Estrogen in the Prevention of Atherosclerosis Trial - EPAT


The goal of the EPAT trial was to determine the effect of unopposed estrogen replacement therapy (ERT) on the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease.


Unopposed ERT significantly reduces the progression of subclinical atherosclerosis in healthy postmenopausal women.

Study Design

Study Design:

Patients Screened: 422
Patients Enrolled: 199
Mean Follow Up: 2 years
Mean Patient Age: mean age 62 years
Female: 100

Patient Populations:

Postmenopausal women (a serum estradiol <20 pg/ml), age >=45 years, no clinical evidence of cardiovascular disease, and an LDL cholesterol level >=130 mg/dL.


Breast or gynecologic cancer diagnosed in the past 5 years or if these cancers were identified during screening; previously used HRT for >10 years or had used HRT within 1 month of the first screening visit; >=5 hot flushes daily that interfered with daily activity and precluded randomization; diastolic blood pressure >110 mm Hg; untreated thyroid disease; life-threatening disease with a survival prognosis of <5 years; total triglyceride level of >=400 mg/dL); HDL level <30 mg/dL; serum creatinine concentration >2.5 mg/dL); current smokers.

Primary Endpoints:

The rate of change at the right distal common carotid artery (CCA)- far wall intima-media thickness (IMT) as measured by computer-image processed B-mode ultrasonography obtained at baseline and every 6 months on trial.

Drug/Procedures Used:

Patients were randomized to unopposed micronized 17b-estradiol (1 mg/d) (n=97) versus placebo (n=102). All women received dietary counseling (<200 mg/d cholesterol, 25% of energy as total fat calories, 7% of energy as saturated fat calories).

Concomitant Medications:

Women who had low-density lipoprotein (LDL) cholesterol levels >160 mg/dL (n = 122) received lipid-lowering medication (primarily HMG-CoA reductase inhibitor), which accounted for 57% of the women in the estradiol group and 66% of the placebo group.

Principal Findings:

Baseline characteristics were well matched between the 2 arms. Pill compliance was high and did not differ by treatment arm (overall, 92% placebo vs 95% estradiol, p=0.08). In the primary intent-to-treat analysis, patients on average had >5 IMT measurements. The annualized progression rate of carotid IMT was significantly lower with estradiol versus placebo (-0.0017 mm/y vs 0.0036; mean difference 0.0053 mm/y; p=0.046). For the 77 patients who received no lipid-lowering therapy, the treatment group difference was significantly greater (mean difference between estradiol and placebo 0.0147 mm/y; p=0.002), mainly due to a greater progression rate in the placebo group (0.0134 mm/y). However, among patients receiving lipid-lowering medication, there was no significant difference between the study groups (-0.0019 mm/y for estradiol vs -0.0016 mm/y for placebo; difference, 0.0003 mm/y p>0.2). Although the study was not powered to look at events, researchers noted that there were 9 total cardiovascular events in 7 subjects with no difference between treatment groups. One placebo patient had breast cancer, and there were no other cancers, nor were there any deep vein thromboses or pulmonary emboli.


Among healthy postmenopausal women without preexisting cardiovascular disease, treatment with the unopposed ERT estradiol was associated with a reduction in carotid IMT progression through 2 years of follow-up. Recently, questions have been raised regarding the value of hormone replacement therapy (HRT) for preventing cardiovascular events. The Heart and Estrogen/progestin Replacement Study (HERS) (JAMA 1998; 280:605-613) did not support the general optimism about the use of HRT for prevention of cardiovascular disease that had been inspired by other studies. After an average of 4.1 years of follow up, there were no significant differences between the groups, either in the primary endpoint of nonfatal myocardial infarction (MI) or CHD death, or in secondary outcomes such as required revascularization or the occurrence of unstable angina. More disturbing, however, was the finding in HERS of a significant trend suggesting more CHD events in the treated group compared to the placebo group at 1 year, followed by fewer in the treated group at 4 and 5 years. There were also more venous thromboembolic events in the treated group.

A similar lack of overall benefit was found in the Estrogen Replacement and Atherosclerosis (ERA) study, a randomized HRT trial with angiographic endpoints. The ERA trial studied the effects of HRT in postmenopausal women with established coronary disease. The researchers could not rule out a small beneficial effect of HRT but it was unlikely to be as substantial as that reported for lipid-lowering therapy.

The EPAT investigators used unopposed micronized 17b-estradiol and not conjugated equine estrogen, which was used in both of the previously mentioned studies. Also, unlike the HERS and ERA trials, EPAT enrolled patients with no evidence of established cardiovascular disease.

While there appeared to be no increased risk associated with HRT in this study, benefits were only seen in patients not receiving lipid-lowering therapy, a relatively small subgroup. HRT was associated with no additional preventive benefits in patients receiving lipid-lowering therapy. Based on the considerable data establishing the safety and efficacy of lipid-lowering therapy, there seems to be a much stronger argument for using lipid-lowering as preventive therapy rather than HRT.


1) Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu Cr CR, Liu Ch CH, Azen SP. Estrogen in the Prevention of Atherosclerosis. Ann Intern Med. 2001;135:939-953. 2) Presented at AHA 2000, Clinical Trials, by Howard N. Hodis, MD

Keywords: Myocardial Infarction, Atherosclerosis, Estradiol, Cholesterol, LDL, Estrogens, Conjugated (USP), Postmenopause, Counseling, Breast Neoplasms, Coronary Disease, Venous Thrombosis, Estrogen Replacement Therapy

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