Abstract
Background: A considerable proportion of acute noncardiogenic ischemic stroke patients continue to experience recurrent ischemic events after standard therapy.
Aim: We aimed to identify risk factors for recurrent ischemic event prediction at an early stage. Methods: 286 non-cardioembolic ischemic stroke patients with the onset of symptoms within 24 hours were enrolled. Vascular risk factors, routine laboratory data on admission, thromboelastography test seven days after clopidogrel therapy and any recurrent events within one year were assessed. Patients were divided into case group (patients with clinical adverse events, including ischemic stokes, transient ischemic attack, myocardial infarction and vascular related mortality) and control group (events-free patients). The risk of the recurrent ischemic events was determined by the receiver operating characteristic curve and multivariable logistic regression analysis. Results: Clinical adverse events were observed in 43 patients (case group). The mean levels of Mean Platelet Volume (MPV), Platelet/Lymphocyte Ratio (PLR), Lymphocyte Count (LY) and Fibrinogen (Fib) on admission were significantly higher in the case group as compared to the control group (P<0.001). Seven days after clopidogrel therapy, the ADP-induced platelet inhibition rate (ADP%) level was lower in the case group, while the Maximum Amplitude (MA) level was higher in the case group as compared to the control group (P<0.01). The Area Under the Curve (AUC) of receiver operating characteristic(ROC) curve of LY, PLR, , Fib, MA, ADP% and MPV were 0.602, 0.614, 0.629, 0.770, 0.800 and 0.808, respectively. The logistic regression analysis showed that MPV, ADP% and MA were indeed predictive factors. Conclusion: MPV, ADP% and MA were risk factors of recurrent ischemic events after acute noncardiogenic ischemic stroke. Urgent assessment and individual drug therapy should be offered to these patients as soon as possible.Keywords: Ischemic stroke, ischemic event, receiver operating characteristic curve, logistic regression analysis, risk factors, prediction.
[1]
Grotta JC. Antiplatelet therapy after ischemic stroke or TIA. N Engl J Med 2018; 379(3): 291-2.
[http://dx.doi.org/10.1056/NEJMe1806043] [PMID: 29766754]
[http://dx.doi.org/10.1056/NEJMe1806043] [PMID: 29766754]
[2]
Kernan WN, Ovbiagele B, Black HR, et al. 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(7): 2160-236.
[http://dx.doi.org/10.1161/STR.0000000000000024] [PMID: 24788967]
[http://dx.doi.org/10.1161/STR.0000000000000024] [PMID: 24788967]
[3]
Oza R, Rundell K, Garcellano M. Recurrent ischemic stroke: strategies for prevention. Am Fam Physician 2017; 96(7): 436-40.
[PMID: 29094912]
[PMID: 29094912]
[4]
Le Quellec S, Bordet JC, Negrier C, Dargaud Y. Comparison of current platelet functional tests for the assessment of aspirin and clopidogrel response. A review of the literature. Thromb Haemost 2016; 116(4): 638-50.
[PMID: 27440202]
[PMID: 27440202]
[5]
Yin T, Miyata T. Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res 2011; 128(4): 307-16.
[http://dx.doi.org/10.1016/j.thromres.2011.04.010] [PMID: 21592545]
[http://dx.doi.org/10.1016/j.thromres.2011.04.010] [PMID: 21592545]
[6]
Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56(12): 919-33.
[http://dx.doi.org/10.1016/j.jacc.2010.04.047] [PMID: 20828644]
[http://dx.doi.org/10.1016/j.jacc.2010.04.047] [PMID: 20828644]
[7]
Frelinger AL III, Bhatt DL, Lee RD, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol 2013; 61(8): 872-9.
[http://dx.doi.org/10.1016/j.jacc.2012.11.040] [PMID: 23333143]
[http://dx.doi.org/10.1016/j.jacc.2012.11.040] [PMID: 23333143]
[8]
Shuldiner AR, O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009; 302(8): 849-57.
[http://dx.doi.org/10.1001/jama.2009.1232] [PMID: 19706858]
[http://dx.doi.org/10.1001/jama.2009.1232] [PMID: 19706858]
[9]
Jiang XL, Samant S, Lesko LJ, Schmidt S. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet 2015; 54(2): 147-66.
