Women’s Estrogen–Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial - WELL-HART


The goal of the WELL-HART trial was to evaluate the effect of estrogen therapy and estrogen-progestin therapy for the progression of atherosclerosis in postmenopausal women with coronary artery disease (CAD).

Study Design

Study Design:

Patients Screened: 1,369
Patients Enrolled: 226
Mean Follow Up: 3.3 years
Mean Patient Age: mean age 63.5 years
Female: 100

Patient Populations:

Postmenopausal women with or without a uterus, age ≤75 years, low-density lipoprotein cholesterol 100-250 mg/dl, total triglyceride level <400 mg/dl, and had at least one coronary artery lesion occluding ≥30% of the luminal diameter


Smoked >15 cigarettes/day, diagnosis of breast cancer or gynecologic cancer within five years, life-threatening disease and projected survival <5 years, diastolic blood pressure >110 mm Hg, fasting serum glucose >200 mg/dl, thyroid disease, serum creatinine >2.5 mg/dl, congestive heart failure, >5 hot flashes/day that interfered with daily activities, plans to undergo a coronary artery revascularization within six months after the first screening visit, baseline coronary angiogram within six months after a revascularization procedure, or myocardial infarction <6 weeks before the first screening visit

Primary Endpoints:

Per patient change between baseline and follow-up coronary angiograms in the percent stenosis per quantitative coronary angiography

Secondary Endpoints:

Change in MLD and the global change score (indicator of regression, no change, or progression)

Drug/Procedures Used:

Patients were randomized to usual care (control group; n=76), estrogen therapy with micronized 17beta-estradiol alone (estrogen group; n=76), or 17beta-estradiol plus sequentially administered medroxyprogesterone acetate (estrogen-progestin group; n=74). Follow-up angiography was scheduled three years after the baseline angiogram.

Concomitant Medications:

Dietary intervention (25% of calories from fat and 7% from saturated fats; <200 mg of dietary cholesterol per day) and lipid-lowering therapy (primarily with an HMG-CoA reductase inhibitor)

Principal Findings:

The mean time from menopause to randomization was 18.2 years. Mean level of compliance with study treatment was >90% in all arms. The mean change in the percent stenosis in the 169 participants who had a pair of matched angiograms was 1.89 ± 0.78 percentage points in the control group, 2.18 ± 0.76 in the estrogen group, and 1.24 ± 0.80 in the estrogen-progestin group (p=0.66 for the comparison among the three groups), for a mean difference between the estrogen group and the control group of 0.29 percentage point (95% confidence interval [CI] -1.88 to 2.46), and a mean difference between the estrogen-progestin group and the control group of -0.65 (95% CI -2.87 to 1.57).

Likewise, there was no difference in change in minimal lumen diameter (MLD) by the treatment group (-0.13 mm in the control arm, -0.15 mm in the estrogen arm, -0.11 in the estrogen-progestin arm; p=0.33). Stenosis progression was nearly twice as high in diabetic patients compared with nondiabetic patients. Most participants had progression of coronary artery atherosclerosis (58.6%), with no difference in global change score by treatment group (progression 56% in the control arm, 63% in the estrogen arm, 57% in estrogen-progestin arm; p=0.79).


Among postmenopausal women with CAD, treatment with estrogen therapy and estrogen-progestin therapy was not associated with a difference in the primary endpoint of change in percent stenosis at a mean of 3.3 years of follow-up.

Data from the present study are similar to those of other trials of hormone replacement therapy for atherosclerosis in women with pre-existing cardiovascular disease, such as ERA and WAVE. However, the results of this trial differ from what was seen in the sister trial, EPAT, which studied postmenopausal women without pre-existing cardiovascular disease. EPAT showed that relative to placebo, oral 17beta-estradiol alone slowed the progression of carotid intima-media thickness.

The differences may be explained in part by the different study populations (with vs. without pre-existing cardiovascular disease), as well as the different imaging modalities and endpoints (angiographic stenosis vs. carotid intima-media thickness). The authors note that carotid wall thickness is a measure of early, subclinical, asymptomatic atherosclerosis, whereas coronary angiography is used to evaluate late-stage, symptomatic atherosclerosis.


Hodis HN, Mack WJ, Azen SP, et al., for the Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. N Engl J Med 2003;349:535-45.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Lipid Metabolism, Nonstatins, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Echocardiography/Ultrasound, Nuclear Imaging

Keywords: Progestins, Coronary Artery Disease, Medroxyprogesterone Acetate, Atherosclerosis, Follow-Up Studies, Estradiol, Carotid Intima-Media Thickness, Cholesterol, LDL, Constriction, Pathologic, Estrogen Replacement Therapy, Uterus, Menopause, Coronary Angiography, Confidence Intervals, Triglycerides, Diabetes Mellitus

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