Menopausal Hormone Therapy and Cardiovascular Risk in Midlife Women With Vasomotor Symptoms

Importance: Vasomotor symptoms in perimenopause are associated with increased future cardiovascular (CVD) risk. Most clinical trials on menopausal hormone therapy (MHT) and CVD risk have focused on postmenopausal women, with limited study of the perimenopausal period when hormonal fluctuations and symptoms are greatest. Moreover, these trials were not designed to evaluate CVD risk with MHT among women with vasomotor symptoms. Objective: To estimate the effect of MHT on CVD risk among perimenopausal and recently postmenopausal women with vasomotor symptoms and assess the extent to which timing of MHT use relative to menopause and race and ethnicity modify this effect. Design, Setting, and Participants: Cohort data from the Study of Women's Health Across the Nation (SWAN, 1997-2017)-a multiethnic, multicenter, longitudinal study of the menopause transition-were used to emulate a sequence of target trials. Eligible participants were women who self-reported any vasomotor symptoms (ie, hot flashes and/or night sweats over the past 2 weeks) and who were CVD-free, with no prior MHT use. Data were analyzed from January 2023 to December 2025. Exposure: MHT use (systemic estrogen with/without progestogens, verified from medication containers). Main Outcomes and Measures: CVD events (myocardial infarction, stroke, heart failure, and revascularization) were self-reported. CVD-related death was recorded from death certificates. Results: Of 2737 women who reported any vasomotor symptoms, 755 initiated MHT (mean [SD] age, 53.7 [4.6] years) over the 20-year follow-up period, during which 224 fatal and nonfatal CVD events occurred. Overall, the estimated adjusted hazard ratio (aHR) of CVD events for MHT initiation vs noninitiation was 0.78 (95% CI, 0.62-0.98). The estimated aHR was 0.73 (95% CI, 0.58-0.93) and 1.53 (95% CI, 0.66-3.52) among women initiating MHT 10 or fewer years vs more than 10 years from the onset of menopause, respectively (P value for interaction: .02). Race and ethnicity modified the MHT initiation effect, with Black women showing protective effect (aHR, 0.51; 95% CI, 0.33-0.81), while no clear effects were observed in White women or women of other races (P value for interaction = .007). Conclusions and Relevance: The presented results are pooled from all target trials and found that MHT initiation during perimenopause or recently postmenopausal women with vasomotor symptoms was estimated to reduce CVD risk by 22%. Benefits were more pronounced in Black women and women who initiated MHT within 10 years of menopause onset. However, all estimates warrant caution given the potential for residual confounding. Given the inconsistency of the cardiovascular benefits and the need to consider overall risk-benefit balance, these findings should not be used to support MHT for CVD prevention.