Author + information
- Received January 15, 2018
- Accepted February 6, 2018
- Published online April 16, 2018.
- Grant W. Reed, MD, MSca,b,
- Mouin S. Abdallah, MD, MSca,b,
- Mingyuan Shao, MSa,
- Kathy Wolski, MPHa,
- Lisa Wisniewski, RNa,
- Neville Yeomans, MDc,
- Thomas F. Lüscher, MDd,
- Jeffrey S. Borer, MDe,
- David Y. Graham, MDf,
- M. Elaine Husni, MD, MPHg,
- Daniel H. Solomon, MD, MPHh,
- Peter Libby, MDh,
- Venu Menon, MDa,b,
- A. Michael Lincoff, MDa,b and
- Steven E. Nissen, MDa,b,∗ ()
- aDepartment of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
- bCleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
- cUniversity of Melbourne Department of Medicine, Austin Health, Melbourne, Victoria, and Western Sydney University, Campbelltown, New South Wales, Australia
- dRoyal Brompton & Harefield Hospitals Trust and Imperial College, London, United Kingdom
- eSchiavone Cardiovascular Translational Research Institute, State University of New York, Downstate Medical Center and College of Medicine, Brooklyn and New York, New York
- fBaylor College of Medicine, Veterans Affairs Medical Center, Houston, Texas
- gDepartment of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio
- hBrigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Steven E. Nissen, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk J2-3, Cleveland, Ohio 44195.
Background The safety of nonsteroidal anti-inflammatory drug (NSAID) and aspirin coadministration is uncertain.
Objectives The aim of this study was to compare the safety of combining NSAIDs with low-dose aspirin.
Methods This analysis of the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) trial included 23,953 patients with osteoarthritis or rheumatoid arthritis at increased cardiovascular risk randomized to celecoxib, ibuprofen, or naproxen. The on-treatment population was used for this study. Outcomes included composite major adverse cardiovascular events, noncardiovascular death, gastrointestinal or renal events, and components of the composite. Cox proportional hazards models compared outcomes among NSAIDs stratified by aspirin use following propensity score adjustment. Kaplan-Meier analysis was used to compare the cumulative probability of events.
Results When taken without aspirin, naproxen or ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (hazard ratio [HR]: 1.52; 95% confidence interval [CI]: 1.22 to 1.90, p <0.001; and HR: 1.81; 95% CI: 1.46 to 2.26; p <0.001, respectively). Compared with celecoxib, ibuprofen had more major adverse cardiovascular events (p < 0.05), and both ibuprofen and naproxen had more gastrointestinal (p < 0.001) and renal (p < 0.05) events. Taken with aspirin, ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (HR: 1.27; 95% CI: 1.06 to 1.51; p < 0.01); this was not significantly higher with naproxen (HR: 1.18; 95% CI: 0.98 to 1.41; p = 0.08). Among patients on aspirin, major adverse cardiovascular events were similar among NSAIDs, and compared with celecoxib, ibuprofen had more gastrointestinal and renal events (p < 0.05), while naproxen had more gastrointestinal events (p < 0.05), without a difference in renal events. Similar results were seen on adjusted Kaplan-Meier analysis.
Conclusions Celecoxib has a more favorable overall safety profile than naproxen or ibuprofen when taken without aspirin. Adding aspirin attenuates the safety advantage of celecoxib, although celecoxib is still associated with fewer gastrointestinal events than ibuprofen or naproxen and fewer renal events than ibuprofen. (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen [PRECISION]; NCT00346216)
This study was funded by Pfizer. Mr. Shao has received grant support from Pfizer to the institution for the PRECISION trial. Ms. Wolski has received grant support from Pfizer to the institution for the PRECISION trial. Ms. Wisniewski has received grant support from Pfizer to the institution for the PRECISION trial. Dr. Yeomans has received payment for membership on a Pfizer advisory board. Dr. Luscher has received grant support to the institution from Abbott, AstraZeneca, Bayer Health Care, Biotronik, Boston Scientific, Eli Lilly, Medtronic, Novartis, Servier, and St. Jude; and personal fees from Bayer Health Care for membership on the adjudication committee in the ARIVE trial. Dr. Borer served as chair of a data and safety monitoring board for an unrelated product being developed by Pfizer; has served as a consultant, trial executive committee member, data and safety monitoring board member, or cardiac event adjudication committee member for unrelated products for Amgen, Novartis, AstraZeneca, Takeda, Biotronik, Servier, GlaxoSmithKline, Gilead, and ARMGO; and owns stock in BioMarin and ARMGO. Dr. Graham is a consultant for RedHill Biopharma regarding novel Helicobacter pylori therapies; has received research support from RedHill Biopharma for culture of H. pylori; is the principal investigator of an international study of the use of antimycobacterial therapy for Crohn’s disease; and is a consultant for BioGaia in relation to probiotic therapy for H. pylori infection and for Takeda in relation to H. pylori therapies. Dr. Husni has received an institution grant to perform the PRECISION trial; has received a Sanofi Genzyme investigator grant; and has served on advisory boards for AbbVie, Bristol-Myers Squibb, Amgen, UCB, Regeneron, and Janssen. Dr. Solomon has received a research grant from Pfizer for unrelated work; and has received royalties from UpToDate for a chapter about NSAIDs. Dr. Libby has been an unpaid consultant to or has been involved in clinical trials for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Merck, Novartis, Pfizer, Sanofi-Regeneron, Takeda Pharmaceuticals, and XBiotech; has served as a member of scientific advisory boards for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, and Novartis; and his laboratory has received research funding in the past 2 years from Novartis. Dr. Menon has received grant support to the institution to perform the PRECISION trial. Dr. Lincoff has received grant support to the institution to perform the PRECISION trial; is a consultant for Amgen, Novo, Nordisk, Sanofi, Abbott, Sarpeta, and Sermonix; and has received research grants to his institution from Pfizer, AstraZeneca, Esperion, AbbVie, Eli Lilly, and Roche. Dr. Nissen has received grant support to the institution to perform the PRECISION trial. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received January 15, 2018.
- Accepted February 6, 2018.
- 2018 American College of Cardiology Foundation