title: Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.
abstract: OBJECTIVE
  We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials.
  
  
  METHODS
  The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6.
  
  
  METHODS
  The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States.
  
  
  METHODS
  The trials enrolled 27,347 postmenopausal women, aged 50-79 y.
  
  
  METHODS
  We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.
  
  
  METHODS
  Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.
  
  
  RESULTS
  Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68-1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86-2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57-1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69-1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified.
  
  
  CONCLUSIONS
  Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results.
authors.affiliation: Department of Medicine, George Washington University, Washington, DC, United States of America. jhsia@mfa.gwu.edu
authors.forename: Judith
authors.initials: J
authors.lastname: Hsia
authors.forename: Joann E
authors.initials: JE
authors.lastname: Manson
authors.forename: Lewis
authors.initials: L
authors.lastname: Kuller
authors.forename: Mary
authors.initials: M
authors.lastname: Pettinger
authors.forename: John H
authors.initials: JH
authors.lastname: Choe
authors.forename: Robert D
authors.initials: RD
authors.lastname: Langer
authors.forename: Marian
authors.initials: M
authors.lastname: Limacher
authors.forename: Albert
authors.initials: A
authors.lastname: Oberman
authors.forename: Judith
authors.initials: J
authors.lastname: Ockene
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: O'Sullivan
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Robinson