PEPI: Heart Disease Risk Factors

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women.

Objective: To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women.

Design: A 3-year, multi-center, randomized, double-blind, placebo-controlled trial.

Participants: A total of 875 healthy post-menopausal women aged 45 to 64 years who had no known contraindication to hormone therapy.

Intervention: Participants were randomly assigned in equal numbers to the following groups:

1. placebo;
2. Premarin, conjugated equine estrogen, (CEE), 0.625 mg per day;
3. CEE, 0.625 mg per day, taken with cyclic medroxyprogesterone acetate (MPA), 10 mg per day for 12 days a mo;
4. CEE, 0.625 mg per day, plus consecutive MPA, 2.5 mg per day;
5. CEE, 0.625 mg per day, plus cyclic micronized progesterone (MP), 200 mg per day for 12 days a mo.

Primary Endpoints: Four endpoints were chosen to represent four biological systems related to the risk of cardiovascular disease:

1. high-density lipoprotein cholesterol (HDL-C);
2. systolic blood pressure;
3. serum insulin;
4. fibrinogen [a protein in the blood-clotting process].

Analysis: Analyses presented are by intention to treat P values for primary endpoints are adjusted for multiple comparisons; 95% confidence intervals around estimated effects were calculated without this adjustment.

Results: Mean changes in HDL-C segregated treatment regimens into three statistically distinct groups:

1. placebo (decrease of 0.03 mmol/L [1.2 mg/dL]);
2. MPA regimens (increases of 0.03 to 0.04 mmol/L [1.2 to 1.6 mg/dL]);
3. CEE with cyclic MP (increase of 0.11 mmol/L [4.1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6 mg/dL]). Active treatments decreased mean low-density lipoprotein cholesterol (0.37 to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean triglyceride (0.13 to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated with a significantly greater increase in mean fibrinogen than any active treatment (0.10 g/L compared with -0.02 to 0.06 g/L); differences among active treatments were not significant. Systolic blood pressure increased and post-challenge insulin levels decreased during the trial, but neither varied significantly by treatment assignment. Compared with other active treatments, unopposed estrogen was associated with a significantly increased risk of adenomatous or atypical hyperplasia (34% vs 1%) and of hysterectomy (6% vs 1%). No other adverse effect differed by treatment assignment or hysterectomy status.

Conclusions: Estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on insulin or blood pressure. Unopposed estrogen is the optimal regimen post-challenge for elevation of HDL-C, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, CEE with cyclic MP has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia.

--The Writers Group.

Published in JAMA 1995 Dec 6;274(21):1676

Journal of the American Medical Association (JAMA)

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