Warfarin was no better than aspirin in reducing the composite of stroke of any kind or death in heart failure patients in sinus rhythm, but had an advantage for reducing ischemic stroke, a randomized trial found.

The rate of time to first event of a composite of ischemic stroke, Hemorrhagic stroke, or death from any cause was 7.47 events per 100 patient-years in the warfarin arm versus 7.93 in the aspirin arm, reported Shunichi Homma, MD, of Columbia University Medical Center in New York City, and colleagues.

Over time, however, warfarin had a marginally significant advantage over aspirin (P=0.046), particularly by the fourth year, they reported online in the New England Journal of Medicine.

Heart failure patients are at risk for left ventricular thrombus formation, but the role of oral anticoagulants has not been fully studied, particularly in those in sinus rhythm.

To gain a better understanding of this issue, Homma and colleagues conducted the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, a double-blind, randomized study.

Researchers presented results from the study earlier this year at the American Stroke Association’s International Stroke Conference in New Orleans.

Trial enrollees came from 168 centers in 11 countries. The mean age was 61. Patients with a clear indication for warfarin were not eligible. The target international normalized ratio (INR) was 2.0 to 3.5. Patients in the warfarin group had an INR in the therapeutic range for 62.6% of the follow-up time.

To be included, patients had to have a left ventricular ejection fraction (LVEF) of 35% or less 3 months before randomization. The mean LVEF for all patients in the study was 24.7%.

More men (80%) than women were in each arm and 75% of patients in each group were white. All other baseline characteristics were similar between the two arms including blood pressure, body mass index, and smoking status.

Of the 2,305 patients in the trial, 1,119 came from the U.S. and Canada, while 1,186 came from Europe and Argentina. Patients were followed for a mean of 3.5 years.

A total of 27% of all patients had a primary outcome: 85% deaths, 13.5% ischemic strokes, and 1.1% intracerebral hemorrhages. Researchers found no significant differences between the two arms regarding primary outcome. The hazard ratio with warfarin was 0.93 (95% CI 0.79 to 1.10, P=0.40).

However, the hazard ratio for warfarin decreased each year, becoming borderline significant at 4 years (HR 0.76, P=0.04).

In addition, those on warfarin had a decreased risk of ischemic stroke (HR 0.52, 95% CI 0.33 to 0.82, P=0.005). The researchers said that this result confirms similar findings in other studies, particularly the WATCH trial.

But patients in the warfarin group also had a nonsignificant increased risk of intracerebral hemorrhage and a significant risk for major hemorrhages, primarily driven by gastrointestinal bleeding (HR 2.35), followed by bleeding characterized as “other,” (HR 3.06), which offset the ischemic benefit, researchers noted.

The warfarin group also displayed significantly more minor hemorrhages (HR 1.65).

Homma and colleagues found no difference in the rate of the secondary outcome, which was the time to the first event of the primary outcome, myocardial infarction, or hospitalization for heart failure. However, they observed a trend for more hospitalizations in the warfarin group.

The study was limited by a smaller number of patients enrolled in the trial than originally anticipated, the authors said, and the relatively small number of patients still being followed in years five and six.

Primary source: New England Journal of Medicine
Source reference: Homma S, et al “Warfarin and aspirin in patients with heart failure and sinus rhythm” N Engl J Med 2012; DOI:
10.1056/NEJMoa1202299.