Low-dose combo no better than aspirin alone in secondary prevention

February 04, 2002

DALLAS, Feb. 5 - Giving heart attack patients a combined low dose of the anticoagulant drug warfarin with low-dose aspirin does not prevent second heart attacks or strokes better than aspirin alone, researchers report in today's Circulation: Journal of the American Heart Association.

A study among heart attack patients at 78 Veterans Administration medical centers found the blood-thinning benefits of daily aspirin are not enhanced by concurrent treatment with low doses of the more expensive blood thinner warfarin (Coumadin), which is given to reduce risk of bleeding, report principal researchers Louis D. Fiore, M.D., and Michael D. Ezekowitz, M.D., Ph.D. "We had hoped this might double the effectiveness of the drugs, but it didn't," says Fiore. "Lower anticoagulant levels of warfarin simply had no effect on preventing subsequent heart attacks or strokes. It was a bust."

Both drugs slow blood clotting. Blood clots can block vessels that carry blood to the heart, causing a heart attack, or to the brain, causing an ischemic stroke. Aspirin affects the blood platelets. Warfarin inhibits circulating clotting proteins in the blood.

Many clinicians say that warfarin may be a better blood thinner than aspirin in preventing heart attacks and strokes. However, warfarin costs more and is associated with a higher risk of bleeding. Recent studies have found that regular use of aspirin may reduce the risk of coronary heart disease (CHD) by 28 percent in people who have never had a heart attack or stroke, but who are at increased risk. Those considered at increased risk are men over age 40, post-menopausal women, and younger persons with CHD risk factors (smoking, diabetes, hypertension, etc.).

Fiore and colleagues at the Department of Veterans Affairs Cooperative Study Program, in New Haven, Conn., conducted a randomized, open-label study comparing aspirin alone with combined aspirin and warfarin in preventing death, second heart attacks, strokes and major hemorrhage in 5,059 heart attack survivors, average age 62. Patients were given warfarin (1.5 to 2.5 International Units) and 81 mg of aspirin administered daily, or 162 mg of chewable aspirin alone daily. That latter dosage is in accordance with antithrombotic therapy guidelines. The standard dose of warfarin for treating heart attack patients is 2.5 to 3.5 units. Patients began therapy within 14 days of suffering a heart attack and were followed for an average of 2.7 years.

Among the combined therapy group, 17.6 percent of patients died, compared with 17.3 percent in the aspirin-only group. A second heart attack occurred in 13.3 percent of those taking combination therapy, compared with 13.1 percent taking aspirin. Stroke occurred in 3.5 percent of patients who received both drugs compared with 3.1 percent in the aspirin group. The authors wondered if there might be a synergistic blood-thinning effect if low-dose warfarin was administered with a lower-than-normal dose of aspirin to patients after a heart attack, and if the combination might produce acceptable bleeding rates. Older studies have shown high bleeding rates in heart valve patients receiving combined therapy, which has led to some resistance to testing the therapy in clinical settings, Fiore notes.

In this study, major bleeding episodes (primarily gastrointestinal) occurred nearly twice as often in the combination therapy patients compared with the aspirin-only patients. Fourteen patients in each group suffered more serious intracranial bleeding. This bleeding proved fatal for seven patients in the aspirin group and 10 patients who received combined therapy. Death was not associated with delay in starting therapy in either group.

Both open-label drug administration and differences in follow-up care in the combined treatment group may have influenced results. Patients in the combination group were seen more often than those in the aspirin group, "resulting in inherent informational biases" that might have affected the cumulative number and classification of reported bleeding episodes, Fiore says. According to the American Heart Association, about 530,000 Americans die from heart attacks and other forms of CHD each year. Aspirin may increase the incidence of gastrointestinal bleeding and cause a small increase in the incidence of hemorrhagic strokes, which result from bleeding in the brain. Although the benefits of aspirin outweigh the harm for people with an increased risk of CHD, the harmful effects may exceed the benefits for those who are at average or low risk for heart disease. Patients should discuss these risks and benefits with their health care professional.
Co-authors include: Mary T. Brophy, M.D; David Lu, M.D.; Joseph Sacco, M.D.; and Peter Peduzzi, Ph.D., for the Combination Hemotherapy and Mortality Prevention (CHAMP) Study Group.

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American Heart Association

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