Abstract
To evaluate the prevalence and risk factors of antiplatelet drug resistance and its association with early neurological deterioration (END) and recurrent ischemic stroke (RIS) in patients with acute minor stroke. Antiplatelet drug resistance was assessed by platelet aggregation assay in 426 patients with minor stroke who were receiving combined treatment of aspirin and clopidogrel. All patients were followed up for 90 days. The primary endpoint of the study was END within 10 days after admission. The secondary endpoints included RIS, myocardial infarction and death during 90 days of treatment. The safety endpoints were intracerebral or extracranial hemorrhagic events. Cox proportional hazard regression analysis was performed to determine the risk factors for the primary endpoint and secondary endpoints. Among the 426 patients, 24.4 % exhibited aspirin resistance, 35.9 % exhibited clopidogrel resistance, and 19.2 % displayed concomitant aspirin and clopidogrel resistance. In multivariate analysis, diabetes mellitus and high level of low density lipoprotein-cholesterol were independent risk factors for aspirin resistance, while diabetes mellitus was the only independent risk factor for clopidogrel resistance. END was observed in 93 (21.8 %) patients. Diabetes mellitus, high fasting blood glucose level, and concomitant aspirin and clopidogrel resistance were independent risk factors for END. RIS was observed in 40 (9.4 %) patients. Diabetes mellitus, hypertension, and concomitant aspirin and clopidogrel resistance were independent risk factors for RIS. Antiplatelet drug resistance is common in acute minor ischemic stroke patients and is associated with END and RIS after acute minor ischemic stroke in the Chinese population.
Clinical Trial Registration Information: http://www.chictr.org/. Unique Identifier: ChiCTR-OCH-14004724.
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References
Zhao D, Liu J, Wang W, Zeng Z, Cheng J, Liu J et al (2008) Epidemiological transition of stroke in China: twenty-one-year observational study from the Sino-MONICA-Beijing Project. Stroke 39:1668–1674. doi:10.1161/STROKEAHA.107.502807
Wang YL, Wu D, Liao X, Zhang W, Zhao X, Wang YJ (2007) Burden of stroke in China. Int J Stroke 2:211–213. doi:10.1111/j.1747-4949.2007.00142.x
Smith EE, Fonarow GC, Reeves MJ, Cox M, Olson DM, Hernandez AF et al (2011) Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from Get With The Guidelines-Stroke. Stroke 42:3110–3115. doi:10.1161/STROKEAHA.111.613208
Nedeltchev K, Schwegler B, Haefeli T, Brekenfeld C, Gralla J, Fischer U et al (2007) Outcome of stroke with mild or rapidly improving symptoms. Stroke 38:2531–2535. doi:10.1161/STROKEAHA.107.482554
Alawneh JA, Moustafa RR, Baron JC (2009) Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke 40:e443–e450. doi:10.1161/STROKEAHA.108.532465
Yi X, Lin J, Wang C, Zhang B, Chi W (2014) A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. J Stroke Cerebrovasc Dis 23:1975–1981. doi:10.1016/j.jstrokecerebrovasdis.2014.01.022
Lovett JK, Coull AJ, Rothwell PM (2004) Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 62:569–573
Ois A, Gomis M, Rodriguez-Campello A, Cuadrado-Godia E, Jimenez-Conde J, Pont-Sunyer C et al (2008) Factors associated with a high risk of recurrence in patients with transient ischemic attack or minor stroke. Stroke 39:1717–1721. doi:10.1161/STROKEAHA.107.505438
Maas MB, Lev MH, Ay H, Singhal AB, Greer DM, Smith WS et al (2009) Collateral vessels on CT angiography predict outcome in acute ischemic stroke. Stroke 40:3001–3005. doi:10.1161/STROKEAHA.109.552513
Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C et al (2013) Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 369:11–19. doi:10.1056/NEJMoa1215340
Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD et al (2014) 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 45:2160–2236. doi:10.1161/STR.0000000000000024
CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group (1997) Lancet 349:1641–1649
