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Aspirin for Primary Prevention of Atherothrombotic Vascular Events: How Much “Conclusive” Is “Conclusive?”

      Low-dose aspirin has been shown to be effective in preventing atherothrombotic vascular events (nonfatal myocardial infarction, nonfatal stroke, or vascular death) in a meta-analysis including 9 primary prevention trials (50,868 subjects were treated with aspirin and 49,170 received placebo or control).
      • Bartolucci A.A.
      • Tendera M.
      • Howard G.
      Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin.
      Because meta-analyses aim to identify the effect of an intervention as early as possible, they are usually updated when new trials are published, so that repeated analyses are made on accumulating data. These multiple analyses induce repeated significance testing (usually with p value criterion, α = 5% for a 2-sided test), which leads to an increased risk of random error and subsequent misleading evidence in results. To distinguish real effects from random errors, it is necessary that the required number of participants in a meta-analysis (i.e., information size) should be at least as large as an adequately powered single trial.
      • Brok J.
      • Thorlund K.
      • Wetterslev J.
      • Gluud C.
      Apparently conclusive meta-analyses may be inconclusive—trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses.
      Trial sequential analysis (TSA) is a new statistical technique that aims to improve the interpretation of meta-analyses, reducing the risk of random errors due to repetitive testing by adopting trial sequential monitoring boundaries to evaluate the accumulating data obtained from updates in meta-analyses.
      • Brok J.
      • Thorlund K.
      • Wetterslev J.
      • Gluud C.
      Apparently conclusive meta-analyses may be inconclusive—trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses.
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      References

        • Bartolucci A.A.
        • Tendera M.
        • Howard G.
        Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin.
        Am J Cardiol. 2011; 107: 1796-1801
        • Brok J.
        • Thorlund K.
        • Wetterslev J.
        • Gluud C.
        Apparently conclusive meta-analyses may be inconclusive—trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses.
        Int J Epidemiol. 2009; 38: 287-298

      Linked Article

      • Meta-Analysis of Multiple Primary Prevention Trials of Cardiovascular Events Using Aspirin
        American Journal of CardiologyVol. 107Issue 12
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          Several meta-analyses have focused on determination of the effectiveness of aspirin (acetylsalicylic acid) in primary prevention of cardiovascular (CV) events. Despite these data, the role of aspirin in primary prevention continues to be investigated. Nine randomized trials have evaluated the benefits of aspirin for the primary prevention of CV events: the British Doctors' Trial (BMD), the Physicians' Health Study (PHS), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment (HOT) study, the Primary Prevention Project (PPP), the Women's Health Study (WHS), the Aspirin for Asymptomatic Atherosclerosis Trial (AAAT), the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial, and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial.
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