Aspirin as Effective as Warfarin in Heart Failure: WARCEF

February 3, 2012 (New Orleans, Louisiana) — Results of a large randomized comparison of aspirin vs warfarin in patients with heart failure and reduced ejection fraction show no overall difference in the combined primary outcome of death, ischemic stroke, or intracranial hemorrhage between treatment groups.

However, there was a treatment by time interaction in which patients on warfarin appeared to derive more benefit after about 4 years of treatment, researchers report. Warfarin reduced ischemic stroke risk throughout the trial, but was associated with more major hemorrhage; intracerebral and intracranial hemorrhage were similar between groups.

"In terms of clinical implications, given no overall benefit of warfarin and increased risk of bleeding, in spite of suggestive benefit at 4 years of treatment and beyond, there is no compelling evidence to use warfarin or aspirin for all patients," lead author Shunichi Homma, MD, Margaret Milliken Hatch professor of medicine at Columbia University in New York City, concluded.

"At the same time, given clear effectiveness in preventing stroke and possible benefit of warfarin after 4 years, analyses are being conducted to identify groups of patients that will benefit from 1 medication or the other," he told a press conference.

These results, from the Warfarin vs Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, were presented here at the American Stroke Association's International Stroke Conference (ISC) 2012. The study was funded by the National Institutes of Neurological Disorders and Stroke.

Risk for Thromboembolism

Heart failure patients are at an increased risk for death and stroke caused by thromboembolic events, Dr. Homma noted. "Warfarin and aspirin are often given to these patients, but they have not been compared with each other in a large group of heart failure patients," he said.

The aim of WARCEF was to determine the superiority of warfarin or aspirin over the other agent on the combined endpoint of death, ischemic stroke, or intracerebral hemorrhage in patients with a left ventricular ejection fraction (LVEF) of less than 35% in sinus rhythm.

The main secondary aim was to compare these treatments for the prevention of the combined outcome of death, ischemic stroke, intracerebral hemorrhage, plus myocardial infarction (MI) or heart failure hospitalization.

Patients were included if they were in normal sinus rhythm, had an LVEF of < 35%, had no defined cardioembolic source, and were receiving optimum heart failure treatment.

The trial was a double-blind multicenter trial comparing warfarin with a target International Normalized Ratio of 2 to 3.5 with aspirin given in a dose of 325 mg daily. A center echo core lab was used to confirm LVEF. Recruitment started in 2002 and ended in January 2010, with follow-up to July 2011.

A total of 2305 patients from 176 sites in 11 countries were enrolled and followed for a total of 4045 patient-years in the warfarin group and for a total of 4033 patient-years in the aspirin group. Mean follow-up was 3.5 years with a range of 1 to 6 years. Only 3% of patients were lost to follow-up.

The average age of patients was about 61 years; 80% were male. Of the patients receiving warfarin, 13.6% had had a previous stroke or transient ischemic attack (TIA); 12.0% of patients receiving aspirin had had at least one or the other of those events. Most patients fell into class II or III the New York Heart Association functional classification system, indicating mild to moderate impairment of function. The mean ejection fraction was 25% in each group, "so this is a significantly impaired left ventricular ejection fraction," Dr. Homma noted.

Almost all patients were receiving angiotensin-converting enzyme (ACE) inhibitors or beta-blockers, which was optimal treatment, he said.

Overall, no significant difference was observed in the primary endpoint between groups, Dr. Homma said.

Table 1. WARCEF: Primary Endpoint

Endpoint	Aspirin n (% per year)	Warfarin n (% per year)	Hazard Ratio (95% Confidence Interval)	P
Death, ischemic stroke, or intracerebral hemorrhage	320 (7.93)	302 (7.47)	0.93 (0.79 - 1.10)	.40

Dr. Homma noted, however, that the incidence curves crossed at about 4 years follow-up, violating the proportional hazards assumption and enabling the investigators to undertake a time by treatment interaction analysis. When they calculated hazard ratios by the year of follow-up, they found a significant interaction of treatment by time (hazard ratio multiplier per year, 0.894; P = .046).

When the primary endpoint events were studied separately, the investigators found no difference in death rates between groups; intracerebral hemorrhage was very infrequent in both groups, but there was a highly significant reduction in ischemic stroke among those receiving warfarin as compared with those receiving aspirin.

Table 2. WARCEF: Primary Outcome Components

Endpoint	Warfarin n (% per year)	Aspirin n (% per year)	Hazard Ratio (95% Confidence Interval)	P
Death	268 (6.63)	263 (6.52)	1.01 (0.85 - 1.21)	0.91
Ischemic stroke	29 (0.72)	55 (1.36)	0.52 (0.33 - 0.82)	.005
Intracerebral hemorrhage	5 (0.12)	2 (0.05)	2.22 (0.43 - 11.66)	.35

The main secondary outcome looked at primary endpoint outcomes plus MI and heart failure hospitalizations; there was no difference between the groups on this endpoint.

Table 3. WARCEF: Secondary Endpoint

Endpoint	Aspirin n (% per year)	Warfarin n (% per year)	Hazard Ratio (95% Confidence Interval)	P
Death, ischemic stroke, or intracerebral hemorrhage, myocardial infarction, heart failure hospitalization	435 (12.15)	447 (12.70)	1.07 (0.93 - 1.23)	.33

Major hemorrhage was significantly higher with warfarin, although there were no significant differences in intracerebral or intracranial hemorrhage. "Much of the difference in the major hemorrhage came from the difference in gastrointestinal hemorrhage" with warfarin, Dr. Homma noted.

Important Question

Asked to comment on these findings, Mark Alberts, MD, professor of neurology at the Northwestern University Feinberg School of Medicine, Chicago, Illinois, pointed out that WARCEF answers an important clinical question.

"It's a conundrum that we face every day between cardiology and neurology, which is, should those patients be anticoagulated long-term to prevent cardioembolic strokes and other vascular events, or do they do okay on aspirin?" he told Medscape Medical News.

"Basically, it's a negative study with some intriguing subgroups," he said. However, given there is no difference, "we would offer aspirin, because it's safer to use, easier to use, and patients tolerate it pretty well, there are no food interactions, and it's inexpensive."

Newer oral anticoagulants now becoming available, dabigatran and rivaroxaban, which are already approved, and apixaban, which is expected to be approved soon, might open this question, he added.

The 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. The authors and Dr. Alberts have disclosed no relevant financial relationships.

International Stroke Conference (ICF) 2012: Abstract #LB-12-4372. Presented February 3, 2012.

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Cite this: Aspirin as Effective as Warfarin in Heart Failure: WARCEF - Medscape - Feb 03, 2012.