Clopidogrel preventive effect based on cytochrome P450 2C19 genotype in ischaemic stroke: protocol for multicentre observational study

Tae-Jin Song, Jinkwon Kim, Sang Won Han, Young Dae Kim, Jong Yun Lee, Seong Hwan Ahn, Hye Sun Lee, Yo Han Jung, Kyung-Yul Lee, Tae-Jin Song, Jinkwon Kim, Sang Won Han, Young Dae Kim, Jong Yun Lee, Seong Hwan Ahn, Hye Sun Lee, Yo Han Jung, Kyung-Yul Lee

Abstract

Introduction: Clopidogrel is an antiplatelet agent that is widely used for the secondary prevention of cardiovascular and cerebrovascular events. The genotype of cytochrome P450 2C19 (CYP2C19) differentially affects the liver's metabolism of clopidogrel, which may influence the drug's response and efficacy for cardiovascular event prevention. In contrast to prior studies of patients with coronary artery diseases, little is known about whether the CYP2C19 genotype influences the preventive efficacy of clopidogrel in patients who had a stroke. We hypothesise that, among patients who had an acute ischaemic stroke who are prescribed clopidogrel, the patients with a loss-of-function CYP2C19 genotype (poor and intermediate metabolisers) may be at a higher risk of composite cardiovascular events than those who are non-carriers (extensive metabolisers).

Methods and analysis: This prospective observational multicentre study was designed to determine whether composite cardiovascular events would differ among patients who had an ischaemic stroke prescribed clopidogrel according to CYP2C19 genotype (poor or intermediate vs extensive metabolisers). Inclusion criteria were patients who had an acute ischaemic stroke who underwent CYP2C19 genotype evaluation and received clopidogrel within 72 hours of stroke onset. The primary outcome is composite cardiovascular events (stroke, myocardial infarction, or cardiovascular death) within 6 months after acute ischaemic stroke between patients categorised as poor or intermediate metabolisers and those categorised as extensive metabolisers according to their CYP2C19 genotype.

Ethics and dissemination: The Institutional Review Board of Severance Hospital, Yonsei University College of Medicine approved this study (3-2019-0195). We received study approval from the institutional review board of each participating hospital. We plan to disseminate our findings at relevant conferences and meetings and through peer-reviewed journals.

Trial registration number: NCT04072705.

Keywords: neurogenetics; neurology; stroke.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

References

    1. Hess CN, Hiatt WR. Antithrombotic therapy for peripheral artery disease in 2018. JAMA 2018;319:2329–30. 10.1001/jama.2018.5422
    1. Yusuf S, Zhao F, Mehta SR, et al. . Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 10.1056/NEJMoa010746
    1. Bhatt DL, Fox KAA, Hacke W, et al. . Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–17. 10.1056/NEJMoa060989
    1. CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329–39. 10.1016/S0140-6736(96)09457-3
    1. Plosker GL, Lyseng-Williamson KA. Clopidogrel: a review of its use in the prevention of thrombosis. Drugs 2007;67:613–46. 10.2165/00003495-200767040-00013
    1. Lau WC, Waskell LA, Watkins PB, et al. . Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003;107:32–7. 10.1161/
    1. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005;45:1157–64. 10.1016/j.jacc.2005.01.034
    1. Mega JL, Close SL, Wiviott SD, et al. . Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354–62. 10.1056/NEJMoa0809171
    1. Simon T, Verstuyft C, Mary-Krause M, et al. . Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363–75. 10.1056/NEJMoa0808227
    1. Wang Y, Zhao X, Lin J, et al. . Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack. JAMA 2016;316:70–8. 10.1001/jama.2016.8662
    1. McDonough CW, McClure LA, Mitchell BD, et al. . CYP2C19 metabolizer status and clopidogrel efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. J Am Heart Assoc 2015;4:e001652. 10.1161/JAHA.114.001652
    1. Han SW, Kim Y-J, Ahn SH, et al. . Effects of triflusal and clopidogrel on the secondary prevention of stroke based on cytochrome P450 2C19 genotyping. J Stroke 2017;19:356–64. 10.5853/jos.2017.01249
    1. Adams HP, Bendixen BH, Kappelle LJ, et al. . Classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. TOAST. trial of ORG 10172 in acute stroke treatment. Stroke 1993;24:35–41. 10.1161/01.STR.24.1.35
    1. Scott SA, Sangkuhl K, Stein CM, et al. . Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 2013;94:317–23. 10.1038/clpt.2013.105
    1. Hicks JK, Sangkuhl K, Swen JJ, et al. . Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017;102:37–44. 10.1002/cpt.597
    1. Chang Y, Kim J, Kim Y-J, et al. . Inter-arm blood pressure difference is associated with recurrent stroke in non-cardioembolic stroke patients. Sci Rep 2019;9:12758. 10.1038/s41598-019-49294-8
    1. Thygesen K, Alpert JS, Jaffe AS, et al. . Fourth universal definition of myocardial infarction (2018). Eur Heart J 2019;40:237–69. 10.1093/eurheartj/ehy462
    1. 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;135:21–33. 10.1161/CIRCULATIONAHA.116.024913
    1. Jeong Y-H. Clopidogrel resistance. Korean J Med 2013;85:1–9. 10.3904/kjm.2013.85.1.1
    1. Lin Y-J, Li J-W, Zhang M-J, et al. . The association between CYP2C19 genotype and of in-stent restenosis among patients with vertebral artery stent treatment. CNS Neurosci Ther 2014;20:125–30. 10.1111/cns.12173
    1. Jia D-mei, Chen Z-bin, Zhang M-juan, et al. . CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China. Stroke 2013;44:1717–9. 10.1161/STROKEAHA.113.000823
    1. Qiu L-N, Sun Y, Wang L, et al. . Influence of CYP2C19 polymorphisms on platelet reactivity and clinical outcomes in ischemic stroke patients treated with clopidogrel. Eur J Pharmacol 2015;747:29–35. 10.1016/j.ejphar.2014.11.037

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