Vioxx recall raises prescribing questions

There are many other treatment options for people with arthritis, and physicians are considering them patient by patient.

By Susan J. Landers — Posted Oct. 25, 2004

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Washington -- Physicians are pulling out their risk-versus-benefit calculators once more to determine which patients, if any, should be switched to another COX-2 inhibitor in light of the fate of the popular drug Vioxx (rofecoxib), which was pulled from the market abruptly Sept. 30.

Merck & Co., Vioxx's manufacturer, voluntarily withdrew the drug after data from a prospective, randomized, controlled clinical trial pointed to increased cardiovascular risk for patients who took the drug for at least 18 months. "We are taking this action because we believe it best serves the interests of patients," said Raymond V. Gilmartin, chair, president and chief executive officer of Merck.

But this decision has now led some to cast doubt on the safety of other drugs in the same class of COX-2 inhibitors, including Pfizer's Celebrex (celecoxib) and Bextra (valdecoxib).

So far, these questions have not been given an official nod.

"At this time, we have not made any further decisions regarding review of COX-2s already on the market," according to a Food and Drug Administration statement, although the agency is monitoring these medicines closely.

Physicians, however, need to make decisions now, and they are.

"It would surprise me if this is not a class effect," said Michael Fleming, MD, a family physician in Shreveport, La., and president of the American Academy of Family Physicians. He has decided not to prescribe another similar COX-2 drug for his patients who had been taking Vioxx.

"I hesitate to pull people off one thing and put them on another only to have them hear something about that drug."

In addition, Dr. Fleming's patients are opting for other treatments. Shortly after the recall was announced, all the patients who called, "and that was a lot," were given a choice of taking another COX-2 inhibitor or trying something else. All opted to at least try another treatment, he said.

What to do

Dr. Fleming is recommending that his patients who were on Vioxx try acetaminophen and, perhaps, a heating pad. Other nondrug remedies include diet and exercise.

It is important to evaluate each patient individually, said C. Kent Kwoh, MD, professor of medicine and epidemiology at the University of Pittsburgh School of Medicine. "The question to ask is, 'Why was the patient on Vioxx?' "

For patients with a bleeding ulcer and no cardiovascular risk, another COX-2 inhibitor could be appropriate, Dr. Kwoh said. "It's not clear at this point whether this is a class effect or a drug effect." Problems with increased cardiovascular disease, hypertension and fluid retention seemed more prevalent with Vioxx than with other drugs in the same class, he said.

Pfizer, the manufacturer of Celebrex and Bextra, would agree. "Each COX-2 inhibitor has a distinct chemical structure, and we would not expect them to have the same side-effect profile," said Joe Feczko, MD, Pfizer's president of worldwide development. "The data we've accumulated over time demonstrate that Celebrex does not increase the risk of serious cardiovascular events in patients with arthritis and pain, even at higher-than-recommended doses."

Bextra's cardiovascular safety profile is also well-established in long-term studies, he said.

Nonetheless, Eric L. Matteson, MD, MPH, a consultant in rheumatology and professor of medicine at Mayo Clinic in Rochester, Minn., finds that there is legitimate reason to think that the cardiovascular risks associated with Vioxx could be a class effect.

"The issue has not been well-studied by the companies, and the adverse outcome of interest has always been gastrointestinal bleeding and other major gastrointestinal problems rather than problems with stroke or heart attack," he said.

"And many patients taking COX-2 inhibitors don't really need them because they aren't in a high-risk group for gastrointestinal bleeding," Dr. Matteson said. "So they may be just as well off with another nonsteroidal or other pain drug." Another option is an older NSAID taken with a stomach-protecting medication, he said.

Boyd Buser, DO, associate dean of clinical affairs at the University of New England College of Osteopathic Medicine, is in the situation of having prescribed Vioxx to only a small number of his patients with arthritis, opting instead for osteopathic manipulative treatment, or OMT, a hands-on approach to pain relief that is taught in colleges of osteopathic medicine.

"We always want to give our patients the least possible medicine, and I think that being able to use OMT is helpful," he said. For most medicines, the risk increases the longer they are taken, he said. "For aspirin, if you take it long enough, your stomach is going to bleed. If you take ibuprofen or naproxen at high doses or for too long, you are at risk for liver or kidney problems. None of these medications are without risk."

Stoking the fire

In the midst of this discussion, two editorials in The New England Journal of Medicine arrived on the scene to fuel the debate.

The editorials, or perspectives, had been scheduled to run in the Oct. 21 issue but were released early because of the Vioxx withdrawal. Both heaped blame on the FDA and on Merck for failing to resolve questions of cardiovascular safety much earlier.

"This represents the largest prescription drug withdrawal in history, but had the many warning signs along the way been heeded, such a debacle could have been prevented," Eric J. Topol, MD, a director of the Cleveland Clinic's heart center, wrote in his perspective.

Garret A. FitzGerald, MD, professor of cardiovascular medicine at the University of Pennsylvania, also called on the FDA to go beyond "watchful waiting" and provide guidance on how best to use the drugs. "We must remember that the absence of evidence is not the evidence of absence," he wrote.

Possible cardiovascular risks associated with COX-2 inhibitors were noted after an analysis of all available data on the two drugs in August, 2001, Dr. Topol said, and a clinical trial was requested at that time. "Unfortunately, such a trial was never done."

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Trials and tribulations

  • Vioxx (rofecoxib), manufactured by Merck & Co., was approved by the Food and Drug Administration in May 1999 for the treatment of pain and inflammation caused by arthritis.
  • Merck's VIGOR trial (Vioxx GI Outcomes Research) looked at the effects of Vioxx on stomach ulcers and bleeding. Submitted to the FDA in June 2000, the study showed that patients taking Vioxx had fewer stomach ulcers than those taking naproxen, but had more heart attacks.
  • The results of the VIGOR study led to new safety labeling requirements in April, 2002, advising of the increased risk of heart attacks.
  • Merck began a new trial in 2000, the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial, to see if a 25 mg dose of Vioxx was more effective at preventing the recurrence of colon polyps than was a placebo. This trial was stopped early because it showed there was an increased risk for serious cardiovascular events, such as heart attacks and strokes, when the drug was taken for 18 months.
  • Vioxx was voluntarily withdrawn from the market by Merck Sept. 30.

Source: Food and Drug Administration

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External links

Food and Drug Administration public health advisory on Vioxx (link)

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