Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.
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.
Waters
David D
DD
Division of Cardiology, Room 5G1, San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA 94110, USA. dwaters@medsfgh.ucsf.edu
Alderman
Edwin L
EL
Hsia
Judith
J
Howard
Barbara V
BV
Cobb
Frederick R
FR
Rogers
William J
WJ
Ouyang
Pamela
P
Thompson
Paul
P
Tardif
Jean Claude
JC
Higginson
Lyall
L
Bittner
Vera
V
Steffes
Michael
M
Gordon
David J
DJ
Proschan
Michael
M
Younes
Naji
N
Verter
Joel I
JI
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*
D000975:Antioxidants; D004966:Estrogens, Conjugated (USP); D008074:Lipoproteins; D014810:Vitamin E; D017258:Medroxyprogesterone Acetate; D001205:Ascorbic Acid