Researchers Confirm Vioxx Risks

Heart Problems Nearly Doubled in Cancer Study

The largest prospective trial to examine the anti-inflammatory drug Vioxx as a chemoprevention agent found that the risk of developing a heart attack or stroke almost doubled in patients who received the drug, compared to patients who took the placebo, according to a study published online in the Feb. 15 issue of The New England Journal of Medicine.

The risk, discovered and reported in September 2004 by the study's safety monitoring board, led to the shutdown of the colon cancer chemoprevention trial approximately two months before its planned completion, and the subsequent withdrawal of the drug from the U.S. market.

The trial, known as APPROVe (Adenomatous Polyp Prevention on Vioxx), was the longest test of Vioxx as a chemoprevention agent. It was designed to determine whether the drug could prevent the re-growth of precancerous colon polyps in people who already had polyps removed.

A total of 2,586 participants from 108 centers in 29 countries were randomized to receive either 25 mgs. of Vioxx or a placebo drug daily for three years. Robert Bresalier, M.D., the study's lead author, reports that 46 of the 1,287 patients randomized to take Vioxx daily had confirmed cardiovascular events - mostly heart attacks or strokes - during the three-year period. There were 26 events in the 1,299 patients who were given a placebo. Both groups, 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, professor and chair of M. D. Anderson's Department of Gastrointestinal Medicine and Nutrition and a member of the study's steering committee.

Problems begin after 18 months

Patients didn't begin to experience cardiovascular problems until after 18 months of treatment. Other cardiac problems, such as hypertension-related events, pulmonary edema and congestive heart failure-related events, presented earlier and were much more prevalent in the Vioxx-treated group compared to the placebo group.

Unlike heart attacks or strokes, these problems weren't validated by a separate committee, Bresalier says. Since this wasn't a cardiovascular trial, investigators reported all events but only fully examined the most serious ones.

"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 and treatment of precancerous lesions, not only in the colon but also in the esophagus and many other organs," Bresalier says. "What we don't know is if the cardiovascular results seen in Vioxx represent a class effect of COX-2 inhibitors, or if this is an individual effect of this drug. I don't think we can tell from this one trial or from the trials that are out there at the moment."

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