Steven E. Nissen, M.D., Neville D. Yeomans, M.D., Daniel H. Solomon, M.D., M.P.H., Thomas F. Lüscher, M.D., Peter Libby, M.D., M. Elaine Husni, M.D., David Y. Graham, M.D., Jeffrey S. Borer, M.D., Lisa M. Wisniewski, R.N., Katherine E. Wolski, M.P.H., Qiuqing Wang, M.S., Venu Menon, M.D., Frank Ruschitzka, M.D., Michael Gaffney, Ph.D., Bruce Beckerman, M.D., Manuela F. Berger, M.D., Weihang Bao, Ph.D., and A. Michael Lincoff, M.D., for the PRECISION Trial Investigators*
N Engl J Med 2016; :2519-2529December 29, 2016DOI: 10.1056/NEJMoa1611593
The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain.
Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated.
A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). CONCLUSIONS At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216.) Supported by Pfizer. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Dr. Solomon and Dr. Lüscher report receiving grant support to their institutions from Pfizer; Dr. Libby, receiving consulting fees from MedIntelligence, lecture fees from MedIntelligence, Omniprex, and HealthScience Media, and travel support from the Academy for Continued Healthcare Learning (ACHL), Healthcare21 Communications, PSL Group Services, MEDCON International, Regeneron Pharmaceuticals, Esperion Therapeutics, Takeda, Bayer Yakuhin, and Amgen, serving on advisory boards (uncompensated) for Regeneron Pharmaceuticals, Merck, and Novartis, chairing a peer review of grant applications (uncompensated) for Healthmatters Communications, providing consulting (uncompensated) for GlaxoSmithKline, Medintelligence, and Regeneron Pharmaceuticals, and giving talks (uncompensated) at meetings held by Rx Worldwide Meetings, Pri-Med, VHA-UHC Alliance NewCo (now Vizient), AstraZeneca, and Tarsus; Dr. Husni, receiving fees for serving on advisory boards from AbbVie, Bristol-Myers Squibb, Amgen, UCB Pharma, Regeneron, and Janssen, and grant support from Sanofi–Genzyme; Dr. Borer, receiving fees for serving on data and safety monitoring boards from Cardiorentis, Novartis, Celladon, GlaxoSmithKline, and Pfizer, fees for serving on executive committees from Servier and Biotronik, fees for serving on event adjudication committees from AstraZeneca and Takeda, fees for serving on an advisory board from ARMGO Pharma, consulting fees from Boehringer Ingelheim, Abbott Laboratories, Sarepta Therapeutics, Amgen, Servier, and Gilead Sciences, and holding stock in BioMarin Pharmaceutical; Dr. Ruschitzka, receiving personal fees from St. Jude Medical, Servier, ZOLL Medical, AstraZeneca, HeartWare, Sanofi, Cardiorentis, Novartis, Amgen, and Bristol-Myers Squibb, and grant support from St. Jude Medical; Dr. Gaffney, Dr. Beckerman, Dr. Berger, and Dr. Bao, being employees of Pfizer; and Dr. Lincoff, receiving fees for serving on advisory panels for the Food and Drug Administration from Abbott, Amgen, and Sarepta, and grant support to his institution from Eli Lilly, Roche, CSL Behring, Esperion Therapeutics, and AstraZeneca. No other potential conflict of interest relevant to this article was reported. This article was published on November 13, 2016, and last updated on December 2, 2016, at NEJM.org. SOURCE INFORMATION From the Cleveland Clinic, Cleveland (S.E.N., M.E.H., L.M.W., K.E.W., Q.W., V.M., A.M.L.); Western Sydney University, Campbelltown, NSW, Australia (N.D.Y.); Brigham and Women’s Hospital, Harvard Medical School, Boston (D.H.S., P.L.); University Hospital Zurich, Zurich, Switzerland (T.F.L., F.R.); Baylor College of Medicine, Veterans Affairs Medical Center, Houston (D.Y.G.); and State University of New York, Downstate Health Sciences Center (J.S.B.) and Pfizer (M.G., B.B., M.F.B., W.B.), New York. Address reprint requests to Dr. Nissen at Cleveland Clinic J2-230, 9500 Euclid Ave., Cleveland, OH 44195, or at email@example.com. A complete list of the committees, study centers, and investigators participating in the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial is provided in the Supplementary Appendix, available at NEJM.org. [/et_pb_text][/et_pb_column][/et_pb_row][/et_pb_section]