Background: Clopidogrel reduces the risk of non-cardioembolic ischemic stroke, but it is unclear whether it affects the severity and outcome of stroke. We aimed at evaluating the effect of prior treatment with clopidogrel on acute non-cardioembolic ischemic stroke severity and in-hospital outcome. Methods: We prospectively studied 608 consecutive patients (39.5% males, age 79.1 ± 6.6 years) who were admitted with acute ischemic stroke. The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS ≥21. The outcome was assessed using the dependency rates that prevailed at the time of discharge (i.e. modified Rankin scale between 2 and 5) and with in-hospital mortality. Results: At admission, 397 patients did not have atrial fibrillation or heart valve disease. Among these 397 patients, 69 were receiving monotherapy with clopidogrel prior to stroke, 69 were receiving monotherapy with aspirin and 236 patients were not on any antiplatelet treatment. The prevalence of severe stroke was lower in patients who were receiving clopidogrel than in patients who were receiving aspirin and patients who were not on antiplatelets (1.4, 13.0 and 11.0%, respectively; p < 0.05). Independent predictors of severe stroke at admission were male gender (relative risk (RR) 0.31, 95% CI 0.12-0.78, p < 0.05) and treatment with clopidogrel prior to stroke compared with no antiplatelet treatment (RR 0.13, 95% CI 0.02-0.97, p < 0.05). Treatment with aspirin prior to stroke did not predict severe stroke compared with no antiplatelet treatment (RR 1.24, 95% CI 0.51-2.98, p = NS). The rate of dependency at discharge did not differ between patients who were receiving clopidogrel, patients who were receiving aspirin and those who were not on antiplatelets (57.9, 47.8 and 59.7%, respectively; p = NS). Independent predictors of dependency at discharge were age (RR 1.12, 95% CI 1.05-1.19, p < 0.001) and NIHSS at admission (RR 1.67, 95% CI 1.46-1.92, p < 0.001). In-hospital mortality rate also did not differ between patients who were receiving clopidogrel, patients who were receiving aspirin and those who were not on antiplatelets (4.3, 4.3 and 5.0%, respectively; p = NS). The only independent predictor of in-hospital mortality was NIHSS at admission (RR 1.22, 95% CI 1.14-1.30, p < 0.001). Conclusions: Treatment with clopidogrel prior to acute non-cardioembolic ischemic stroke attenuates the severity of stroke at admission but does not appear to affect the functional outcome at discharge or the in-hospital mortality of these patients.

Keywords:
Non-cardioembolic stroke, Clopidogrel, Antiplatelets, Aspirin, Outcome, Mortality, Severity
1.
Bejot Y, Caillier M, Ben Salem D, Couvreur G, Rouaud O, Osseby GV, Durier J, Marie C, Moreau T, Giroud M: Ischaemic stroke subtypes and associated risk factors: a French population based study. J Neurol Neurosurg Psychiatry 2008;79:1344-1348.
2.
Marnane M, Duggan CA, Sheehan OC, Merwick A, Hannon N, Curtin D, Harris D, Williams EB, Horgan G, Kyne L, McCormack PM, Duggan J, Moore A, Crispino-O'Connell G, Kelly PJ: Stroke subtype classification to mechanism-specific and undetermined categories by TOAST, A-S-C-O, and causative classification system: direct comparison in the North Dublin population stroke study. Stroke 2010;41:1579-1586.
3.
Díaz-Guzmán J, Egido JA, Gabriel-Sánchez R, Barberá-Comes G, Fuentes-Gimeno B, Fernández-Pérez C; IBERICTUS Study Investigators of the Stroke Project of the Spanish Cerebrovascular Diseases Study Group: Stroke and transient ischemic attack incidence rate in Spain: the IBERICTUS study. Cerebrovasc Dis 2012;34:272-281.
4.
Leyden JM, Kleinig TJ, Newbury J, Castle S, Cranefield J, Anderson CS, Crotty M, Whitford D, Jannes J, Lee A, Greenhill J: Adelaide stroke incidence study: declining stroke rates but many preventable cardioembolic strokes. Stroke 2013;44:1226-1231.
5.
Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, Johnston SC, Kasner SE, Kittner SJ, Mitchell PH, Rich MW, Richardson D, Schwamm LH, Wilson JA; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease: Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160-2236.
6.
CAPRIE Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
7.
Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW; PRoFESS Study Group: Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-1251.
8.
Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, Creager MA, Eckel RH, Elkind MS, Fornage M, Goldstein LB, Greenberg SM, Horvath SE, Iadecola C, Jauch EC, Moore WS, Wilson JA; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; Council on Hypertension: Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:3754-3832.
