title: Nonsteroidal anti-inflammatory drugs and cardiovascular outcomes in women: results from the women's health initiative.
abstract: BACKGROUND
  Conclusive data about cardiovascular toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for cardiovascular events in postmenopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 when compared with cox-1 inhibition.
  
  
  RESULTS
  Postmenopausal women enrolled in the Women's Health Initiative were classified as regular users or nonusers of nonaspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total cardiovascular disease defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (eg, celecoxib), nonselective agents with cox-2>cox-1 inhibition (eg, naproxen), and nonselective agents with cox-1>cox-2 inhibition (eg, ibuprofen) with the primary outcome. Overall, 160 801 participants were available for analysis (mean follow-up, 11.2 years). Regular NSAID use at some point in time was reported by 53 142 participants. Regular NSAID use was associated with an increased hazard for cardiovascular events versus no NSAID use (hazard ratio [HR], 1.10; 95% confidence interval, 1.06-1.15; P<0.001). Selective cox-2 inhibitors were associated with a modest increased hazard for cardiovascular events (hazard ratio, 1.13; 1.04-1.23; P=0.004 and celecoxib only: HR, 1.13; 1.01-1.27; P=0.031). Among aspirin users, concomitant selective cox-2 inhibitor use was no longer associated with increased hazard for cardiovascular events. There was an increased risk for agents with cox-2>cox-1 inhibition (HR, 1.17; 1.10-1.24; P<0.001 and naproxen only: HR, 1.22; 1.12-1.34; P<0.001). This harmful association remained among concomitant aspirin users. We did not observe a risk elevation for agents with cox-1>cox-2 inhibition (HR, 1.01; 0.95-1.07; P=0.884 and ibuprofen only: HR, 1.00; 0.93-1.07; P=0.996).
  
  
  CONCLUSIONS
  Regular use of selective cox-2 inhibitors and nonselective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for cardiovascular events. Nonselective agents with cox-1>cox-2 inhibition were not associated with increased cardiovascular risk.
  
  
  BACKGROUND
  www.clinicaltrials.gov. Unique identifier: NCT00000611.
authors.affiliation: From the North Florida/South Georgia Veterans Health System, Gainesville, FL (A.A.B); Division of Cardiovascular Medicine, University of Florida, Gainesville (A.A.B., M.C.L.); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (F.T., K.C.J.); Division of Preventive Medicine, University of California, San Diego, La Jolla (M.A.); MedStar Health Research Institute, Hyattsville, MD (B.V.H.); Health Research and Policy/Cardiovascular Medicine, Stanford University, CA (M.H.); and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.). bavryaa@medicine.ufl.edu.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Bavry
authors.affiliation: From the North Florida/South Georgia Veterans Health System, Gainesville, FL (A.A.B); Division of Cardiovascular Medicine, University of Florida, Gainesville (A.A.B., M.C.L.); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (F.T., K.C.J.); Division of Preventive Medicine, University of California, San Diego, La Jolla (M.A.); MedStar Health Research Institute, Hyattsville, MD (B.V.H.); Health Research and Policy/Cardiovascular Medicine, Stanford University, CA (M.H.); and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.).
authors.forename: Fridtjof
authors.initials: F
authors.lastname: Thomas
authors.affiliation: From the North Florida/South Georgia Veterans Health System, Gainesville, FL (A.A.B); Division of Cardiovascular Medicine, University of Florida, Gainesville (A.A.B., M.C.L.); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (F.T., K.C.J.); Division of Preventive Medicine, University of California, San Diego, La Jolla (M.A.); MedStar Health Research Institute, Hyattsville, MD (B.V.H.); Health Research and Policy/Cardiovascular Medicine, Stanford University, CA (M.H.); and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Allison
authors.affiliation: From the North Florida/South Georgia Veterans Health System, Gainesville, FL (A.A.B); Division of Cardiovascular Medicine, University of Florida, Gainesville (A.A.B., M.C.L.); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (F.T., K.C.J.); Division of Preventive Medicine, University of California, San Diego, La Jolla (M.A.); MedStar Health Research Institute, Hyattsville, MD (B.V.H.); Health Research and Policy/Cardiovascular Medicine, Stanford University, CA (M.H.); and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.).
authors.forename: Karen C
authors.initials: KC
authors.lastname: Johnson
authors.affiliation: From the North Florida/South Georgia Veterans Health System, Gainesville, FL (A.A.B); Division of Cardiovascular Medicine, University of Florida, Gainesville (A.A.B., M.C.L.); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (F.T., K.C.J.); Division of Preventive Medicine, University of California, San Diego, La Jolla (M.A.); MedStar Health Research Institute, Hyattsville, MD (B.V.H.); Health Research and Policy/Cardiovascular Medicine, Stanford University, CA (M.H.); and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.).
authors.forename: Barbara V
authors.initials: BV
authors.lastname: Howard
authors.affiliation: From the North Florida/South Georgia Veterans Health System, Gainesville, FL (A.A.B); Division of Cardiovascular Medicine, University of Florida, Gainesville (A.A.B., M.C.L.); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (F.T., K.C.J.); Division of Preventive Medicine, University of California, San Diego, La Jolla (M.A.); MedStar Health Research Institute, Hyattsville, MD (B.V.H.); Health Research and Policy/Cardiovascular Medicine, Stanford University, CA (M.H.); and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.).
authors.forename: Mark
authors.initials: M
authors.lastname: Hlatky
authors.affiliation: From the North Florida/South Georgia Veterans Health System, Gainesville, FL (A.A.B); Division of Cardiovascular Medicine, University of Florida, Gainesville (A.A.B., M.C.L.); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (F.T., K.C.J.); Division of Preventive Medicine, University of California, San Diego, La Jolla (M.A.); MedStar Health Research Institute, Hyattsville, MD (B.V.H.); Health Research and Policy/Cardiovascular Medicine, Stanford University, CA (M.H.); and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.).
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.affiliation: From the North Florida/South Georgia Veterans Health System, Gainesville, FL (A.A.B); Division of Cardiovascular Medicine, University of Florida, Gainesville (A.A.B., M.C.L.); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (F.T., K.C.J.); Division of Preventive Medicine, University of California, San Diego, La Jolla (M.A.); MedStar Health Research Institute, Hyattsville, MD (B.V.H.); Health Research and Policy/Cardiovascular Medicine, Stanford University, CA (M.H.); and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.).
authors.forename: Marian C
authors.initials: MC
authors.lastname: Limacher
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D016387:Women's Health
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal
keywords: anti-inflammatory agents, non-steroidal; coronary artery disease; myocardial infarction; stroke