Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm

A recent study demonstrated no significant difference in time to ischemic stroke, intracerebral hemorrhage, or death from any cause in patients with reduced left ventricular ejection fraction (LVEF) and sinus rhythm who were treated with warfarin or aspirin. A reduction in ischemic stroke risk with warfarin was offset by an increased risk of major hemorrhage, suggesting that an individualized approach to treatment choice should be used in these patients, according to the authors. Results were reported online in the New England Journal of Medicine [10.1056/NEJMoal202299].

Sponsored by the National Institutes of Health (NIH), the double-blind, randomized study was performed in 11 countries. Patients were eligible for participation if they were ≥18 years of age, and had normal sinus rhythm, no contraindications to warfarin therapy, and an LVEF of ≤35%. Eligible participants were randomized to receive warfarin or aspirin. Both groups underwent routine international normalized ratio (INR) monitoring, with plausible INR results fabricated for patients taking aspirin to maintain study blinding. Patient follow-up was performed monthly, by telephone or during office visits for blood draws.

The primary outcome of the trial was the time to the first event in a composite of ischemic stroke, intracerebral hemorrhage, or death from any cause. The secondary end point was time to the first event in the primary composite outcome, plus myocardial infarction or hospitalization for heart failure.

The trial enrolled 2305 patients between October 2002 and January 2010, with a mean follow-up time of 3.5 years. Among those enrolled, 622 (27.0%) experienced an event in the primary composite outcome. Rates of reaching the primary composite outcome were 7.47 and 7.93 per 100 patient-years with warfarin and aspirin, respectively, with no significant difference between groups. Meanwhile, investigators noted a constant, significant benefit with warfarin in the prevention of ischemic stroke over time.

There was no significant difference between warfarin and aspirin treatment groups in time to the secondary composite end point. However, warfarin was associated with a trend toward a higher rate of hospitalization for heart failure.

In addition, the rate of major hemorrhage was significantly higher with warfarin compared with aspirin, with 1.78 events and 0.87 events per 100 patient-years in the warfarin and aspirin treatment groups, respectively. Of note, rates of intracerebral and intracranial hemorrhage combined did not differ considerably between groups. Compared with aspirin, warfarin resulted in significantly higher rates of major gastrointestinal bleeding.

Over the follow-up period, patients in the warfarin group did not receive the assigned medication (receiving open-label therapy instead) 34% of the time. In the aspirin group, patients did not receive the assigned medication 32% of the time.

Investigators cautioned that their study was limited by a smaller number of patients enrolled than had been anticipated, and by a relatively small number of patients still followed in years 5 and 6 of follow-up. They also noted that newer antithrombotic treatment options may be easier to administer, increasing patients’ time in the therapeutic range and reducing the time during which patients do not receive the assigned therapy. This, the authors wrote, could make these agents more effective than warfarin or aspirin.