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.

1.
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.
2.
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.
3.
Hart RG, Pearce LA, Miller VT, Anderson DC, Rothrock JF, Albers GW, Nasco E: Cardioembolic versus 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.
4.
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.
5.
Evans A, Perez I, Yu G, Kalra L: Secondary stroke prevention in atrial fibrillation: lessons from clinical practice. Stroke 2000;31:2106-2111.
6.
Wang TJ, Massaro JM, Levy D, Vasan RS, Wolf PA, D'Agostino RB, Larson MG, Kannel WB, Benjamin EJ: A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. JAMA 2003;290:1049-1056.
7.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151.
8.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L: Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.
9.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.
10.
Hart RG, Pearce LA, Aguilar MI: Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-867.
11.
Furie KL, Goldstein LB, Albers GW, Khatri P, Neyens R, Turakhia MP, Turan TN, Wood KA: Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:3442-3453.
12.
Hart RG, Halperin JL: Atrial fibrillation and stroke: concepts and controversies. Stroke 2001;32:803-808.
13.
Lip GY, Tse HF, Lane DA: Atrial fibrillation. Lancet 2012;379:648-661.
14.
Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA 3rd, Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM, Fuster V, Ryden LE, Cannom DS, Le Heuzey JY, Crijns HJ, Olsson SB, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Guyton RA, Tarkington LG, Yancy CW: 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:104-123.
15.
Miller VT, Rothrock JF, Pearce LA, Feinberg WM, Hart RG, Anderson DC: Ischemic stroke in patients with atrial fibrillation: effect of aspirin according to stroke mechanism. Stroke Prevention in Atrial Fibrillation Investigators. Neurology 1993;43:32-36.
16.
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ: Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-1463.
17.
Okura H, Takada Y, Kubo T, Iwata K, Mizoguchi S, Taguchi H, Toda I, Yoshikawa J, Yoshida K: Tissue Doppler-derived index of left ventricular filling pressure, E/E', predicts survival of patients with non-valvular atrial fibrillation. Heart 2006;92:1248-1252.
18.
Kopecky SL, Gersh BJ, McGoon MD, Whisnant JP, Holmes DR Jr, Ilstrup DM, Frye RL: The natural history of lone atrial fibrillation. A population-based study over three decades. N Engl J Med 1987;317:669-674.
19.
Lip GY, Blann AD: Does hypertension confer a prothrombotic state? Virchow's triad revisited. Circulation 2000;101:218-220.
20.
Fatkin D, Kelly RP, Feneley MP: Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961-969.
21.
Kim YD, Cha MJ, Kim J, Lee DH, Lee HS, Nam CM, Nam HS, Heo JH: Increases in cerebral atherosclerosis according to CHADS2 scores in patients with stroke with nonvalvular atrial fibrillation. Stroke 2011;42:930-934.
22.
Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, Glahn J, Brandt T, Hacke W, Diener HC: Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001;32:2559-2566.
23.
Roquer J, Campello AR, Gomis M: Sex differences in first-ever acute stroke. Stroke 2003;34:1581-1585.
24.
Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL: Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 2000;35:183-187.
25.
Lip GY, Frison L, Grind M: Stroke event rates in anticoagulated patients with paroxysmal atrial fibrillation. J Intern Med 2008;264:50-61.
26.
Capucci A, Santini M, Padeletti L, Gulizia M, Botto G, Boriani G, Ricci R, Favale S, Zolezzi F, Di Belardino N, Molon G, Drago F, Villani GQ, Mazzini E, Vimercati M, Grammatico A: Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers. J Am Coll Cardiol 2005;46:1913-1920.
27.
Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, Morillo CA, Carlson M, Themeles E, Kaufman ES, Hohnloser SH: Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120-129.
28.
Predictors of thromboembolism in atrial fibrillation. II. Echocardiographic features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992;116:6-12.
29.
Echocardiographic predictors of stroke in patients with atrial fibrillation: A prospective study of 1,066 patients from 3 clinical trials. Arch Intern Med 1998;158:1316-1320.
30.
Olshansky B, Heller EN, Mitchell LB, Chandler M, Slater W, Green M, Brodsky M, Barrell P, Greene HL: Are transthoracic echocardiographic parameters associated with atrial fibrillation recurrence or stroke? Results from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study. J Am Coll Cardiol 2005;45:2026-2033.
31.
Lee SH, Choi S, Chung WJ, Byun YS, Ryu SK, Pyun WB, Rim SJ: Tissue Doppler index, E/E', and ischemic stroke in patients with atrial fibrillation and preserved left ventricular ejection fraction. J Neurol Sci 2008;271:148-152.
32.
Rader VJ, Khumri TM, Idupulapati M, Stoner CN, Magalski A, Main ML: Clinical predictors of left atrial thrombus and spontaneous echocardiographic contrast in patients with atrial fibrillation. J Am Soc Echocardiogr 2007;20:1181-1185.
33.
Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study. Circulation 2000;102:1788-1794.
34.
Sohn DW, Song JM, Zo JH, Chai IH, Kim HS, Chun HG, Kim HC: Mitral annulus velocity in the evaluation of left ventricular diastolic function in atrial fibrillation. J Am Soc Echocardiogr 1999;12:927-931.
35.
Hillis GS, Moller JE, Pellikka PA, Gersh BJ, Wright RS, Ommen SR, Reeder GS, Oh JK: Noninvasive estimation of left ventricular filling pressure by E/E' is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360-367.
36.
Wang M, Yip GW, Wang AY, Zhang Y, Ho PY, Tse MK, Lam PK, Sanderson JE: Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820-826.
37.
Agarwal S, Hachamovitch R, Menon V: Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med 2012;172:623-631.
38.
Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Yusuf S: Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903-1912.
39.
Perez-Gomez F, Iriarte JA, Zumalde J, Berjon J, Salvador A, Alegria E, Maluenda MP, Asenjo S, Perez-Saldana R, de la Torre RG, Bover R, Fernandez C: Antithrombotic therapy in elderly patients with atrial fibrillation: effects and bleeding complications: a stratified analysis of the NASPEAF randomized trial. Eur Heart J 2007;28:996-1003.
40.
Hur J, Kim YJ, Lee HJ, Ha JW, Heo JH, Choi EY, Shim CY, Kim TH, Nam JE, Choe KO, Choi BW: Cardiac computed tomographic angiography for detection of cardiac sources of embolism in stroke patients. Stroke 2009;40:2073-2078.
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.