The popular anti-inflammatory drug rofecoxib (Vioxx) was voluntarily withdrawn by its manufacturer, Merck & Co, Inc, on September 30, 2004. The withdrawal was the result of findings that the drug is associated with an increased risk for cardiovascular events.
In the Adenomatous Polyp Prevention on VIOXX (APPROVe) trial, investigators were evaluating the efficacy of 25 mg of rofecoxib in preventing the recurrence of colorectal polyps in patients who had previously had colorectal adenomas. The investigators' analysis found that patients on rofecoxib were at increased relative risk for myocardial infarction, stroke, and other cardiovascular events, compared to the placebo arm. These effects were evident beginning after 18 months of treatment.
The FDA acknowledged the voluntary withdrawal in a press release and also issued a Public Health Advisory to inform patients of the action and to advise them to consult with a physician about alternative medications.
"Merck did the right thing by promptly reporting these findings to the FDA and voluntarily withdrawing the product from the market," acting FDA Commissioner Dr. Lester M. Crawford said in the statement. "Although the risk ... is very small, the study that was halted suggests that, overall, patients taking the drug chronically face twice the risk of a heart attack compared to patients receiving a placebo."
The American College of Rheumatology acknowledged the withdrawal in a statement on its Web site and advised patients who had been taking rofecoxib to "discontinue the medication and to work with their doctors to determine what other medication may be indicated in its place."
Rofecoxib is one of several anti-inflammatory agents that selectively inhibit cyclo-oxygenase-2 (COX-2) and are called COX-2 inhibitors or coxibs.
APPROVe was designed as a multicenter, randomized, placebo-controlled, double-blind study. The investigators wanted to know whether 3 years of rofecoxib therapy had any preventive value regarding the recurrence of colorectal polyps. The trial enrolled 2,600 patients and began enrollment in 2000.
In an interview with CiaoMed, Lee Simon, MD, pointed out several important issues for physicians to consider regarding the withdrawal of rofecoxib. Dr. Simon is an associate clinical professor of medicine at Harvard Medical School in Boston and has been an investigator in several trials of various COX-2 inhibitors.
"These findings might be unique to rofecoxib and not a class effect," he told CiaoMed. "There is no evidence that increased cardiovascular risk is a class effect." For example, "some data show that patients on celecoxib are at decreased risk of a cardiovascular event." He noted that two ongoing celecoxib studies are also assessing that drug's role in preventing the recurrence of colon polyps. "These studies have not been stopped and have been going on twice as long as the rofecoxib study that was stopped."
Dr. Simon told CiaoMed that when physicians treat patients with osteoarthritis who are at risk of gastrointestinal complications, they have several treatment options. "There is a benefit to being on a COX-2 inhibitor for patients at risk of GI complications," he said. "Therefore, switching to another COX-2 inhibitor may be appropriate for those patients." Alternatively, physicians may switch such patients to a non-selective nonsteroidal anti-inflammatory drug (NSAID) and use a proton pump inhibitor as a gastroprotective agent.
"Physicians should also be aware that the COX-2 agents differ chemically and that this difference may mean that the drugs have different cardiovascular effects," said Dr. Simon. "Those differences may be important," he told CiaoMed. "This possibility has not been extensively studied."
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