Does warfarin or aspirin cut thromboembolic risk in HF? Still no answer

June 20, 2006

Amsterdam, the Netherlands - The evidence base still doesn't provide a good answer as to whether warfarin can protect against thromboembolic events in patients with heart failure, even with release in the June 2006 issue of the European Journal of Heart Failure of a third randomized exploration of the issue [1].

In the latest trial, the international Heart Failure Long-Term Antithrombotic Study (HELAS), no significant clinical-end-point differences or evidence of thromboembolic events were observed over two years in 197 patients with ischemic or nonischemic HF randomized to warfarin or control groups. But enrollment at the 40 participating centers was slow and had fallen far short of the 6000-patient target when the investigators stopped randomizing patients and proceeded with the analysis, according to the authors, Dr Dennis V Cokkinos (University of Athens, Greece) and associates.

Thromboembolic events are rare among HF patients in sinus rhythm, and "there is no evidence, as yet, that the rate can be reduced by anticoagulant or antiplatelet treatment based on three randomized controlled trials," the authors write. "It is unclear, at present, whether the benefits outweigh the risks for any antithrombotic agent in patients with chronic heart failure in sinus rhythm."

The group's HELAS experience somewhat mirrors that of the Warfarin and Antiplatelet Therapy in Heart Failure Trial (WATCH), an earlier, much larger trial that entered 1587 patients, or only about 40% of its target enrollment [2]. Conducted in North America and the UK, the study randomized HELAS-like patients to warfarin, clopidogrel, or aspirin and followed them for an average of almost two years. The rates of death, MI, and stroke—as individual end points and a composite—turned out about the same in the three groups.

It is unclear, at present, whether the benefits outweigh the risks for any antithrombotic agent in patients with chronic heart failure in sinus rhythm .

Cokkinos and associates note also that their trial is "very similar" to the Warfarin/Aspirin Study in Heart Failure (WASH) comparison of warfarin, aspirin, or neither in 279 patients with HF [3]. The study found no significant differences in the primary end point of death, nonfatal MI, or nonfatal stroke over an average of 27 months. The trial was covered by heart wire at its 2004 publication, and WATCH was reported when it was presented at the American College of Cardiology 2004 Scientific Sessions.

The double-blind HELAS trial separately randomized 115 patients with HF related to ischemic heart disease to receive either warfarin or aspirin and 82 patients with HF and dilated cardiomyopathy (DCM) to receive either warfarin or placebo. There were no significant differences in the primary composite end point of death, MI, hospitalization, HF exacerbation, or hemorrhage over 312 patient years. No peripheral or pulmonary thromboemboli were observed, according to the group.

On the other hand, echocardiography at two years disclosed a mean two-point increase in LVEF among warfarin recipients, a significant difference driven by a mean four-point rise among DCM patients on warfarin (p<0.05 for both differences). Patients with ischemic disease did not show a significant LVEF benefit.

Aspirin showed signs of harm in both of the two other studies, Cokkinos et al observe. As reported by heart wire , aspirin therapy in both WATCH and WASH was associated with significant increases in the rate of HF hospitalization. Observers of the two trials have proposed that those findings may have been related to coadministration of aspirin and ACE inhibitors, which has been linked to adverse outcomes. But other research has suggested that there is no such interaction between the two drugs [4].

"We could not identify a similar hazard in our study, but the rate of use of ACE inhibitors was relatively low compared with previous studies," the HELAS authors write, noting that they were used in only 60% of their patients.


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