The Risk of Major NSAID Toxicity with Celecoxib, Ibuprofen, or Naproxen: A Secondary Analysis of the PRECISION Trial

Am J Med. 2017 Dec;130(12):1415-1422.e4. doi: 10.1016/j.amjmed.2017.06.028. Epub 2017 Jul 26.


Background: The relative safety of long-term use of nonsteroidal anti-inflammatory drugs is unclear. Patients and providers are interested in an integrated view of risk . We examined the risk of major nonsteroidal anti-inflammatory drug toxicity in the PRECISION trial.

Methods: We conducted a post hoc analysis of a 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 to 200 mg twice daily, ibuprofen 600 to 800 mg thrice daily, or naproxen 375 to 500 mg twice daily. All patients were provided with a proton pump inhibitor. The outcome was major nonsteroidal anti-inflammatory drug 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 sustained any major toxicity in the celecoxib arm, 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 20% (95% CI 4-39) higher risk of major toxicity than celecoxib users and that 38% (95% CI 19-59) 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 1 in 20 experienced a major toxicity over 1 to 2 years. Patients using naproxen or ibuprofen experienced significantly higher risk of major toxicity than those using celecoxib.

Keywords: Cox-2 selective inhibitor; Drug toxicity; NSAID; Nonsteroidal anti-inflammatory drug; Randomized controlled trial.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Arthritis, Rheumatoid / drug therapy*
  • Celecoxib / adverse effects*
  • Cyclooxygenase 2 Inhibitors / adverse effects*
  • Double-Blind Method
  • Female
  • Humans
  • Ibuprofen / adverse effects*
  • Male
  • Middle Aged
  • Naproxen / adverse effects*
  • Osteoarthritis / drug therapy*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Naproxen
  • Celecoxib
  • Ibuprofen