The risk of cardiovascular thrombotic events with selective cyclooxygenase-2 inhibitors.

Abstract

The selective cyclooxygenase-2 (COX-2) inhibitors celecoxib and rofecoxib are now widely prescribed instead of the traditional nonsteroidal antiinflammatory agents (NSAIDs). Short-term randomized controlled trials (RCTs) documented that both agents were superior to placebo, with comparable efficacy and better upper gastrointestinal (GI) adverse-event profiles than traditional NSAIDs, including ibuprofen, naproxen, and diclofenac. However, these RCTs were not powered to demonstrate GI tolerability equivalent to placebo, and consequently the GI warning common to the NSAID class remained in both celecoxib and rofecoxib labels. The Celecoxib Long-term Arthritis Safety Study (CLASS) and the Vioxx Gastrointestinal Outcomes Research (VIGOR) trials were designed to demonstrate GI safety superior to that of traditional NSAIDs, as used in regular clinical practice, assessed by “clinically meaningful” upper GI events, at twice recommended clinical doses for long-term use (celecoxib 400 mg twice daily; rofecoxib 50 mg daily) (1,2). Although both large outcome trials shared similar designs, they differed in several important aspects (Table 1). Comparator NSAIDs in CLASS were ibuprofen and diclofenac, and in VIGOR it was naproxen. Only patients with rheumatoid arthritis (RA) were enrolled in VIGOR; in CLASS, RA patients represented 28% of the study population, and osteoarthritis (OA) patients represented the other 72%. Enrolled patient numbers were similar: in CLASS, 3,987 patients took celecoxib, 1,996 patients took diclofenac (75 mg twice daily), and 1,985 patients took ibuprofen (800 mg 3 times daily); in VIGOR 4,047 patients took rofecoxib and 4,029 took naproxen (500 mg twice daily). Patient populations differed at baseline predominantly by risk factors for cardiovascular (CV) and GI events (Table 2). Enrollment of patients taking prophylactic lowdose aspirin ( 325 mg/day) or other antiplatelet agents (such as ticlopidine) was permitted in CLASS and proscribed in VIGOR. Patients with angina or congestive heart failure with symptoms at rest or with minimal activity were excluded from participation in VIGOR. The population enrolled in CLASS included more patients at risk for thromboembolic CV disease. During presentations at the FDA Arthritis Advisory Committee meetings, February 7–8, 2001, where results of the CLASS and the VIGOR trial were reviewed, CV safety issues potentially associated with administration of COX-2 selective agents were raised (3,4). This editorial will discuss these data and possible explanations for the findings.