Casting Light On New Arthritis Drugs
Vioxx was withdrawn from the market for raising the risk of heart attack and stroke. 'Second generation' versions could be delayed by further scrutinyNov 1, 2004 | Los Angeles Times
The withdrawal of the arthritis drug Vioxx from the market continues to have ripple effects.
Two similar medications will soon become the focus of studies on whether they like Vioxx raise the risk of heart attack and stroke with long-term use. And the future of a highly anticipated "second generation" version of these drugs, known as Cox-2 inhibitors, now appears in doubt.
Researchers are making a strong case for this experimental drug, called Arcoxia, saying that it appears to work as well as other Cox-2 inhibitors. In defending the drug, they cite a study presented last month at the American College of Rheumatology's annual meeting.
In that study, Arcoxia didn't appear to raise the risk of cardiovascular events, although the research followed participants only for an average of nine months.
The study, designed to see how the drug affected the gastrointestinal tract, included 7,111 patients with osteoarthritis who took either Arcoxia or an older medication, diclofenac, which is a traditional nonsteroidal anti-inflammatory drug.
Traditional NSAIDs, such as ibuprofen and acetaminophen, increase the risk of ulcers and gastrointestinal bleeding with long-term use. Cox-2 drugs, which are known as selective NSAIDs, were designed to limit stomach side effects. Arcoxia was developed with the goal of providing even better pain control while keeping stomach side effects at a minimum.
In the new study, fewer people taking Arcoxia dropped out of the trial due to stomach problems compared with people taking diclofenac. Arcoxia may also be better at relieving pain than the first generation of Cox-2 drugs, said Dr. Herbert Baraf, the lead investigator of the trial and director of the Center for Rheumatology and Bone Research in Wheaton, Md.
"I don't see any difference in gastrointestinal issues between this drug and any of the Cox-2 drugs, but there does appear to be an efficacy difference, in particular with patients with ankylosing spondylitis and rheumatoid arthritis," he said.
Manufacturer Merck & Co. is seeking approval of Arcoxia for treating osteoarthritis, rheumatoid arthritis, chronic low back pain, acute pain, menstrual pain, acute gouty arthritis and ankylosing spondylitis.
But the effect of Cox-2s on cardiovascular disease has taken the spotlight away from the drugs' ability to minimize pain and reduce the risk of stomach problems. And that means Arcoxia's safety is far from settled. Besides following patients for only about nine months, the study was not designed to look for heart attacks and strokes.
"The difference in heart attacks and strokes in Vioxx and placebo did not become apparent until 18 months," said Dr. Mark Fendrick, a professor of internal medicine, health management and policy at the University of Michigan and co-editor in chief of the American Journal of Managed Care. The Food and Drug Administration probably will want to examine the side effects of Arcoxia when used 18 months or longer, he said.
Merck has additional long-term data on Arcoxia that show no increased cardiovascular risk, said Dr. Sean Curtis, senior director of clinical research at Merck. Moreover, the company is conducting a three-to-four-year study of 23,500 patients to look specifically at cardiovascular safety. That study is expected to be completed in early 2006.
Curtis said Merck would eventually collect cardiovascular data on about 35,000 patients in randomized trials taking either Arcoxia or another drug. He added that some people would have been on Arcoxia for more than three years.
No one can assume that, because Vioxx caused more cardiovascular problems, Arcoxia will too, said Curtis. "It's important to remember that Vioxx and Arcoxia are distinct compounds."
But without distinct studies no one knows whether the two Cox-2 medications that remain on the market, as well as Arcoxia, might raise the risk of heart attacks and strokes, Fendrick said. Researchers don't know what it is about Vioxx that elevated the risk of cardiovascular problems or why the risk only became apparent after 18 months of use. "We really don't have a clear mechanism," he said.
Many experts suggest that more research is needed before a second generation of Cox-2 drugs emerges. Merck is awaiting an FDA decision on its application to market Arcoxia.
Another second-generation Cox-2 drug, Prexige, is also under investigation. A large study on Prexige, published in August, showed the drug did not appear to increase heart problems. But some doctors contend that study participants were too healthy overall for heart problems to appear. Prexige is made by Novartis.
After the Vioxx withdrawal, FDA officials said they would require substantial long-term data on any Cox-2 medication under review.
Other Cox-2 inhibitors
The maker of two remaining Cox-2 inhibitors, Celebrex and Bextra, has announced that it will conduct further studies to assess their effects on people with cardiovascular disease.
Although researchers don't understand why Vioxx, which is made by Merck, raised the risk of heart attacks and strokes in a recent study or whether the effect applies to all Cox-2 drugs, Pfizer officials said they would work with Food and Drug Administration officials to devise additional safety studies on Celebrex and Bextra.
More than 4,000 patients who have osteoarthritis and a history of heart attack will be enrolled in a study of Celebrex beginning early next year. Participants will be randomly assigned to take Celebrex or a placebo for at least two years.
Pfizer also announced that two recent studies showed its Cox-2 drug Bextra increased cardiovascular events in people who had undergone a coronary artery bypass graft. The company said it would conduct further studies to examine the long-term cardiovascular profile of Bextra.