SAN ANTONIO, Texas – More than 5,000 rheumatologists and allied health-care professionals attending the 2004 annual meeting of the American College of Rheumatology heard last night the first report of the scientific data that led to removal of the cyclooxygenase-2 (COX-2) inhibitor rofecoxib (VIOXX) from the marketplace.

In a hastily convened session that filled one conference hall and two overflow rooms, scientists detailed the results and considered consequences of the removal of the popular medication.

Robert Bresalier, MD, Professor and Chair of the Department of Gastrointestinal Medicine and Nutrition at the University of Texas M.D. Anderson Cancer Center, Houston, said the results of the Adenomatous Polyps Prevention with VIOXX (APPROVe) trial showed that patients taking rofecoxib to prevent the cancerous growth had nearly a two-fold increased risk of suffering an adverse cardiovascular event compared with those taking placebo.

"Although these results reflect an increased relative risk over the entire study period," Dr. Bresalier said, "the results for the first 18 months did not show an increased relative risk of confirmed cardiovascular events." He noted that the cardiovascular events in the placebo arm of the study appeared to stop occurring after 18 months, while the events in the rofecoxib arm continued. However, no differences in overall mortality were observed between treatment groups.

Dr. Bresalier said that 25 confirmed cardiovascular events in 3315 patients occurred among the patients on placebo, or 0.75 events for each 100 patient-years of treatment. These findings contrasted with the 45 confirmed events uncovered in the rofecoxib group of 3,041 patients, translating to 1.48 events per 100 patient years, a 1.96 relative risk characterized as statistically significant (p=.007).

Before describing the results, Alise Reicin, MD, Vice President for Clinical Research at Merck Research Laboratories, Rahway, New Jersey, described the history of rofecoxib and its relationship to cardiovascular events. She said earlier trials offered a signal that there might be a cardiovascular risk, but other trials appeared to indicate that there was no greater risk with rofecoxib than with placebo, citing, in particular, a study in Alzheimer's disease patients.

In a press briefing after the scientific presentation, Dr. Reicin said that while Merck halted the APPROVe trial – as well as other trials involving rofecoxib – the company was continuing to investigate the role of rofecoxib as a chemopreventive agent and, therefore, would complete the colonoscopies and other data retrieval efforts. She said Merck intends to report those results, possibly in 2005.

Commenting on the fate of rofecoxib and addressing how the study might affect other drugs in the COX-2 class, Janet Woodcock, MD, acting deputy director of the Food and Drug Administration (FDA), said other clinical trials assessing the efficacy of celecoxib in the prevention of colon polyps and in the treatment of Alzheimer's disease were continuing. "We have no reason to stop these trials," Dr. Woodcock said, noting that different COX-2 inhibitors appear to have different cardiovascular risk factors. "Careful scrutiny of new agents as they come on the market will be brought to bear by the FDA," she said. "We plan to seek a public advisory committee to discuss how to evaluate the cardiovascular safety issue sometime next year."

Some members of the audience were dissatisfied with the discussion. "I think Merck took VIOXX off the market too quickly," said Paul Andreini, MD, a private practice rheumatologist in Nederland, Texas. He suggested that Merck researchers had not probed deeply enough into the control group, and speculated that since rofecoxib was an excellent pain reliever, patients in the rofecoxib group would not need extra pain relief.

On the other hand, Dr. Andreini said, patients in the control group might take over-the-counter medications, such as aspirin, to relieve pain – and in the process reduce their risk of cardiovascular events caused by clotting.

"This wasn't a study of pain," Dr. Reicin said, so the level of pain in each group was not recorded. "We have no way of evaluating if patients in the control group took medications surreptitiously."