Benefit of Warfarin Compared With Aspirin in Heart Failure Patients in Sinus Rhythm: A Subgroup Analysis of WARCEF, a Randomized Controlled Trial

Study Questions:

Are there subgroups of patients with left ventricular (LV) systolic dysfunction and no overt indication for anticoagulation who gain benefit from warfarin use?


This was a secondary analysis of the WARCEF (Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction) trial, which was a multicenter, double-blind, randomized trial of warfarin (international normalized ratio 2-3.5) versus aspirin (325 mg daily) in patients with an LV ejection fraction ≤35% and a normal sinus rhythm. The primary aim was to determine if patient characteristics conferred a warfarin or aspirin treatment effect for the composite outcome of time to first occurrence of ischemic stroke, intracerebral hemorrhage, or death.


There were 622 events in 2,305 patients randomized to warfarin versus aspirin (n = 302 events in the warfarin and n = 320 in aspirin groups). Patients under age 60 years with systolic heart failure had improved outcomes on warfarin compared with aspirin alone (adjusted hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.48-0.84). In patients over age 60 years, there was no difference in outcome with warfarin versus aspirin use (HR, 1.09; CI, 0.88-1.35). In terms of primary outcome, patients under age 60 years treated with warfarin had fewer ischemic strokes (HR, 0.51; CI, 0.32-0.81) and lower mortality (HR, 0.65; CI, 0.48-0.89) than those treated with aspirin, and the p value for the age*treatment group interaction was 0.003. Rates of major hemorrhage did not differ by treatment in those <60 years, but subjects over age 60 years treated with warfarin had a high risk of bleeding (HR, 1.25; 95% CI, 1.02-1.53).


The authors concluded that warfarin use in patients under 60 years of age reduces the risk of adverse events in systolic heart failure, but does not improve outcome in patients over 60 years.


This substudy sheds more light on the use of warfarin in patients with LV systolic dysfunction and no other indications for anticoagulation. First, older patients clearly have an increased risk of adverse events, and warfarin does not appear to improve outcomes. In fact, use of warfarin increased risks for major hemorrhage in the elderly in his cohort. Thus, in most patients in sinus rhythm over 60 years of age, aspirin seems appropriate. In those patients <60 years, there may be a reduction in adverse events with the use of warfarin. However, this study does not tease out the question of ‘who under age 60’ is most likely to benefit. Does LV dimension matter? Does LV ejection fraction matter? Are patients with right ventricular dysfunction at greater risk for bleeding due to hepatic congestion? Before placing all young patients with systolic dysfunction on warfarin, we need more information in the form of a randomized trial.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Acute Heart Failure, Chronic Heart Failure

Keywords: International Normalized Ratio, Stroke, Warfarin, Confidence Intervals, Heart Failure, Systolic, Ventricular Dysfunction, Left, Hemorrhage, Ventricular Dysfunction, Right, Cerebral Hemorrhage

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