Estrogen in the Prevention of Atherosclerosis

Coronary heart disease is the leading cause of death in women, and mortality rates from this disease substantially and steadily increase after menopause (13). Population studies indicate that estrogen reduces the incidence of coronary heart disease i... show more

Coronary heart disease is the leading cause of death in women, and mortality rates from this disease substantially and steadily increase after menopause (13). Population studies indicate that estrogen reduces the incidence of coronary heart disease in women. Bilateral oophorectomy before natural menopause increases the risk for coronary heart disease (4). This pattern of risk for coronary heart disease suggests that endogenous estrogens, including 17-estradiol, play a cardioprotective role before menopause. More than 40 observational studies have suggested that hormone replacement therapy (HRT) reduces cardiovascular morbidity and mortality in postmenopausal women (5, 6). Most of these studies were conducted in healthy postmenopausal women who used unopposed estrogen replacement therapy (ERT). Although observational studies are important, selection bias is a potential problem, especially when studying HRT, since healthier women tend to use hormones (7). Only randomized, controlled trials can ensure that patients are assigned to treatment in an unbiased manner and can establish the efficacy of HRT for reducing the progression of atherosclerosis and its clinical sequelae. The effect of unopposed ERT on progression of atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease remains untested in randomized, controlled trials. We report the results of the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), a randomized, double-blind, placebo-controlled trial designed to test whether unopposed micronized 17-estradiol reduces progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. Our primary hypothesis was that unopposed ERT significantly reduces the progression of subclinical atherosclerosis. Methods Study Design Potential participants were prescreened by telephone and seen at three screening visits 2 to 4 weeks apart to collect baseline data and to determine final study eligibility. Women were eligible if they were postmenopausal (serum estradiol level < 73.4 pmol/L [<20 pg/mL]), 45 years of age or older, and had a low-density lipoprotein (LDL) cholesterol level of 3.37 mmol/L or greater ( 130 mg/dL). Women were excluded if breast or gynecologic cancer had been diagnosed in the past 5 years or if these cancers were identified during screening; if they had previously used HRT for more than 10 years or had used HRT within 1 month of the first screening visit; if they had five or more hot flushes daily that interfered with daily activity and precluded randomization, diastolic blood pressure greater than 110 mm Hg, untreated thyroid disease, life-threatening disease with a survival prognosis of less than 5 years, total triglyceride level of 4.52 mmol/L or greater ( 400 mg/dL), high-density lipoprotein (HDL) cholesterol level less than 0.78 mmol/L (<30 mg/dL), or serum creatinine concentration greater than 221 mol/L (>2.5 mg/dL); or if they were current smokers. All women, including those with diabetes mellitus, were included provided that their fasting blood glucose level was less than 11.1 mmol/L (<200 mg/dL). All participants gave written informed consent, and the study protocol was approved by the University of Southern California Institutional Review Board. Packets of study medications were prepared in a blinded manner (to both the clinical staff and participants) before the start of the study. Computer-generated random numbers were used to assign participants to unopposed estradiol or placebo in one of eight strata, defined by LDL cholesterol level (<4.15 mmol/L [<160 mg/dL] or 4.15 mmol/L), previous duration of HRT use (<5 years or 5 years), and diabetes mellitus (yes or no). As a new participant was determined to be eligible for randomization, the next packet in sequence in the appropriate stratum was obtained and recorded. The Data Coordinating Center monitored adherence to sequential assignment of medication packets. The participants, gynecologists, clinical staff, and image analysts were blinded to treatment assignment. The data monitor and data analyst were blinded to treatment assignment until analyses were completed. Participants were followed every month for the first 6 months and every other month thereafter for a total of 2 years. All participants received dietary counseling according to step II American Heart Association dietary recommendations: 200 mg of cholesterol or less per day, 25% of energy as total-fat calories, and 7% of energy as saturated-fat calories. Dietary intake was monitored at each clinic visit by using 3-day dietary booklets (Nutrition Scientific, South Pasadena, California). Participants received lipid-lowering medication (primarily hydroxymethylglutaryl coenzyme A reductase inhibitors) if their LDL cholesterol level exceeded 4.15 mmol/L (160 mg/dL). Vital signs; clinical events; adherence; and use of nonstudy medications, dietary supplements, and nutriceuticals were ascertained at each visit. Carotid artery ultrasonography was performed at baseline (two visits 1 to 3 weeks apart) and every 6 months thereafter. The baseline intimamedia thickness was the average of the two measurements. Pelvic examination (and uterine ultrasonography in participants with a uterus), Papanicolou smear, and mammography were done yearly in all participants. Uterine biopsy was performed if endometrial thickness was 5 mm or more. Adverse clinical symptoms and bleeding were assessed by the study gynecologist, who was blinded to treatment assignment. The primary trial end point was the rate of change in intimamedia thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms (815). Power calculations indicated that a sample size of 200 (100 participants per treatment group) was needed to detect a treatment effect size (the standardized difference in progression rates between the two treatment groups) of 0.40 or greater with 80% power show less