Supplementary Material for: Causes of Ischemic Stroke in Patients with Non-Valvular Atrial Fibrillation

Background: Oral anticoagulants (OACs) reduce the incidence of embolic events associated with non-valvular atrial fibrillation (NVAF); however, ischemic stroke can still occur in such patients. Although there are various causes of ischemic stroke in patients with NVAF, their medication status at onset has scarcely been studied. This retrospective study aimed to determine the underlying causes of ischemic stroke in patients with NVAF in relation to pre-stroke anticoagulation. Methods: Among Japanese patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to May 2013, 1,302 patients with NVAF who had been hospitalized within 24 h of onset were included in this study, and their backgrounds, pre-stroke use of OACs and prothrombin time-international normalized ratio (PT-INR) on admission were investigated. Strokes were regarded as being non-cardioembolic (CE) type when causes other than NVAF had been identified. The sub-therapeutic range (TR) for warfarin was defined according to Japanese guidelines for pharmacotherapy of atrial fibrillation. Results: Atrial fibrillation had been diagnosed prior to onset of stroke in 704 of 1,302 patients (54%). However, it had not been detected before or on admission, but identified later during hospitalization in 270 patients (21%). Of the patients who had atrial fibrillation on admission but had not been diagnosed as having it, 108 (8%) had not received any medication before onset of stroke and 220 (17%) had received medications other than OACs. OACs had been administered to 415 (59%) of the patients with known atrial fibrillation. The proportion of pre-stroke CHADS₂ or CHA₂DS₂-VASc scores ≥1 ranged from 93 to 99% depending on whether atrial fibrillation had been diagnosed or anticoagulation therapy administered before stroke onset. The PT-INR was in the sub-TR on admission in 283 of 399 patients (71%) receiving warfarin. Male sex, smoking and previous stroke were more prevalent in patients with values within or over the TR of PT-INR than in those in the sub-TR. Non-CE stroke was more prevalent in patients with values above the lower therapeutic limit of the recommended PT-INR than in those in the sub-TR (p < 0.001). The number of CE strokes was much smaller in patients with high admission PT-INR values; this was not observed for non-CE ischemic strokes (p < 0.001). Conclusions: In the clinical setting, under-diagnosis, underuse and sub-therapeutic doses of OACs are major causes of ischemic stroke in patients with NVAF. However, non-CE ischemic strokes may develop in patients receiving therapeutic doses of warfarin.