Major Adverse Cardiovascular Events Following Vaginal Estrogen Therapy 2004–2023

Importance This study reports on prescription patterns during years when estrogen use may have been influenced by a U.S. Food and Drug Administration black box warning. Objective The objective of this study was to evaluate whether vaginal estrogen prescription for genitourinary syndrome of menopause (GSM) is associated with major adverse cardiovascular events (MACE). Study Design This was a retrospective cohort analysis using the TriNetX database of women with GSM. MACE was evaluated using inverse probability of treatment weighted logistic regression and Cox proportional hazard models. High-risk patients had MACE 91 days to 2 years before the index; low-risk patients had no MACE during this period. Comparisons were made between women with and without vaginal estrogen prescription within 1 year of GSM diagnosis. Results Between January 1, 2004, and May 16, 2023, 301,701 women were included in the analysis. Of these, 6,152 (2.0%) had a history of recent MACE. Overall, 159,776 (53%) received at least 1 estrogen (estradiol or conjugated estrogens) prescription following GSM diagnosis, of whom 81,446 (51%) only received vaginal estrogen. Compared with controls, the vaginal estrogen cohort had lower odds of MACE (odds ratio [OR]: 0.87, 95% confidence interval [CI]: 0.84–0.89) and no significant difference in MACE hazard (hazard ratio: 0.98, 95% CI: 0.95–1.01). Recent MACE history (OR: 12.3, 95% CI: 11.7–13.0) and obesity (OR: 1.25, 95% CI: 1.21–1.29; hazard ratio: 1.23, 95% CI: 1.19–1.27) were strongly associated with MACE. Conclusions Recent MACE history was strongly associated with subsequent MACE. Vaginal estrogen prescription was associated with lower odds of MACE and no increase in MACE hazard.