Rofecoxib (Vioxx) voluntarily withdrawn from market

Merck & Co. announced Sept. 30 a voluntary worldwide withdrawal of rofecoxib (Vioxx) after a study showed patients taking the drug on a long-term basis face twice the risk of a heart attack compared with patients receiving placebo.

The 3-year clinical trial called APPROVe (Adenomatous Polyp Prevention of Vioxx), which was halted in late September (2 months before it was scheduled to end), was evaluating the efficacy of rofecoxib in preventing the recurrence of colorectal polyps among patients with a history of colorectal adenomas. It revealed an increased relative risk for serious cardiovascular events, including heart attacks and strokes, beginning after 18 months of treatment among patients taking rofecoxib that was about twice that of patients taking placebo. The results for the first 18 months of the study did not show any increased risk.

The randomized, placebo-controlled, double-blind study enrolled 2600 patients at 100 sites. According to Merck Frosst Canada, when the study was halted 25 of those taking placebo had suffered a cardiovascular event, and 45 of those taking rofecoxib had suffered an event (relative risk 1.8). The absolute risk difference is about 1.5% over the period of the study.

No one died, said Dr. François Bertrand, executive director of medical research for Merck Frosst Canada. The study's external safety monitoring board recommended that the trial be halted, but “because of the nature of the events and the availability of other drugs, we decided the right thing was to discontinue [the drug],” said Bertrand.

The risk of a patient having a cardiovascular event related to rofecoxib is “very small,” stated Acting US Food and Drug Administration (FDA) Commissioner Dr. Lester M. Crawford, but “overall, patients taking the drug chronically face twice the risk of a heart attack compared to patients receiving a placebo.” Crawford said the FDA will closely monitor other drugs in this class for similar side effects.

Rofecoxib, a selective COX-2 inhibitor, nonsteroidal anti-inflammatory drug (NSAID) gained Canadian approval in 1999. It is currently approved for the treatment of acute and chronic symptoms of osteoarthritis, rheumatoid arthritis, acute pain and menstrual pain.

At the time of approval, the company's trials indicated there was not an increased risk of cardiovascular events with rofecoxib compared with placebo or other NSAIDs.

However, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, released in March 2000, did indicate an increased risk compared with naproxen. Health Canada issued an advisory in 2002 about increased risk of cardiovascular events related to the drug's use. Since then Health Canada has been monitoring all COX-2 inhibitors for gastrointestinal and cardiovascular events. (See also CMAJ 2002; 166 [12]:1692-3.)

The lead author of the VIGOR study, Dr. Claire Bombardier, said withdrawing the drug was “pretty honourable and gutsy of [Merck].” She was part of an advisory group to the company in September; many members recommended the drug not be withdrawn because patients need various drug options.

“They are withdrawing a drug that was very effective,” said Bombardier, director of rheumatology at the University of Toronto.

The puzzling thing, she adds, is why the increased risk didn't show up until after 18 months. The question that remains is whether the increased risk applies only to rofecoxib or to all COX-2 inhibitors. “I really think the regulatory agencies should ask all COX-2 manufacturers to do this kind of study.”

Dr. James Wright, a professor of pharmacology at the University of British Columbia, has long maintained (CMAJ 2002; 167[10]: 1131-7) that continued licensing of this class of drug “should be dependent on demonstrating they are safe.”

He advocates for RCTs comparing these drugs to a nonselective NSAID, such as ibuprofen. “We should have started this a long time ago.”

COX-2 inhibitors block 1 enzyme, which Wright says strikes an inbalance in the bleeding/clotting action toward clotting. “Rofecoxib is more potent so it emerged as the worse, but the same property would apply to all COX-2 inhibitors.”

Rofecoxib, which is available in more than 80 countries, had worldwide sales of $2.5 billion in 2003. IMS Health Canada reports that rofecoxib was the number 10 top-selling drug in Canada in 2003, with 3.3 million prescriptions written and retail sales totalling $194 million.

“The fact that so many are prescribed is unfortunate,” says Wright. “Doctors should be cautious about any of these drugs.”

Health Canada has posted an advisory about the drug's withdrawal (www.hc-sc.ga.ca). Spokesperson Jirina Vik said rofecoxib will be withdrawn at wholesalers, pharmacies and physicians' offices.

Health Canada advises patients taking rofecoxib to contact their physician about alternative treatments and to return any leftover rofecoxib to their pharmacy for a refund.

For more details, physicians can contact Merck at 888 368-4699 or at www.merck.com. — Barbara Sibbald, CMAJ

Figure. Rofecoxib was available and promoted in 80 countries, including China. Photo by: Merck Sharp & Dohme (Asia) Ltd.