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Background: Atrial fibrillation confers higher risk of ischemic stroke, but the contribution of low-density lipoprotein cholesterol (LDL-C) levels to this risk remains unclear. We examined the association between LDL-C levels and incident stroke in patients with atrial fibrillation treated with direct oral anticoagulants (DOACs).Methods: This study was conducted using the electronic database of Clalit Health Services in Israel. Included were 21,229 patients with first-time diagnosis of nonvalvular atrial fibrillation treated with DOACs between 2010 and 2017. Patients were categorized into 4 groups according to the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], type 2 diabetes, previous stroke or transient ischemic attack [doubled], vascular disease, age 65-74 years, and sex category) score (1-2, 3-4, 5-6, 7-9). Each group was further stratified to 4 sub-groups according to LDL-C levels (<70, 70-99, 100-130, >130 mg/dL). Ischemic stroke rates were compared among the 4 LDL-C subgroups of each CHA2DS2-VASc category.Results: During 56,467 person-years of follow-up, there were 2481 incidents of ischemic stroke. Higher CHA2DS2-VASc score was associated with significantly increased risk of ischemic stroke (17.5, 26.9, 46.3, 94.9 cases per 1000 person-years, for patients with CHA2DS2-VASc score of 1-2, 3-4, 5-6, and 7-9, respectively; P < .001). However, there was no association between LDL-C levels and incident ischemic stroke within each CHA2DS2-VASc score group, even following a multivariate adjustment. Subanalyses of patients with previous stroke and those treated with statins also failed to show any association between LDL-C levels and incident ischemic stroke.Conclusions: Unlike the general population, LDL-C levels were not associated with ischemic stroke risk among patients with atrial fibrillation treated with DOACs. The findings support the noninclusion of dyslipidemia in ischemic stroke risk stratification of patients with atrial fibrillation. [ABSTRACT FROM AUTHOR]