Rofecoxib withdrawn worldwide by Merck

Whitehouse Station, NJ - Merck has withdrawn its selective COX-2 inhibitor rofecoxib (Vioxx^®) from all markets worldwide, following the availability of new three-year data from the Adenomatous Polyp Prevention on VIOXX (APPROVE) trial showing an increased risk of cardiovascular events with the drug.

Rofecoxib was launched in 1999 for the treatment of arthritis and had worldwide sales last year of $2.5 billion. Merck's share price plunged on the announcement, falling by 26% within hours of the news.

Multiple other studies have also suggested an increased cardiovascular risk with rofecoxib, but until now Merck has denied there was any safety issue with the drug, and the APPROVE study was conducted in part to ascertain more information on this.

The APPROVE trial, which is being stopped, was testing rofecoxib 25 mg vs placebo in the prevention of the recurrence of colorectal polyps in 2600 patients with a history of colorectal adenoma. The study showed an increased relative risk for MI and stroke with rofecoxib, which became evident after 18 months of treatment. Merck told heartwire that the figures for confirmed cardiovascular events were 45 in the rofecoxib group vs 25 in the placebo group, giving rates of 1.48% vs 0.75%, respectively. There was no difference in the incidence of mortality, with five deaths in each group. This is the first time that a prospective study has shown more harm with rofecoxib than with placebo, and it was this finding that prompted the withdrawal, the company said.

The FDA is reporting slightly different figures, saying that 3.5% of patients in the rofecoxib group had a "thrombotic" event such as a stroke or heart attack, compared with 1.9% in the placebo group.

Raymond V Gilmartin, chair, president, and chief executive officer of Merck, said: "We are taking this action because we believe it best serves the interests of patients. Although we believe it would have been possible to continue to market Vioxx with labeling that would incorporate these new data, given the availability of alternative therapies and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take."

The APPROVE trial was started in 2000, following the results of the VIOXX Gastrointestinal Outcomes Research (VIGOR) study, which indicated an increased risk of cardiovascular events with rofecoxib vs naproxen. Merck argued that naproxen was exerting a protective cardiovascular effect and rofecoxib did not have a cardiac safety issue, which it claimed was supported by phase 3 studies in which no increased risk of cardiovascular events with rofecoxib were seen vs placebo or other non-naproxen NSAIDs.

Peter Kim (president of Merck Research Laboratories) said: "Merck has always believed that prospective, randomized, controlled clinical trials are the best way to evaluate the safety of medicines. APPROVE is precisely this type of studyand it has provided us with new data on the cardiovascular profile of Vioxx. While the cause of these results is uncertain at this time, they suggest an increased risk of confirmed cardiovascular events beginning after 18 months of continuous therapy."

While the other selective COX-2 inhibitors, such as celecoxib (Celebrex^®, Pfizer) and valdecoxib (Bextra^®, Pfizer) will now come under close scrutiny, they are not believed to have such a negative cardiovascular profile as rofecoxib. Merck has a second selective COX-2 inhibitor, etoricoxib (Arcoxia^®), which is available in 47 countries, and the company says that the cardiovascular safety issue with rofecoxib is not necessarily applicable to others in the class but will work with regulatory authorities to assess whether changes to the prescribing information for etoricoxib is warranted. Etoricoxib is not yet available in the US, but Merck said it will continue to seek approval and will continue its clinical-trial program with this drug.

One cardiologist who has long maintained that rofecoxib had an unacceptable cardiovascular safety profile is Dr Eric Topol (Cleveland Clinic, OH). He commented to heartwire that "Merck has finally got it right," although it was "too bad it took so long for them to accept the truth." He added: "Ironically, the validation of our concern came from a colon polyp trial in patients without any known heart disease." He said the other COX-2 inhibitors seemed safer, but "it was hard to know."

Another high-profile cardiologist has a somewhat different opinion on this issue. Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) commented to heartwire that rofecoxib caused a small but measurable increase in risk of cardiovascular events, but that other ongoing placebo controlled trials do not show the same effect. "From what we can piece together from the poor studies that are available, it looks like naproxen may be the only one that reduces riskwe just don't know about celecoxib, etc. Any chronically given drug that affects inflammation will have cardiovascular effects. Not doing long-term trials to inform the public about the balance of risks and benefits is like playing Russian rouletteyou just don't know which chambers have bullets unless you look."

He added that: "It's a shame the drug has to be pulled from the market. It would be best to inform doctors and patients of the risk and let them make a choice, but because of the dominance of lawsuits in therapeutics, obviously Merck can't afford to do that."

The FDA said that Merck did the right thing by voluntarily withdrawing the product from the market. Acting FDA commissioner Dr Lester M Crawford commented: "Although the risk that an individual patient would have a heart attack or stroke related to Vioxx 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 with patients receiving a placebo." He added that FDA will closely monitor other drugs in this class for similar side effects.

Heartwire from Medscape © 2004 

Cite this: Rofecoxib withdrawn worldwide by Merck - Medscape - Sep 30, 2004.