Current issues of ACP Journal Club are published in Annals of Internal Medicine


Estrogen plus progestin was not effective for secondary prevention of coronary heart disease in postmenopausal women

ACP J Club. 1999 Jan-Feb;130:8. doi:10.7326/ACPJC-1999-130-1-008

Source Citation

Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998 Aug 19; 280:605-13.



Can estrogen plus progestin prevent recurrent nonfatal myocardial infarction (MI) and coronary heart disease (CHD) mortality in postmenopausal women with established CHD?


Randomized, double-blind, placebo-controlled trial with mean follow-up of 4.1 years (Heart and Estrogen/progestin Replacement Study [HERS]).


20 U.S. outpatient and community settings.


2763 postmenopausal women between 44 and 79 years of age (mean age 67 y, 89% white) with established CHD who had not had a hysterectomy. Exclusion criteria were CHD event ≤ 6 months or sex hormone use ≤ 3 months before entry, deep venous thrombosis, pulmonary embolism, hyperplasia or endometrial cancer, abnormal results on mammography or Papanicolaou test, elevated serum triglyceride levels, geographic inaccessibility, other fatal disease, congestive heart failure, alcoholism, drug abuse, uncontrolled hypertension, diabetes, participation in another study, < 80% compliance with prestudy placebo, or intolerance to hormone therapy. Follow-up was 100%.


1380 women were allocated to hormone replacement therapy (HRT) of conjugated equine estrogens, 0.625 mg, and medroxyprogesterone acetate, 2.5 mg once/d; 1383 were allocated to placebo.

Main outcome measures

The combined rate of nonfatal MI and CHD mortality was the primary outcome. Secondary outcomes included coronary artery bypass graft surgery, percutaneous coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, other CHD events, peripheral arterial disease, stroke or transient ischemic attack, all-cause and cancer mortality, and adverse events.

Main results

Analysis was by intention to treat. The combined rate of nonfatal MI and CHD mortality did not differ between women who received HRT (12.5%) and those who received placebo (12.7%, relative hazard [RH] 0.99, 95% CI 0.80 to 1.22). Similarly, rates of nonfatal MI and CHD mortality, secondary cardiovascular outcomes, cancer mortality, and all-cause mortality did not differ between groups. At 1 year, women who received HRT had a greater decrease in mean low-density lipoprotein cholesterol level, increase in mean high-density lipoprotein cholesterol level, and increase in mean triglyceride level than did those who received placebo (P < 0.001 for all). These changes were not associated with subsequent primary CHD events. Women who received HRT had greater rates of venous thromboembolic events (RH 2.89, CI 1.50 to 5.58) and gallbladder disease (RH 1.38, CI 1.00 to 1.92) than those who received placebo.


Estrogen plus progestin did not reduce the rate of nonfatal myocardial infarction and coronary heart disease mortality in postmenopausal women with established coronary disease.

Sources of funding: Wyeth-Ayerst Research.

For correspondence: Dr. S. Hulley, UCSF, San Francisco, Box 0886, San Francisco, CA 94143, USA. FAX 415-597-9213.


HERS was a well-designed clinical trial of combined HRT for secondary prevention of CHD in postmenopausal women with a uterus. Most previous studies were observational and suggested that HRT was associated with a ≥ 50% reduction in cardiovascular events (1). However, the protective benefits of HRT may have been overestimated because women who receive HRT may have other healthy behaviors (2).

One other major trial of HRT, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, examined the surrogate outcome of risk factor changes rather than disease events and found that HRT improved the lipid profile (3). The effects on high-density lipoprotein cholesterol levels differed by treatment regimen. The regimen used in HERS, estrogen plus medroxyprogesterone acetate (E+MPA), elevated HDL cholesterol levels less effectively than did estrogen alone or estrogen plus micronized progesterone. Therefore, less benefit from E+MPA on coronary events might have been expected. HERS found no benefit after 4 years and even showed an increase in early coronary events, which remains unexplained.

The HERS results may have implications beyond women with CHD because they also highlight the need for clinical trial evidence in primary prevention. However, the Women's Health Initiative includes an HRT treatment arm of 28 000 women and will provide generalizable results in the year 2005. Meanwhile, estrogen combined with progestins other than MPA deserves consideration, as does estrogen alone. Women at high cardiovascular risk who are newly treated with HRT should be reassessed and those receiving an established regimen might continue with caution. As noted by the authors, the controversy over the role of HRT in practice raised by HERS should encourage physicians to increase their efforts to use proven therapies for secondary prevention (e.g., β-blockers, aspirin, smoking cessation, and lipid-lowering agents).

Robert D. Langer, MD, MPH
University of California, San DiegoLa Jolla, California, USA


1. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-37.

2. Barrett-Connor E.Postmenopausal estrogen and prevention bias. Ann Intern Med. 1991; 115:455-6.

3. The Writing Group for the PEPI Trial. JAMA. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. 1995;273:199-208.