Authors
Homma S, Thompson J, Pullicino PM, et al.
Title
Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm
References
N Engl J Med 2012;366:1859-69
Background
Heart failure is associated with a hypercoagulable state, however, conclusive evidence for the use of oral anticoagulation or aspirin in heart failure patients are lacking as previous prospective studies have been too small.
Purpose
To determine the efficacy of warfarin as compared to aspirin for morbidity and mortality in patients with reduced ejection fraction and normal sinus rhythm.
Design
  • Multicenter, cooperative, double-blind, double-dummy trial
  • 2305 patient, ≥18 years of age, normal sinus rhythm, no contraindication to warfarin and LVEF ≤35%
  • All NYHA functional class patients eligible (with no more than 20% of total patients with NYHA class I)
  • Modified Rankin score of ≤4
  • β-blocker, ACE inhibitor (ARB if intolerant to ACE inhibitor) or hydralazine and nitrates
Exclusion Criteria
  • Clinical indication for warfarin or aspirin
  • High risk of cardiac embolism (atrial fibrillation, mechanical heart valve, endocarditis, intracardiac mobile or pedunculated thrombus)
Follow-Up
Mean of 3.8 +/- 1.8 years
Treatment Regimen
Active warfarin + placebo aspirin vs. placebo warfarin + active aspirin 325 mg daily
  • Target INR 2.75 (target range 2.0-3.5); fabricated plausible INRs provided for patients in active aspirin + placebo warfarin arm
Results

Primary Endpoints
First event of composite endpoint of ischemic stroke, intracerebral hemorrhage, or death from any cause:

  • 7.47 events/100 patient-years (warfarin) vs. 7.93 events/100 patient years (aspirin)
  • 26.4% (warfarin) vs. 27.5% (aspirin); HR with warfarin, 0.93 (0.79-1.10), p=0.40
    • For ischemic stroke, a significant benefit with warfarin (2.5%) as compared to aspirin (4.7%) was seen, HR 0.52 (0.33-0.82), p=0.005
    • The two groups did not significantly differ for rates of death (p=0.91) or intracerebral hemorrhage (p=0.35)

    Secondary Endpoints
    First event in a composite of the primary outcome, myocardial infarction, or hospitalization for heart failure: 39.1% (warfarin) vs. 37.4% (aspirin); HR 1.07 (0.93-1.23), p=0.33

    Safety
    All major hemorrhage (intracerebral, intracranial, gastrointestinal, other):1.78 events/100 patient-years (warfarin) vs. 0.87 events/100 patient-years (aspirin), adjusted rate ratio 2.05 (1.36-3.12), p<0.001

    • rates of intracerebral and intracranial hemorrhages did not significantly differ between the two groups, 0.27 events/100 patient-years (warfarin) vs. 0.22 events/100 patient-years (aspirin), p=0.82
    • major gastrointestinal bleeding more frequent in the warfarin group (0.94 events/100 patient years vs. 0.45 events/100 patient years with aspirin, p=0.01)
Summary
No significant difference between warfarin and aspirin was demonstrated in patients with reduced LVEF and normal sinus rhythm. There was a significant reduction in ischemic stroke with warfarin but at an increase risk of major bleeding.