirin for patients with a markedly increased 10-year risk of cardiovascular disease mortality.
      • Graham I.
      • Atar D.
      • Borch-Johnsen K.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice: executive summary Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts).
      The 2009 US Preventive Services Taskforce guideline panel makes separate recommendations for aspirin according to patient age and sex, and provides thresholds of 10-year coronary heart disease risk (men) and stroke risk (women) at which the number of nonfatal cardiovascular events and serious bleeds is closely balanced.
      Aspirin for the prevention of cardiovascular disease U.S. Preventive Services Task Force recommendation statement.
      The 2009 Antithrombotic Trialists' Collaboration overview interprets the primary prevention data differently. By contrasting the lack of a significant mortality benefit of aspirin in primary prevention trials with the 10% reduction in mortality in the secondary prevention trials, the Antithrombotic Trialists' Collaboration writing group concluded that aspirin is of uncertain net value in patients without documented cardiovascular disease because the reduction in ischemic events is closely matched by the increase in major bleeding, irrespective of an individual's baseline risk of cardiovascular disease.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      Since the publication of the aforementioned guidelines,
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      • Pearson T.A.
      • Blair S.N.
      • Daniels S.R.
      • et al.
      AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases American Heart Association Science Advisory and Coordinating Committee.
      • Buse J.B.
      • Ginsberg H.N.
      • Bakris G.L.
      • et al.
      Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association.
      • Graham I.
      • Atar D.
      • Borch-Johnsen K.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice: executive summary Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts).
      • Patrono C.
      • Baigent C.
      • Hirsh J.
      • Roth G.
      Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      Aspirin for the prevention of cardiovascular disease U.S. Preventive Services Task Force recommendation statement.
      JBS 2 Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice.
      the results of 3 additional randomized controlled trials of aspirin for the primary prevention of cardiovascular disease involving more than 7000 subjects have been published.
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      Subjects in these trials did not have a history of symptomatic cardiovascular disease but were at increased risk of cardiovascular events because of diabetes or a reduced ankle-brachial index.
      We performed a meta-analysis of all randomized controlled trials of aspirin for the primary prevention of cardiovascular disease to obtain best estimates of aspirin compared with placebo or no aspirin on all-cause and cardiovascular mortality and on other major cardiovascular outcomes, including myocardial infarction, stroke, and bleeding.

      Materials and Methods

      We adopted the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for the reporting of this meta-analysis.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      A protocol was prospectively developed detailing the study objectives, primary and secondary outcomes, criteria for study selection, approach to assessing study quality, data synthesis, and statistical analyses.

       Data Sources and Searches

      We identified relevant published randomized controlled trials comparing aspirin with placebo or no aspirin treatment in individuals without a history of symptomatic cardiovascular disease. Two investigators (MST, NR) independently searched MEDLINE (1966 to May 2010), EMBASE (1980 to May 2010), CINAHL (1982 to May 2010), and the Cochrane library (to May 2010) using the terms aspirin, acetylsalicylic acid, cardiovascular disease, myocardial infarction, stroke, cerebrovascular disease, mortality, death, survival, randomized trial, controlled trial, random, prevent, and primary prevention. Bibliographies of journal articles were hand-searched, and a “related article” PubMed search was performed to identify additional relevant articles. We also searched the National Institutes of Health Clinical Trials Registry (www.clinicaltrials.gov) and contacted experts to identify unpublished studies.

       Study Selection

      Two investigators (MST, NR) independently evaluated studies for inclusion using predefined criteria. Relevance was assessed using a hierarchic approach based on title, abstract, and full text publication. Disagreement on study eligibility was resolved by discussion and involvement of a third reviewer (JWE).
      To be eligible for inclusion, studies had to meet the following criteria: (a) randomized controlled trial; (b) include adults without a history of symptomatic cardiovascular disease (>95% of enrolled participants); (c) compare aspirin (any dose) with placebo or no aspirin treatment for the prevention of cardiovascular disease; and (d) report at least one of the following outcomes: all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and bleeding. Randomized controlled trials in which aspirin was combined with a second antithrombotic agent were not included, unless there were separate placebo and aspirin-only treatment groups, in which case only the data from these groups were included.

