Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events (from the BRAVO Trial)

Published:September 17, 2008DOI:
      Despite aspirin's established role in the treatment of atherosclerotic vascular disease, considerable controversy exists regarding its most effective dosing strategy. In a retrospective observational study, we examined the relation between prescribed aspirin dose (<162 mg vs ≥162 mg/day aspirin) and clinical outcome in 4,589 placebo-treated patients enrolled in the Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial over a median follow-up of 366 days. Standard Cox regression analysis was employed because propensity analysis was not feasible. Compared with lower aspirin doses, higher doses were associated with lower unadjusted all-cause mortality (2.9 vs 1.6%, respectively; log rank chi-square 8.6, p = 0.0034). Higher aspirin dose remained independently predictive of lower all-cause mortality in a multivariable Cox proportional hazards model (hazard ratio 0.64, 95% confidence interval 0.42 to 0.97, p = 0.037). However, there was no significant difference in the incidence of the composite endpoint death, nonfatal myocardial infarction, or nonfatal stroke (6.1% vs 6.2%, p = 0.74). Higher aspirin dose was a significant independent predictor of any (hazard ratio 1.32, 95% confidence interval 1.12 to 1.55, p = 0.001) but not serious bleeding. In conclusion, our findings suggest that aspirin doses of ≥162 mg/day may be more beneficial than those <162 mg/day at preventing death.
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        • Roderick P.J.
        • Wilkes H.C.
        • Meade T.W.
        The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials.
        Br J Clin Pharmacol. 1993; 35: 219-226
        • Serebruany V.L.
        • Steinhubl S.R.
        • Berger P.B.
        • Malinin A.I.
        • Baggish J.S.
        • Bhatt D.L.
        • Topol E.J.
        Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials.
        Am J Cardiol. 2005; 95: 1218-1222
        • Antithrombotic Trialists Collaboration
        Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
        BMJ. 2002; 324: 71-86
        • Kong D.F.
        • Hasselblad V.
        • Kandzari D.E.
        • Newby L.K.
        • Califf R.M.
        Seeking the optimal aspirin dose in acute coronary syndromes.
        Am J Cardiol. 2002; 90: 622-625
      1. ALDUSA Investigators. Aspirin at Low Dose in Unstable Angina pilot study: report from the co-ordinating center. Unité de Pharmacologie Clinique, Lyons: UPC, 1987.

        • O'Connor C.M.
        • Meese R.B.
        • McNulty S.
        • Lucas K.D.
        • Carney R.J.
        • LeBoeuf R.M.
        • Maddox W.
        • Bethea C.F.
        • Shadoff N.
        • Trahey T.F.
        • et al.
        A randomized factorial trial of reperfusion strategies and aspirin dosing in acute myocardial infarction: the DUCCS-II Investigators.
        Am J Cardiol. 1996; 77: 791-797
        • The Dutch TIA Trial Study Group
        A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke.
        N Engl J Med. 1991; 325: 1261-1266
        • Topol E.J.
        • Easton D.
        • Harrington R.A.
        • Amarenco P.
        • Califf R.M.
        • Graffagnino C.
        • Davis S.
        • Diener H.C.
        • Ferguson J.
        • Fitzgerald D.
        • et al.
        Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease.
        Circulation. 2003; 108: 399-406
        • Topol E.J.
        • Easton J.D.
        • Amarenco P.
        • Califf R.
        • Harrington R.
        • Graffagnino C.
        • Davis S.
        • Diener H.C.
        • Ferguson J.
        • Fitzgerald D.
        • et al.
        Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial.
        Am Heart J. 2000; 139: 927-933
        • Rubin D.B.
        Estimating causal effects from large data sets using propensity scores.
        Ann Intern Med. 1997; 127: 757-763
        • Joffe M.M.
        • Rosenbaum P.R.
        Invited commentary: propensity scores.
        Am J Epidemiol. 1999; 150: 327-333
        • Patrignani P.
        • Filabozzi P.
        • Patrono C.
        Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects.
        J Clin Invest. 1982; 69: 1366-1372
        • Maree A.O.
        • Curtin R.J.
        • Dooley M.
        • Conroy R.M.
        • Crean P.
        • Cox D.
        • Fitzgerald D.J.
        Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease.
        J Am Coll Cardiol. 2005; 46: 1258-1263
        • FitzGerald G.A.
        • Oates J.A.
        • Hawiger J.
        • Maas R.L.
        • Roberts II, L.J.
        • Lawson J.A.
        • Brash A.R.
        Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.
        J Clin Invest. 1983; 71: 676-688
        • Tantry U.
        • Bliden K.P.
        • Gurbel P.A.
        • DiChiara J.
        Inconsistency in the prevalence of platelet aspirin resistance as measured by COX-1 non-specific assays in patients treated with 81, 162 and 325 mg aspirin.
        J Am Coll Cardiol. 2006; 47 ([Abstract]): 290A
        • Gurbel P.A.
        • Bliden K.P.
        • DiChiara J.
        • Newcomer J.
        • Weng W.
        • Neerchal N.K.
        • Gesheff T.
        • Chaganti S.K.
        • Etherington A.
        • Tantry U.S.
        Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study.
        Circulation. 2007; 115: 3156-3164
        • Mehta S.R.
        Clopidogrel in non–ST-segment elevation acute coronary syndromes.
        Eur Heart J. 2006; 8: G25-G30
        • Bhatt D.L.
        • Fox K.A.
        • Hacke W.
        • Berger P.B.
        • Black H.R.
        • Boden W.E.
        • Cacoub P.
        • Cohen E.A.
        • Creager M.A.
        • Easton J.D.
        • et al.
        Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
        N Engl J Med. 2006; 354: 1706-1717