Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatorydrugs for osteoarthritis and rheumatoid arthritis - The CLASS study: A randomized controlled trial

Context Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are asso ciated with a spectrum of toxic effects, notably gastrointestinal (GI) effe cts, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specifi c inhibitors are associated with fewer clinical GI toxic effects is unknown . Objective To determine whether celecoxib, a COX-2-specific inhibitor, is as sociated with a lower incidence of significant upper GI toxic effects and o ther adverse effects compared with conventional NSAIDs. Design The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-bli nd, randomized controlled trial conducted from September 1998 to March 2000 . Setting Three hundred eighty-six clinical sites in the United States and Ca nada. Participants A total of 8059 patients (greater than or equal to 18 years ol d) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in t he study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. Interventions Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 m g twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (les s than or equal to 325 mg/d) was permitted. Main Outcome Measures Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period. Results For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs N SAIDs were 0.76% vs 1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectiv ely. For patients not taking aspirin, the annualized incidence rates of upp er GI ulcer complications alone and combined with symptomatic ulcers for ce lecoxib vs NSAIDs were 0.44% vs 1.27% (P = .04) and 1.40% vs 2.91% (P = .02 ). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxi b vs NSAIDs were 2.01% vs 2.12% (P = .92) and 4.70% vs 6.00% (P = .49). Few er celecoxib-treated patients than NSAID-treated patients experienced chron ic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No dif ference was noted in the incidence of cardiovascular events between celecox ib and NSAIDs, irrespective of aspirin use. Conclusions In this study, celecoxib, at dosages greater than those indicat ed clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important tox ic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly.