No Advantage for Warfarin in Heart Failure: WARCEF Published

Megan Brooks

May 04, 2012

May 4, 2012 — Results of a large randomized trial show that for patients with heart failure in sinus rhythm, there was no overall difference in the risk for a composite of ischemic stroke, intracerebral hemorrhage, or death from any cause with treatment with warfarin vs aspirin.

Although warfarin reduced ischemic stroke, it was also associated with higher bleeding risk.

"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 reduced LVEF [left ventricular ejection fraction] who are in sinus rhythm," lead author Shunichi Homma, MD, Margaret Milliken Hatch professor of medicine at Columbia University in New York City, and colleagues conclude. They suggest the choice between warfarin and aspirin be "individualized."

Dr. Shunichi Homma

The Warfarin vs Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial results were first presented in February at the International Stroke Conference (ISC) 2012 and reported by Medscape Medical News at that time. They are now published online May 2 in the New England Journal of Medicine.

The results provide clinicians with "clear answers" to the question of whether warfarin is better than aspirin for patients with heart failure, note the authors of an editorial accompanying the publication.

The WARCEF trial results "provide little support for the use of warfarin in preference to aspirin in patients with heart failure," write John W. Eikelboom, MB, BS, and Stuart J. Connolly, MD, both from the Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

A WARCEF Recap

Patients with heart failure are at an increased risk for death and stroke caused by thromboembolic events. Warfarin and aspirin are often given to these patients, but until WARCEF, they had not been compared with each other in a large group of patients with heart failure.

WARCEF enrolled 2305 patients from 176 sites in 11 countries with an LVEF of less than 35% in sinus rhythm. This double-blind multicenter trial compared warfarin with a target international normalized ratio of 2 to 3.5 with aspirin given at a dosage of 325 mg daily.

Dr. Eikelboom and Dr. Connolly point out in their editorial that only 43% of patients had evidence of underlying ischemic heart disease. "This, together with the exclusion of patients with known atrial fibrillation, meant that the trial was primarily testing whether anticoagulant therapy for the prevention of an embolism emanating from the left ventricle or caused by subclinical atrial fibrillation would lead to a reduction in the [primary] composite end point of stroke or death," they write.

Mean follow-up in the trial was 3.5 years (range, 1 - 6 years). Only 3% of patients were lost to follow-up. The primary outcome was a composite of ischemic stroke, intracerebral hemorrhage, or death from any cause.

As compared with aspirin, warfarin did not significantly reduce the rate of the primary outcome (7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group). The hazard ratio (HR) with warfarin was 0.93 (95% confidence interval [CI], 0.79 - 1.10; P = .40).

In a time-varying analysis, the HR changed over time, "slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant" (P = .046), the investigators say, and "of uncertain clinical significance."

Fewer Strokes, More Bleeding With Warfarin

Throughout the study, warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke (0.72 event vs 1.36 events per 100 patient-years; HR, 0.52; 95% CI, 0.33 - 0.82; P = .005).

However, the benefit of warfarin in reducing the rate of ischemic stroke was offset by a significant increase in the rate of major bleeding (1.78 events per 100 patient-years vs 0.87 in the aspirin group; P < .001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the warfarin and aspirin groups (0.27 and 0.22 event per 100 patient-years, respectively; P = .82).

Dr. Eikelboom and Dr. Connolly note that the results of the WARCEF trial are consistent with those of 3 previous smaller randomized, controlled trials in showing that warfarin anticoagulant therapy, as compared with aspirin, is not associated with a reduction in mortality among patients with heart failure.

"The WARCEF trial provides clear evidence that anticoagulant therapy prevents strokes, probably embolic stroke, in patients with heart failure who have severe systolic dysfunction, but the rates of strokes are too low to justify the routine clinical use of warfarin in most patients with heart failure, in light of the increase in the risk of bleeding," they conclude.

Future Trials

However, they say there are subgroups of patients with heart failure who might benefit from warfarin anticoagulant therapy: patients with heart failure who also have atrial fibrillation and those with a history of cardioembolic stroke or formation of left ventricular thrombus, as well as patients with atherothrombotic coronary artery disease, "the most common underlying cause of heart failure and a disease process that is responsive to anticoagulant therapy."

"Warfarin," note Drs. Eikelboom and Connolly, "would be expected to reduce the rates of both ischemic stroke and nonfatal or fatal myocardial infarction in patients with heart failure who also have coronary artery disease, because warfarin is highly effective for the prevention of major cardiovascular events in survivors of myocardial infarction."

"We believe that any future evaluation of anticoagulants in patients with heart failure should focus on patients with underling coronary heart disease who do not have advanced systolic dysfunction," they conclude.

The WARCEF study was funded by the National Institute of Neurological Disorders and Stroke. Warfarin and warfarin placebo were provided by Taro Pharmaceuticals USA, and aspirin and aspirin placebo by Bayer Healthcare. A complete list of author disclosures is listed with the original articles.

N Engl J Med. 2012. Published online May 2, 2012. Abstract Editorial

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