Ever since the anti-inflammatory drugs, Celebrex and Vioxx, came on the market two and a half years ago, questions have surrounded them. Do these costly drugs offer a safer alternative to other arthritis drugs? Do they have a lower rate of the gastrointestinal side effects associated with older painkillers, such as aspirin, ibuprofen, and acetaminophen? If so, is this benefit canceled by heart-related risks linked to Celebrex and Vioxx?
A new analysis of all clinical trials that had attempted to answer these questions was conducted by Debabrata Mukherjee, MD, and colleagues at the Cleveland Clinic Foundation. But before their analysis appeared in the Journal of the American Medical Association last month, a controversy erupted over the validity of the results from the largest and most important clinical trial involving Celebrex. Its manufacturer, Pharmacia, withheld long- term data, which made Celebrex appear safer than it really is.
Celebrex and Vioxx belong to a relatively new class of drugs called selective COX-2 inhibitors, which control inflammation by blocking enzymes called prostaglandins. Celebrex was the first COX-2 inhibitor to appear on the market (in 1999); Vioxx followed soon after. Both are prescribed for osteoarthritis, rheumatoid arthritis, and other chronically painful conditions.
The question of whether these COX-2 inhibitors can reduce the risk of gastric hemorrhage or ulcers is critical to justifying their high cost. These adverse effects may occur, sometimes without warning, with all drugs in a class called non-steroidal, anti-inflammatory drugs (NSAIDs), which includes aspirin, ibuprofen, acetaminophen, diclofenac, and naproxen. NSAID-induced gastrointestinal bleeding causes about 15,000 deaths and 70,000 more hospitalizations yearly. Most NSAIDs can be purchased in their low cost generic versions at a fraction of the cost of Celebrex and Vioxx. If the makers of Celebrex and Vioxx can prove their drugs reduce the likelihood of gastrointestinal damage, then insurance companies, HMOs, and Medicare would find the $85 monthly cost acceptable.
Two large clinical trials dominated the new analysis conducted by Dr. Mukherjee and colleagues. The one that produced suspect results was sponsored by Pharmacia, and they appeared to favor its drug. Celebrex reduced the rate of gastrointestinal complications without increasing the risk of "cardiovascular events" (e.g., heart attacks, stroke). This trial had randomly assigned 8,059 people with osteoarthritis to take daily doses of Celebrex, ibuprofen, or diclofenac. (All three drugs are NSAIDs.) Dr. Mukherjee and colleagues pointed out that reduced incidence of heart-related side effects could be due to the fact that the study participants were allowed to continue the low-aspirin regimen followed by many older people as a heart attack preventive.
Pharmacia released only the six-month results of its study, though the trial had lasted 13 months. When the longer-term results came to the attention of the Food and Drug Administration's advisory panel, they cast doubt on Celebrex's purported reduced incidence of gastrointestinal complications because they began to show up in the second half of the study. Ultimately, the participants taking Celebrex had the same rate of gastrointestinal side effects as those taking the two older NSAIDs. Significantly, this trial was not designed to answer the question of whether Celebrex is a more effective painkiller than the older NSAIDs..
Vioxx had its own large trial that had randomly assigned 8,076 people with rheumatoid arthritis to take either Vioxx or another NSAID, Naproxen. Unlike the Celebrex trial, the participants were not permitted to take aspirin. At the end of this trial, which lasted nine months, serious cardiovascular events had occurred in 45 patients who were taking Vioxx and in 20 of those who had been taking Naproxen. It is not known whether this difference is due to the clot-busting effect of Naproxen or a clot-causing effect of Vioxx.
The review of these large trials and other smaller studies led Dr. Mukherjee and colleagues to conclude that COX-2 inhibitors may carry a small risk of heart attack, but more long-term research is needed. Though the ads for Celebrex and Vioxx emphasize the words excellence and efficacy, neither has been proven a more effective painkiller than the older NSAIDs. People with osteoarthritis should consider the over-the-counter supplement, glucosamine, which has been proven to be an effective pain reliever in clinical trials.
Maryann Napoli is the associate director of the Center for Medical Consumers in New York City.
COPYRIGHT 2001 Center for Medical Consumers, Inc.
COPYRIGHT 2001 Gale Group