title: Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis.
abstract: 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).
  
  
  
  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 .).
authors.affiliation: 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.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
authors.affiliation: 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.
authors.forename: Neville D
authors.initials: ND
authors.lastname: Yeomans
authors.affiliation: 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.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Solomon
authors.affiliation: 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.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: 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.
authors.forename: M Elaine
authors.initials: ME
authors.lastname: Husni
authors.affiliation: 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.
authors.forename: David Y
authors.initials: DY
authors.lastname: Graham
authors.affiliation: 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.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Borer
authors.affiliation: 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.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wisniewski
authors.affiliation: 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.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Wolski
authors.affiliation: 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.
authors.forename: Qiuqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Venu
authors.initials: V
authors.lastname: Menon
authors.affiliation: 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.
authors.forename: Frank
authors.initials: F
authors.lastname: Ruschitzka
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Gaffney
authors.affiliation: 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.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beckerman
authors.affiliation: 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.
authors.forename: Manuela F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: 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.
authors.forename: Weihang
authors.initials: W
authors.lastname: Bao
authors.affiliation: 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.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy*; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000401:mortality; D000068579:Celecoxib / Q000009:adverse effects* / Q000627:therapeutic use; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects* / Q000627:therapeutic use; D057194:Intention to Treat Analysis; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000009:adverse effects* / Q000627:therapeutic use; D012306:Risk
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D009288:Naproxen; D000068579:Celecoxib; D007052:Ibuprofen