Cardiovascular Risks of Cyclooxygenase-2 Inhibitors: Where We Stand Now

Nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs), including nonselective nonaspirin NSAIDs and cyclooxygenase-2 selective (COX-2) inhibitors, are widely used for various arthritides and pain syndromes. Cyclooxygenase-2 inhibitors in particular have been an enormous financial success, with more than $5 billion in sales in the United States in 2003 (1). That market took a huge hit recently with the withdrawal of rofecoxib (Vioxx, Merck & Co., Inc., Whitehouse Station, New Jersey) after the release of the worrisome data on the excessive cardiac morbidity attributed to rofecoxib in a trial attempting to prove that it could reduce the occurrence of colonic adenomas. The nearly simultaneous report by Pfizer, Inc., of the adverse cardiac effects of valdecoxib (Bextra, Pfizer, Inc., New York, New York) after cardiac surgery (1) raised the issue of whether other drugs in the class are safe to use. Patients and clinicians are anxious to know whether cardiotoxicity is a class effect, and thereby applicable to any COX-2 inhibitor, or whether cardiotoxicity is limited to certain drugs in the class. In this issue, Kimmel and colleagues (2) shed some light on this question by examining whether the risk for cardiotoxicity differs among the COX-2 inhibitors celecoxib (Celebrex, Pfizer, Inc.) and rofexocib and nonselective nonaspirin NSAIDs.

Traditional nonselective nonaspirin NSAIDs inhibit both isoforms of the COX enzyme, COX-1 and COX-2. Cyclooxygenase catalyzes the conversion of arachadonic acid to prostaglandins, prostacyclin, and thromboxane. The COX-1 enzyme is expressed constitutively in tissues, such as the gastrointestinal mucosa, where it induces mucoprotective prostaglandins, while the COX-2 enzyme expression is inducible, in particular by inflammation. The inhibition of the COX-1–related production of prostaglandins by nonselective nonaspirin NSAIDs increases the risk for gastrointestinal bleeding. The recognition of 2 isoforms of COX soon led to the hypothesis that selective COX-2 inhibitors would have the beneficial properties of nonselective …