The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group (1997) Lancet 349:1569–1581
Sandercock PA, Counsell C, Gubitz GJ, Tseng MC (2008) Antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev CD000029. doi:10.1002/14651858.CD000029.pub2
Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS et al (2000) Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 31:1240–1249
Committee CS (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348:1329–1339
Makkar RR, Eigler NL, Kaul S, Frimerman A, Nakamura M, Shah PK et al (1998) Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J 19:1538–1546
Yi X, Zhou Q, Lin J, Chi L (2013) Aspirin resistance in Chinese stroke patients increased the rate of recurrent stroke and other vascular events. Int J Stroke 8:535–539. doi:10.1111/j.1747-4949.2012.00929.x
Yin T, Miyata T (2011) Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res 128:307–316. doi:10.1016/j.thromres.2011.04.010
Patrono C (2014) Role of clinical pharmacology in the development of antiplatelet drugs. Clin Ther 36:2096–2111. doi:10.1016/j.clinthera.2014.10.012
Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R et al (2010) Working group on high on-treatment platelet reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 56:919–933. doi:10.1016/j.jacc.2010.04.047
Jia DM, Chen ZB, Zhang MJ, Yang WJ, Jin JL, Xia YQ et al (2013) CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China. Stroke 44:1717–1719. doi:10.1161/STROKEAHA.113.000823
Yi X, Lin J, Zhou Q, Wu L, Cheng W, Wang C (2016) Clopidogrel resistance increases rate of recurrent stroke and other vascular events in chinese population. J Stroke Cerebrovasc Dis 25:1222–1228. doi:10.1016/j.jstrokecerebrovasdis.2016.02.013
Schwammenthal Y, Tsabari R, Shenkman B, Schwartz R, Matetzky S, Lubetsky A et al (2008) Aspirin responsiveness in acute brain ischaemia: association with stroke severity and clinical outcome. Cerebrovasc Dis 25:355–361. doi:10.1159/000118382
Han SW, Kim SH, Lee JY, Chu CK, Yang JH, Shin HY et al (2007) A new subtype classification of ischemic stroke based on treatment and etiologic mechanism. Eur Neurol 57:96–102. doi:10.1159/000098059
Yi X, Zhou Q, Lin J, Chi L, Han Z (2013) Platelet response to aspirin in Chinese stroke patients is independent of genetic polymorphisms of COX-1 C50T and COX-2 G765C. J Atheroscler Thromb 20:65–72
Uzun F, Biyik I, Akturk IF, Erturk M, Yalcin AA, Surgit O et al (2015) Antiplatelet resistance and the role of associated variables in stable patients treated with stenting. Postepy Kardiol Interwencyjnej 11:19–25. doi:10.5114/pwki.2015.49180
Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM (2003) Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107:2908–2913. doi:10.1161/01.CIR.0000072771.11429.83
Wang Q, Chen C, Chen XY, Han JH, Soo Y, Leung TW et al (2012) Low-molecular-weight heparin and early neurologic deterioration in acute stroke caused by large artery occlusive disease. Arch Neurol 69:1454–1460. doi:10.1001/archneurol.2012.1633
Weimar C, Mieck T, Buchthal J, Ehrenfeld CE, Schmid E, Diener HC et al (2005) Neurologic worsening during the acute phase of ischemic stroke. Arch Neurol 62:393–397. doi:10.1001/archneur.62.3.393
Yi X, Chi W, Wang C, Zhang B, Lin J (2015) Low-molecular-weight heparin or dual antiplatelet therapy is more effective than aspirin alone in preventing early neurological deterioration and improving the 6-month outcome in ischemic stroke patients. J Clin Neurol 11:57–65. doi:10.3988/jcn.2015.11.1.57
Smock KJ, Saunders PJ, Rodgers GM, Johari V (2011) Laboratory evaluation of clopidogrel responsiveness by platelet function and genetic methods. Am J Hematol 86:1032–1034. doi:10.1002/ajh.22112
Grundmann K, Jaschonek K, Kleine B, Dichgans J, Topka H (2003) Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol 250:63–66. doi:10.1007/s00415-003-0954-y
Lordkipanidze M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG (2007) A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 28:1702–1708. doi:10.1093/eurheartj/ehm226
