Merck withdraws arthritis drug worldwide

The pharmaceutical company Merck last week initiated a voluntary immediate worldwide withdrawal of its bestselling arthritis drug rofecoxib (Vioxx), because new research shows that it almost doubles the risk of myocardial infarction and stroke if taken for 18 months or more.

Rofecoxib, a cyclo-oxygenase-2 selective inhibitor, has been on the market since 1999 and is used by 2 million people in over 80 countries worldwide with 400 000 taking it in the United Kingdom. It is indicated for osteoarthritis and rheumatoid arthritis, and higher dose strengths are indicated for short term relief of acute pain (VioxxAcute).

The new study, called APPROVe (adenomatous polyp prevention on Vioxx), was a multicentre, randomised placebo controlled double blind trial to determine the effect of three years of treatment with rofecoxib on the recurrence of neoplastic polyps of the large bowel in patients with a history of colorectal adenoma.

The trial, which started in 2000, enrolled 2600 patients and compared rofecoxib 25 mg to placebo. After 18 months, 25 patients taking placebo and 45 patients taking rofecoxib had had a confirmed serious thromboembolic event.

Raymond Gilmartin: “Withdrawal is the responsible course”

Credit: KATHY WILLENS/AP

The absolute event rates were about 3 per 400 patient years for placebo and 6 per 400 patient years for rofecoxib—that is, an absolute increase in risk of about 3 thromboembolic events per 400 patient years of treatment. The new data relate specifically to rofecoxib and is not generalised to other cyclo-oxygenase-2 selective inhibitors.

The cardiovascular safety of rofecoxib has been questioned since 2000 when Merck submitted a study called VIGOR (Vioxx gastrointestinal outcomes research) to the US Food and Drug Administration (New England Journal of Medicine 2000;343: 1520-8). An analysis of the VIGOR study by cardiologist Eric Topol and colleagues at the Cleveland Clinic in Ohio showed that patients taking rofecoxib had a higher relative risk of developing adverse cardiovascular events than patients taking naproxen (JAMA 2001;286: 954-9). This led to warnings of this risk on the drug's label.

The FDA issued a statement saying it was in the process of carefully reviewing other recent studies showing similar findings when Merck informed them of the new data and the company's decision to withdraw the drug.

The decision to withdraw has already taken its toll on the pharmaceutical giant. In 2003, global sales of rofecoxib amounted to $2.5bn (£1.4bn; €2.0bn). Within a day of announcing the withdrawal, more than £14bn was wiped from the company's stock market value, equivalent to a quarter of its worth and the share price plunged to an eight year low.

Also, a day after the announcement, the first lawsuit against Vioxx and Merck was filed in Oklahoma on behalf of a local resident with the likelihood of more to follow, including class action cases.

Merck's chairman Raymond Gilmartin said, “Although we believe it would have been possible to continue to market Vioxx with labelling that would incorporate these new data, we concluded that a voluntary withdrawal is the responsible course to take.”