The Estrogen Replacement and Atherosclerosis (ERA) Study

Abstract

The Estrogen Replacement and Atherosclerosis (ERA) trial is a three-arm, randomized, placebo-controlled, double-blind trial to evaluate the effects of estrogen replacement therapy (0.625 mg/day oral conjugated estrogen) with or without continuous low-dose progestin (2.5 mg oral medroxyprogesterone acetate/day) versus placebo on progression of atherosclerosis. A total of 309 postmenopausal women at five sites underwent baseline coronary angiography and were randomized. Participants will have repeat coronary angiography after an average of 3.25 years of treatment. The primary outcome of interest will be change in minimum diameter of the major epicardial segments, as assessed by quantitative coronary angiography. The primary aim is to test the hypothesis that either form of hormone therapy will slow the progression or induce regression of coronary atherosclerosis compared to placebo. The secondary aims are to assess the effects of the two treatments versus placebo on endothelial function (measured using flow-mediated vasodilator responses), on several presumed mediators of estrogen's effect on atherosclerosis (i.e., plasma lipids and lipoproteins, blood pressure, glucose metabolism, hemostatic factors, and antioxidant activity), on other factors that influence the development of coronary heart disease (i.e., diet, smoking status, exercise, weight, and health-related quality of life issues), and on clinical cardiovascular events.

The ERA trial is the first angiographic endpoint clinical trial to examine the effects of postmenopausal hormone replacement on coronary atherosclerosis in women. It will provide an unparalleled opportunity to determine if either regimen of hormone therapy is effective in slowing the progress of angiographically defined coronary atherosclerosis. This study will complement other estrogen replacement trials, such as the PEPI, HERS, and Women's Health Initiative studies, to provide a more comprehensive examination of the effects of estrogen replacement on cardiovascular risk factors, anatomic and functional manifestations of atherosclerosis, and risk for coronary heart disease in postmenopausal women. Control Clin Trials 2000;21:257–285

Introduction

Cardiovascular disease (CVD) is the most common cause of death and disability in women, accounting for 57% of all deaths, far more than breast or other cancers [1]. Because of the increased risk of coronary heart disease (CHD) in women around menopause, it has been speculated that endogenous estrogen has an important cardioprotective effect. This speculation has been supported by observational and case-control studies demonstrating that estrogen replacement therapy in postmenopausal women is associated with lower risk for CHD 2, 3, 4, 5, 6, 7. In epidemiologic meta-analyses 8, 9, 10, long-term use of postmenopausal estrogen was associated with a 50% lower risk of CVD. The relationship observed between estrogen replacement and CHD risk is even more striking in older women with coronary artery disease 11, 12.

Despite the observational data suggesting estrogen's cardioprotective effect, its actual benefits and risks have not been fully evaluated. In 1998, the Heart and Estrogen/progestin Replacement Study (HERS) showed no benefit of 4.1 years of estrogen plus progestin therapy for secondary prevention of heart disease in postmenopausal women [13]. Within the overall null effect, there was a reduction in risk after 2 years of treatment unexpectedly offset by an increased risk during the first year. It remains unclear whether this pattern of changing risk over time was simply a chance occurrence combined with no real effect of the regimen, or due to an early adverse and late beneficial effect of the regimen.

A major question concerning the HERS trial results is whether the addition of the progestin medroxyprogesterone acetate (MPA, Provera®) blocked estrogen's cardioprotective effects. Currently, clinicians administer a progestin with estrogen to prevent unopposed estrogen-induced endometrial carcinoma in women with intact uteri. However, MPA and 19-nor testosterone progestins blunt the favorable changes in high-density lipoprotein cholesterol (HDL-C) associated with estrogen use 14, 15. Furthermore, in nonhuman primates, continuous low-dose MPA substantially reduced estrogen's favorable effect on the progression of coronary atherosclerosis [16]. On the other hand, the attenuation of estrogen-induced increases in HDL-C may be offset by the progestins' protection against estrogen-induced increases in triglycerides and factor VII 17, 18. Observational studies provide no evidence that combined therapy increases the risk of CHD compared with estrogen alone 19, 20, 21. Use of continuous low-dose progesterone may also improve long-term compliance with estrogen replacement therapy regimens by inducing amenorrhea after 6–12 months of therapy. Thus, the hope has been that the combination of estrogen plus continuous low-dose MPA would retain the cardioprotective effects of estrogen while protecting against endometrial hyperplasia.

More definitive information about the effects of estrogen with and without progestins on anatomic manifestations of atherosclerosis would help in interpreting the HERS results and their relationship to the large body of observational data on estrogen replacement and CHD risk. To clarify these issues, we designed an angiographic endpoint trial comparing unopposed estrogen, or estrogen plus continuous low-dose MPA, versus placebo in women with established coronary atherosclerosis.

Our trial, entitled “Estrogen Replacement and Atherosclerosis” (ERA), will use quantitative coronary angiography and measures of endothelial function to determine the effects of estrogen replacement therapy on the anatomic and functional sequelae of atherosclerosis in coronary and peripheral arteries of postmenopausal women. The ERA trial will complement other estrogen replacement trials, including the Postmenopausal Estrogen/Progestin Intervention (PEPI) study [15], HERS, and the Women's Health Initiative (WHI) [22], to provide a more comprehensive examination of estrogen replacement's effects on cardiovascular risk factors, anatomic and functional manifestations of atherosclerosis, and CHD risk in postmenopausal women.