Abstract-Postmenopausal hormone replacement therapy (HRT) is associated with low cardiovascular morbidity and mortality in epidemiological studies. Yet, no randomized trial has examined whether HRT is effective for prevention of coronary heart disease (CHD) in women with increased risk. bservational studies consistently found a 30% to 35% decreased risk of coronary heart disease (CHD) among postmenopausal women who use hormone replacement therapy (HRT). 1,2 There is no evidence that HRT influences the risk of stroke. 3 Several effects of estrogen on the cardiovascular system suggest a potential for protection. 4 The only randomized trial with clinical end points (Heart and Estrogen/ progestin Replacement Study, HERS) failed to demonstrate the efficacy of estrogen plus medroxyprogesterone for secondary prevention in women with CHD. 5 Among other reasons, medroxyprogesterone acetate, which is known to attenuate some of the beneficial effects of estrogen, 6 -9 has been discussed as a cause for the unexpected results of HERS. 10 Initiation of HRT after myocardial infarction is no longer recommended. 11 To date, no randomized trial has addressed the efficacy of HRT for women with increased risk for CHD who potentially benefit most, as indicated by epidemiological data. 1,12 Intima-media thickness (IMT) of the carotid arteries correlates with the presence, extent, and severity of atherosclerosis in coronary and other arteries. [13][14][15][16][17] IMT of the carotid arteries consistently and partially independently of traditional risk factors predicts future myocardial infarction and stroke. 18 -22 Change of carotid IMT is currently an established intermediate end point for clinical trials that study the inhibitory effect of an intervention on atherogenesis. 23,24 The present randomized, controlled, observer-blind trial investigated the hypothesis that HRT with estrogen and progestin inhibits progression of carotid artery IMT in postmenopausal women with increased IMT as a sign of subclinical disease and increased risk for CHD and stroke. It was further hypothesized that the inhibitory effect of estrogen balanced with low-dose progestin would be superior to the combination with high-dose progestin.
Methods
SubjectsBetween March 1995 and September 1996, women living in the greater Munich area who heard about the study through the local media contacted us for more detailed information (Figure). They were eligible if they had passed natural (cessation of bleeding) or surgical menopause for Ն1 year or, in case of hysterectomy, had follicle-stimulating hormone (FSH) levels Ͼ40 IU/L, were between 40 and 70 years old, had Ͼ1 mm IMT in Ն1 of the predefined segments of the carotid arteries, and gave informed consent. (For exclusion criteria, please see supplemental Methods section at