Vioxx's Heart Risk Lingered Long After Use Ended

Oct. 15 --

MONDAY, Oct. 13 (HealthDay News) -- When the pain killer Vioxx was pulled from the market in 2004 over concerns that it increased the risk of heart attack, stroke and death, many assumed that stopping the drug would end the risk.

But a new study finds that "the risk was increased close to twofold, and the risk persisted for approximately a year," said co-author Dr. Robert Bresalier, a professor of medicine at the M.D. Anderson Cancer Center in Houston.

"The good news is that, after a year, the risk seemed to go back down toward normal," he said.

However, the study's researchers and other experts also believe that long-term use of most non-aspirin painkilling drugs in this class -- called non-steroidal anti-inflammatory drugs (NSAIDs) -- also boost users' risks of heart attack, stroke and death to some degree.

NSAIDs include cox-2 inhibitor drugs such as the now-banned Vioxx and Bextra, as well as the remaining cox-2 on the market, Celebrex. Those drugs target the cyclooxygenase 2 (cox-2) enzyme involved in inflammation.

NSAIDs also include less targeted anti-inflammatory medications such as ibuprofen (Advil, Motrin) and naproxen (Aleve).

The report was published online in the Oct. 14 issue of The Lancet.

For the study, Bresalier's group followed people who had participated in the international APPROVe trial, which compared Vioxx to placebo over 3 years in an attempt to see whether the drug could cut the recurrence of cancerous colon polyps. The trial was stopped early in 2004 because of the increased risk for heart attacks and stroke.

The researchers in the new study were able to contact 84 percent of the almost 2,600 people who had participated in the trial.

They found that a year after discontinuing Vioxx, ex-users still had a 79 percent increased risk of heart attack, stroke or death compared with those who had received placebo.

This finding was consistent with the increased risk observed during the trial, where the odds for cardiovascular trouble was more than double for those taking Vioxx. For individual patients, the risk of heart attack or stroke was doubled during the year after stopping the drug. The increased risk of dying was 31 percent compared with those who had taken placebo, the researchers noted.

Bresalier's group did find that Vioxx was able to reduce the recurrence of colon polyps, but this benefit has to be weighed against the increase in cardiovascular risk, they said.

Bresalier suspects that long-term use of all non-aspirin NSAIDs can raise the odds of cardiovascular trouble to some extent.

"Similar data has been evident for some of the other cox-2 inhibitors," he noted. "In fact, it seems to be a class effect for most if not all NSAIDs. There is a dose-dependent risk with Celebrex as well, whose magnitude was not that much different from Vioxx," he said.

Bresalier believes that certain patients should not take high doses of these drugs over a long period. "If you have a history of cardiovascular disease, speak to your doctor to understand the relative risks and benefits. If you're somebody who really needs to take these drugs because of chronic pain or severe arthritis, be aware of the issues. But you shouldn't be afraid to take these drugs if you need them," he said.

For people who take these drugs only intermittently -- for short-term pain relief, for example -- the risk is very small, Bresalier said. "It doesn't mean if you take one or two pills you're going to get a heart attack. For the vast majority of people taking these drugs, these are very good and safe drugs," he said.

Dr. Eric J. Topol, director of the Scripps Translational Science Institute and Chief Academic Officer of Scripps Health in La Jolla, Calif., was not surprised that the risk for heart attack and stroke continued even after Vioxx was stopped.

"What this does is help further demonstrate not only the risk of Vioxx, but the temporal duration," Topol said. "Now, we have compelling data that the risk extends a year after stopping the drug," he said.

Topol, who was one of the first to sound the alarm about Vioxx, is not sure that this is a class effect of all cox-2 inhibitors, however.

"There was always a signal that it [the risk] was worse for Vioxx that other cox-2 inhibitors. Whether or not other drugs like Celebrex shared that isn't known. That has not been demonstrated in studies of Celebrex. But you have to be suspicious, particularly since high doses of Celebrex have heart attack and stroke risk. But there's never been a study to show that it's a long-lasting liability," he said.

In response to the Lancet study, Vioxx manufacturer Merck issued the following statement: "Merck believes that this post-hoc analysis using limited data from a prematurelyterminated study needs to be interpreted very cautiously and in the context of the rest of thedata from the extensive clinical development program for Vioxx."

More information

For more about pain relievers, visit the U.S. National Library of Medicine.

SOURCES: Robert Bresalier, M.D., professor, medicine, M.D. Anderson Cancer Center, University of Texas, Houston; Eric J. Topol, M.D., director, Scripps Translational Science Institute, Chief Academic Officer, Scripps Health, La Jolla, Calif; Oct. 13, 2008, online edition, The Lancet; Oct. 13, 2008, statement, Merck & Co., Whitehouse Station, N.J.