Combining aspirin (search) with the painkiller Bextra (search) may magnify the heart-related risks associated with Bextra and similar drugs.

Two new studies offer new clues about the role of Bextra in heart disease. They suggest that combining Bextra with aspirin may increase the risk of blood clots that could trigger a heart attack or stroke.

Last month, the FDA added anew warning to Bextra, which states that Bextra should not be used in patients undergoing heart bypass surgery after a clinical trial showed an increase in heart problems in bypass patients using Bextra.

A similar drug, Vioxx (search), was removed from the market in September 2004 because of an increase in heart attacks and stroke in patients taking the drug for at least 18 months. A third, similar drug, Celebrex, was linked to heart attacks last month as well.

Bextra is a member of a class of drugs called Cox-2 inhibitors (search). Like the other Cox-2 inhibitors, Vioxx and Celebrex (search), it was designed to treat arthritis and other painful conditions. Older drugs like ibuprofen (search) and naproxen (search) treat pain and inflammation by blocking two enzymes, Cox-1 and Cox-2. However, blocking the Cox-1 enzyme has been linked with side effects such as stomach ulcers. Bextra and related drugs treat inflammation and pain by blocking only Cox-2, thus decreasing the side effect of stomach ulcers.

Researchers 'Amazed'

In the studies, which appear in the Jan. 17 issue of Circulation: Journal of the American Heart Association, researchers examined some potential mechanisms behind the increase in heart problems associated with Cox-2 inhibitors.

In the first study, researchers studied the effects of Bextra and aspirin on hardening of the arteries (atherosclerosis) in mice prone to the condition. They found that low-dose aspirin slowed the development of atherosclerosis in the mice, but it seemed ineffective once the disease was established.

Adding a Cox-2 inhibitor didn’t enhance the beneficial effects of aspirin. Instead, researchers found the combination of Bextra and aspirin produced potentially dangerous changes in the makeup of the plaque within the arteries.

"We were amazed," says researcher Karine Egan, PhD, of the University of Pennsylvania, in a news release. "Addition of the Cox-2 inhibitor caused changes that, if they occurred in humans, would result in a loss of stability of the plaque, making it more likely to rupture and activate clotting, causing heart attack or stroke."

Researchers say aspirin protects against atherosclerosis by blocking Cox-1. By adding a Cox-2 inhibitor, researchers say the beneficial effects of aspirin may be lost by tipping the balance in favor of the Cox-1 enzyme. This could increase the chance of developing dangerous blood clots that could lead to a heart attack or stroke.

More Heart Problems for Bextra

In a related editorial, researchers presented the combined results of two clinical studies of the drug Bextra and Dynastat (search).

Dynastat is an intravenous drug that is converted to the active ingredient in Bextra within minutes by the body. In the first study, about 400 people undergoing heart bypass surgery received 40 mg of Dynastat followed by 40 mg of Bextra for 14 days. In the second, larger study, the Bextra dose was reduced to 20 mg for 10 days.

Despite the reduction of dose and duration of therapy, the results showed that a cluster of heart problems was again apparent.

In combining the results of the two studies, researchers found people who used these drugs were three times more likely to have heart problems than those who received a placebo.

Researchers caution that these results should not be taken out of context, and both of these studies involved people at high risk of heart problems because they were undergoing heart bypass surgery.

However, they say the findings represent a class effect of the Cox-2 inhibitors and suggest that doctors should be alerted to the potential for heart problems associated with the use of Cox-2 inhibitors, especially among those at moderate to high risk for heart disease.

“The circumstances under which Cox-2 inhibitors can safely be administered for extended periods to patients at low risk of cardiovascular disease remain to be defined,” write Curt Furberg, MD, PhD, of Wake Forest University School of Medicine, and colleagues.

By Jennifer Warner, reviewed by Michael W. Smith, MD

SOURCES: Egan, K. Circulation: Journal of the American Heart Association, Jan. 17, 2005; vol 111. News release, American Heart Association. News release, University of Pennsylvania Medical Center. WebMD Medical News: “Heart Warning Added to Bextra Label.”