COX 2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense.
THE CONCEPT WAS APPEALING IN ITS SIMPLICITY. TRAditional nonsteroidal anti inflammatory drugs (NSAIDs) inhibited both isoforms of the enzyme cyclooxygenase responsible for the first step in the conversion of arachidonic acid into a variety of prostaglandins, thromboxanes, and leukotrienes throughout the body. The anti inflammatory and pain relieving effects of NSAIDs resulted from inhibition of prostaglandin synthesis mediated by cyclooxygenase 2 (COX 2) at the site of tissue injury, while gastrointestinal tract complications were due to inhibition of prostaglandin synthesis mediated by cyclooxygenase 1 (COX 1) in the gastrointestinal mucosa. The allure of COX 2 inhibitors was the prospect of treating pain without gastrointestinal toxicity. Celecoxib and rofecoxib were the first of these new agents to gain approval and, with heavy promotion and direct to consumer advertising, quickly became the most widely prescribed NSAIDs in the United States. Lurking in the background was the concern that selective COX 2 inhibition might suppress endothelial cell synthesis of prostacyclin, leaving platelet thromboxane A2 mediated by COX 1 relatively unopposed. With loss of the antiplatelet and vasodilatory effects of prostacyclin, a relative excess of thromboxane A2 would favor vasoconstriction, platelet aggregation, and thrombosis. Disturbing red flags for cardiovascular risk were noted in the preapproval application for rofecoxib submitted to the US Food and Drug Administration (FDA) in November 1998, but were dismissed because of the FDA's practice of requiring "complete certainty" before acting on safety concerns. Indeed, as noted by Psaty and Furberg, "Safety signals were recognized by the medical officer of the Food and Drug Administration (FDA) who observed that in 6 week studies, thromboembolic events are more frequent in patients receiving rofecoxib [12 (0.6% of 1780] than placebo [1 (0.24% of 412]" Within months of rofecoxib's approval in May 1999, the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial reported a 50% reduction in serious gastrointestinal outcomes, but a 5 fold increase in thromboembolic cardiovascular events (primarily acute myocardial infarction [MI] among patients treated with 50 mg/d of rofecoxib compared with 1000 mg/d of naproxen. For nearly 2 years after these results became known, rofecoxib's label remained unchanged while the company aggressively marketed the drug, claiming that it did not increase the risk of MI and that naproxen was cardioprotective. During this period, the FDA warned the company that its promotion of rofecoxib made "unsubstantiated claims," "promoted off label use," and was "false, lacking in fair balance, or otherwise misleading. Meanwhile, a Pfizer study of celecoxib in Alzheimer disease, which was completed in 2000 but not revealed until January 2005, showed an increase in cardiovascular risk with that drug. Then, in 2004, Merck withdrew rofecoxib from the market after its Adenomatous Polyp Prevention on Vioxx (APPROVe) trial showed a 2 fold increase in cardiovascular risk with 25 mg/d of rofecoxib compared with placebo. Based on an unplanned post hoc analysis, the company claimed that risk increased only after 18 months of continuous use, which if true, would reduce the company's liability substantially because most rofecoxib use was for much shorter periods. Against this backdrop, public concern was heightened by announcements that celecoxib, valdecoxib, and naproxen might also increase MI risk. For example, analysis of the Adenoma Prevention with Celebrex study showed at least a tripling of risk for 400 mg of celecoxib twice daily. Subsequently, the FDA labeled all COX 2 selective and nonselective NSAIDs as increasing cardiovascular risk, adding to public anxiety and confusion. In 2006, Merck announced that it had performed an incorrect statistical test in its post hoc analysis of the APPROVe trial. More importantly, the analysis was performed improperly because it relied on a censoring rule that violated widely accepted intention to treat principles. When ana
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