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Background: While stroke risk in heart failure with reduced ejection fraction is well established, it is uncertain whether heart failure with preserved ejection fraction (HFpEF) is associated with an increased risk of ischemic stroke.Methods: We performed a retrospective cohort study using inpatient and outpatient data from a nationally representative 5% sample of Medicare beneficiaries ≥66 years of age from 2008-2015. Our exposure of interest was a diagnosis of HFpEF, and our primary outcome was ischemic stroke. Both variables were ascertained using previously validated ICD-9-CM diagnosis codes. Patients were censored at the time of ischemic stroke, death, end of Medicare coverage, or September 30, 2015. Survival statistics were used to calculate stroke incidence and Cox proportional hazards analysis was used to compare the association of HFpEF with ischemic stroke after adjustment for demographics, stroke risk factors, and Charlson comorbidities. Since patients with HFpEF face a particularly increased risk of atrial fibrillation, in a secondary analysis, we censored patients at the time of atrial fibrillation diagnosis to attempt to better isolate the association between HFpEF and ischemic stroke.Results: Among 1,709,029 Medicare beneficiaries, 58,929 (3.45%) were diagnosed with HFpEF. Compared to patients without HFpEF, patients with HFpEF were older (mean age, 78.9 versus 73.1 years), more often female, and had more stroke risk factors. Over 4.6 (±2.3) years of follow-up, 81,981 (4.8%) patients developed an ischemic stroke. The annual incidence of ischemic stroke in patients with HFpEF was 2.2% (95% CI, 2.1-2.3%) compared to 1.0% (95% CI, 1.0-1.0%) in patients without HFpEF. After adjustment for demographics, stroke risk factors, and Charlson comorbidities, HFpEF was not substantially associated with ischemic stroke (HR, 1.08; 95% CI, 1.04-1.13). Our results were similar when censoring patients at the time of atrial fibrillation diagnosis (HR, 1.06; 95% CI, 1.00-1.12).Conclusions: In a nationally representative cohort of Medicare beneficiaries, we found no clinically significant association between HFpEF and risk of ischemic stroke.