Clinical Drug Experience Knowledgebase

BACKGROUND:

The life expectancy of American women is 78 years. More than one-third of those years are postmenopausal, during which time the risk of coronary heart disease is increased. The current United States estimate of more than 40 million women over the age of 50 indicates a large segment of the population at increased risk for coronary heart disease. Heart disease accounts for a third of all deaths in 50-69 year old women. In 1978, for example, approximately 66,000 of the 210,000 deaths in women 50-69 were attributed to heart disease.

Premenopausal women have a lower rate of ischemic heart disease compared to men of similar age. Surgically induced or natural early menopause increases the risk of ischemic heart disease. These facts have focused interest on estrogens as possible mediators of the beneficial effects, and pointed to the need for further study of their relationship to atherosclerosis risk factors.

Estimates from the Lipid Research Clinics Program indicate estrogen use in approximately one third of postmenopausal women. Analysis of Lipid Research Clinics data confirmed that administration of estrogens results in lower plasma low density lipoprotein levels and elevated plasma high density lipoprotein levels. Thus, the ratio of high density lipoprotein/low density lipoprotein levels is substantially increased. Given the inverse relationship between high density lipoprotein levels and coronary heart disease risk, this effect of estrogens on the plasma lipoproteins could be expected to further reduce coronary heart disease risk in women.

Although the bulk of currently available evidence suggests benefit, some controversy concerning the effects of postmenopausal estrogens on morbidity and mortality from coronary heart disease persists. Analysis of the Lipid Research Clinics Follow-up Study population indicated a potentially profound beneficial effect of postmenopausal estrogen use. Mortality from all causes decreased considerably in postmenopausal estrogen users, and the effect was most pronounced in hysterectomized and oophorectomized women. Similar results have been observed for cardiovascular deaths. These benefits appeared to be mediated by the higher high density lipoprotein levels associated with postmenopausal estrogen use. Framingham data are the primary sources reporting possible detrimental effects of postmenopausal estrogen use on cardiovascular morbidity; mortality from all cause and cardiovascular disease was not reported to vary by use.

NHLBI convened a Trans-NIH Estrogen Working Group to make recommendations to NHLBI on the feasibility of undertaking a clinical trial of the effects of postmenopausal estrogen use on cardiovascular disease mortality. The Working Group identified a number of important research questions which needed to be answered to elucidate the effects of postmenopausal estrogen use on risk factors for cardiovascular disease and osteoporosis. This initiative was the result of the Working Group's deliberations and recommendations.

DESIGN NARRATIVE:

There were seven clinical centers and a coordinating center in this randomized, double-blind clinical trial. The women were allocated to one of five treatment arms: placebo; conjugated equine estrogen (CEE), 0.625 milligrams per day; conjugated equine estrogen, 0.625 milligrams per day plus cyclic medroxyprogesterone acetate (MPA), 10 milligrams per day for 12 days per month; CEE, 0.625 milligrams per day plus consecutive MPA, 2.5 milligrams per day; CEE, 0.625 milligrams per day plus cyclic micronized progesterone (MP), 200 milligrams per day for 12 days a month. The four primary endpoints were chosen to represent four biological systems related to the risk of cardiovascular disease and included high density lipoprotein cholesterol (HDL-C), systolic blood pressure, serum insulin, and fibrinogen. Recruitment began in October 1989 and ended in February 1991. Baseline data collected included blood pressure, resting heart rate, weight, waist/hip ratios and endometrial biopsy. Laboratory evaluations included lipid panel, high density lipoprotein cholesterol, insulin and glucose, bone density, fibrinogen, and in three clinics, additional hemostasis factors, renin substrate, plasma renin activity, aldosterone, and oral post-heparin lipase activity. All women underwent an endometrial aspiration biopsy at baseline and annually thereafter. Additional biopsy specimens were obtained if there was noncyclic endometrial bleeding. All women also had baseline and annual mammograms. Other data were collected on quality of life, exercise, diet, alcohol use, and smoking. Participants were followed at three, six and twelve months post-randomization, and at six month intervals thereafter for three years. Post-trial analyses of existing data sets were funded for three years by the cooperative agreement mechanism beginning August 1, 1994. A three-year safety follow-up funded through the contract mechanism began in 1994. It included three annual visits at which endometrial biopsies, mammograms, and some limited health information were obtained.

The study completion date listed in this record was obtained from the "End Date" entered in the Protocol Registration and Results System (PRS) record.