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Women's Health Initiative - WHI
Description:
The goal of the Women's Health Initiative (WHI) was to evaluate the effect of hormone replacement therapy (HRT) for prevention of coronary heart disease (CHD) and cancer in postmenopausal women.
Hypothesis:
What is the effect of postmenopausal HRT, dietary modification, and calcium supplementation on the incidence of heart disease, colorectal cancer, and breast cancer in women?
Study Design
Study Design:
Patients Screened: 373,092
Patients Enrolled: 16,608
Mean Follow Up: mean 5.2 years
Mean Patient Age: mean age 63.3 years
Female: 100
Patient Populations:
Postmenopausal women between the ages of 50 to 79 years
Exclusions:
Any medical condition likely to be associated with a predicted survival of <3 years, prior breast cancer, other prior cancer within the last 10 years except nonmelanoma skin cancer, low hematocrit or platelet counts, alcoholism, or dementia
Primary Endpoints:
HRT: 1) CHD, defined as nonfatal MI or death due to CHD, and 2) invasive breast cancer; dietary modification (DM): breast cancer; and calcium and vitamin D (CaD): hip fractures
Secondary Endpoints:
HRT: hip and other fractures; DM: colorectal cancer, CHD; and CaD: colorectal cancer, combined fractures
Drug/Procedures Used:
In the HRT trial, patients with an intact uterus were randomized to conjugated equine estrogens (0.625 mg/day) plus medroxyprogesterone acetate (2.5 mg/day; n=8506) or placebo (n=8102). Other WHI trials included dietary modification (fat intake not to exceed 20% of total daily calories; high fruit, vegetable, and grain diet), calcium supplementation (1000 mg of calcium carbonate and 400 international units of vitamin D daily), and estrogen alone in women who have had a hysterectomy.
Principal Findings:
After a mean of 5.2 years of follow-up, the HRT trial of estrogen plus progestin versus placebo was stopped early at the recommendation of the Data Safety and Monitoring Board (DSMB) because the overall risks exceeded the benefits. Estrogen plus progestin was associated with an increased risk in the primary endpoint of CHD (188 cases vs. 147 cases, 39 cases per 10,000 person-years vs. 33 cases per 10,000 person-years, adjusted hazard ratio [HR] 1.24, nominal 95% confidence interval [CI] 1.00-1.54, adjusted 95% CI 0.97-1.60).
The increase in risk was highest at one year (HR 1.81, 95% CI 1.09-3.01). HR for nonfatal myocardial infarction (MI) was 1.28, and for death due to CHD was 1.10. There were no significant differences in coronary revascularization (HR 1.01, 95% CI 0.83-1.22), hospitalization for angina (HR 0.86, 95% CI 0.70-1.05), confirmed angina (HR 0.82, 95% CI 0.63-1.06), acute coronary syndrome (HR 1.03, 95% CI 0.88-1.21), or congestive heart failure (HR 0.99, 95% CI 0.76-1.29). Similar patterns of hazard ratios for CHD were observed in subgroup analysis. Estrogen plus progestin was also associated with an increased risk of breast cancer (HR 1.26, 95% CI 1.00-1.59), stroke (HR 1.41, 95% CI 1.07-1.85), and pulmonary embolism (HR 2.13, 95% CI 1.39-3.25).
Interpretation:
Among postmenopausal women with an intact uterus, treatment with the HRT estrogen plus progestin was associated with an increased risk of CHD compared with placebo during a mean 5.2 year follow-up. Overall health risks exceeded benefits, causing the trial to be discontinued early at the recommendation of the DSMB.
The recent HERS trial showed no overall difference in CHD associated with HRT, but an increase in CHD during the first year of therapy in the HRT arm; however, patients in HERS all had documented CHD prior to randomization, so it was unclear if similar results would be observed in the primary prevention setting. Data from the present trial, along with data from the recent HERS trial, demonstrate that this regimen should not be initiated or continued for prevention of CHD in postmenopausal women.
References:
1. Rossouw JE, Anderson GL, Prentice RL, et al., for the Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
2. Manson JE, Hsia J, Johnson KC, et al., for the Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-34.
3. National Institutes of Health. Women's Health Initiative. Available from: URL: http://whi.nih.gov.
4. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials 1998;19:61-109.
Keywords: Progestins, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Medroxyprogesterone Acetate, Follow-Up Studies, Food Habits, Pulmonary Embolism, Women's Health, Breast Neoplasms, Estrogen Replacement Therapy, Primary Prevention, Uterus, Calcium Carbonate, Heart Failure, Hysterectomy, Colorectal Neoplasms, Diet, Confidence Intervals, Vitamin D
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