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Jacques E. Rossouw, MD; Ross L. Prentice, PhD; JoAnn E. Manson, MD, DrPH; LieLing Wu, MSc; David Barad, MD; Vanessa M. Barnabei, MD, PhD; Marcia Ko, MD; Andrea Z. LaCroix, PhD; Karen L. Margolis, MD; Marcia L. Stefanick, PhD

JAMA. 2007;297:1465-1477.

Context  The timing of initiation of hormone therapy may influence its effect on cardiovascular disease.

Objective  To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began.

Design, Setting, and Participants  Secondary analysis of the Women's Health Initiative (WHI) randomized controlled trials of hormone therapy in which 10 739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16 608 postmenopausal women who had not had a hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998.

Main Outcome Measures  Statistical test for trend of the effect of hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials.

Results  In the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 379 cases of CHD and 239 cases of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval [CI], 0.50-1.16); 10 to 19 years, 1.10 (95% CI, 0.84-1.45); and 20 or more years, 1.28 (95% CI, 1.03-1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was –6 per 10 000 person-years; for women 10 to 19 years since menopause began, 4 per 10 000 person-years; and for women 20 or more years from menopause onset, 17 per 10 000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI, 0.65-1.33) and the absolute excess risk was –2 per 10 000 person-years; 60 to 69 years, 0.98 (95% CI, 0.79-1.21) and –1 per 10 000 person-years; and 70 to 79 years, 1.26 (95% CI, 1.00-1.59) and 19 per 10 000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06).

Conclusions  Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms.

Trial Registration  clinicaltrials.gov Identifier: NCT00000611

Author Affiliations: National Heart, Lung, and Blood Institute, Bethesda, Md (Dr Rossouw); Fred Hutchinson Cancer Research Center, Seattle, Wash (Drs Prentice and LaCroix and Ms Wu); Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (Dr Manson); Departments of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, New York, NY (Dr Barad); Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee (Dr Barnabei); Division of Women's Health Internal Medicine, Mayo Clinic, Scottsdale, Ariz (Dr Ko); Berman Center for Clinical Research, University of Minnesota, Minneapolis (Dr Margolis); Department of Medicine, Stanford University, Palo Alto, Calif (Dr Stefanick).

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