No advantage for warfarin in heart failure: WARCEF published

Megan Brooks

May 04, 2012

Boston, MA - Results of a large randomized trial show that for heart-failure patients in sinus rhythm, there was no overall difference in the risk of a composite of ischemic stroke, intracerebral hemorrhage, or death from any cause with treatment with warfarin vs aspirin[1].

While 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 who are in sinus rhythm," lead author Dr Shunichi Homma (Columbia University, New York City) and colleagues conclude. They suggest the choice between warfarin and aspirin be "individualized."

The Warfarin vs Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial results were first presented in February at the International Stroke Conference 2012 . They are now published online May 2, 2012 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 paper[2].

The WARCEF trial results "provide little support for the use of warfarin in preference to aspirin in patients with heart failure," write Drs John W Eikelboom and Stuart J Connolly (McMaster University, Hamilton, ON).

A WARCEF recap

Heart-failure patients 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 heart-failure patients.

WARCEF enrolled 2305 patients from 176 sites in 11 countries with an LVEF of less than 35% in sinus rhythm. This double-blind trial studied the results of warfarin treatment with a target INR of 2 to 3.5 vs aspirin given in a dose of 325 mg daily.

Eikelboom and 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, with a range of one to six 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 arm and 7.93 in the aspirin arm). The hazard ratio (HR) with warfarin was 0.93 (95% CI 0.79-1.10; p=0.40),

In a time-varying analysis, the hazard ratio changed over time, "slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant" (p=0.046), 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 events vs 1.36 events per 100 patient-years; HR 0.52, 95% CI 0.33-0.82; p=0.005).

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<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the warfarin and aspirin groups (0.27 and 0.22 events per 100 patient-years, respectively; p=0.82).

Eikelboom and Connolly note that the results of the WARCEF trial are consistent with those of three 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 warfarin 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: namely, 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 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 underlying coronary heart disease who do not have advanced systolic dysfunction," they conclude.

The WARCEF study was funded by the National Institute of Neurolo gical Disorders and Stroke . Warfarin and warfarin placebo were provided by Taro Pharmaceuticals USA and aspirin and aspirin placebo by Bayer Healthcare. Homma reports receiving payment from AGA Medical (now St Jude Medical) for his work as a member of a data and safety monitoring board and consulting fees from Boehringer Ingelheim . Disclosures for the coauthors are listed in the paper. Co nnolly and Eikelboom report they have no conflicts of interest.

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