Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.
Level 2 - randomized trial
Individual randomized controlled trial
PubMed 23048011 · doi:10.1136/bmj.e6409
What was done
An open-label randomized controlled trial in Denmark evaluated the long-term effects of hormone replacement therapy in 1006 healthy women aged 45-58 who were recently postmenopausal or perimenopausal with postmenopausal follicle-stimulating hormone levels. Participants were randomized to receive hormone replacement therapy (n=502; triphasic estradiol and norethisterone acetate for women with an intact uterus, or 2 mg/day estradiol for hysterectomized women) or no treatment (n=504). Treatment was stopped after approximately 11 years due to safety reports from other trials, with follow-up continuing up to 16 years. The primary composite endpoint was death, hospital admission for heart failure, and myocardial infarction.
What was found
After 10 years of intervention, the primary composite endpoint occurred in 16 women in the treatment group versus 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87, P=0.015). Mortality occurred in 15 treated versus 26 control women (hazard ratio 0.57, 95% confidence interval 0.30 to 1.08, P=0.084). No significant increases were observed for any cancer (36 vs 39; hazard ratio 0.92, 95% confidence interval 0.58 to 1.45), breast cancer (10 vs 17; hazard ratio 0.58, 95% confidence interval 0.27 to 1.27), deep vein thrombosis (2 vs 1; hazard ratio 2.01, 95% confidence interval 0.18 to 22.16), or stroke (11 vs 14; hazard ratio 0.77, 95% confidence interval 0.35 to 1.70). The reduction in the primary outcome persisted at 16 years.
Why it matters
These findings suggest that initiating hormone replacement therapy early in the postmenopausal transition provides long-term cardiovascular benefit without the excess risks reported when treatment is initiated at older ages.
Limits
The trial used an open-label design with no placebo, introducing potential reporting or assessment bias. Intervention was terminated early at 11 years based on external trial alerts. Event numbers were low for rare outcomes such as deep vein thrombosis and stroke, producing wide confidence intervals and limiting statistical power for these endpoints.
Cited by
- partial In the Danish Osteoporosis Prevention Study (DOPS), women receiving hormone replacement therapy for 11 years had reduced cardiovascular disease mortality and heart failure risk over 16 years of follow-up without increased thromboembolism or cancer.