Dose escalation and the safety of celecoxib, ibuprofen, and naproxen: Analysis of the precision trial

Background: The PRECISION trial demonstrated the non-inferiority of celecoxib to ibuprofen or naproxen for cardiovascular (CV) safety in patients with arthritis. A comparison of the overall safety of each agent stratifed by drug dose has yet to be reported. Methods: Patients were randomized to lower-dose celecoxib 100 mg BID, ibuprofen 600 mg TID, or naproxen 375 mg BID. Patients could increase to higher-dose celecoxib 200 mg BID (for rheumatoid arthritis), ibuprofen 800 mg TID, or naproxen 500 mg BID for analgesia. The endpoint was composite major adverse cardiovascular events (CV death, myocardial infarction, unstable angina, stroke, transient ischemic attack), non-CV death, gastrointestinal, or renal events. Results were reported in the on-treatment population utilizing χ2 and logistic regression stratifed by dose. Results: Among the 23,947 patients randomized, 9,326 (38.9%) escalated dose (Table). In the lower-dose group, safety events were fewest with celecoxib compared to ibuprofen or naproxen (P<0.001). After adjustment, the odds of an event remained signifcantly greater for ibuprofen vs celecoxib (P<0.001), and borderline signifcant for naproxen vs celecoxib (P=0.054). In the higher-dose group, the safety event rate was similar among agents for all comparisons. Conclusion: At lower-dose, celecoxib associates with fewer safety events than ibuprofen or naproxen. The overall safety of celecoxib, naproxen, and ibuprofen is similar if these agents are taken at higher-dose.