       Data Extraction and Quality Assessment

      Two investigators (MST, NR) independently extracted data on study design, participant characteristics, eligibility criteria, intervention and comparator, quality, and the following outcomes: all-cause mortality, cardiovascular mortality, major cardiovascular events, myocardial infarction, all-cause stroke, ischemic stroke, hemorrhagic stroke, major bleeding, and gastrointestinal bleeding. We accepted investigators' definitions of outcomes and did not retrospectively reclassify events. Authors were contacted in cases in which study methodology or study data required clarification.
      Risk of bias was assessed using criteria adapted from the Cochrane Methods Group Guidelines on Systematic Reviews of Interventions.
      • Higgins J.P.T.
      Assessment of study quality Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006];Section 6.
      These criteria include proper generation of the treatment allocation sequence; proper concealment of the allocation sequence; blinding of participants, investigators, and outcome assessors; completeness of follow-up; intention to treat analysis; and treatment compliance.

       Data Synthesis and Analysis

      Interobserver agreement for full text study selection was measured using Cohen's unweighted kappa statistic. Results are presented using relative risk, and all effect estimates are presented with 95% confidence intervals (CIs). Relative risks for the prespecified primary and secondary outcomes were calculated by pooling individual trial data with the DerSimonian-Laird random-effects model using Cochrane Collaboration Review Manager software, version 5.0 (The Nordic Cochrane Centre, Copenhagen, The Cochrane Collaboration, 2008). Results obtained with a random-effects model were compared with those obtained using a fixed-effects model. A 2-sided P value of.05 was considered statistically significant. Heterogeneity was assessed using the I2 statistic and chi-square test, and potential sources of statistical heterogeneity were explored by examining differences in trial populations, the dose of aspirin, co-interventions, outcome definitions, and trial quality.
      Sensitivity analyses were performed by exclusion of studies deemed to be of lower quality (open-label studies, incomplete follow-up), studies using a higher dose of aspirin (>150 mg/d), and studies completed before 2000 to assess the robustness of our results.

      Results

       Study Selection

      The process of study selection is outlined in Figure 1. Reviewer agreement at the level of study selection from full text articles as assessed by Cohen's unweighted kappa was 0.86 (standard error 0.14).

       Study Characteristics

      Nine studies involving 100,076 participants were included. Study and participant characteristics are summarized in Table 1. Three of the nine studies, the British Doctors Trial (BDT),
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      Physicians' Health Study (PHS),
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      and Thrombosis Prevention Trial (TPT),
      Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
      did not include women, whereas the Women's Health Study (WHS)
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      exclusively enrolled women. The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      and Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD)
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      recruited only patients with diabetes mellitus. The Aspirin for Asymptomatic Atherosclerosis (AAA)
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      study enrolled men and women without a history of symptomatic cardiovascular disease but with an ankle-brachial index0.95. Two studies, BDT
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      and the Hypertension Optimal Trial (HOT),
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
      included a small proportion of participants (<5%) with a history of ischemic heart disease, stroke, or transient ischemic attack.
      Table 1Study and Participant Characteristics
      Study Name (Publication Year)Patients (n)Aspirin DoseDesignAdditional TherapiesMale (%)Mean Follow-Up (y)Current Smokers (%)DM (%)HT (%)Mean Age(y)Elderly
      BDT
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      (1988)
      5139300-500 mg/dOpen labelNone100631210N/A14% >70 y
      PHS
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      (1989)
      22,071325 mg alternate dayDouble blindedBeta carotene10051129N/A7% >70 y
      HOT
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
      (1998)
      18,79075 mg/dDouble blindedFelodipine + other agents to achieve target BP533.816810061.532% >65 y
      TPT
      Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
      (1998)
      254075 mg/dDouble blindedWarfarin1006.44122657.3N/A
      PPP
      • de Gaetano G.
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
      (2001)
      4495100 mg/dOpen labelVitamin E423.615176864.450% >65 y
      WHS
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      (2005)
      39,876100 mg alternate dayDouble blindedVitamin E and beta carotene010.11332654.610% >65 y
      JPAD
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      (2008)
      253981 mg or 100 mg/dOpen labelNone554.4 (median)211005864.554% >65 y
      POPADAD
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      (2008)
      1276100 mg/dDouble blindedAntioxidant446.7 (median)31100N/A60.352% >60 y
      AAA
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      2010
      3350100 mg/dDouble blindedNone288.2333N/A62.0N/A
      BDT, British Doctors' Trial; PHS, Physicians' Health Study; TPT, Thrombosis Prevention Trial; HOT, Hypertension Optimal Treatment study; PPP, Primary Prevention Project trial; WHS, Women's Health Study; JPAD, Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes trial; POPADAD, Prevention Of Progression Of Arterial Disease And Diabetes trial; AAA, Aspirin for Asymptomatic Atherosclerosis trial; DM, diabetes mellitus; HT, hypertension; N/A, not available.

