|Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women|
|Wednesday, 19 August 1998 00:00|
"Objective. - To determine if estrogen plus progestin therapy alters the risk for CHD [Coronary Heart Disease] events in postmenopausal women with established coronary disease.
Design. - Randomized, double-blind, placebo-controlled secondary prevention trial.
Setting. - Outpatient and community settings at 20 US clinical centers.
Participants. - A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.
Intervention. - Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 years, and 75% ad the end of 3 years.
Main Outcome Measures. - The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischaemic attack, and peripheral arterial disease. All-cause mortality was also considered.
Results. - Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower-density lipoprotein cholesterol level and a 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.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%, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There was no significant difference in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).
Conclusions. - 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. 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, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue."
"HERS [Heart and Estrogen/progestin Replacement Study] is the first large trial of the effect of postmenopausal estrogen plus progestin therapy on risk of CHD events. The findings differ from those of observational studies and studies with surrogate outcomes, emphasizing the importance of basing treatment policies on randomized controlled trials."
"... in the population studied in HERS [Heart and Estrogen/progestin Replacement Study], ie, postmenopausal women with established coronary disease and an average age of 66.7 years, daily use of conjugated equine estrogens and plus medroxyprogesterone acetate did not reduce the overall risk for MI [Myocardial Infarction] and CHD [Coronary Heart Disease] death or any other cardiovascular outcome during an average of 4.1 years of follow-up. This therapy did increase the risk of venous thromboembolic events and gallbladder disease."
Hulley, S. MD; Grady, D. MD; Bush T. PhD; Furberg, C. MD, PhD; Herrington, D. MD; Riggs, B. MD; and Vittinghoff, E. PhD for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group, "Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women", JAMA, August 19, 1998, Vol. 280, Num. 7, pp. 605-613