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).
Patients Screened: 1,369
Patients Enrolled: 226
Mean Follow Up: 3.3 years
Mean Patient Age: mean age 63.5 years
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
Per patient change between baseline and follow-up coronary angiograms in the percent stenosis per quantitative coronary angiography
Change in MLD and the global change score (indicator of regression, no change, or progression)
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.
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)
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, Atherosclerotic Disease (CAD/PAD), Hypertriglyceridemia, 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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