Vioxx Withdrawn, Patients Urged to Contact Physicians

The widely used drug Vioxx was withdrawn from the market on September 30 by the drug's manufacturer, Merck & Co., Inc., after a growing body of data led the company to conclude that the arthritis and pain medication may nearly double patients' risk of heart attack and stroke.

Approved for use by the Food and Drug Administration (FDA) in 1999, Vioxx is one of the coxibs, a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs) known as "COX-2 inhibitors." Experts locally and nationwide have cautioned people who have been taking Vioxx to consult with their physicians before "self-medicating" with other arthritis drugs or painkillers.

"Vioxx was voluntarily recalled by the company," said Mike Gillard, PharmD, BCPS, Assistant Director of Pharmacy - Drug Policy Management at Froedtert Hospital. "Merck came forward based on preliminary results and one of their arthritis trials. This has been smoldering in the background for a while, particularly with Vioxx versus Celebrex and Bextra (the two other coxibs still on the market)."

Research published as early as 2000 began to hint at an association between Vioxx and an increase in cardiovascular events in patients. The FDA data and safety monitoring board this year ended a large-scale trial of Vioxx early because it more clearly revealed the high rate of heart attack and stroke. Merck made the decision to withdraw the drug after the latest trial, known as "APPROVe," was halted.

"They of course didn't expect that in the first study, so the trial wasn't statistically powered to evaluate whether this was a drug phenomenon or just chance, said Gillard. "It was sort of pushed aside. But then, having this other bigger trial scrutinized more closely by the FDA, it was probably more of a public relations issue to make sure that they weren't marketing a drug that was potentially harming the public in large numbers."

Market Share, Side Effects
"We have pulled Vioxx off the shelves and pulled samples from Froedtert & Medical College clinics where we've been able to find samples," said Gillard. "Currently, our pharmacy department recommendation is to not straightaway convert people to another agent in this class. This poses a problem for some people, because they've maybe been through other agents and this class of drugs has been best in terms of the side effect profile."

The FDA is currently considering how to proceed in evaluating Celebrex, Bextra, and other coxibs not yet approved for use. Coxibs sales in general are at $10 billion worldwide annually, a lion's share of the NSAID prescription drug market. Vioxx alone generated $2.5 billion a year for Merck and was used by nearly two million people. Gillard noted that one of the reasons coxibs are heavily prescribed is that they have shown moderate benefit in reducing side effects, such as gastrointestinal bleeding and ulcers, as compared to other painkilling drugs.

"Stomach problems, typically, or fluid retention problems have a slightly lower incidence with these particular COX-2 inhibitors than with other NSAIDs," said Gillard. "It puts some people in a bind, because there are not many options out there now. You have to be cautious of the two that are left (sulfa drugs Celebrex and Bextra). If you get an allergy to sulfa drugs, those types of allergies can be very severe."

"We were lucky to have only one patient who was here in the hospital post-operatively taking Vioxx. He couldn't take Bextra or Celebrex because of the sulfa allergy. It does impact the ability to manage somebody's pain. Potentially, it may mean going back to a 'traditional' NSAID, ibuprofen and that type of drug, or narcotic analgesics like Tylenol 3, Percocet or Vicodin."

Theories on how Vioxx works in the body to raise the risk of heart attack are still being developed, Gillard said. "We believe it has a lot to do with the fluid edema and blood pressure changes that can occur. Some finger pointing has been that, if you would look closely at these patients who have these events, they get hypertension, elevated blood pressure. Obviously, there are some biochemical physiologic things that are going on to cause those elevations in blood pressure and fluid retention."

More Study and Scrutiny
The withdrawal of Vioxx may change how the FDA considers this entire class of these heavily marketed drugs, Gillard said. "Two authors in the New England Journal of Medicine (October 21, 2004) are basically condemning the FDA for allowing this to occur, and also calling into question the entire class of drugs. The early warning signs with this class of drugs came back in 2000 because of what the data showed. That was a signal that this drug was increasing the baseline rate of cardiovascular events, granted that it was a non-controlled retrospective study carrying with it flaws compared to true clinical study data.

"But still, it's interesting enough and raised the concern, and then you have this APPROVe trial further validating what was seen in the earlier trial. We don't have a large long-term trial published yet for Celebrex that might show that this rate is slightly higher for an increased risk of cardiovascular events, and Bextra has simply not been studied long term, either.

"Interestingly, there are two more drugs of this class, one of which is another Merck drug, waiting to be approved or soon to be evaluated for approval. One of the best things that the FDA could do would be to hold off on approving any new drugs in this class and require anybody who wants to bring one of these new drugs to market to do additional longer term studies to evaluate the risk that was called into question by Vioxx."

As for Vioxx, it has left the market and will likely never return. "Nobody can use it, and nobody should be using it," said Gillard. "In the outpatient pharmacy, we've contacted the patients in our system that we knew were taking Vioxx chronically. The first thing patients who had been taking Vioxx should do, certainly, is to get in touch with their physician to discuss alternatives. That's the best advice, as a pharmacist, I would give anybody."

Dan Ullrich
HealthLink Contributing Writer

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.