Postmenopausal Hormone Replacement Therapy and Cardiovascular Disease: The PEPI Trial

28 Jun
2010

The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was an experimental study primarily designed to evaluate the effect of HRT on cardiovascular disease. This randomized, double-blind, placebo-controlled trial compared estrogen monotherapy with continuous or cyclic estrogen-plus-pro-gestin combination therapy. Two forms of progestins were assessed, medroxyprogesterone acetate (MPA) and micronized progesterone (MP). This study confirmed that all HRT therapies increased HDL-cholesterol, with the greatest increase seen in the estrogen monotherapy treatment group. The addition of either progestin decreased this effect, but MP therapy was associated with less blunting. In addition to the effects on HDL-cholesterol, all active groups experienced a decrease in LDL-cholesterol and an increase in triglycerides. Among patients receiving HRT, treatment did not affect blood pressure or postchallenge insulin levels, and decreased fibrinogen levels were observed across all HRT groups.

The PEPI trial addressed the question of how the addition of progestins to HRT affects serum lipoproteins, blood pressure, and carbohydrate metabolism. However, the endpoints assessed in this study were intermediate outcomes. Questions concerning the effect of HRT regimens on final CHD outcomes such as acute myocardial infarction (AMI), strokes, and CHD death were not addressed. Apcalis Oral Jelly

The HERS Trials

HERS I

The Heart and Estrogen/Progestin Replacement Study (HERS) was an experimental trial that primarily evaluated the effect of HRT on final CHD outcomes among postmenopausal women with established cardiovascular disease (secondary pre-vention). Final CHD events were defined as nonfatal AMI and CHD death. Secondary outcomes included hospitalization for coronary revascularization, resuscitated cardiac arrest, unstable angina, congestive heart failure, transient ischemic attack (TIA), stroke, or peripheral arterial disease. Postmenopausal women with established coronary artery disease under the age of 80 years (mean = 66.7 years) with an intact uterus were included.

Subjects were randomly assigned to receive continuous combined estrogen and progestin (conjugated equine estrogens [CEEs] 0.625 mg/day with MPA 2.5 mg/day) or placebo and were observed for 4.1 years. This regimen was most likely selected because 0.625 mg of conjugated estrogens was the most common dosage used in the Nurses’ Health Study. Because women included in the HERS trial had an intact uterus, concomitant administration of a progestin was necessary to decrease the risk of endometrial hyperplasia and cancer. Continuous combined HRT with CEEs 0.625 mg and MPA 2.5 mg daily is a very common combination.

Study results showed a positive change in the serum lipopro-teins among subjects receiving HRT. On average, LDL-choles-terol concentrations decreased by 14% from baseline values and HDL-cholesterol concentrations increased by 8%, both reaching statistical significance when compared with placebo. Despite these changes in serum lipoproteins, HRT showed no benefit for the prevention of cardiovascular events among women with established CHD.

Primary CHD events were similar between groups (relative hazard [RH] = .99, 95°% CI, 0.80-1.22) over the four-year observation period. Further data analysis showed that the risk of a CHD event was most pronounced during the first year of HRT treatment (RH = 1.52) but decreased every year afterward (RH = 0.67 in years four and five). The number of deaths from other causes, including cancer, was similar between groups. The rate of venous thrombosis was higher in the HRT group (RH = 2.89, 95% CI, 1.50-5.58), and there was an increased incidence of gallbladder disease (RH = 1.38, 95% CI, 1.00-1.92). The incidence of breast, endometrial, or other cancers, as well as fractures, was similar between groups. cheap cialis canadian pharmacy

The HERS I trial had a few limitations. Physicians were allowed to initiate medications for the treatment of dyslipidemia during the study period, and more women in the placebo group received statins than did women in the HRT group. When the study was concluded, a trend showing decreased CHD risk was apparent among subjects receiving HRT for three to four years, and it was unknown whether this trend would persist. Investigators continued the trial in HERS II to address these questions.

HERS II

The HERS II trial was a continuation of the HERS trial. It was designed like the previous study except that, after the initial four years, the HERS II trial was not double-blinded; it was an open-label, unblinded study. Subjects were randomly assigned to receive either HRT (CEEs and MPA) or no HRT at the discretion of their personal physicians. The women were monitored for an additional 2.7 years to evaluate whether the reduced cardiovascular risk that had been observed after year one in the HERS trial would be maintained with continued therapy. Most of the HERS subjects (93% of those surviving) re-enrolled for continued monitoring in the HERS II trial.

The results of the HERS II trial demonstrated that the trend showing decreased risk did not persist with continued therapy. No difference in cardiovascular risk existed between groups observed in HERS II (RH = 1.00, 95% CI, 0.77-1.29). The combined data from both trials supported these findings (RH = 0.99, 95% CI, 0.84-1.17). During the HERS II study, the data were adjusted for potential confounders, including statin use. This did not alter the results, and no differences were found between groups (RH = 0.97, 95°% CI, 0.82-1.14).

Summary of HERS I and II

The results of the HERS and HERS II trials suggest that treatment with daily, continuous combined CEEs and MPA provides no protection from secondary cardiovascular events among women with established cardiovascular disease over a 6.8-year period. Because of the transient increase in the risk of CHD events during the first year of therapy, followed by the absence of continued benefit, initiation of CEEs 0.625 mg and MPA 2.5 mg each day is not recommended for the sole indication of CHD protection.

These two studies provided valuable information concerning the use of HRT for the prevention of postmenopausal CHD. It is important to note that these studies were not powered to detect a difference in cancer rates, fracture rates, or total mortality between the groups studied. Because the study population consisted of postmenopausal women with established CHD who were not using HRT, it did not address whether HRT would be beneficial among healthy postmenopausal women who did not have CHD.

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