The article, an analysis of clinical trials, suggests a potential increase in the rate of heart attack, stroke and other cardiovascular events among patients treated with the new anti-inflammatory drugs.

Debabrata Mukherjee, M.D., currently with the University of Michigan and formerly of the Cleveland Clinic Foundation, Cleveland, and Steven E. Nissen, M.D., and Eric J. Topol, M.D., of the Cleveland Clinic Foundation, analyzed randomized trials performed with selective COX-2 inhibitors to determine if these medications are associated with a protective or a hazardous effect on the risk of cardiovascular events.

COX-2 inhibitors were introduced in 1999. For the 12-month period ending in July 2000, more than 100 million prescriptions for the COX-2 inhibitors rofecoxib and celecoxib were written.

The drugs were developed to fight inflammation (such as from arthritis) without the gastrointestinal side effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs).

COX-2 inhibitors selectively block the COX-2 enzyme, impeding production of chemical messengers that cause the pain and swelling of inflammation.

According to background information cited in the article, COX-2 inhibitors may potentially fight the development of atherosclerosis, a process with inflammatory features. But COX-2 inhibitors may also promote formation of clots in blood vessels by decreasing production of a biochemical compound that promotes the widening of the vessels.

The authors studied two major randomized trials -- the Vioxx Gastrointestinal Outcomes Research Study (VIGOR) and the Celecoxib Long-Term Arthritis Safety Study (CLASS) -- as well as two smaller trials.

The VIGOR study of 8,076 patients compared the occurrence of gastrointestinal toxicity of rofecoxib with the NSAID naproxen during long-term treatment for patients with rheumatoid arthritis. Aspirin use was not permitted in this study.

"The VIGOR trial demonstrated significantly increased risk of cardiovascular event rates with use of rofecoxib, although the study enrolled patients who did not require aspirin for protection from ischemic events," the authors write.

A total of 45 patients who took rofecoxib and 20 in the naproxen group were judged to have serious cardiovascular events: myocardial infarction (MI); unstable angina; cardiac thrombus; resuscitated cardiac arrest; sudden or unexplained death; ischemic stroke and transient ischemic attacks.

Patients in the VIGOR study treated with rofecoxib had about twice the risk of developing a confirmed cardiovascular event as those who received naproxen.

"The results of the VIGOR study can be explained by either a significant pro-thrombotic effect from rofecoxib or an anti-thrombotic effect from naproxen (or conceivably both)," the authors suggest.

CLASS was a controlled trial in which 8,059 patients received one of three medications: celecoxib, the NSAID ibuprofen, or the NSAID diclofenac. Aspirin use was permitted in the study.

"In contrast to the VIGOR study, the CLASS study with celecoxib did not show a significant increase in cardiovascular event rates compared with NSAIDs, possibly due to the use of low-dose aspirin in the CLASS trial or to pharmacological differences in the NSAID agents used as controls in the two studies," the authors write.

The authors also examined results from a meta-analysis of several large prevention trials. The meta-analysis of the U.S. Physicians' Health Study, the U.K. Doctors Study, the Thrombosis Prevention Trial and the Hypertension Optimal Treatment trials included 48,540 patients (25,133 treated with aspirin and 23,407 who were given placebo).

"The annualized MI rate in the placebo group in this meta-analysis was 0.52 percent," the authors report. "The annualized MI rates for both the VIGOR and the CLASS trials were higher: 0.74 percent with rofecoxib and 0.80 percent with celecoxib."

"The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors," the authors write.

"Given the remarkable exposure and popularity of this new class of medications, we believe that it is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents.

"Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular morbidity."

(Reference: JAMA. 2001; 286:954-959)

22-Aug-2001