Multi-center trial compares three medications in patients with heart failure

By Maureen McInaney

Results of an international study led by researchers at the San Francisco VA Medical Center (SFVAMC) suggest that there is no major difference between three medications often prescribed for patients with chronic heart failure to prevent death, heart attack and stroke. However, the results leave important questions unresolved, according to the lead investigator.

The three medications are known as antithrombotic agents. Barry Massie, MD, UCSF professor of medicine and chief of cardiology at the SFVAMC, headed the study.

## Results of the Warfarin and Antiplatelet Trial in Chronic Heart Failure

(WATCH)—the largest trial of antithrombotic therapies conducted in chronic heart failure patients—were presented today at the annual meeting of the American College of Cardiology in New Orleans.

Study results showed no major differences among the three medications—warfarin (Coumadin), aspirin and clopidogrel (Plavix)—when investigators analyzed the primary endpoint, which was a combination of death, non-fatal heart attacks and strokes.

However, the study was terminated early, so clinically important differences cannot be excluded with certainty, according to the researchers. Massie noted that a second endpoint—hospitalizations for worsening heart failure—occurred significantly less frequently in patients treated with warfarin than in those receiving aspirin.

“We were not surprised by the finding of more heart failure with aspirin because it is consistent with findings from smaller studies. However, this result must be interpreted with caution because it was one of many analyses performed and the primary endpoints of the study did not show major differences between these agents,” he said.

Earlier analyses and studies had suggested that aspirin itself may have a negative effect in CHF patients, possibly as a result of reducing the effectiveness of angiotensin converting enzymes (ACE) inhibitors, which are a cornerstone of treatment in chronic heart failure patients. ACE inhibitors act to prevent blood vessel narrowing, thus reducing blood pressure and also prevent the progression of heart dysfunction. The WATCH investigators examined this question by comparing aspirin with clopidogrel, which has similar effects as aspirin but works by a different mechanism.

“The bottom line is that the jury is still out on the role of these three drug therapies in treating heart failure. Unfortunately, we will have to await additional studies to determine whether one of these therapies is more effective and whether it might be appropriate to avoid aspirin in patients with severe heart failure.”

One of these additional studies includes the ongoing Warfarin vs. Aspirin in Reduced Ejection Fraction (WARCEF) trial sponsored by the National Institute of Neurological Diseases and Stroke, which is comparing warfarin and aspirin in 2860 CHF patients with regard to the endpoints of death and stroke. The study will provide additional information about the relative effectiveness of these two agents and a combined analysis of the WARCEF and WATCH studies is planned, according to Massie.

The WATCH study enrolled 1587 patients from 132 centers in the United States, Canada, and the United Kingdom. Enrollment began in October 1999 with the goal of recruiting 4,500 patients, but the trial was terminated early in June 2003 because recruitment was slower than anticipated.

The WATCH trial was supported and administered by the Cooperative Studies Program of the Department of Veterans Affairs Research and Development Service and by unrestricted grants from Bristol Myers Squibb, Sanofi-Synthelabo and Dupont pharmaceuticals companies. Funding for the arm of the study conducted at SFVAMC was administered by the Northern California Institute for Research and Education (NCIRE).

Additional researchers on the study include William F. Krol, PhD, study statistician, and Joseph F. Collins, DSc, chief, VA SCP Coordinating Center, Perry Point, MD; Susan E. Ammon, BSN, principal study coordinator, SFVAMC; Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada; John G. Cleland, MD, University of Hull, United Kingdom;; Michael Ezekowitz, MD, Temple University, Philadelphia, PA; Syed M. Jafri, MD, Henry Ford Hospital, Detroit, MI; Christopher M. O’Connor, MD, and Kevin A. Schulman, MD Duke University, Durham, NC; Milton Packer, MD, Columbia University, New York; Koon Teo, MD, McMaster University, Hamilton Ontario, Canada; Stuart Warren, Pharm D, VA CSP Pharmacy Coordinating Center, Albuquerque, NM.