Heart and Estrogen/Progestin Replacement Study - HERS


The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, blinded, placebo-controlled secondary prevention trial of estrogen plus progestin for secondary prevention of coronary heart disease (CHD) in postmenopausal women.


The objective was to determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 2,763
Mean Follow Up: 4.1 years
Mean Patient Age: 66.7
Female: 100

Patient Populations:

Postmenopausal women younger than 80 years and established coronary disease (one or more of the following: MI, coronary artery bypass graft surgery, percutaneous coronary revascularization, or angiographic evidence of at least a 50% occlusion of one or more major coronary arteries)


• Hysterectomy
• CHD event within six months of randomization
• Serum triglyceride level higher than 3.39 mmol/l (300 mg/dl)
• Use of oral, parenteral, vaginal, or transdermal sex hormones within three months of the screening visit
• History of deep vein thrombosis or pulmonary embolism
• History of breast cancer, or breast examination or mammogram suggestive of breast cancer
• History of endometrial cancer
• Abnormal uterine bleeding
• Endometrial hyperplasia, or endometrium thickness >5 mm on baseline evaluation
• Abnormal or unobtainable Papanicolaou test result
• Serum aspartate aminotransferase level >1.2 times normal
• Unlikely to remain geographically accessible for study visits for at least four years
• Disease (other than CHD) judged likely to be fatal within four years
• New York Heart Association class IV or severe class III congestive heart failure
• Alcoholism or other drug abuse
• Uncontrolled hypertension (diastolic blood pressure ≥105 mm Hg or systolic blood pressure ≥200 mm Hg)
• Uncontrolled diabetes (fasting blood glucose level ≥16.7 mmol/l [300 mg/dl])
• Participation in another investigational drug or device study
• <80% compliance with a placebo run-in prior to randomization
• History of intolerance to hormone therapy

Primary Endpoints:

Nonfatal MI or CHD death

Secondary Endpoints:

• Coronary revascularization
• Unstable angina
• Congestive heart failure
• Resuscitated cardiac arrest
• Stroke or transient ischemic attack
• Peripheral arterial disease
• Total mortality
• Cancer death
• Non-CHD, noncancer death
• Breast, endometrial, and other cancer
• Deep vein thrombosis
• Pulmonary embolism
• Hip and other fracture
• Gallbladder disease

Drug/Procedures Used:

Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in one tablet daily or placebo

Principal Findings:

Women were randomized between hormone therapy (n=1,380) and placebo (n=1,383) groups. At the end of the first year, the proportion who reported taking study medication was 82% in the hormone group and 91%in the placebo group; by the end of the third year, these proportions had declined to 75% and 81%.

Primary CHD events occurred in 172 women in the hormone group (33.1/1,000 women per year) and in 176 women in the placebo group (33.6/1,000 women per year) (relative hazard [RH] 0.99, 95% confidence interval [CI] 0.80-1.22). These primary events were composed of CHD deaths (RH 1.24, 95% CI 0.87-1.75) and nonfatal myocardial infarctions (MIs) (RH 0.91, 95% CI 0.71-1.17). None of these differences was statistically significant. Overall, there were no significant differences in any of the secondary cardiovascular outcomes.

The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each p<0.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1, and fewer in years 4 and 5.

More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs. 12; RH 2.89, 95% CI 1.50-5.58) and gallbladder disease (84 vs. 62, RH 1.38; 95% CI 1.00-1.92). There were no significant differences in several other endpoints for which power was limited, including fracture, cancer, and total mortality (131 vs. 123 deaths, RH 1.08, 95% CI 0.84-1.38).


During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. This conclusion runs contrary to several observational studies that had suggested cardiovascular benefit from hormonal replacement therapy. The treatment did increase the rate of thromboembolic events and gallbladder disease.

Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, the investigators did not recommend starting this treatment for the purpose of secondary prevention of CHD. The net benefit of hormonal therapy may be different for other indications or patient populations.


Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.

Keywords: Progestins, Medroxyprogesterone Acetate, Myocardial Infarction, Follow-Up Studies, Lipoproteins, Gallbladder Diseases, Estrogen Replacement Therapy, Percutaneous Coronary Intervention, Cholesterol, Secondary Prevention, Postmenopause, Estrogens, Confidence Intervals, Coronary Artery Bypass

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