Evidence is accumulating that the heart attack and stroke risks linked to the pain reliever Vioxx (rofecoxib) are not confined to this drug but are present for all COX-2 inhibitors, such as Celebrex (celecoxib) and Bextra (valdecoxib), new research suggests.

Last September, Merck pulled Vioxx from the market after reports surfaced tying the drug to an increased risk of cardiovascular events. Since then, however, the question has remained whether this elevated risk was specific to Vioxx or whether it applied to other members of the COX-2 inhibitor class of drugs as well.

The current findings support this possibility, showing an elevated cardiovascular risk for the oldest COX-2 inhibitor, Celebrex, as well as for two newer agents, Bextra and Dynastat (parecoxib).

The results stem from three studies that will appear in the March 17th edition of The New England Journal of Medicine, but were released early due to possible public health implications. Their release coincides with a highly anticipated US Food and Drug Administration meeting taking place later this week.

Using data from the Adenoma Prevention with Celecoxib study, Dr. Scott D. Solomon, from Brigham and Women’s Hospital in Boston, and colleagues assessed the occurrence of cardiovascular events in 2035 patients treated with Celebrex, at a dose of 200 milligrams or 400 milligrams twice daily, or with inactive “placebo”.

The primary outcome the researchers looked for was a combination of death from heart-related causes, heart attack, stroke, or heart failure. The patients were followed for about 3 years.

The rates of the primary outcome in low- and high-dose Celebrex users were 2.3 and 3.4 percent, respectively, both significantly higher than the rate among placebo users - 1.0 percent.

In the second study, Dr. Nancy A. Nussmeier, from St. Luke’s Episcopal Hospital in Houston, and colleagues assessed the cardiovascular effects of Dynastat and Bextra when used for pain control after coronary artery bypass surgery. The study involved 1671 patients who were treated with intravenous Dynastat then oral valdecoxib, intravenous placebo then oral Bextra, or just placebo for the first 10 days after surgery.

The rate of harmful effects in both COX-2 inhibitor groups was 7.4 percent, while the rate in the placebo only group was 4.0 percent. Of particular concern, patients treated with Dynastat and Bextra were nearly four times more likely to experience a heart attack or stroke than those given placebo.

Results from the third study, known as the Adenomatous Polyp Prevention on Vioxx Trial, provide further evidence that Vioxx use is associated with an elevated risk of heart attack and stroke.

In the study of 2586 patients, Dr. Robert S. Bresalier, from M. D. Anderson Cancer Center in Houston, and colleagues found that Vioxx users (25 milligrams daily) were nearly twice as likely as placebo users to experience a heart attack or stroke. This elevated risk was first apparent after 18 months of use.

“It sure looks like (the elevated cardiovascular risk) is a class effect,” Dr. Bruce M. Psaty, co-author of an accompanying editorial, told Reuters Health. “This is the best evidence we have so far of the cardiovascular risks associated with the COX-2 inhibitors.”

As to why the risks seen with COX-2 inhibitors were not identified and reported earlier, Psaty, from the University of Washington in Seattle, cites problems with initial trial designs and with the FDA.

“As early as 1996, it was recognized that COX-2 inhibitors had actions that could increase the risk” of heart attacks and stroke, Psaty noted. However, the initial studies looking at these drugs were designed to assess pain relief, not to look for these problems, he added.

Another issue is the relative “powerlessness” of the FDA once a drug is on the market, Psaty said. “It’s very difficult for the FDA to protect the health of the public. They need to be given more authority so that they can force drugmakers to make necessary changes in a timely fashion. In the case of Vioxx, Merck and the FDA were in negotiations for 2 years to revise the label.”

An FDA panel will be discussing the cardiovascular risks of COX-2 inhibitors later this week. Today, a veteran scientist with the FDA who was scheduled to present unpublished data at the meeting said he would not be presenting these data, citing intimidation by senior officials.

SOURCE: New England Journal of Medicine, March 17 edition, released February 15, 2005.