Menopausal Hormone Therapy and Cardiovascular Diseases in Women With Vasomotor Symptoms: A Secondary Analysis of the Women's Health Initiative Randomized Clinical Trials.

Abstract

Importance: Identification of appropriate patients for treatment of vasomotor symptoms (VMS) with menopausal hormone therapy (HT) is challenging.

Objective: To assess risk of cardiovascular disease (CVD) due to HT in women with VMS.

Design, setting, and participants: In this secondary analysis of 2 randomized clinical trials of HT, postmenopausal women aged 50 to 79 years from 40 US clinical centers were included. Data were collected from November 1993 to September 2012, and data were analyzed from December 2024 to May 2025.

Interventions: Conjugated equine estrogens (CEE), 0.625 mg per day, or CEE with medroxyprogesterone acetate (MPA), 2.5 mg per day, vs placebo.

Main outcomes and measures: Atherosclerotic CVD (ASCVD; defined as composite of nonfatal myocardial infarction, hospitalization for angina, coronary revascularization, ischemic stroke, peripheral arterial disease, carotid artery disease, or CVD death).

Results: Of 27 347 included postmenopausal women, the mean (SD) age was 63.4 (7.2) years; a total of 10 739 (39.3%) had a hysterectomy, and 16 608 (60.7%) had an intact uterus. The median (IQR) follow-up was 7.2 (6.4-8.1) years and 5.6 (4.8-6.5) years for those in the CEE alone trial and the CEE plus MPA trial, respectively. In the CEE alone trial, moderate or severe VMS were present at baseline in 905 (27.6%), 705 (14.7%), and 220 (8.7%) women aged 50 to 59 years, 60 to 69 years, and 70 to 79 years, respectively; in the CEE plus MPA trial, moderate or severe VMS was present in 1225 (22.4%), 649 (8.7%), and 172 (4.8%), respectively. Among women with moderate or severe VMS at enrollment, 3382 (96.7%) recalled having symptoms near menopause onset. CEE alone reduced VMS by 41% across all age groups (overall relative risk [RR], 0.59; 95% CI, 0.53-0.66). However, in the CEE plus MPA trial, VMS reduction was attenuated with age (age 50-59 years: RR, 0.41; 95% CI, 0.35-0.48; age 60-69 years: RR, 0.72; 95% CI, 0.61-0.85; age 70-79 years: RR, 1.20; 95% CI, 0.91-1.59; interaction P for trend < .001). Both CEE alone and CEE plus MPA appeared to have neutral effects on ASCVD in women with moderate or severe VMS aged 50 to 59 years (CEE alone: hazard ratio [HR], 0.85; 95% CI, 0.53-1.35; CEE plus MPA: HR, 0.84; 95% CI, 0.44-1.57). While the estimated risk was higher for CEE alone in women with VMS aged 60 to 69 years, there was no clear signal of harm (CEE alone: HR, 1.31; 95% CI, 0.90-1.90; CEE plus MPA: HR, 0.84; 95% CI, 0.51-1.39). However, women with VMS 70 years and older had increased risks of ASCVD (CEE alone: HR, 1.95; 95% CI, 1.06-3.59; 217 excess events per 10 000 person-years; interaction P for trend = .03; CEE plus MPA: HR, 3.22; 95% CI, 1.36-7.63; 382 excess events per 10 000 person-years; interaction P for trend = .02).

Conclusions and relevance: In this secondary analysis of 2 randomized clinical trials, among younger postmenopausal women aged 50 to 59 years, both CEE alone and CEE plus MPA reduced VMS without significantly affecting ASCVD risk. In women with VMS 70 years and older, risks for ASCVD were increased in both trials. The findings support guideline recommendations for treatment of VMS with HT in women aged 50 to 59 years, caution if initiating HT in women aged 60 to 69 years, and avoidance of HT in women 70 years and older.

Trial registration: ClinicalTrials.gov Identifier: NCT00000611.