Recurrent Ischemic Stroke and Vaginal Estradiol in Women With Prior Ischemic Stroke: A Nationwide Nested Case-Control Study

BACKGROUND: Systemic estrogen replacement therapy is contraindicated in women with a history of ischemic stroke due to the risk of stroke recurrence. There are currently no published data available describing the association between vaginal estrogen use and recurrent ischemic stroke in women with a history of ischemic stroke. This study aimed to examine the association between vaginal estradiol tablet use and the rate of recurrent ischemic stroke in women with a history of ischemic stroke.

METHODS: Using nationwide registers, we conducted a nationwide nested case-control study including all women aged ≥45 years who developed a first ischemic stroke between January 1, 2008, and December 31, 2017, with no history of vaginal estrogen use before stroke diagnosis. Using incidence density sampling, we matched cases with recurrent ischemic stroke 1:1 to controls based on birth year. The index date was defined as the date of recurrent ischemic stroke diagnosis. Exposure to vaginal estradiol tablets was assessed using prescription data and categorized as current use (0-3 months before index), recent use (3-24 months before index), and past use (>24 months before index).

RESULTS: From a cohort of 56 642 women with a first-time stroke, we identified 3353 recurrent cases, which were matched by birth year with 3353 controls. The median age was 75 (SD, 12) years. When adjusted for comorbidity, medications, income, and education, exposure to vaginal estradiol tablets was not associated with an increased rate of recurrent ischemic stroke (current use: adjusted hazard ratio, 0.79 [95% CI, 0.52-1.20]; P=0.27; recent use: adjusted hazard ratio, 1.09 [95% CI, 0.73-1.63]; P=0.67; and past use: adjusted hazard ratio, 1.48 [95% CI, 0.95-2.30]; P=0.08).

CONCLUSIONS: In this nested case-control study, use of vaginal estradiol tablets was not associated with an increased rate of recurrent ischemic stroke in women with a history of ischemic stroke. Based on our findings, vaginal estradiol tablets are not likely to increase the risk of recurrent ischemic stroke in women with prior stroke.