Background: Some ischemic strokes in patients with atrial fibrillation (AF) are caused by noncardioembolic etiologies (AF-unrelated stroke), but not AF itself (AF-related stroke). However, most clinical trials on the risk of stroke in AF have not distinguished between these. We investigated the frequency and features of AF-unrelated versus AF-related strokes in patients with AF plus ischemic stroke. We hypothesized that certain clinical factors, including chronicity of AF, treatment at the time of stroke onset and echocardiographic findings, may help to discriminate between AF-related and AF-unrelated strokes. The mechanisms and antithrombotic medications at the time of stroke recurrence in the two groups were also examined. Methods: Consecutive patients with ischemic stroke within 7 days of symptom onset and with AF were included. Patients were classified according to the previously published criteria. Clinical factors including CHADS2 and CHA2DS2-VASc scores and transthoracic echocardiographic (TTE) findings were evaluated. Results: Of 522 patients, 424 (81.2%) were grouped as AF-related stroke and the remaining 90 (17.2%) were classified as AF-unrelated stroke. Among the patients with AF-unrelated stroke, 51 (9.8%) were categorized as possible large artery atherosclerosis and 38 (7.3%) as possible small artery occlusion; 1 patient (0.2%) was assigned to miscellaneous cause. The AF-related and AF-unrelated strokes had similar CHADS2 and CHA2DS2-VASc scores. However, compared to AF-unrelated stroke, AF-related stroke was independently associated with female sex (odds ratio, OR, 2.19; 95% confidence interval, CI, 1.18-4.05), sustained AF (OR, 2.09; 95% CI, 1.21-3.59), inadequate anticoagulation at stroke onset (OR, 3.21; 95% CI, 1.33-7.75) and left ventricular dysfunction on TTE (OR, 2.84; 95% CI, 1.40-5.74). We identified 26 patients who experienced 2 strokes during the study period. The initial stroke subtype was a strong predictor of the recurrent stroke mechanism (p < 0.001). Among 17 events of AF-related recurrent stroke in these subpopulation, only 2 strokes (11.8%) occurred in a setting of adequate anticoagulation, whereas 4 out of 9 patients (44.4%) who had AF-unrelated strokes at recurrence were sufficiently anticoagulated at the time of admission (p = 0.138). Conclusion: AF is not always a culprit of stroke in patients with AF plus ischemic stroke; approximately one sixth of these cases are unrelated to AF and have distinct characteristics compared to AF-related stroke. There are significant differences in terms of some clinical and TTE parameters between AF-related and AF-unrelated stroke. Future studies are warranted to optimize strategies for risk stratification, treatment and prevention of stroke in these patients.

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