COX-2 inhibitors--lessons in drug safety.

Approximately six years after the cyclooxygenase-2 (COX-2) inhibitors were approved for use in the United States, the results of three randomized, placebo-controlled trials provide new evidence about the cardiovascular risks of rofecoxib, celecoxib, and valdecoxib. 1-3 The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, a study of patients with a history of colorectal adenomas, was stopped early because rofecoxib doubled the risk of major cardiovascular events (relative risk, 1.92; 95 percent confidence interval, 1.19 to 3.11). These findings confirmed the increased risk of myocardial infarction previously seen in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial 4 and some observational studies. 5 The public announcement of the APPROVe results, which coincided with Merck’s withdrawal of rofecoxib from the market in September 2004, prompted scientists to review the cardiovascular-safety results of a similar trial, the Adenoma Prevention with Celecoxib (APC) Study. 2 At either 200 or 400 mg twice a day, celecoxib in the APC trial was associated with a tripling of the risk of cardiovascular events (relative risk, 2.8; 95 percent confidence interval, 1.3 to 6.3). In the third COX-2 inhibitor trial reported in this issue of the Journal, 3 the short-term use of valdecoxib and its prodrug parecoxib was associated with increased cardiovascular risk in patients undergoing coronary bypass surgery. After millions of Americans have used COX-2 inhibitors, which were intended to avert the gastrointestinal complications common to other nonsteroidal antiinflammatory drugs (NSAIDs), serious adverse cardiovascular events have now been reported for three members of the class. Physicians are dismayed, pharmaceutical companies are embarrassed and financially threatened, and patients are injured. Indeed, the integrity of the American drug-safety system has been questioned. How did such problems arise, and how can they be prevented in the future? COX-2 inhibitors not only lack the antiplatelet effects of aspirin; by inhibiting the production of prostacyclin, they also disable one of the primary defenses of the endothelium against platelet aggregation, hypertension, and atherosclerosis. 6 COX-2 inhibitors also promote an imbalance in favor of vasoconstriction. These biologic actions, known since 1998, suggest that COX-2 inhibitors may increase the risk of cardiovascular events, including myocardial infarction, stroke, hypertension, and heart failure. To use COX-2 inhibitors wisely, patients and physicians need complete information about benefits and risks, including any cardiovascular risks. Before rofecoxib was approved, 5435 patients received the drug, usually in small, short-term trials that were adequately powered to examine outcomes such as pain relief. 7 Adverse events, including cardiovascular ones, were identified incidentally, by self-report. Although only 371 and 381 patients received doses of 12.5 mg and 25 mg, respectively, for more than one year, safety signals were recognized by the medical officer of the Food and Drug Administration (FDA), who observed “that in 6-week studies, thomboembolic events are more frequent in patients receiving rofecoxib [12 (0.67%) of 1780] than placebo [1 (0.24%) of 412].” 7 Still, rofecoxib was approved in May 1999. The tradeoff between gastrointestinal benefit and cardiovascular harm was highlighted in the VIGOR trial, which compared rofecoxib (50 mg daily) with naproxen (500 mg twice daily) in 8076 patients with rheumatoid arthritis. 4 Subjects with recent cardiovascular events were excluded, and so were those taking aspirin. Cardiovascular events were not a prespecified end point and were not adjudicated for the VIGOR trial itself. The occurrence of myocardial infarction, which was five times as high in the rofecoxib group as in the naproxen group, was reported only in preliminary form in the original article. 4,8 Revisions of the rofecoxib label took more than two years to complete. In contrast, the Women’s Health Initiative (WHI) study is an example of a trial designed to assess risks and benefits with equal scientific rigor. 9 In the evaluation of hormone-replacement therapy, the WHI treated the potential risks of breast cancer and venous thrombosis just as seriously as the hypothesized benefits with regard to myocardial infarction and stroke. Criteria for all these end points and the methods of case identification were defined in the protocol, and outcome data were collected prospectively and adjudicated blindly. Early on, the WHI’s