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Warfarin combined with low dose aspirin in myocardial infarction did not provide clinical benefit beyond that of aspirin alone
  1. Vernon M Oh, MD, FRCP
  1. National University Hospital
 Singapore, Republic of Singapore

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 QUESTION: In patients who have survived an acute myocardial infarction (MI), is warfarin combined with aspirin more effective than aspirin alone?

    Design

    Randomised (allocation concealed*), unblinded,* controlled trial with a median 2.7 years of follow up.

    Setting

    78 Department of Veterans Affairs medical centres in the US.

    Patients

    5059 patients (median age 62 y, 98% men) who had an acute MI within the previous 14 days. Exclusion criteria included comorbid conditions that limited life expectancy to <2 years, ongoing bleeding, drug or alcohol dependence, and hypersensitivity to aspirin or warfarin. Vital status was obtained for 99% of the patients.

    Intervention

    2522 patients were assigned to warfarin (target international normalised ratio [INR] 1.5 to 2.5 IU) plus aspirin (81 mg/d), and 2537 were assigned to aspirin alone (162 mg/d).

    Main outcome measures

    The primary outcome was all-cause mortality. Secondary outcomes were recurrent MI, stroke, and major haemorrhage.

    Main results

    Analysis was by intention to treat. The median INR in the warfarin group was 1.8 IU. Groups did not differ for all cause mortality, recurrent MI, or stroke (table). The study had an 80% power for detecting a 15% reduction in annual mortality with combination treatment relative to that with aspirin alone. More major bleeding occurred in patients in the warfarin plus aspirin group than in those assigned to aspirin alone (1.28 v 0.72 events per 100 person y of follow up, p <0.001). Intracranial haemorrhage rates were identical in the 2 groups (14 patients per treatment group).

    Conclusions

    In patients who have survived an acute myocardial infarction, warfarin combined with low dose aspirin did not provide a clinical benefit beyond that achieved with aspirin alone. Major bleeding occurred more frequently with combination treatment.

    Commentary

    The long term use of low dose antiplatelet drugs (eg, aspirin and clopidogrel) to prevent recurrent infarction is established practice. Aiming to enhance survival after MI, some research groups have studied combined warfarin anticoagulation treatment with the antithrombotic action of aspirin.

    The CHAMP study shows that combining low intensity warfarin anticoagulation treatment (median INR < 2.0) with aspirin for about 3 years does not prolong life beyond the effect of aspirin alone, regardless of when the treatment was started after MI. Moreover, the combination decreased neither MI recurrence nor stroke. The results concur with a similar study in patients with acute coronary syndromes, which suggested better survival at 3 months only. Short term prophylaxis merits further study.

    Could some subsets of patients receive particular benefit from a warfarin plus aspirin treatment? In the CHAMP study, the infarction location and left ventricular function did not affect total mortality. Bleeding risks increase with biological age, but we do not know at what age the risks for antithrombotic action begin to outweigh the survival gain; therefore, we cannot use age as a guide.

    Combined treatment in the CHAMP study caused 1.7 times more major bleeding than did aspirin alone, without adding any further benefit. The careful patient monitoring done during a trial would be expected to minimise major bleeding; so this finding is probably an underestimate of the harm that would occur in usual clinical practice. The evidence argues against adding low intensity warfarin anticoagulation treatment to aspirin in patients who have survived MI.

    A regimen adding moderate intensity (INR >2) or high intensity (INR >3) warfarin anticoagulation treatment to aspirin, with or without clopidogrel, will probably cause even more bleeding than antiplatelet treatment alone and offset any additional survival gain.1 Likewise, we need to weigh the haemorrhagic risk associated with such regimens as clopidogrel plus aspirin against their antithrombotic efficacy. Laboratory study evidence suggests that clopidogrel plus aspirin inhibits platelet aggregation more effectively than does aspirin alone.2 Furthermore, the combination was more effective than aspirin alone in unstable angina with non-ST segment elevation MI.3

    References

    Warfarin plus aspirin (W+A) v aspirin alone (A) in acute myocardial infarction (MI) at a median of 2.7 years†

    
 
 QUESTION: In patients who have survived an acute myocardial infarction (MI), is warfarin combined with aspirin more effective than aspirin alone?

    View Abstract

    Footnotes

    • Sources of funding: Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; DuPont Pharmaceuticals; Bayer Pharmaceuticals.

    • For correspondence: Dr L Fiore, VA Boston Healthcare System, Boston, Massachusetts, USA. louis.fiore{at}med.va.gov

    • * See glossary.

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