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:
- placebo;
- Premarin, conjugated equine estrogen, (CEE), 0.625
mg per day;
- CEE, 0.625 mg per day, taken with cyclic medroxyprogesterone
acetate (MPA), 10 mg per day for 12 days a mo;
- CEE, 0.625 mg per day, plus consecutive MPA, 2.5
mg per day;
- 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:
- high-density lipoprotein cholesterol (HDL-C);
- systolic blood pressure;
- serum insulin;
- 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:
- placebo (decrease of 0.03 mmol/L [1.2 mg/dL]);
- MPA regimens (increases of 0.03 to 0.04 mmol/L [1.2
to 1.6 mg/dL]);
- 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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