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.

Keywords:
Brain infarction, Anticoagulants, Atrial fibrillation
1.
Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, Wyse DG, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC Jr, Klein WW, Alonso-Garcia A, Blomstrom-Lundqvist C, de Backer G, Flather M, Hradec J, Oto A, Parkhomenko A, Silber S, Torbicki A; American College of Cardiology/American Heart Association/European Society of Cardiology Board: ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation). Developed in Collaboration with the North American Society of Pacing and Electrophysiology. Circulation 2001;104:2118-2150.
2.
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-e76.
3.
Verheugt FW, Granger CB: Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs. Lancet 2015;386:303-310.
4.
Kamouchi M, Matsuki T, Hata J, Kuwashiro T, Ago T, Sambongi Y, Fukushima Y, Sugimori H, Kitazono T; FSR Investigators: Prestroke glycemic control is associated with the functional outcome in acute ischemic stroke: the Fukuoka stroke registry. Stroke 2011;42:2788-2794.
5.
Kumai Y, Kamouchi M, Hata J, Ago T, Kitayama J, Nakane H, Sugimori H, Kitazono T; FSR Investigators: Proteinuria and clinical outcomes after ischemic stroke. Neurology 2012;78:1909-1915.
6.
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ: Validation of clinical classification schemes for predicting stroke: results from the national registry of atrial fibrillation. JAMA 2001;285:2864-2870.
7.
Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ: Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro heart survey on atrial fibrillation. Chest 2010;137:263-272.
8.
JCS Joint Working Group: Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013). Circ J 2014;78:1997-2021.
9.
Hart RG, Pearce LA, Miller VT, Anderson DC, Rothrock JF, Albers GW, Nasco E: Cardioembolic vs. noncardioembolic strokes in atrial fibrillation: frequency and effect of antithrombotic agents in the stroke prevention in atrial fibrillation studies. Cerebrovasc Dis 2000;10:39-43.
10.
Evans A, Perez I, Yu G, Kalra L: Should stroke subtype influence anticoagulation decisions to prevent recurrence in stroke patients with atrial fibrillation? Stroke 2001;32:2828-2832.
11.
Indredavik B, Rohweder G, Lydersen S: Frequency and effect of optimal anticoagulation before onset of ischaemic stroke in patients with known atrial fibrillation. J Intern Med 2005;258:133-144.
12.
Gladstone DJ, Bui E, Fang J, Laupacis A, Lindsay MP, Tu JV, Silver FL, Kapral MK: Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 2009;40:235-240.
13.
Rose AJ, Ozonoff A, Grant RW, Henault LE, Hylek EM: Epidemiology of subtherapeutic anticoagulation in the United States. Circ Cardiovasc Qual Outcomes 2009;2:591-597.
14.
Albertsen IE, Rasmussen LH, Overvad TF, Graungaard T, Larsen TB, Lip GY: Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis. Stroke 2013;44:1329-1336.
15.
Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HP Jr, Jackson CM, Pullicino P; Warfarin-Aspirin Recurrent Stroke Study Group: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444-1451.
16.
Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Kasner SE, Benesch CG, Sila CA, Jovin TG, Romano JG; Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators: Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005;352:1305-1316.
17.
Evans A, Perez I, Yu G, Kalra L: Secondary stroke prevention in atrial fibrillation: lessons from clinical practice. Stroke 2000;31:2106-2111.
© 2016 S. Karger AG, Basel
2016
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.