Canadian Medical Association Journal

The study, which was halted last week (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 3-year, multicentre, randomized, placebo-controlled, double-blind study enrolled 2600 patients. Among those taking placebo, 25 suffered a cardiovascular event, while 45 of those taking rofecoxib 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. Francois 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, non-steroidal anti-inflammatory drug (NSAID) was approved in North America in 1999 for the reduction of pain and inflammation. At the time of approval, the company's trials indicated there was not an increased risk of cardiovascular events with rofecoxib compared to placebo or other NSAIDs.

However, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, released in March 2000, did indicate an increased risk compared to naproxen. (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 She was part of an advisory group to the company last week, many of whom recommended the drug not be withdrawn because patients need various drug options.

“They are withdrawing a drug that was very effective,” said Bombardier, the 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, 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 non-selective NSAID, such as ibuprofen. “We should have started this a long time ago.”

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,” said Wright. “Doctors should be cautious about any of these drugs.”

Immediately following Merck's announcement, the US FDA issued a public health advisory (http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#vioxx).

Health Canada will soon post a similar advisory (www.hc-sc.gc.ca). Spokesperson Jirina Vik said Health Canada was not advised ahead of time about the withdrawal. In Canada , rofecoxib will be withdrawn at wholesales, pharmacies and physicians' offices, said Vik.

Health Canada advises patients currently taking rofecoxib to contact their health care providers to discuss discontinuing use of the drug and possible alternative treatments. Patients who want to dispose of the drug should bring it to their pharmacy. Health care professionals are urged to contact Merck at 888 368-4699 or at www.merck.com .

— Barbara Sibbald, eCMAJ