By Daniel DeNoon
October 7, 2004
Now that we know Vioxx wasn’t safe, can we trust its sister drugs, Bextra and Celebrex?
No, argues a New England Journal of Medicine (NEJM) editorial.
Vioxx, like Bextra and Celebrex (and two more drugs not approved in the U.S.) are members of a family called Cox-2 selective inhibitors. All fight pain and inflammation by blocking a molecule called Cox-2.
Blocking Cox-2 also predisposes people to heart attacks, according to a five-year-old theory by Garret FitzGerald, MD, director of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania in Philadelphia.
“Now, with Vioxx, we see the manifestation of a risk entirely consistent with precisely the mechanism we proposed,” FitzGerald tells WebMD. “That puts the burden of proving safety on the manufacturers of these [other] drugs.”
Vioxx: 160,000 Heart Attacks and Strokes
This call for safety studies has a familiar ring to it. In August 2001, Eric J. Topol, MD, chairman of the Cleveland Clinic cardiology department, was troubled by heart-safety data in Vioxx clinical trials. He called on the FDA to demand specially designed heart-safety studies. That never happened. Instead, three years later, a study looking at whether Vioxx could prevent colon polyps found the drug posed an unacceptably high heart risk.
Ten million people have taken Vioxx, partly due to an aggressive direct-to-consumer advertising campaign. Topol calculates that 160,000 of these patients had a Vioxx-caused heart attack or stroke.
“I believe that there should be a full Congressional review of this case,” Topol writes in an NEJM editorial. “The senior executives at Merck and the leadership at the FDA share responsibility for not having taken appropriate action and not recognizing that they are accountable for the public health.”
In a written statement, Merck says that it worked hard to assess Vioxx safety.
“Dr. Topol neglects to mention the fact that Merck undertook three separate prospective, randomized clinical studies designed, collectively, to assess the cardiovascular safety of Vioxx versus placebo,” the statement says. “It was precisely one of those studies, the APPROVe trial, in which there was an increased relative risk for confirmed cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking Vioxx compared to those taking placebo.” The editors of The Lancet — notes that heart safety was not the focus of these trials.
Merck notes that its trials included people both with and without risk factors for heart disease and stroke. But in a Lancet editorial published last August, Topol says clinical trials of Cox-2 inhibitors regularly leave out anyone with known, pre-existing heart disease.
Vioxx Prompts Desire for Proof
FitzGerald admits that the warning signs of heart risk were much stronger for Vioxx than for other Cox-2 drugs. But given the known risk of Vioxx, he says the time has passed for studies of why these drugs might or might not be risky. The time has come for studies proving the drugs are safe.
“We know the [Vioxx] risk exists,” FitzGerald says. “This shifts the burden of proving absence of risk to those who say it is a Cox-2-independent effect of Vioxx. They now have to show why it doesn’t apply to their drugs.”
Pfizer, which makes both Bextra and Celebrex, did not respond to telephone messages left by WebMD. Given the known dangers of Vioxx, the FDA says it’s keeping a wary eye on Celebrex, Bextra, and newer Cox-2 drugs.
“We will be evaluating with the other sponsors of approved drugs what long-term trials they have under way to assess what additional information we may be receiving on these drugs and then make decisions about what other data to request,” an FDA spokesperson tells WebMD. “The issues raised by Vioxx will make us more concerned about the need for long-term data. We have not made any decisions on these issues as of yet. However, the agency will continue to monitor these products, and since becoming aware of the results from the Vioxx study, we are much more sensitized to the possibility of seeing this adverse event occurring in Cox-2s and will monitor very closely for any signal [of heart risk].”
SOURCES: FitzGerald, G.A. The New England Journal of Medicine, Oct. 21, 2004; vol 351: pp 1709-1711. Topol, E.J. The New England Journal of Medicine, Oct. 21, 2004; vol 351: pp 1707-1709. The Lancet, Oct. 9, 2004; vol 364: pp 1287-1288. Topol, E.J. The Lancet, Aug. 21, 2004; vol 364: pp 639-640. Garret FitzGerald, MD, director, institute for translational medicine and therapeutics, University of Pennsylvania, Philadelphia. News release, Merck. News release, Pfizer. FDA.