NEW ORLEANS – The largest, best controlled comparison of aspirin and warfarin ever done in patients with heart failure showed no overall difference between the two drugs for preventing thromboembolic events that cause death or stroke.
As a consequence, for the time being physicians should feel comfortable prescribing either drug to patients with a left ventricular ejection fraction of 35% or less and in sinus rhythm, Dr. Shunichi Homma reported at the International Stroke Conference.
"Most heart failure patients are put on aspirin or warfarin" to deal with their elevated risk for thromboembolic events," said Dr. Homma, a cardiologist and professor of medicine at Columbia University in New York, and until now it’s remained an open question whether one drug surpassed the other. The study compared a daily 325-mg aspirin dosage with a warfarin regimen targeted to maintain patients at a target international normalized ratio (INR) of 2.75.
"Overall, there was no benefit of one over the other" for the study’s primary end point of the combined rate of death, ischemic stroke, or intracerebral hemorrhage, he said in an interview. Aspirin is more convenient and cheaper than a warfarin regimen that requires regular INR monitoring, and the results also showed that aspirin led to significantly fewer hemorrhagic events. In addition, total major hemorrhagic events, including intracranial, intracerebral, and gastrointestinal bleeding, ran 0.9% in the aspirin patients and 1.8% in the warfarin patients, a statistically significant difference.
Dr. Shunichi Homma
But findings from the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial also showed advantages for warfarin. While the primary, combined end point showed a virtual dead heat of a 6.6% event rate with warfarin and a 6.5% rate with aspirin, warfarin treatment showed a statistically significant edge over aspirin for preventing ischemic strokes. This end point occurred in 0.7% of the warfarin patients and in 1.4% of those on aspirin, a significant difference.
In addition, warfarin treatment produced a hard-to-explain advantage for the study’s primary end point that appeared once patients were followed for more than 3 years. Although average follow-up for all 2,305 patients in the study was 3.5 years, follow-up for more than 1,000 of the enrollees extended to 4 years, and nearly 700 patients had a follow-up of 5 years. After 4 years, warfarin produced a statistically significant, roughly 25% reduction in the study’s primary end point compared with aspirin, an advantage maintained through 5 years and then out to 6 years.
Because this separate analysis of the study results after prolonged follow-up was a prespecified end point, it represented a major finding of the trial, although its full interpretation will need additional analysis and its clinical implications are not yet clear, Dr. Homma said.
"While there was no overall difference in the outcomes, there is a group of patients, those followed for 4 or more years, who benefited from warfarin. We don’t know who they are or why this happens. It’s important to find out, before we decide to [routinely use] warfarin," he said. "Also, in years 1-3 there was no significant difference between the two drugs, and given the bleeding risk with warfarin we need to clarify the characteristics of the patients who might benefit from one medication or the other."
For the time, being, until a better understanding of the long-term warfarin effect is available, "I think the results of our study will tip physicians toward using aspirin over warfarin," he said.
Dr. J.L.P. Thompson
"We suspected, based on prior results, that there might be a change in the effect [of warfarin] over time," said J.L.P. Thompson, Ph.D., professor of clinical biostatistics and clinical neurology at Columbia and co-principal investigator on the study. "The benefit from warfarin is modest, but it is there. It does not lead to a clinical recommendation at the moment, but it is an unexpected finding and the clinical investigators want to look at it further," he said in an interview.
An additional, important observation was that daily aspirin treatment led to a strong trend toward a reduced rate of heart failure hospitalizations compared with the warfarin arm. Results from a prior study that compared aspirin and warfarin in heart failure patients, the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial, had indicated that aspirin boosted the rate of heart failure hospitalizations for acute exacerbations, and at the least the new findings "show that aspirin certainly did not make hospitalization any worse," and may possibly have even reduced the heart-failure hospitalization rate, Dr. Homma said.