Venous Thromobembolic Events with and Without Vaginal Estrogen Therapy

Objectives: To evaluate whether vaginal estrogen therapy for genitourinary syndrome of menopause (GSM) is associated with a risk of subsequent venous thromboembolic events (VTE) after risk stratification for tobacco use.

Methods: This is a retrospective cohort analysis using the TriNetX international claims-based database of women with a diagnosis of GSM by ICD10 code. Patients were excluded if a diagnosis of VTE occurred within 3 month prior. High-risk patients were defined as those with a diagnosis of tobacco use by ICD10 code any time prior to first GSM diagnosis. Low-risk patients were defined as those without tobacco use prior. The two cohorts were further divided based on exposure to vaginal estrogen. The treatment group included those with a vaginal estrogen prescription within 1 year after GSM diagnosis. The control group included women without any vaginal estrogen prescriptions after GSM diagnosis. Using 1:1 nearest neighbor with a caliper of 0.1 standard deviations of the propensity score, matching was performed on risk factors for VTE including age, race, ethnicity, prior VTE, disorders of lipid metabolism, obesity, immobility, malignancy, diabetes or hypertensive disease, and use of anticoagulation or antiplatelet therapies.

Results: We identified 566,019 women who had a diagnosis of GSM at any time between April 2004 and April 2024. In total, 53.8% were treated with vaginal estrogen. Of the initial cohort, 1.7% were high-risk. After propensity score matching, the sub-groups for treatment and control each included 4,116 high-risk women. A subsequent VTE diagnosis occurred among 3.1% of high-risk women treated with vaginal estrogen and 3.3% of not-treated high-risk women [Hazard Ratio 0.934 (95%CI 0.733, 1.189) p=0.648]. After propensity score matching, the treatment and control groups each included 250,150 low-risk women. A subsequent VTE diagnosis occurred among 2.3% of low-risk women treated with vaginal estrogen and 2.8% of not treated low-risk women [Hazard Ratio 0.900 (95%CI 0.869, 0.932) p=0.781].
Table 1: Cohort characteristics of women with a diagnosis of smoking (high-risk) before and after propensity score matching. Treatment group received a vaginal estrogen prescription within 1 year of GSM diagnosis.
Table 2: Cohort characteristics of women without a diagnosis of smoking (low-risk) before and after propensity score matching. Treatment group received a vaginal estrogen prescription within 1 year of GSM diagnosis.

Conclusions: Vaginal estrogen therapies have a black-box warning for increased risk of deep vein thrombosis. In this large, claims-based analysis using propensity score matching there was no significant association between the use of vaginal estrogen for the treatment of GSM and subsequent VTE after stratifying by tobacco use. In this cohort of women being diagnosed with GSM, just over half are prescribed vaginal estrogen.