9.
Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C, Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvanne M, Scholte op Reimer WJ, Vrints C, Wood D, Zamorano JL, Zannad F; European Association for Cardiovascular Prevention and Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG): European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635-1701.
10.
Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A: Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849-1860.
11.
Kalra L, Perez I, Smithard DG, Sulch D: Does prior use of aspirin affect outcome in ischemic stroke? Am J Med 2000;108:205-209.
12.
Wilterdink JL, Bendixen B, Adams HP Jr, Woolson RF, Clarke WR, Hansen MD: Effect of prior aspirin use on stroke severity in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Stroke 2001;32:2836-2840.
13.
Dowlatshahi D, Hakim A, Fang J, Sharma M; Investigators of the Registry of the Canadian Stroke Network: Pre admission antithrombotics are associated with improved outcomes following ischaemic stroke: a cohort from the registry of the Canadian stroke network. Int J Stroke 2009;4:328-334.
14.
Jung JM, Choi J, Eun MY, Seo WK, Cho KH, Yu S, Oh K, Hong S, Park KY: Prestroke antiplatelet agents in first-ever ischemic stroke: clinical effects. Neurology 2015;84:1080-1089.
15.
Karepov V, Bornstein NM, Hass Y, Korczyn AD: Does daily aspirin diminish severity of first-ever stroke? Arch Neurol 1997;54:1369-1371.
16.
Sivenius J, Cunha L, Diener HC, Forbes C, Laakso M, Lowenthal A, Smets P, Riekkinen P Sr: Antiplatelet treatment does not reduce the severity of subsequent stroke. European Stroke Prevention Study 2 Working Group. Neurology 1999;53:825-829.
17.
Greisenegger S, Tentschert S, Weber M, Ferrari J, Lang W, Lalouschek W: Prior therapy with antiplatelet agents is not associated with outcome in patients with acute ischemic stroke/TIA. J Neurol 2006;253:648-652.
18.
Ricci S, Lewis S, Sandercock P; IST Collaborative Group: Previous use of aspirin and baseline stroke severity: an analysis of 17,850 patients in the international stroke trial. Stroke 2006;37:1737-1740.
19.
Rist PM, Buring JE, Kase CS, Kurth T: Effect of low-dose aspirin on functional outcome from cerebral vascular events in women. Stroke 2013;44:432-436.
20.
Kwok CS, Skinner J, Metcalf AK, Potter JF, Myint PK: Prior antiplatelet or anticoagulant therapy and mortality in stroke. Heart 2012;98:712-717.
21.
Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
22.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-470.
23.
Antithrombotic Trialists' Collaboration: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
24.
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.
25.
Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P; ESC Committee for Practice Guidelines (CPG): 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European heart rhythm association. Eur Heart J 2012;33:2719-2747.
26.
Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE: Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-1026.
27.
Tziomalos K, Giampatzis V, Bouziana SD, Spanou M, Kostaki S, Papadopoulou M, Dourliou V, Sofogianni A, Savopoulos C, Hatzitolios AI: Adequacy of preadmission oral anticoagulation with vitamin K antagonists and ischemic stroke severity and outcome in patients with atrial fibrillation. J Thromb Thrombolysis 2015, Epub ahead of print.
28.
Schwammenthal Y, Bornstein N, Schwammenthal E, Schwartz R, Goldbourt U, Tsabari R, Koton S, Grossman E, Tanne D: Relation of effective anticoagulation in patients with atrial fibrillation to stroke severity and survival (from the National Acute Stroke Israeli Survey [NASIS]). Am J Cardiol 2010;105:411-416.
29.
Hannon N, Callaly E, Moore A, Ní Chróinín D, Sheehan O, Marnane M, Merwick A, Kyne L, Duggan J, McCormack PM, Dolan E, Crispino-O'Connell G, Harris D, Horgan G, Williams D, Kelly PJ: Improved late survival and disability after stroke with therapeutic anticoagulation for atrial fibrillation: a population study. Stroke 2011;42:2503-2508.
30.
Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, Singer DE: Thirty-day mortality after ischemic stroke and intracranial hemorrhage in patients with atrial fibrillation on and off anticoagulants. Stroke 2012;43:1795-1799.
31.
van Kooten F, Ciabattoni G, Patrono C, Dippel DW, Koudstaal PJ: Platelet activation and lipid peroxidation in patients with acute ischemic stroke. Stroke 1997;28:1557-1563.
32.