       Risk of Bias

      With the exception of the BDT, PHS, and WHS,
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      which did not specify the method of allocation concealment, all studies reported the process of sequence generation and concealment of allocation. The PHS, TPT, WHS, POPADAD, AAA, and HOT
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
      were double-blinded studies, and the remaining 3 trials, the BDT, JPAD, and Primary Prevention Project (PPP),
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      • de Gaetano G.
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
      were open-label. Although the open-label design is unlikely to have biased the main outcome of mortality, it may have influenced ascertainment of nonfatal cardiovascular outcomes, in particular when outcomes were self-reported. In all trials, outcome adjudicators were blinded to treatment allocation.
      All studies reported completeness of follow-up. Vital status was determined for all participants in the BDT, PHS, and TPT.
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
      Loss to follow-up was highest (7.6%) in the JPAD study,
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      followed by the HOT (2.6%),
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
      and was less than 1% in the other studies. The numbers lost to follow-up exceeded the total number of primary events in the HOT, WHS, and JPAD.
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
      Treatment adherence was not reported for the WHS
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      and ranged from 50% to 93% for the other studies with the lowest adherence in the POPADAD trial.
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      All studies were analyzed according to an intention-to-treat principle. Three studies were terminated prematurely, the PHS and PPP
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      • de Gaetano G.
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
      because of the apparent therapeutic advantage of aspirin, and the AAA
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      because of the improbability of finding a difference in the primary end point and an increased risk of bleeding with aspirin.

       Outcomes

       All-Cause Mortality

      Aspirin therapy was associated with a 6% reduction in all-cause mortality (3.65% vs 3.74%, RR 0.94; 95% CI, 0.88-1.0) (Figure 2, Table 2). With the exception of TPT,
      Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
      the point estimate in each study suggested a reduction in mortality, although none of the studies were powered to detect a mortality benefit of aspirin. There was no statistical evidence of heterogeneity among the studies for the outcome of all-cause mortality (I2 = 0%, χ2 = 1.70, P=.99).
      Figure thumbnail gr2
      Figure 2Relative risk of all-cause mortality and cardiovascular mortality in participants treated with and without aspirin.
      Table 2Pooled Estimates of the Benefits and Risks of Aspirin in Primary Prevention of Cardiovascular Disease
      OutcomeTotal Events in Aspirin Arm (%)Total Events in Non-Aspirin Arm (%)Pooled Relative Risk (95% CI)Relative Risk Reduction (95% CI)
      All-cause mortality1859 (3.65)1838 (3.74)0.94 (0.88-1.00)6% (0-12)
      Cardiovascular mortality627 (1.23)583 (1.18)0.96 (0.84-1.09)4% (−9 to 16)
      Major cardiovascular events1861 (3.66)1957 (3.98)0.88 (0.83-0.94)12% (6-17)
      Myocardial infarction854 (1.68)942 (1.91)0.83 (0.69-1.00)17% (0-31)
      All-cause stroke720 (1.42)733 (1.49)0.93 (0.82-1.05)7% (−5 to 18)
      Ischemic stroke403 (0.97)439 (1.10)0.86 (0.75-0.98)14% (2-25)
      Hemorrhagic stroke112 (0.27)76 (0.19)1.36 (1.01-1.82)−36% (−1 to −82)
      Gastrointestinal bleed1947 (4.10)1560 (3.28)1.37 (1.15-1.62)−37% (−15 to −62)
      Major bleed406 (0.83)234 (0.50)1.66 (1.41-1.95)−66% (−41 to −95)
      CI = Confidence interval.

       Cardiovascular Mortality

      There was no reduction in the risk of cardiovascular mortality in participants assigned to aspirin (Figure 2, Table 2). Only the JPAD
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      showed a reduction in cardiovascular death with aspirin, but this was based on only 11 events.

       Major Cardiovascular Events (Composite of Cardiovascular Mortality, Nonfatal Myocardial Infarction, and Nonfatal Stroke)

      Aspirin use was associated with a 12% reduction in major cardiovascular events (3.66% vs 3.98%, RR 0.88; 95% CI, 0.83-0.94) with no statistical evidence of heterogeneity (I2 = 0%, χ2 = 7.56, P=.48) (Figure 3, Table 2). The reduction in major cardiovascular events was primarily attributable to a reduction in myocardial infarction.
      Figure thumbnail gr3
      Figure 3Ischemic cardiovascular events in participants treated with and without aspirin.

