Abstract 4369715: Hormone Replacement Therapy and Arrhythmia Risk in Menopause: A Comprehensive Nationwide Analysis

Background: Hormone replacement therapy (HRT) is commonly prescribed to alleviate menopausal symptoms, but its cardiovascular safety—especially its impact on arrhythmias and acute heart failure hospitalizations—remains debated. This study primarily evaluated the association of HRT use with arrhythmia risk, and secondarily with acute heart failure hospitalizations, in menopausal women. Methods: This retrospective study utilized TriNetX, a federated health research network including data from 91 healthcare organizations across the U.S. Two cohorts were defined: menopausal women with HRT use and those without HRT. Propensity score matching (1:1) was performed on age and sex to balance baseline characteristics. Outcomes assessed included atrial fibrillation (AF), atrial flutter, ventricular tachycardia (VTach), supraventricular tachycardia (SVT), and acute heart failure hospitalizations, evaluated up to 3 years after cohort entry. Statistical analyses included risk differences, odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs). A p-value <0.05 was considered significant. Results: After matching, 172,086 patients (86,043 per group) were analyzed. HRT use was associated with significantly higher risks of AF (risk difference 0.018, 95% CI [0.016, 0.019], HR 2.74, 95% CI [2.55, 2.95]), atrial flutter (risk difference 0.002, 95% CI [0.001, 0.002], HR 2.79, 95% CI [2.16, 3.60]), VTach (risk difference 0.004, 95% CI [0.003, 0.004], HR 2.04, 95% CI [1.79, 2.32]), and SVT (risk difference 0.014, 95% CI [0.013, 0.016], HR 2.33, 95% CI [2.17, 2.51]), all p<0.001. Additionally, HRT use was associated with a higher risk of acute heart failure hospitalization (risk difference 0.003, 95% CI [0.003, 0.004], HR 2.19, 95% CI [1.90, 2.54], p<0.001). Survival probabilities at the end of follow-up were consistently lower in the HRT group across all outcomes. Conclusions: In this large, propensity-matched cohort study, HRT use in menopausal women was associated with a significantly increased risk of arrhythmias and acute heart failure hospitalizations. The elevated HRs highlight the potential impact of HRT on cardiac electrophysiology and heart failure risk. These findings underscore the need for careful risk-benefit discussions when considering HRT, particularly in women with underlying cardiovascular risk factors. Further research should focus on understanding the mechanisms driving these and identifying subgroups at highrisk for personalized decision-making.