[http://dx.doi.org/10.1007/s40262-014-0230-6] [PMID: 25559342]
[http://dx.doi.org/10.1007/s40262-014-0230-6] [PMID: 25559342]
[10]
Zhang S, Lai X, Li W, et al. VASP phosphorylation and genetic polymorphism for clopidogrel resistance in chinese patients with non-cardioembolic ischemic stroke. Thromb Res 2014; 134(6): 1272-7.
[http://dx.doi.org/10.1016/j.thromres.2014.10.001] [PMID: 25457586]
[http://dx.doi.org/10.1016/j.thromres.2014.10.001] [PMID: 25457586]
[11]
Pan Y, Chen W, Xu Y, et al. Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Circulation 2017; 135(1): 21-33.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024913] [PMID: 27806998]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024913] [PMID: 27806998]
[12]
Zhang C, Wang Y, Zhao X, et al. Prediction of recurrent stroke or transient ischemic attack after noncardiogenic posterior circulation ischemic stroke. Stroke 2017; 48(7): 1835-41.
[http://dx.doi.org/10.1161/STROKEAHA.116.016285] [PMID: 28626054]
[http://dx.doi.org/10.1161/STROKEAHA.116.016285] [PMID: 28626054]
[13]
Akturk IF, Caglar FN, Erturk M, et al. Hypertension as a risk factor for aspirin and clopidogrel resistance in patients with stable coronary artery disease. Clin Appl Thromb Hemost 2014; 20(7): 749-54.
[http://dx.doi.org/10.1177/1076029613481102] [PMID: 23493759]
[http://dx.doi.org/10.1177/1076029613481102] [PMID: 23493759]
[14]
Nakagawa I, Park HS, Yokoyama S, et al. Influence of diabetes mellitus and cigarette smoking on variability of the clopidogrel-induced antiplatelet effect and efficacy of active management of the target p2y12 reaction unit range in patients undergoing neurointerventional procedures. J Stroke Cerebrovasc Dis 2016; 25(1): 163-71.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.09.010] [PMID: 26493334]
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.09.010] [PMID: 26493334]
[15]
Efe E, Kocayiğit I, Türker PM, et al. Platelet-to-lymphocyte ratio but not neutrophil-to-lymphocyte ratio predicts high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndrome. Indian J Pharmacol 2016; 48(4): 355-9.
[http://dx.doi.org/10.4103/0253-7613.186205] [PMID: 27756943]
[http://dx.doi.org/10.4103/0253-7613.186205] [PMID: 27756943]
[16]
Li W, Xie X, Wei D, et al. Baseline platelet parameters for predicting early platelet response and clinical outcomes in patients with non-cardioembolic ischemic stroke treated with clopidogrel. Oncotarget 2017; 8(55): 93771-84.
[http://dx.doi.org/10.18632/oncotarget.21622] [PMID: 29212188]
[http://dx.doi.org/10.18632/oncotarget.21622] [PMID: 29212188]
[17]
Çiçek G, Açıkgoz SK, Bozbay M, et al. Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio combination can predict prognosis in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Angiology 2015; 66(5): 441-7.
[http://dx.doi.org/10.1177/0003319714535970] [PMID: 24834932]
[http://dx.doi.org/10.1177/0003319714535970] [PMID: 24834932]
[18]
Sönmez O, Ertaş G, Bacaksız A, et al. Relation of neutrophil-to-lymphocyte ratio with the presence and complexity of coronary artery disease: an observational study. Anadolu Kardiyol Derg 2013; 13(7): 662-7.
[http://dx.doi.org/10.5152/akd.2013.188] [PMID: 23912788]
[http://dx.doi.org/10.5152/akd.2013.188] [PMID: 23912788]
[19]
Kaya H, Ertaş F, İslamoğlu Y, et al. Association between neutrophil to lymphocyte ratio and severity of coronary artery disease. Clin Appl Thromb Hemost 2014; 20(1): 50-4.
[http://dx.doi.org/10.1177/1076029612452116] [PMID: 22790659]
[http://dx.doi.org/10.1177/1076029612452116] [PMID: 22790659]
[20]
Thomson SP, Gibbons RJ, Smars PA, et al. Incremental value of the leukocyte differential and the rapid creatine kinase-MB isoenzyme for the early diagnosis of myocardial infarction. Ann Intern Med 1995; 122(5): 335-41.
