Trial Results on Vioxx Do Not Explain Mechanism Behind Adverse Events

Jane Salodof MacNeil

October 19, 2004

Oct. 19, 2004 (San Antonio) — The reason for the increased risk of heart attack and stroke with the withdrawn arthritis drug rofecoxib (Vioxx) is a mystery neither the drug's maker Merck and Co. Inc. nor the U.S. Food and Drug Administration (FDA) has been able to explain.

Data released last night showed that patients receiving rofecoxib had roughly twice as many confirmed cardiovascular events compared with patients receiving placebo in the pivotal Adenomatous Polyp Prevention on VIOXX (APPROVe) trial. The most common event was acute myocardial infarction (20 vs 8 events) and ischemic cerebrovascular stroke (11 vs 6 events).

Robert Bresalier, MD, a gastroenterologist at the University of Texas M.D. Anderson Cancer Center in Houston, reported the preliminary analysis on behalf of the trial's steering committee in a special added session at the 68th annual scientific meeting of the American College of Rheumatology. The multicenter study included 2,586 patients randomized to 25 mg of rofecoxib or placebo. The purpose was to determine whether rofecoxib could prevent recurrence of neoplastic polyps in patients with a history of colorectal adenomas. On Sept. 27, the study was stopped early upon recommendation of the study's data safety monitoring board.

Dr. Bresalier repeated Merck's assertion that no difference in cardiovascular events was noted during the first 18 months of the study. Later preliminary analyses found 45 confirmed thrombotic events in 3,041 patient-years for rofecoxib, a rate of 1.48 events per 100 patient-years. In comparison, 25 confirmed thrombotic events were recorded in 2,315 patient-years for placebo, for a rate of 0.75 events per 100 patient-years.

The investigators calculated the relative risk of a confirmed cardiac event as 1.96 with rofecoxib. No difference in mortality was observed.

Alise Reicin, MD, vice president of clinical research at Merck, reported that the company has so far been unable to identify a mechanism behind the increased risk. Subset analysis has shown a twofold difference in cardiovascular events with rofecoxib regardless of whether patients were classified as high risk or low risk for cardiovascular disease, according to Dr. Reisin.

"We've been looking extensively at hypertension, and we have been unable in preliminary analyses to make a correlation between blood pressure and events," she said at a press briefing after the session. She described the effect as too large to be explained by blood pressure alone.

Of the 1,287 patients receiving rofecoxib, 36% had hypertension and 29% were at high risk for cardiovascular events. The proportions were 34% and 26%, respectively, for the 1,299 patients receiving placebo.

FDA acting deputy commissioner Janet Woodcock, MD, told an overflow crowd of physicians at the session that her agency did not have "any definitive evidence" of a class effect, which would raise safety concerns about other cyclooxygenase-2 (COX-2) inhibitors, but she also did not have evidence to rule it out. The agency will convene an advisory panel early next year to discuss how to evaluate the cardiovascular safety of new drugs coming on the market, she said.

Two other nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively target COX-2 are approved in the U.S. — celecoxib (Celebrex) and valdecoxib (Bextra) — and several others, including a Merck successor to rofecoxib, are under investigation. Dr. Woodcock said the FDA is hoping a clinical trial would produce "more certainty" about the safety of celecoxib compared with placebo, but that the agency was "going to explore ways of further evaluating valdecoxib."

Traditional nonselective NSAIDs such as ibuprofen and naproxen may also differ in their cardiovascular toxicity profiles, according to Dr. Woodcock, but comparisons were not done when these over-the-counter drugs were investigated. The selectivity of some newer NSAIDs in targeting COX-2 might be a factor in raising risk, she continued, adding that dose responses are another possibility.

A separate unanswered question is whether rofecoxib was effective as an anticancer drug. The colonoscopy data recorded in the APPROVe study is still blinded. Dr. Reicin said analysis is ongoing and results would be reported at a future scientific meeting that is to be determined.

Dr. Reicin also said the patients would be followed for a year after they stopped therapy. Originally, this was in the trial protocol to determine whether rofecoxib continued to be effective against cancer. Now the investigators will also ask whether the drug continued to have an effect on cardiovascular events.

ACR 68th Annual Scientific Meeting: Added abstract. Presented Oct. 18, 2004.

Reviewed by Gary D. Vogin, MD

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