More heart risks found for COX-2 inhibitors

Washington -- More trouble was spotted in the family of medicines that includes the recently withdrawn Vioxx.

Pfizer Inc., which markets the COX-2 inhibitors Celebrex (celecoxib) and Bextra (valdecoxib), released new information on Dec. 17, 2004, indicating that Celebrex, like Merck & Co.'s Vioxx (rofecoxib), appears to pose an increased cardiovascular risk.

Meanwhile, new information on Bextra has placed it under a similar cloud of suspicion. Correspondence released early by the New England Journal of Medicine strongly cautioned doctors against prescribing Bextra "until there are convincing data supporting its cardiovascular safety."

The correspondence was to run in the journal's Dec. 23, 2004, issue.

Cautions about Celebrex surfaced when the National Cancer Institute stopped using the drug for all participants in a large colorectal cancer prevention trial after an independent analysis found there was an increased risk of major fatal and nonfatal cardiovascular events for participants taking the drug compared with those taking a placebo.

Patients in the trial who were taking 400 mg of Celebrex twice daily had 3.4 times greater risk of cardiovascular events than did those taking a placebo. For patients taking 200 mg of Celebrex twice a day, the risk was 2.5 times greater. Average duration of treatment in the trial was 33 months.

COX-2 drugs are being used in more than 40 National Institutes of Health studies for the prevention and treatment of cancer, rheumatoid and osteoarthritis, dementia and other diseases. The agency said it is currently re-evaluating their use.

Physicians were urged by Pfizer to factor the new information -- as well as a patient's risk of gastrointestinal bleeding -- into prescribing decisions. Pfizer also stopped advertising the drug.

While Celebrex remained on the market as of late December 2004, the Food and Drug Administration advised physicians to consider other therapies for patients taking Celebrex and, if they determine that its continued use is appropriate for certain patients, it should be prescribed at its lowest effective dose.

Celebrex and Bextra are the only two COX-2 inhibitors currently licensed in the United States.

A third COX-2 inhibitor, Vioxx, was pulled from the market in September 2004, because it increased cardiovascular risk among patients who took the drug for at least 18 months.

Meanwhile, the FDA on Dec. 9, 2004, strengthened requirements for Bextra's label to reflect the cardiovascular risks it carries as well as concern about severe skin reactions.

Bextra's label will carry a "boxed" warning alerting physicians to the risk it poses of life-threatening skin reactions and a bolded warning to highlight new data about cardiovascular risks.

The new cardiovascular warning for Bextra was issued when results from a recently completed study by Pfizer, the drug's manufacturer, revealed that heart attacks, strokes, deep vein thrombosis and pulmonary embolisms occurred more often among patients taking the drug.

The heightened warning for skin reactions was necessary, according to the FDA, because, despite earlier warnings, the agency had received reports of 87 cases of severe skin reactions associated with Bextra, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Twenty of the 87 patients had a known allergy to sulfa. Thirty-six of the 87 were hospitalized, and four died.

The skin reactions are most likely to occur in the first two weeks of treatment. In addition, although other COX-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs also carry a risk of serious skin reactions, the rate among Bextra users appeared higher, according to the FDA.

The FDA plans to hold a public advisory committee meeting in February to sort through the emerging safety concerns for all COX-2 drugs.