       Myocardial Infarction (Composite of Fatal and Nonfatal Myocardial Infarction)

      The largest measured benefit of aspirin was in the prevention of myocardial infarction with a relative risk reduction of 17% (1.68% vs 1.91%, RR 0.83; 95% CI, 0.69-1.00) (Figure 3, Table 2). Heterogeneity in myocardial infarction results (I2 = 71%, χ2 = 27.51, P=.0006) was not explained by differences in trial populations, aspirin dose, or methodological quality of the studies (data not shown), but statistical heterogeneity was no longer evident after removing the PHS from the analyses.
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      The PHS was stopped early because of benefit, which can result in an inflated estimate of treatment effect.
      • Bassler D.
      • Briel M.
      • Montori V.M.
      • et al.
      Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis.

       Stroke (Composite of Fatal and Nonfatal Stroke)

      Aspirin reduced the risk of ischemic stroke (0.97% vs 1.10%, RR 0.86; 95% CI, 0.75-0.98, P for heterogeneity=0.48), but this was offset by a concomitant increase in hemorrhagic stroke (0.27% vs 0.19%, RR 1.36; 95% CI, 1.01-1.82, P for heterogeneity=0.63). Thus, there was no reduction in all-cause stroke (Figure 3, Figure 4, Table 2).
      Figure thumbnail gr4
      Figure 4Relative risk of hemorrhagic stroke, major bleeding, and gastrointestinal bleeding in participants treated with and without aspirin.

       Bleeding

      Aspirin increased the risk of major bleeding (RR 1.66; 95% CI, 1.41-1.95) with no statistical evidence of heterogeneity (I2 = 0%, χ2 = 6.01, P=.42) (Figure 4). Aspirin also increased the risk of gastrointestinal bleeding. Statistical heterogeneity for the outcome of gastrointestinal bleeding was not explained by differences in study populations, aspirin dose, or study quality (data not shown).

       Sensitivity Analyses

      Sensitivity analysis performed by excluding studies considered to be at higher risk of bias (open label: BDT, JPAD, and PPP;
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      • de Gaetano G.
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
      high loss to follow-up (>5%): JPAD;
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      early termination of study: PHS, PPP, AAA
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      • de Gaetano G.
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
      ) demonstrated a consistent treatment effect of aspirin on all-cause mortality (data not shown). Similarly, consistent results were seen when studies using aspirin at a dosage of>150 mg/d (BDT, PHS)
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      were excluded (RR 0.94; 95% CI, 0.88-1.01) and when studies published before 2000 were excluded (BDT, PHS, HOT, TPT)
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      Final report on the aspirin component of the ongoing Physicians' Health Study
      Steering Committee of the Physicians' Health Study Research Group.
      Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
      (data not shown).

       Assessment of Publication Bias

      Begg's adjusted-rank correlation test
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      provided no evidence of publication bias for any of the outcomes that we examined (data not shown).

      Discussion

      Our meta-analysis of 9 aspirin primary prevention trials involving 100,076 patients demonstrates that long-term aspirin compared with placebo or no aspirin reduces all-cause mortality, myocardial infarction, and ischemic stroke; does not reduce cardiovascular mortality; and increases hemorrhagic stroke, major bleeding, and gastrointestinal bleeding.
      In the absence of a mortality benefit of aspirin, treatment guidelines for the use of aspirin for primary prevention of cardiovascular disease have based their recommendations on the trade-off between the reduction of nonfatal myocardial infarction and the increase in bleeding. Applying this trade-off in clinical practice can be challenging because the balance between a reduction in nonfatal ischemic events and an increase in bleeding is strongly influenced by individual patient values and preferences. The authors of the 2009 Antithrombotic Trialists' Collaboration overview suggested that the benefits and harms of aspirin were so finely balanced that aspirin was of uncertain value in patients without previous cardiovascular disease, irrespective of their baseline cardiovascular risk.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      Our results demonstrating that aspirin reduces all-cause mortality in individuals without a history of symptomatic cardiovascular disease tilts the balance in favor of the use of aspirin for primary prevention and should be taken into account by clinicians and future treatment guidelines.
      The most likely reason why our meta-analysis reported a reduction in mortality when aspirin is used for the primary prevention of cardiovascular disease whereas previous meta-analyses did not is that our meta-analysis included more patients and more outcome events, thereby improving the precision of the estimates of treatment effect. The 3 recently published trials (POPADAD, JPAD, AAA) included in this meta-analysis involved patients with diabetes or asymptomatic atherosclerosis who were underrepresented in previous trials. Further information regarding the efficacy and safety of aspirin for primary prevention of cardiovascular disease and in specific populations will be provided by the results of ongoing randomized controlled trials of aspirin in the elderly (Aspirin in Reducing Events in the Elderly trial),
      • Nelson M.
      • Reid C.
      • Beilin L.
      • et al.
      Rationale for a trial of low-dose aspirin for the primary prevention of major adverse cardiovascular events and vascular dementia in the elderly: Aspirin in Reducing Events in the Elderly (ASPREE).
      patients with diabetes (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes; A Study of Cardiovascular Events in Diabetes),
      • De Berardis G.
      • Sacco M.
      • Evangelista V.
      • et al.
      Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins.
      A study of cardiovascular events in diabetes (ASCEND).
      and in different ethnic groups (eg, Japanese Primary Prevention Project).
      Japanese primary prevention project with aspirin in the elderly with one or more risk factors of vascular events: JPPP.
      We propose 2 possible explanations for why aspirin reduces all-cause mortality but not cardiovascular mortality. The first possible explanation is that aspirin reduces both cardiovascular and noncardiovascular deaths so that when the data for these 2 outcomes are combined, a significant reduction in all-cause mortality becomes evident. Aspirin has been reported to reduce mortality in patients with cancer,
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin use and survival after diagnosis of colorectal cancer.

      Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE. Aspirin intake and survival after breast cancer. J Clin Oncol. 28:1467-1472.

      and the Antithrombotic Trialists' Collaboration meta-analysis also reported fewer noncardiovascular deaths in patients receiving aspirin compared with placebo for the secondary prevention of cardiovascular disease.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      The second possible explanation is that cardiovascular deaths may have been misattributed to noncardiovascular causes.
      A potential limitation of our meta-analysis is that the included studies were conducted over a 30-year period during which there have been major advances in cardiovascular prevention and an increase in the concomitant use of other effective primary prevention strategies, such as blood pressure control and lipid-lowering therapy. Despite an increase in the use of other cardiovascular prevention therapies, the event rates in placebo-treated patients and the relative benefits of aspirin compared with placebo or no aspirin were fairly consistent over time.

      Conclusions

      Our results demonstrate a consistent pattern of reduced mortality in all of the aspirin primary prevention trials and a significant, albeit modest, reduction in all-cause mortality when the data are pooled. This reduction in all-cause mortality tilts the balance between the benefits and risks of treatment in favor of the use of aspirin. The results of our meta-analysis are in agreement with those of the 2009 Antithrombotic Trialists' Collaboration meta-analysis in secondary prevention and demonstrate that aspirin also is beneficial in the primary prevention population.

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      Linked Article

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        The American Journal of MedicineVol. 129Issue 5
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          Uncertainty about the balance between risks and benefits of aspirin in the primary prevention of cardiovascular disease is reflected in conflicting recommendations by guideline panels.
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      • Systematic Reporting Bias in Meta-analyses of Trials of Aspirin for the Primary Prevention of Cardiovascular Disease
        The American Journal of MedicineVol. 125Issue 2
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          I read with interest the meta-analysis of trials of aspirin for the primary prevention of cardiovascular disease.1 After almost 1 million person-years' follow-up, >3500 deaths, and almost 4000 cardiovascular events, treatment with aspirin might have prevented 21 deaths, possibly none cardiovascular, 88 myocardial infarctions, and 13 strokes, and may have caused 387 major gastrointestinal hemorrhages. Incredibly, the authors believe this analysis should persuade people to take, rather than avoid, aspirin.
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      • The Role of Aspirin in Primary Prevention of Vascular Events
        The American Journal of MedicineVol. 125Issue 12
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          We read with interest the meta-analysis conducted by Raju et al1 on the role of aspirin in primary prevention of cardiovascular disease. We are intrigued by the differences between the findings of this meta-analysis and a recent meta-analysis conducted by Seshasai et al.2 Both meta-analyses included the same 9 clinical trials, with similar outcomes. Yet there are discrepancies between the 2 studies with respect to the absolute number of strokes (720 vs 749), total cardiovascular events (1861 vs 2107), total cardiovascular mortality (627 vs 674), and all-cause mortality (1859 vs 1962) in the study by Raju et al compared with the study by Seshasai et al, respectively.
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