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Updated Meta-Analysis of Aspirin in Primary Prevention of Cardiovascular Disease

      To the Editor:
      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.
      Our 2011 meta-analysis of 9 randomized controlled trials involving 100,076 patients demonstrated that when used for primary prevention, aspirin prevented all-cause mortality, myocardial infarction, and stroke, but did not prevent cardiovascular mortality, and increased hemorrhagic stroke and major bleeding.
      • Raju N.
      • Sobieraj-Teague M.
      • Hirsh J.
      • et al.
      Effect of aspirin on mortality in the prevention of cardiovascular disease.
      The reduction in all-cause mortality was small (6% relative risk reduction) and of borderline statistical significance (P = .05), and in the absence of a reduction in cardiovascular mortality, the relevance of this finding has been challenged.
      The recently published Japanese Primary Prevention Project (JPPP),
      • Ikeda Y.
      • Shimada K.
      • Teramoto T.
      • et al.
      Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors.
      an open-label randomized controlled trial comparing aspirin 100 mg once daily with no aspirin in 14,658 participants aged 60 to 85 years with diabetes, hypertension, or hyperlipidemia, has provided additional randomized evidence since 2011. Approximately half of participants in JPPP were over the age of 70 years. Aspirin adherence was 88.9% at 1 year and 76% at 5 years; 9.8% of participants in the nonaspirin arm commenced aspirin during the study, and 10.5% of participants were lost to follow-up. The study was prematurely terminated for futility at a median of 5.02 years follow-up. The results indicate that aspirin did not prevent all-cause or cardiovascular mortality, but similar to previous studies, prevented nonfatal myocardial infarction at the cost of increased extracranial bleeding and hemorrhagic stroke.
      Adding the JPPP to our earlier meta-analysis, 10 randomized trials involving a combined total of 114,734 participants have compared aspirin with control for primary prevention of cardiovascular disease. The pooled data (Table) demonstrate that aspirin prevents myocardial infarction (relative risk 0.78; 95% confidence interval, 0.65-0.94) and increases major and intracranial bleeding, with an effect on all-cause mortality identical to that which we reported in the 2011 meta-analysis (relative risk 0.94; 95% confidence interval, 0.89-1.00), and no reduction in cardiovascular mortality.
      TableAspirin vs No Aspirin for Primary Prevention
      OutcomePatients, n
      Not all participants randomized have contributed to each outcome.
      (Studies, n)
      Events in Aspirin Arm n (%)Events in Non-aspirin Arm n (%)Pooled Relative Risk (95% CI)Relative Risk Reduction/Increase (95% CI)
      All-cause mortality111,190 (9)1980 (3.51)1955 (3.57)0.94 (0.89-1.00)6% (0-11)
      Cardiovascular mortality111,190 (9)648 (1.15)609 (1.11)0.95 (0.84-1.07)5% (−7 to 16)
      Major cardiovascular events92,400 (8)
      Not estimable for Hypertension Optimal Treatment study.
      1623 (3.45)1673 (3.69)0.89 (0.82-0.97)11% (3-18)
      Myocardial infarction111,190 (9)791 (1.40)903 (1.65)0.78 (0.65-0.94)22% (6-35)
      Nonfatal myocardial infarction92,400 (8)
      Not estimable for Hypertension Optimal Treatment study.
      542 (1.15)633 (1.39)0.80 (0.64-0.99)20% (1-36)
      All-cause stroke111,190 (9)803 (1.42)812 (1.48)0.94 (0.84-1.06)6% (−6 to 16)
      Hemorrhagic stroke92,400 (8)
      Not estimable for Hypertension Optimal Treatment study.
      145 (0.31)95 (0.21)1.43 (1.10-1.86)43% (10-86)
      Major bleeding107,520 (7)
      Not estimable for Japanese Primary prevention of Atherosclerosis with aspirin for Diabetes and Prevention Of Progression of Arterial Disease And Diabetes trials.
      4342481.69 (1.43-1.98)69% (43-98)
      Gastrointestinal bleeding106,245 (8)
      Not estimable for British Doctors study.
      2041 (3.84)1583 (2.98)1.64 (1.30-2.07)64% (30-107)
      Not all participants randomized have contributed to each outcome.
      Not estimable for Hypertension Optimal Treatment study.
      Not estimable for Japanese Primary prevention of Atherosclerosis with aspirin for Diabetes and Prevention Of Progression of Arterial Disease And Diabetes trials.
      § Not estimable for British Doctors study.
      The results of our updated meta-analysis support the conclusion that aspirin provides a net benefit when used for the primary prevention of cardiovascular disease. However, the absolute benefits are modest, and clinicians need to carefully weigh the benefits and risks for individual patients. Further information about 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 [ASPREE]) and in patients with diabetes (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes [ACCEPT-D]; A Study of Cardiovascular Events in Diabetes [ASCEND]).

      References

        • Raju N.
        • Sobieraj-Teague M.
        • Hirsh J.
        • et al.
        Effect of aspirin on mortality in the prevention of cardiovascular disease.
        Am J Med. 2011; 124: 621-629
        • Ikeda Y.
        • Shimada K.
        • Teramoto T.
        • et al.
        Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors.
        JAMA. 2014; 312: 2510-2520

      Linked Article

      • Effect of Aspirin on Mortality in the Primary Prevention of Cardiovascular Disease
        The American Journal of MedicineVol. 124Issue 7
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          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.
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