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Coronary heart disease events in the Women’s Health Initiative hormone trials: effect modification by metabolic syndromeA nested case-control study within the Women’s Health Initiative randomized clinical trials

Wild, Robert A. MD, MPH, PhD1; Wu, Chunyuan MS2; Curb, J. D. MD, MPH3✠; Martin, Lisa W. MD4; Phillips, Lawrence MD5; Stefanick, Marcia PhD6; Trevisan, Maurizio MD7; Manson, JoAnn E. MD, DrPH8

Menopause: The Journal of The North American Menopause Society: March 2013 - Volume 20 - Issue 3 - p 254–260
doi: 10.1097/gme.0b013e31826f80e0
Original Articles

Objective Our objective was to determine whether metabolic syndrome (MetS) or its components modified the effect of hormone therapy (HT) on the risk of coronary heart disease (CHD) events in the Women’s Health Initiative clinical trials.

Methods We performed a nested case-control study of incident CHD events during the first 4 years of follow-up in the Women’s Health Initiative HT trials (estrogen plus progestin therapy [EPT] and estrogen therapy [ET]). There were 359 incident cases of CHD during follow-up. After the exclusion of women with cardiovascular disease (n = 90), diabetes, or hypertension at baseline (n = 103), 166 CHD cases were matched to 524 controls on age, randomization date, and hysterectomy status. MetS classification required at least three of five Adult Treatment Panel III criteria. Analyses by χ 2 and t tests for heterogeneity and logistic regression were performed. Postmenopausal women (n = 27,347) aged 50 to 79 years from 40 US clinical centers participated. Daily conjugated equine estrogens (0.625 mg) and medroxyprogesterone acetate (2.5 mg; EPT) or conjugated equine estrogens (0.625 mg; ET) were compared with placebo. The main outcome measure was the odds for CHD with HT use versus placebo by MetS status.

Results MetS modified the risk of CHD events with HT. In the pooled analysis, risk was increased with HT versus placebo in women with MetS (odds ratio, 2.26; 95% CI, 1.26-4.07), whereas women without MetS were not found to have an increased risk for a CHD event with HT (odds ratio, 0.97; 95% CI, 0.58-1.61; P for interaction = 0.03). Results of the EPT and ET trials, when examined separately, were similar. The constellation of MetS variables was more predictive of risk from HT than MetS components assessed individually. When women with diabetes or hypertension were included in the analysis, statistically significant effect modification was not detected.

Conclusions MetS at baseline in women without prior cardiovascular disease, diabetes, or hypertension at baseline identifies women who are more likely to have had adverse coronary outcomes on HT. CHD risk stratification is recommended before initiating HT. The basis for the greater risk of CHD events with HT among women with MetS requires further study.

From the 1Clinical Epidemiology and Obstetrics and Gynecology, Oklahoma University Health Sciences Center, Oklahoma City, OK; 2Fred Hutchinson Cancer Research Center, Seattle, WA; 3Office of Public Health Studies, University of Hawaii, Honolulu, HI; 4Division of Cardiology, George Washington University School of Medicine, Washington, DC; 5Clinical Studies Center, Emory University, Atlanta, GA; 6Stanford Prevention Research Center, Palo Alto, CA; 7Nevada Health Sciences System, Las Vegas, NV; and 8Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Received April 26, 2012; revised and accepted July 9, 2012.


J.E.M. was co-convener.

Funding/support: The Women’s Health Initiative program was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The funding agency participated in the design, oversight, and monitoring of clinical trials, and the Women’s Health Initiative Publications and Presentations committee approved the final manuscript.

Financial disclosure/conflicts of interest: L.W.M. received research support from Merck, Lilly, Amylin, Novo Nordisk, Roche, Diasome, and Sanofi, but has not served as speaker or advisory board member in the past 2years. L.P. received research support from Novo Nordisk, Sanofi, Eli Lilly, Amylin, Novartis, Merck, Roche, and National Institutes of Health.

Address correspondence to: Robert A. Wild, MD, MPH, PhD, 2410 WP, 920 S. L. Young Boulevard, Oklahoma City, OK 73104. E-mail:

© 2013 by The North American Menopause Society.