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Michael J. Langman, MD; Dennis M. Jensen, MD; Douglas J. Watson, PhD; Sean E. Harper, MD; Peng-Liang Zhao, PhD; Hui Quan, PhD; James A. Bolognese, MS; Thomas J. Simon, MD

JAMA. 1999;282:1929-1933.

Context  Nonsteroidal anti-inflammatory drug (NSAID)–induced gastrointestinal (GI) toxic effects, such as upper GI tract perforations, symptomatic gastroduodenal ulcers, and upper GI tract bleeding (PUBs), are thought to be attributable to cyclooxygenase 1 (COX-1) inhibition. Rofecoxib specifically inhibits COX-2 and has demonstrated a low potential for causing upper GI injury.

Objective  To compare the incidence of PUBs in patients with osteoarthritis treated with rofecoxib vs NSAIDs.

Design  Prespecified analysis of all 8 double-blind, randomized phase 2b/3 rofecoxib osteoarthritis trials conducted from December 1996 through March 1998, including one 6-week dose-ranging study, two 6-week efficacy studies vs ibuprofen and placebo, two 1-year efficacy studies vs diclofenac, two 6-month endoscopy studies vs ibuprofen and placebo, and one 6-week efficacy study vs nabumetone and placebo.

Setting  Multinational sites.

Participants  Osteoarthritis patients (N = 5435; mean age, 63 years [range, 38-94 years]; 72.9% women).

Interventions  Rofecoxib, 12.5, 25, or 50 mg/d (n = 1209, 1603, and 545, respectively, combined) vs ibuprofen, 800 mg 3 times per day (n = 847), diclofenac, 50 mg 3 times per day (n = 590); or nabumetone, 1500 mg/d (n = 127) (combined).

Main Outcome Measure  Cumulative incidence of PUBs for rofecoxib vs NSAIDs, based on survival analysis of time to first PUB diagnosis, using PUBs that met prespecified criteria judged by a blinded, external adjudication committee.

Results  The incidence of PUBs over 12 months was significantly lower with rofecoxib vs NSAIDs (12-month cumulative incidence, 1.3% vs 1.8%; P = .046; rate per 100 patient-years, 1.33 vs 2.60; relative risk, 0.51; 95% confidence interval, 0.26-1.00). The cumulative incidence of dyspeptic GI adverse experiences was also lower with rofecoxib vs NSAIDS over 6 months (23.5% vs 25.5%; P = .02), after which the incidence rates converged.

Conclusion  In a combined analysis of 8 trials of patients with osteoarthritis, treatment with rofecoxib was associated with a significantly lower incidence of PUBs than treatment with NSAIDs.

Author Affiliations: Department of Medicine, University of Birmingham, Birmingham, England (Dr Langman); Department of Medicine, University of California, Los Angeles Center for the Health Sciences (Dr Jensen); and Merck Research Laboratories, Merck & Co Inc, West Point, Pa (Drs Watson, Harper, Zhao, Quan, Simon, and Mr Bolognese).

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