Tsai NW, Chang WN, Shaw CF, Jan CR, Chang HW, Huang CR, Chen SD, Chuang YC, Lee LH, Lu CH: Serial change in platelet activation markers with aspirin and clopidogrel after acute ischemic stroke. Clin Neuropharmacol 2010;33:40-45.
33.
Meadows TA, Bhatt DL: Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007;100:1261-1275.
34.
Cha JK, Jeong MH, Lee KM, Bae HR, Lim YJ, Park KW, Cheon SM: Changes in platelet P-selectin and in plasma C-reactive protein in acute atherosclerotic ischemic stroke treated with a loading dose of clopidogrel. J Thromb Thrombolysis 2002;14:145-150.
35.
Heitzer T, Rudolph V, Schwedhelm E, Karstens M, Sydow K, Ortak M, Tschentscher P, Meinertz T, Böger R, Baldus S: Clopidogrel improves systemic endothelial nitric oxide bioavailability in patients with coronary artery disease: evidence for antioxidant and antiinflammatory effects. Arterioscler Thromb Vasc Biol 2006;26:1648-1652.
36.
Webster CM, Hokari M, McManus A, Tang XN, Ma H, Kacimi R, Yenari MA: Microglial P2Y12 deficiency/inhibition protects against brain ischemia. PLoS One 2013;8:e70927.
37.
Özdemir HH, İlhan S, Demir CF, Akgün B, Kapan O, Ataş E, Berilgen MS, Balduz M: Effects of memantine and clopidogrel alone and in combination in a cerebral ischemia-reperfusion model. Neurol Psychiat Br 2015;21:73-77.
38.
Reeves MJ, Vaidya RS, Fonarow GC, Liang L, Smith EE, Matulonis R, Olson DM, Schwamm LH; Get with the Guidelines Steering Committee and Hospitals: Quality of care and outcomes in patients with diabetes hospitalized with ischemic stroke: findings from get with the guidelines-stroke. Stroke 2010;41:e409-e417.
39.
Tziomalos K, Spanou M, Bouziana SD, Papadopoulou M, Giampatzis V, Kostaki S, Dourliou V, Tsopozidi M, Savopoulos C, Hatzitolios AI: Type 2 diabetes is associated with a worse functional outcome of ischemic stroke. World J Diabetes 2014;5:939-944.
40.
Koton S, Tsabari R, Molshazki N, Kushnir M, Shaien R, Eilam A, Tanne D; NASIS Investigators: Burden and outcome of prevalent ischemic brain disease in a national acute stroke registry. Stroke 2013;44:3293-3297.
41.
Roquer J, Giralt-Steinhauer E, Cerdà G, Rodríguez-Campello A, Cuadrado-Godia E, Jiménez-Conde J, Vivanco-Hidalgo RM, Soriano C, Dégano IR, Ois A: Glycated hemoglobin value combined with initial glucose levels for evaluating mortality risk in patients with ischemic stroke. Cerebrovasc Dis 2015;40:244-250.
42.
Park KY, Chung PW, Kim YB, Moon HS, Suh BC, Won YS, Kim JM, Youn YC, Kwon OS: Serum vitamin D status as a predictor of prognosis in patients with acute ischemic stroke. Cerebrovasc Dis 2015;40:73-80.
43.
Yao X, Dong Q, Song Y, Wang Y, Deng Y, Li Y: Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke. Cerebrovasc Dis 2014;38:182-190.
44.
Fonville S, Zandbergen AA, Koudstaal PJ, den Hertog HM: Prediabetes in patients with stroke or transient ischemic attack: prevalence, risk and clinical management. Cerebrovasc Dis 2014;37:393-400.
45.
Hankey GJ, Hacke W, Easton JD, Johnston SC, Mas JL, Brennan DM, Bhatt DL, Fox KA, Topol EJ; CHARISMA Trial Investigators: Effect of clopidogrel on the rate and functional severity of stroke among high vascular risk patients: a prespecified substudy of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management and avoidance (CHARISMA) trial. Stroke 2010;41:1679-1683.
46.
Siller-Matula JM, Trenk D, Schrör K, Gawaz M, Kristensen SD, Storey RF, Huber K; EPA (European Platelet Academy): Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv 2013;6:1111-1128.
47.
Mijajlovic MD, Shulga O, Bloch S, Covickovic-Sternic N, Aleksic V, Bornstein NM: Clinical consequences of aspirin and clopidogrel resistance: an overview. Acta Neurol Scand 2013;128:213-219.
48.
Yang L, Colditz GA: Prevalence of overweight and obesity in the United States, 2007-2012. JAMA Intern Med 2015;175:1412-1413.
49.
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE: Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-149.
© 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.