No compelling reason for warfarin over aspirin for reduced LVEF, study indicates

There was no significant overall difference in the primary outcome between warfarin and aspirin among patients with reduced left ventricular ejection fraction (LVEF) who were in sinus rhythm, researchers reported.

A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage, among other tradeoffs noted in the study.

Researchers designed a cooperative, double-blind, multicenter clinical trial at 168 centers in 11 countries looking at warfarin use with a target international normalized ratio of 2.0 to 3.5 or 325 mg of aspirin per day in patients with a documented LVEF of 35% or lower. The trial was sponsored by the National Institutes of Health (NIH). Researchers followed 2,305 patients for up to six years and looked for the primary outcome of time to ischemic stroke, intracerebral hemorrhage or death from any cause. Results appeared online May 2 at the New England Journal of Medicine.

Overall, 622 patients (27%) had one of the three primary outcomes (531 deaths [85.4%], 84 ischemic strokes [13.5%], and 7 intracerebral hemorrhages [1.1%]). There were 7.47 events per 100 patient-years in the warfarin group and 7.93 events per 100 patient-years in the aspirin group (hazard ratio with warfarin, 0.93; 95% CI, 0.79 to 1.10; P=0.40).

There was a constant and significant benefit with warfarin compared to aspirin for the rate of ischemic stroke (HR, 0.52; 95% CI, 0.33 to 0.82; P=0.005). There was no significant difference between the groups for the first event in the composite of death, ischemic stroke, intracerebral hemorrhage, myocardial infarction, or hospitalization for heart failure (HR with warfarin, 1.07; 95% CI, 0.93 to 1.23; P=0.33). Rates of myocardial infarction and hospitalization for heart failure did not differ significantly between the two groups.

The rate of major hemorrhage was significantly higher with warfarin than with aspirin (1.78 events per 100 patient-years with warfarin vs. 0.87 event per 100 patient-years with aspirin; adjusted rate ratio, 2.05; 95% CI, 1.36 to 3.12; P<0.001). However, the rates of intracerebral and intracranial hemorrhages combined did not differ significantly according to treatment group (0.27 event per 100 patient-years in the warfarin group and 0.22 event per 100 patient-years in the aspirin group; P=0.82). Major gastrointestinal bleeding occurred more frequently in the warfarin group (0.94 event per 100 patient-years vs. 0.45 event per 100 patient-years in the aspirin group; P=0.01).

The authors wrote, “Given the finding that warfarin did not provide an overall benefit and was associated with an increased risk of bleeding, there is no compelling reason to use warfarin rather than aspirin in patients with a reduced LVEF who are in sinus rhythm.”

Editorialists commented that “The careful conduct of this blinded trial, in which patients in the warfarin group had good control of INR levels (mean time in the therapeutic range after a 6-week period of dose adjustment, 62.6%) and which included more than 600 primary outcome events, has provided clinicians with clear answers. ... The lack of an effect of warfarin on mortality suggests that most of the deaths in these patients with heart failure, who had severe impairment of left ventricular function, are unrelated to thromboembolism and, instead, are most likely due to pump failure or ventricular arrhythmias.”