The risk was first discovered and reported last September by the study’s safety monitoring board and led to the shutdown of the colon cancer chemoprevention trial and subsequent withdrawal of the drug from the U.S. market.

The trial, known as APPROVe (Adenomatous Polyp Prevention on Vioxx), was the longest test yet of Vioxx as a chemoprevention agent, and was designed to determine whether the drug could prevent the re-growth of precancerous colon polyps in people who had already had polyps removed. The prospective chemoprevention study randomized 2,586 participants from 108 centers in 29 countries to receive either 25 mgs. of Vioxx daily or a placebo drug for three years, 2001-2004. The trial was stopped September 30, 2004 –– approximately two months before its planned completion.

According to Robert S. Bresalier, M.D., of The University of Texas M. D. Anderson Cancer Center and lead author of The New England Journal of Medicine study, 46 of the 1287 patients randomized to take Vioxx daily had confirmed cardiovascular events over a three year period –– mostly heart attacks or strokes. In the 1,299 patients given a placebo drug, there were 26 events. Each group, however, had the same number of deaths and not all were related to heart attacks or strokes.

“The overall number of cardiovascular events is small, but, nevertheless, the difference between the groups is significant,” says Bresalier, who is professor and chair of the Department of Gastrointestinal Medicine and Nutrition at M. D. Anderson and a member of the study’s steering committee.

This study examined data on the 2,586 patients enrolled in the trial, all of whom had a history of adenomatous colon polyps. The most notable trend, according to Bresalier, was that patients did not begin to experience cardiovascular problems such as heart attacks or strokes until after 18 months of treatment. “In the first 18 months, the risks for the two treatments were similar,” Bresalier says.

Other cardiac problems, such as hypertension-related events, pulmonary edema and congestive heart failure-related events were much more prevalent in the Vioxx-treated group compared to the placebo group and presented earlier. The data on these cases, however, is less firm, Bresalier notes, because, unlike heart attacks or strokes, these problems were not “adjudicated,” or validated by a separate committee. This was not a cardiovascular trial, reminds Bresalier, so while investigators reported all events, only the most serious were fully examined.

"Because patient benefit is the most important criteria for any study, it was appropriate to stop the trial,” Bresalier says. “We don’t know why Vioxx increased this risk, but we now have an opportunity to study whether subpopulations of patients are more susceptible than others.”

“I think it’s unfortunate that we’ve perhaps lost a class of drugs which potentially has very important roles in a variety of diseases ¯ arthritis, cancer prevention, cancer treatment, treatment of Alzheimer’s disease, treatment of precancerous lesions, not only in the colon but in the esophagus and many other organs,” says Bresalier. “What we don’t know is, if the cardiovascular results seen in Vioxx represents a class effect of COX-2 inhibitors or if this is an individual effect to this drug. I don’t think we can tell this from this one trial or from the trials that are out there at the moment. That’s going to be the real question.”

The investigators examined the use of cardio-protective aspirin among patients and found that it did not skew findings on the overall risk of Vioxx treatment.

The study was funded by Merck Research Laboratories, which manufactures Vioxx. Bresalier reports receiving a consulting fee as a member of the APPROVe trial steering committee.

Note: If no author is given, the source is cited instead.

• Vioxx
• Heart Disease
• Diseases and Conditions
• Colon Cancer
• Personalized Medicine
• Pharmacology

• COX-2 inhibitor
• Rofecoxib
• Clinical trial
• Double blind
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