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A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease

Francine Grodstein, ScD; JoAnn E. Manson, MD; Graham A. Colditz, MD; Walter C. Willett, MD; Frank E. Speizer, MD; and Meir J. Stampfer, MD
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Copyright ©2004 by the American College of Physicians


Ann Intern Med. 2000;133(12):933-941. doi:10.7326/0003-4819-133-12-200012190-00008
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Background: Most primary prevention studies have found that long-term users of postmenopausal hormone therapy are at lower risk for coronary events, but numerous questions remain. An adverse influence of hormone therapy on cardiovascular risk has been suggested during the initial year of use; however, few data are available on short-term hormone therapy. In addition, the cardiovascular effects of daily doses of oral conjugated estrogen lower than 0.625 mg are unknown, and few studies have examined estrogen plus progestin in this regard.

Objective: To investigate duration, dose, and type of postmenopausal hormone therapy and primary prevention of cardiovascular disease.

Design: Prospective, observational cohort study.

Setting: Nurses' Health Study, with follow-up from 1976 to 1996.

Patients: 70 533 postmenopausal women, in whom 1258 major coronary events (nonfatal myocardial infarction or fatal coronary disease) and 767 strokes were identified.

Measurements: Details of postmenopausal hormone use were ascertained by using biennial questionnaires. Cardiovascular disease was established by using a questionnaire and was confirmed by medical record review. Logistic regression models were used to calculate relative risks and 95% CIs, adjusted for confounders.

Results: When all cardiovascular risk factors were considered, the risk for major coronary events was lower among current users of hormone therapy, including short-term users, compared with never-users (relative risk, 0.61 [95% CI, 0.52 to 0.71]). Among women taking oral conjugated estrogen, the risk for coronary events was similarly reduced in those currently taking 0.625 mg daily (relative risk, 0.54 [CI, 0.44 to 0.67]) and those taking 0.3 mg daily (relative risk, 0.58 [CI, 0.37 to 0.92]) compared with never-users. However, the risk for stroke was statistically significantly increased among women taking 0.625 mg or more of oral conjugated estrogen daily (relative risk, 1.35 [CI, 1.08 to 1.68] for 0.625 mg/d and 1.63 [CI, 1.18 to 2.26] for ≥ 1.25 mg/d) and those taking estrogen plus progestin (relative risk, 1.45 [CI, 1.10 to 1.92]). Overall, little relation was observed between combination hormone therapy and risk for cardiovascular disease (major coronary heart disease plus stroke) (relative risk, 0.91 [CI, 0.75 to 1.11]).

Conclusions: Postmenopausal hormone use appears to decrease risk for major coronary events in women without previous heart disease. Furthermore, 0.3 mg of oral conjugated estrogen daily is associated with a reduction similar to that seen with the standard dose of 0.625 mg. However, estrogen at daily doses of 0.625 mg or greater and in combination with progestin may increase risk for stroke.

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