Bextra Data Suggests All Cox-2 Drugs Pose Heart Risks

Painkiller linked to cardiovascular dangers in latest research

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HealthDay Reporter

TUESDAY, Jan. 18, 2005 (HealthDayNews) -- New data linking a third cox-2 inhibitor painkiller -- Pfizer Inc.'s Bextra -- to increased risks for heart attack or stroke suggest that long-term use of all drugs in this class may pose cardiovascular dangers.

"I think it points more and more to a class effect -- that all these drugs have similar problems," said Dr. Curt D. Furberg, a researcher at Wake Forest University, and co-author of an editorial on a study published in the current online issue of Circulation.

Bextra (valdecoxib) is one of three federally approved cox-2 inhibitor drugs used over the past decade by millions worldwide to relieve the chronic pain of arthritis and other ailments. The other two drugs in this class are Merck & Co.'s Vioxx, which was pulled from the U.S. market in late September after data linked its long-term use to heightened cardiovascular risk, and Pfizer's Celebrex, which remains on pharmacy shelves despite data released in December linking its use to an increase in cardiovascular events.

In the editorial, the researchers call for a strongly worded "black box" warning label on all cox-2 inhibitors, warning of potential cardiovascular risks. Next month, the U.S. Food and Drug Administration will hold a rare public hearing on the benefits and risks of the entire class of drugs.

In the Bextra study, led by Dr. Garret FitzGerald of the University of Pennsylvania, researchers pooled data from two separate Pfizer-funded studies involving hundreds of heart patients having coronary artery bypass operations. The placebo-controlled studies compared the effects of Bextra to that of an unapproved, experimental form of the drug, called Dynastat, over a period of up to two weeks.

"The results of both of these studies on their own weren't statistically significant," Furberg said. "But then we combined them in what we call a meta-analysis. At that point, the numbers became highly significant. In fact, there's a threefold increase [of heart attack and stroke] in patients taking Bextra" vs. those on placebo, Furberg said.

The researchers stressed that bypass patients typically have abnormally high rates of clotting and plaque rupture, so the threefold risk seen in this population might not be replicated in healthier groups. However, "the concern is that [bypass patients] function here as the 'canary in the coal mine,'" FitzGerald said, "indicating a risk -- albeit a less-pronounced one -- in the broader population."

The data bolsters the notion that the cardiovascular risks seen in the Vioxx, Celebrex and Bextra trials stems from a common mechanism of action. FitzGerald -- who has been studying the cardiovascular effects of these drugs for more than six years -- said all of these drugs decrease blood levels of a cardioprotective fat called prostacyclin, which is produced by the unfettered activity of the cox-2 enzyme.

According to FitzGerald, when drugs inhibit cox-2 activity, prostacyclin levels fall, leaving arteries more vulnerable to clotting, high blood pressure, heart attack and stroke. "So far, everything we have seen is consistent with this mechanism," he said.

A Pfizer spokeswoman refused to comment on the two studies, saying the company hadn't seen them, according to a Washington Post report.

Cox-2 inhibitors are most often used by arthritis sufferers, but Furberg noted that "half of patients with arthritis also have underlying heart disease. That group has never been studied [in cox-2 trials], so I'm nervous about any patients with underlying heart disease, or certainly any previous history of stroke or heart attack, being put on these drugs."

A second study in the same issue of Circulation suggests a possible hazard from combined daily use of aspirin and a cox-2 inhibitor. Karine Egan, a researcher at FitzGerald's lab, led a study in mice genetically engineered to mimic the atherosclerosis (hardening of the arteries) seen in humans with heart disease.

Her study found that the addition of cox-2 drugs to mice already receiving aspirin led to potentially hazardous changes in the fatty plaque that builds up on artery walls.

"We were amazed," Egan said in a statement. "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."

According to Furberg, all of these findings highlight the need for more caution on the part of doctors and patients when considering the use of cox-2 inhibitor medications.

"[Drug] companies are saying, 'our drug is safe until proven harmful,' but I'm saying that they are not safe until we know that they are safe," Furberg said. He believes publicity generated by the Vioxx and Celebrex findings are keeping more and more patients out of potential danger.

"Their use has already been cut in half," he said. "That's a good step, but I think we need to cut that number down even more."

For his part, FitzGerald believes "patients at high risk of cardiovascular disease should avoid members of this [drug] class. However, for patients at low risk of cardiovascular disease, drugs in this class still have value. Patients should consult with their doctors to see if this is the best choice for them."

More information

To learn more about cox-2 inhibitors, go to the Arthritis Foundation.

SOURCES: Curt D. Furberg, M.D., Ph.D., professor, Wake Forest University Baptist Medical Center, Winston-Salem, N.C.; Garret FitzGerald, M.D., director, Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia; Jan. 17, 2005, statement, University of Pennsylvania; Jan. 17, 2005, Circulation online

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