[http://dx.doi.org/10.7326/0003-4819-122-5-199503010-00003] [PMID: 7847644]
[http://dx.doi.org/10.7326/0003-4819-122-5-199503010-00003] [PMID: 7847644]
[21]
Yüksel M, Yıldız A, Oylumlu M, et al. The association between platelet/lymphocyte ratio and coronary artery disease severity. Anatol J Cardiol 2015; 15(8): 640-7.
[http://dx.doi.org/10.5152/akd.2014.5565] [PMID: 25550173]
[http://dx.doi.org/10.5152/akd.2014.5565] [PMID: 25550173]
[22]
Asher E, Fefer P, Shechter M, et al. Increased mean platelet volume is associated with non-responsiveness to clopidogrel. Thromb Haemost 2014; 112(1): 137-41.
[http://dx.doi.org/10.1160/TH13-10-0845] [PMID: 24696016]
[http://dx.doi.org/10.1160/TH13-10-0845] [PMID: 24696016]
[23]
Uzel H, Ozpelit E, Badak O, et al. Diagnostic accuracy of mean platelet volume in prediction of clopidogrel resistance in patients with acute coronary syndrome. Anadolu Kardiyol Derg 2014; 14(2): 134-9.
[http://dx.doi.org/10.5152/akd.2014.4433] [PMID: 24449625]
[http://dx.doi.org/10.5152/akd.2014.4433] [PMID: 24449625]
[24]
Koh YY, Kim HH, Choi DH, et al. Relation between the change in mean platelet volume and clopidogrel resistance in patients undergoing percutaneous coronary intervention. Curr Vasc Pharmacol 2015; 13(5): 687-93.
[http://dx.doi.org/10.2174/1570161112666141017121118] [PMID: 25322834]
[http://dx.doi.org/10.2174/1570161112666141017121118] [PMID: 25322834]
[25]
Du J, Wang Q, He B, et al. Association of mean platelet volume and platelet count with the development and prognosis of ischemic and hemorrhagic stroke. Int J Lab Hematol 2016; 38(3): 233-9.
[http://dx.doi.org/10.1111/ijlh.12474] [PMID: 26992440]
[http://dx.doi.org/10.1111/ijlh.12474] [PMID: 26992440]
[26]
Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter in a fast-moving story. Circulation 2004; 109(25): 3064-7.
[http://dx.doi.org/10.1161/01.CIR.0000134701.40946.30] [PMID: 15226220]
[http://dx.doi.org/10.1161/01.CIR.0000134701.40946.30] [PMID: 15226220]
[27]
Li XG, Ma N, Sun SS, et al. Association of genetic variant and platelet function in patients undergoing neuroendovascular stenting. Postgrad Med J 2017; 93(1103): 555-9.
[http://dx.doi.org/10.1136/postgradmedj-2016-134745] [PMID: 28280103]
[http://dx.doi.org/10.1136/postgradmedj-2016-134745] [PMID: 28280103]
[28]
Kasivisvanathan R, Abbassi-Ghadi N, Kumar S, et al. Risk of bleeding and adverse outcomes predicted by thromboelastography platelet mapping in patients taking clopidogrel within 7 days of non-cardiac surgery. Br J Surg 2014; 101(11): 1383-90.
[http://dx.doi.org/10.1002/bjs.9592] [PMID: 25088505]
[http://dx.doi.org/10.1002/bjs.9592] [PMID: 25088505]
[29]
Zhuo ZL, Xian HP, Long Y, et al. Association between CYP2C19 and ABCB1 polymorphisms and clopidogrel resistance in clopidogrel-treated chinese patients. Anatol J Cardiol 2018; 19(2): 123-9.
[http://dx.doi.org/10.14744/AnatolJCardiol.2017.8097] [PMID: 29350207]
[http://dx.doi.org/10.14744/AnatolJCardiol.2017.8097] [PMID: 29350207]
[30]
Liu R, Zhou ZY, Chen YB, et al. Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in chinese patients with ischemic stroke. Acta Pharmacol Sin 2016; 37(7): 882-8.
[http://dx.doi.org/10.1038/aps.2016.41] [PMID: 27133299]
[http://dx.doi.org/10.1038/aps.2016.41] [PMID: 27133299]