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May 12, 2006 ? Do strokestroke and heart attackheart attack risks linked to the drug Vioxx continue after people stop taking it?
Yes, some leading cardiologists say. No, says Merck, which made Vioxx until pulling the painkiller off the market in September 2004.
It's not a mere moot point. At stake is the continued safety of the many people who took the heavily promoted drug before its risks became known.
The battle is over new data from the APPROVe study. The Merck-sponsored study led to Vioxx's demise. It found that patients taking Vioxx during the first three years of the study had a 92% higher risk of stroke and heart attack than those taking an inactive placebo pill.
New "preliminary" data released yesterday by Merck show that in the year after stopping Vioxx, the 1,721 patients still had a 74% higher stroke/heart attack risk. During that year, 28 patients who had taken Vioxx -- and 16 patients who had taken placebo pills -- had a stroke or heart attack. Most of these events were strokes.
This difference isn't statistically significant, meaning it could be a chance finding. Merck says this means there isn't any risk to people who stop taking Vioxx -- at least, no scientifically proven risk.
Not so, says cardiologist Steve Nissen, MD, interim chairman of the department of cardiovascular medicine at The Cleveland Clinic.
"What this means is the relative risk of an event with Vioxx, even after the drug was stopped, was very similar to the risk while taking the drug," Nissen tells WebMD. "It has profound implications for patients. It means that patients who previously took Vioxx must be followed closely and must be made aware of their increased risk."
Debate Over Meaning of Data
Michael Farkouh, MD, an expert on the heart safety of the class of drugs to which Vioxx belongs, is director of cardiovascular clinical trials at Mount Sinai Medical Center. He largely agrees with Nissen.
"It is concerning there is an ongoing risk from Vioxx," Farkouh tells WebMD. "I would say the numbers are small, but they suggest an ongoing risk from Vioxx in those who stopped taking it. There appears to be this same increase in risk as seen while taking the drug. While the difference is not statistically significant, it is concerning."
Merck declined WebMD's request for an interview but provided the transcript of a telephone conference held Thursday for the financial press. During that news conference, Merck general counsel Ken Frazier said "no significant risk" means "no risk" in both scientific and legal terms.
"The data do not provide a valid basis or a claim that an event that occurred after a patient stopped using the medicine was linked to the drug," Frazier said. "In the off-drug follow-up period for patients in this study, there was not a statistically significant difference in the risk of confirmed [strokestroke or heart attackheart attack] events in the Vioxx group compared to the placebo group. So, from our perspective, we have to base our responses and our defenses on the data as it was presented, and these data do not establish statistically significant risk."
That statement from Merck's lawyer matches one from Merck's chief scientist, Peter S. Kim, PhD, president of Merck Research Laboratories.
"The limited data in the APPROVe study on stroke have to be interpreted in the context of the extensive data we have previously published, which consistently showed no increased risk of strokes in patients taking Vioxx," Kim says in a news release.
"Merck can't claim there isn't anything here," Farkouh says. "To claim there is no risk is not doing patients any service. ... It does suggest there is still ongoing risk after stopping Vioxx, although the numbers are small."
Nissen takes an even stronger stance.
"Merck misrepresented the results of the APPROVe extension in its conference call and press release," he says. "The reason it is upsetting is that people have a right to know what their risks are."
Permanent Damage From Vioxx?
Nissen says the new data indicate that Vioxx may cause permanent damage -- although much more information is needed to know whether this is so.
"This suggests Vioxx has more than a [blood-clot-promoting] effect," he says. "It suggests more is going on with this drug than we thought. I would say it is possible it causes persistent damage to the arteries."
Farkouh says the reassuring thing about Merck's new data is that the risk of stroke and heart attack appears to be getting smaller over time. Whether that will happen with the patients in the APPROVe trial isn't yet known. Merck is still trying to decide whether to try to follow up with these patients.
SOURCES: Michael Farkouh, MD, director, cardiovascular clinical trials, Mount Sinai Medical Center; associate professor of medicine, Mount Sinai School of Medicine, New York. Steve Nissen, MD, interim chairman, department of cardiovascular medicine, The Cleveland Clinic. Merck: "APPROVe Off-Drug Extension: Preliminary Analyses of Thrombotic Cardiovascular Safety." News release, Merck. Thomson Street Events, conference call transcript, May 11, 2006.