MEDICATIONS: POPULAR ANTI-INFLAMMATORY DRUGS MAY INCREASE RISK OF CARDIOVASCULAR EVENTS

August 21, 2001 — 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 popular anti-inflammatory drugs known as COX-2 inhibitors, according to an article in the August 22/29 issue of The Journal of the American Medical Association.

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

COX-2 inhibitors are a class of drugs 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. Both 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 (narrowing and hardening of the arteries), a process with inflammatory features. However, COX-2 inhibitors also may lead to increased pro-thrombotic activity (promoting formation of clots in blood vessels), by decreasing production of a biochemical compound that promotes the widening of blood vessels.

The authors performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. They also reviewed relevant submissions to the U.S. Food and Drug Administration by pharmaceutical companies. The search yielded 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 was a double-blind, randomized group trial of 8,076 patients, comparing 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 the 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 thrombotic cardiovascular events: myocardial infarction (MI; heart attack); unstable angina (chest pain due to inadequate delivery of oxygen to the heart muscle); cardiac thrombus (a blood clot inside a blood vessel or cavity of the heart); resuscitated cardiac arrest; sudden or unexplained death; ischemic stroke (stroke brought on by an interruption of the blood supply to the brain); and transient ischemic attacks (a brain injury similar to a stroke, but lasting only a brief time).

The authors report that patients in the VIGOR study who were 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 double-blind, randomized 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.

In order to compare rates of MI, the authors examined results from a meta-analysis (an overview of clinical trials, combining results of independent studies) 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 [disease]."