NEW ORLEANS—Warfarin and aspirin are equally efficacious for preventing death, ischemic stroke, or intracerebral hemorrhage among heart failure patients with normal sinus rhythm, according to research reported at the 2012 International Stroke Conference.
Of patients receiving aspirin, 320 of 1,163 (7.93% per year) experienced the primary outcome measure of death, ischemic stroke, or intracerebral hemorrhage, compared with 302 of 1,142 (7.47% per year) patients receiving warfarin. Evidence suggested that after four years of treatment, warfarin was more effective than aspirin at preventing ischemic stroke.
“At this point, looking at the overall result, having found no significant difference for all of the patients, there is no compelling reason to use warfarin for patients with reduced left ventricular ejection fraction [LVEF] in sinus rhythm,” Shunichi Homma, MD, the Margaret Milliken Hatch Professor of Medicine at Columbia University in New York City, told Neurology Reviews.
Dr. Homma and J. L. P. Thompson, PhD, Director of Clinical Trials Activities, Biostatistics, at Columbia University’s Mailman School of Public Health, compared the efficacy of warfarin to that of aspirin in patients whose LVEF is lower than 35% in sinus rhythm. In the general population, LVEF ranges from 50% to 55%. The study’s main secondary outcome was whether warfarin or aspirin is superior for preventing the primary outcome in addition to myocardial infarction or heart failure hospitalization.
An Exceptionally Large Patient Population
Drs. Homma and Thompson designed the double-blind, multicenter study in which eligible patients were required to have normal sinus rhythm, an LVEF equal to or lower than 35%, no defined cardioembolic source, and an optimal heart-failure regimen.
The investigators started recruiting patients in October 2002 and ended in January 2010. A total of 2,305 patients participated in the study, which was conducted at 176 sites in 11 countries. Follow-up, which ranged from one to six years (mean, about three and a half years), ended in July 2011. About 3% of patients withdrew consent or were lost to follow-up, and 97% of all patients had follow-up.
After enrollment, patients were randomly assigned treatment with warfarin or aspirin. The total number of patient years was more than 8,000, including 4,000 on each side of the study. The number of participants “was four times larger than the next [largest] study that looked at the issue of warfarin versus aspirin in heart-failure patients,” said Dr. Homma.
The mean age of patients in both arms of the study was 61. Approximately 13% of all patients had had a previous stroke or transient ischemic attack. About 79% of patients receiving warfarin were male, compared with almost 81% of patients receiving aspirin.
Patients’ level of heart function was assessed using the New York Heart Association’s classification system, which divides the stages of heart failure into four categories ranging from mild to severe. About 84% of the patients were categorized as Class II or III, meaning that their heart function was mildly or moderately impaired. The mean value of patients’ LVEF was 25%, however, which indicates significant impairment of heart function, Dr. Homma noted.
Nearly all patients were taking an ACE inhibitor, and roughly 90% were taking beta-blockers at the time of enrollment, which indicated that they were optimally treated for heart failure, according to Dr. Homma. About 83% of patients were taking statins, and 80% were taking diuretics.
Warfarin and Aspirin Yield Similar Results
The researchers found no significant difference between warfarin and aspirin. The incidence curves of the aspirin and warfarin groups crossed, thus violating the assumption of proportional hazard. This result prompted the investigators to analyze the data by timeline treatment interaction, which indicated a possible benefit of warfarin treatment beginning at four years of follow-up.
The number of patient deaths was similar for the two arms of the study. Of patients taking warfarin, 268 died, compared with 263 patients taking aspirin. The incidence of intracerebral hemorrhage also was similar for both groups. Five patients taking warfarin experienced this event, as did two patients taking aspirin.
Patients taking warfarin, however, were nearly half as likely to experience ischemic stroke as patients taking aspirin were. The incidence of ischemic stroke was 0.72% (ie, 29 patients) for the warfarin group, and 1.36% (ie, 55 patients) for the aspirin group.
The researchers found no difference between the two drugs for the main secondary outcome, which included myocardial infarction and heart failure hospitalization in addition to the primary outcome. However, patients receiving warfarin experienced major hemorrhage at a rate of 1.8%, compared with a rate of 0.9% in patients receiving aspirin. “Importantly, for the intracranial and intracerebral hemorrhages, the numbers were small, and there were no significant differences between the warfarin and aspirin arms,” said Dr. Homma.