WARCEF: Warfarin Protects Against Death/Stroke in Younger HF Patients

September 11, 2012

September 11, 2012 (Seattle, Washington) — In a randomized trial that compared outcomes on warfarin vs aspirin in patients in sinus rhythm with systolic heart failure, those who were <60 years of age fared significantly better on the oral anticoagulant compared with the antiplatelet [1].

Dr Shunichi Homma

A subgroup analysis of the Warfarin vs Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found that warfarin was associated with a 37% drop in risk of death, ischemic stroke, or intracranial hemorrhage (ICH) compared with aspirin in the younger age group. "Younger patients benefited from warfarin, while no benefit was seen in older patients," said Dr Shunichi Homma (Columbia University, New York, NY) when presenting the analysis here at the Heart Failure Society of America 2012 Scientific Meeting.

When major hemorrhage was added to the composite clinical end point, he said, "the benefit of warfarin for younger patients remained."

The findings contrast with the trial's primary outcome in its overall population. As previously reported, the 2305-patient WARCEF trial had found no significant difference in the composite death/ischemic stroke/ICH end point between patients who took warfarin and those given aspirin. The WARCEF investigators, as covered by heartwire , concluded that warfarin and aspirin are similarly protective in patients with systolic HF and sinus rhythm.

"We Don't Know"

Assigned to formally comment on the subgroup analysis, Prof John GF Cleland (University of Hull, Kingston-upon-Hull, UK) called WARCEF "the largest and probably the best-executed" of the four randomized trials to compare the antithrombotics in systolic HF. But he questioned the subanalysis conclusion, proposing that there can be other interpretations, given the lack of a control group that took neither agent.

"In younger patients, warfarin could be beneficial and aspirin less so; or alternatively, it could be that warfarin is ineffective and aspirin is harmful," he said. "In older patients, warfarin and aspirin might be equally effective or warfarin and aspirin equally harmful--we don't know."

The other trials looking at the issue--WASH, HELAS, and WATCH--were small compared with WARCEF, which randomized almost twice as many patients as the other three combined, he noted. And collectively the four trials showed little if any clinical benefit and a doubling of the risk of major bleeding with warfarin vs aspirin.

So there is scant clinical-trial support for using any antithrombotic therapy in heart failure, he said, and indeed "the need for any long-term antithrombotic therapy for any group of patients with cardiovascular disease in sinus rhythm, perhaps with the exception of patients with mechanical valves, is uncertain."

But the reality, according to Cleland, is that clinicians will likely continue to use the drugs, especially aspirin, in HF patients in sinus rhythm without any evidence base. Speaking with heartwire , he said it's hard to change "30 years of belief in a myth" that aspirin improves outcomes in that group. And formal recommendations haven't made it easier for clinicians to sort it out: "The guidelines are confused. The guidelines on ischemic heart disease talk about lifelong aspirin, and the guidelines on heart failure cast doubt on whether there's any efficacy from aspirin."

Treatment Interaction With Age: P=0.003

Of 32 variables explored for an interaction with treatment, Homma reported, only age emerged as significant in multivariate analysis that had also included demographics, LVEF, comorbidities, functional performance, and history of statin, antiplatelet, and anticoagulant use.

The significant reduction in the composite end point for patients younger than 60 years for warfarin vs aspirin was driven by a 35% drop in mortality. But warfarin was also associated with more minor bleeding in this group.

Risks of Composite End Point, Its Components, and Major and Minor Bleeding, Warfarin vs Aspirin, by Age Group in WARCEF

End point Age <60 y, HR (95% CI); p Age >60 y, HR (95% CI); p
Death/ischemic stroke/ICD 0.63 (0.48–0.84); 0.001 1.09 (0.88–1.35); 0.442
Death 0.65 (0.48–0.89); 0.007 1.18 (0.94–1.49); 0.158
Ischemic stroke 0.51 (0.32–0.81); 0.005 0.51 (0.32–0.81); 0.005
ICH 2.35 (0.44–12.5); 0.317 2.35 (0.44–12.5); 0.317
Major bleeding 1.30 (0.56–3.07); 0.636 2.73 (1.56–4.97); 0.0002
Minor bleeding 1.95 (1.41–2.71); <0.0001 1.43 (1.08–1.92); 0.014

In patients with heart failure in sinus rhythm, Cleland observed for heartwire , "it's possible that there are real benefits from the antithrombotics but also that there are risks, and the risks of the antithrombotics balance any benefits."

The most obvious risk would be from bleeding, of which there are three potential kinds that could be involved, he said. First, ICH--but that doesn't seem to a significant adverse effect of the drugs in this setting.

Second would be gastrointestinal bleeding, especially those that involve "chronic leaks," according to Cleland. "We know that iron-deficiency anemia is rife in this population, and that may be due to the widespread use of antithrombotic agents. We know that a low hemoglobin and iron deficiency are very strong markers of an adverse prognosis [in heart failure]."

The third type of bleeding that may increase risk from antithrombotic agents in heart failure, he said, is underappreciated. Intraplaque hemorrhage in coronary atheroma "is probably as much a problem as plaque rupture and thrombosis. [With antithrombotics] we may be helping [to prevent] some plaque rupture and thrombosis, but we may also be giving the patients lots of plaque hemorrhage, giving with one hand and taking away with the other."

In his presentation after the WARCEF analysis, Cleland said it's likely there will be a new wave of randomized trials of anticoagulation in heart failure using recently introduced oral agents like rivaroxaban (Xarelto, Bayer/Johnson & Johnson), apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), and dabigatran (Pradaxa, Boehringer Ingelheim).

"The great dilemma will be what to compare these new agents with. Should [they be compared] head-to-head with aspirin or vs placebo on top of aspirin? Or should we do the right thing," which would be to take aspirin out of the picture and "do a clean trial of an antithrombotic against placebo? My money's on placebo."

WARCEF was primarily funded by the National Institutes of Health; warfarin and its placebo were provided by Taro Pharmaceuticals, and aspirin and its placebo were provided by Bayer Healthcare. Cleland discloses consulting for Bayer/Johnson & Johnson.