Cuisset T, Frere C, Poyet R, Quilici J, Gaborit B, Bali L et al (2010) Clopidogrel response: head-to-head comparison of different platelet assays to identify clopidogrel non responder patients after coronary stenting. Arch Cardiovasc Dis 103:39–45. doi:10.1016/j.acvd.2009.11.004
Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N et al (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360:363–375. doi:10.1056/NEJMoa0808227
Bugnicourt JM, Roussel B, Garcia PY, Canaple S, Lamy C, Godefroy O (2011) Aspirin non-responder status and early neurological deterioration: a prospective study. Clin Neurol Neurosurg 113:196–201. doi:10.1016/j.clineuro.2010.11.004
Ruggeri ZM (2002) Platelets in atherothrombosis. Nat Med 8:1227–1234. doi:10.1038/nm1102-1227
Marquardt L, Ruf A, Mansmann U, Winter R, Schuler M, Buggle F et al (2002) Course of platelet activation markers after ischemic stroke. Stroke 33:2570–2574
Marcus AJ, Safier LB, Broekman MJ, Islam N, Fliessbach JH, Hajjar KA et al (1995) Thrombosis and inflammation as multicellular processes: significance of cell-cell interactions. Thromb Haemost 74:213–217
Fateh-Moghadam S, Li Z, Ersel S, Reuter T, Htun P, Plockinger U et al (2005) Platelet degranulation is associated with progression of intima-media thickness of the common carotid artery in patients with diabetes mellitus type 2. Arterioscler Thromb Vasc Biol 25:1299–1303
Serena J, Rodriguez-Yanez M, Castellanos M (2006) Deterioration in acute ischemic stroke as the target for neuroprotection. Cerebrovasc Dis 21(Suppl. 2):40–48
Zhang X, Sun Z, Ding C, Tang Y, Jiang X, Xie Y et al (2016) Metabolic syndrome augments the risk of early neurological deterioration in acute ischemic stroke patients independent of inflammatory mediators: a hospital-based prospective study. Oxid Med Cell Longev 2016:8346301. doi:10.1155/2016/8346301
Watala C, Golanski J, Pluta J, Boncler M, Rozalski M, Luzak B et al (2004) Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin)-its relation to metabolic control. Thromb Res 113:101–113. doi:10.1016/j.thromres.2003.12.016
Ferreiro JL, Gomez-Hospital JA, Angiolillo DJ (2010) Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res 7:251–259. doi:10.1177/1479164110383994
Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer DE, Murphy-Sheehy PM et al (2000) Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA 283:221–228
Erlinge D, Varenhorst C, Braun OO, James S, Winters KJ, Jakubowski JA et al (2008) Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol 52:1968–1977. doi:10.1016/j.jacc.2008.07.068
Collet JP, Cuisset T, Rangé G, Cayla G, Elhadad S, Pouillot C et al (2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367:2100–2109. doi:10.1056/NEJMoa1209979
Depta JP, Fowler J, Novak E, Katzan I, Bakdash S, Kottke-Marchant K et al (2012) Clinical outcomes using a platelet function-guided approach for secondary prevention in patients with ischemic stroke or transient ischemic attack. Stroke 43:2376–2381. doi:10.1161/STROKEAHA
Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB et al (2010) Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 376:1233–1243. doi:10.1016/S0140-6736(10)61088-4
Helgason CM, Tortorice KL, Winkler SR, Penney DW, Schuler JJ, McClelland TJ et al (1993) Aspirin response and failure in cerebral infarction. Stroke 24:345–350
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This study was supported in part by grants from the Deyang City Science and Technology Research Foundation (#2014SZ035) and the Scientific Research Foundation of Chengdu University of Traditional Chinese Medicine (# YYZX1510).
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Yi, X., Wang, C., Liu, P. et al. Antiplatelet drug resistance is associated with early neurological deterioration in acute minor ischemic stroke in the Chinese population. J Neurol 263, 1612–1619 (2016). https://doi.org/10.1007/s00415-016-8181-5
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DOI: https://doi.org/10.1007/s00415-016-8181-5