The risk of major NSAID toxicity with celecoxib, ibuprofen or naproxen : a secondary analysis of the PRECISION trial

Background: The relative safety of long-term utilization of non-steroidal anti-inflammatory drugs (NSAIDs) is unclear. Patients and providers are interested in an integrated view of risk. We examined the risk of major NSAID toxicity in the PRECISION trial. Methods: We conducted a post-hoc analyses of double-blind randomized controlled multicenter trial enrolling 24,081 patients with osteoarthritis or rheumatoid arthritis at moderate or high cardiovascular risk. Patients were randomized to receive celecoxib 100-200mg twice daily, ibuprofen 600-800mg thrice daily, or naproxen 375-500mg twice daily. All patients were provided with a proton pump inhibitor. The outcome was major NSAID toxicity, including time to first occurrence of major adverse cardiovascular events, important gastrointestinal events, renal events and all-cause mortality. Results: During follow-up, 4.1% of subjects in the celecoxib arm sustained any major toxicity, 4.8% in the naproxen arm, and 5.3% in the ibuprofen arm. Analyses adjusted for aspirin use and geographic region found that subjects in the naproxen arm had a 19% (95% CI 1-39%) higher risk of major toxicity than celecoxib users and ibuprofen users had a 41% (95% CI 21-65%) higher risk. These risks translate into numbers needed to harm of 135 (95% CI 72-971) for naproxen and 82 (95% CI 53-173) for ibuprofen, both compared with celecoxib. Conclusions: Among patients with symptomatic arthritis who had moderate to high risk of cardiovascular events, approximately one in twenty experienced a major toxicity over 1-2 years. Patients using naproxen or ibuprofen experienced significantly higher risk of major toxicity than those using celecoxib.