title: Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.
abstract: BACKGROUND
  Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, but no clinical trials have demonstrated benefit to support their use.
  
  
  OBJECTIVE
  To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography.
  
  
  METHODS
  The Women's Angiographic Vitamin and Estrogen (WAVE) Trial, a randomized, double-blind trial of 423 postmenopausal women with at least one 15% to 75% coronary stenosis at baseline coronary angiography. The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada.
  
  
  METHODS
  Patients were randomly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily, or placebo.
  
  
  METHODS
  Annualized mean (SD) change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome.
  
  
  RESULTS
  The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P =.17); and for antioxidant vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P =.32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P =.045), and suggested an increased risk in the active vitamin group (P =.09). Fourteen patients died in the HRT group and 8 in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and 6 in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the 2 treatment interventions.
  
  
  CONCLUSIONS
  In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.
authors.affiliation: Division of Cardiology, Room 5G1, San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA 94110, USA. dwaters@medsfgh.ucsf.edu
authors.forename: David D
authors.initials: DD
authors.lastname: Waters
authors.forename: Edwin L
authors.initials: EL
authors.lastname: Alderman
authors.forename: Judith
authors.initials: J
authors.lastname: Hsia
authors.forename: Barbara V
authors.initials: BV
authors.lastname: Howard
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Cobb
authors.forename: William J
authors.initials: WJ
authors.lastname: Rogers
authors.forename: Pamela
authors.initials: P
authors.lastname: Ouyang
authors.forename: Paul
authors.initials: P
authors.lastname: Thompson
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Lyall
authors.initials: L
authors.lastname: Higginson
authors.forename: Vera
authors.initials: V
authors.lastname: Bittner
authors.forename: Michael
authors.initials: M
authors.lastname: Steffes
authors.forename: David J
authors.initials: DJ
authors.lastname: Gordon
authors.forename: Michael
authors.initials: M
authors.lastname: Proschan
authors.forename: Naji
authors.initials: N
authors.lastname: Younes
authors.forename: Joel I
authors.initials: JI
authors.lastname: Verter
mesh_terms: D000368:Aged; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000097:blood / Q000627:therapeutic use*; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D019587:Dietary Supplements; D004311:Double-Blind Method; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D017258:Medroxyprogesterone Acetate / Q000627:therapeutic use; D008875:Middle Aged; D017698:Postmenopause; D012306:Risk; D018709:Statistics, Nonparametric; D014810:Vitamin E / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D004966:Estrogens, Conjugated (USP); D008074:Lipoproteins; D014810:Vitamin E; D017258:Medroxyprogesterone Acetate; D001205:Ascorbic Acid