Impact of Cyp2c19 Allele 17 Mutase on Clopidogrel Hyper-Responsiveness in Indonesian Patients with Ischemic Stroke

Rakhmad Hidayat; Al Rasyid; Salim Harris; Alida R. Harahap; Herqutanto Herqutanto; Melva Louisa; Erlin Listyaningsih; Aldy Safruddin Rambe; Tonny Loho

doi:10.3889/oamjms.2023.11558

Authors

Rakhmad Hidayat Department of Neurology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Department of Neurology, Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia; Department of Neurology, Universitas Indonesia Hospital, Depok, Indonesia https://orcid.org/0000-0003-4615-5246
Al Rasyid Department of Neurology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Department of Neurology, Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia
Salim Harris Department of Neurology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Department of Neurology, Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia
Alida R. Harahap Department of Neurology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
Herqutanto Herqutanto Department of Neurology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
Melva Louisa Department of Neurology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
Erlin Listyaningsih Biomedical Laboratory, Harapan Kita Hospital, Jakarta, Indonesia
Aldy Safruddin Rambe Department of Neurology, Universitas Sumatera Utara, Medan, Indonesia
Tonny Loho Department of Clinical Pathology, Faculty of Medicine and Health Science, Kristen Krida Wacana University, Jakarta, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2023.11558

Keywords:

Antiplatelet, Bleeding risk, Clopidogrel, CYP2C19, Stroke

Abstract

BACKGROUND: Ischemic stroke dominated up to 76% of the 101.5 million stroke cases globally. One of the treatments for stroke is secondary prevention by administering antiplatelet. Clopidogrel is an add-on antiplatelet to the dual antiplatelet therapy (DAPT) regimen. In its metabolism, clopidogrel can show the nature of resistance and bleeding risk. Studies on resistance have been widely put forward but not with the bleeding. The study of the bleeding risk to Asian races focused only on East Asian races.

AIM: The objective of the study is to determine the bleeding risk in the Indonesian population and the correlation with the polymorphism of CYP2C19 allele 17.

METHODS: There were 112 participants in this study. About 45.5% showed a normal response to clopidogrel, but 40.2% had a bleeding risk. All participants (100.0%) had mutations in CYP2C19 allele 17, with 47.3% being intermediate metabolizers.

RESULTS: The bleeding risk was significantly correlated with clopidogrel (p: 0.02). The Indonesian population has a high bleeding risk from the clopidogrel administration.

CONCLUSION: Compared to DAPT administration, clopidogrel can be a monotherapy for secondary stroke prevention.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Feigin VL, Stark BA, Johnson CO, Roth GA, Bisignano C, Gebreheat G, et al. Global, regional, and national burden of stroke and its risk factors, 1990-2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795-820. https://doi.org/10.1016/S1474-4422(21)00252-0 PMid:34487721 DOI: https://doi.org/10.1016/S1474-4422(21)00252-0

Kementerian Kesehatan Republik Indonesia. Laporan Nasional Riskesdas 2018. Indonesia: Kementerian Kesehatan Republik Indonesia; 2018.

Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, et al. 2021 Guideline for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline from the American heart association/ American stroke association. Stroke. 2021;52(7):E364-467. https://doi.org/10.1161/STR.0000000000000375 PMid:34024117 DOI: https://doi.org/10.1161/STR.0000000000000375

Wiśniewski A, Filipska K. The phenomenon of clopidogrel high on-treatment platelet reactivity in ischemic stroke subjects: A comprehensive review. Int J Mol Sci. 2020;21(17):6408. https://doi.org/10.3390/IJMS21176408 PMid:32899176 DOI: https://doi.org/10.3390/ijms21176408

Tsai TT, Ho PM, Xu S, Powers JD, Carroll NM, Shetterly SM, et al. Increased risk of bleeding in patients on clopidogrel therapy after drug-eluting stents implantation: Insights from the HMO research network-stent registry (HMORN-stent). Circ Cardiovasc Interv. 2010;3(3):230-5. https://doi.org/10.1161/CIRCINTERVENTIONS.109.919001 PMid:20442361 DOI: https://doi.org/10.1161/CIRCINTERVENTIONS.109.919001

Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, et al. Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv. 2018;11(2):181-91. https://doi.org/10.1016/J.JCIN.2017.07.022 PMid:29102571 DOI: https://doi.org/10.1161/CIRCGEN.118.002253

Pereira NL, Rihal C, Lennon R, Marcus G, Shrivastava S, Bell MR, et al. Effect of CYP2C19 Genotype on ischemic outcomes during oral P2Y12 inhibitor therapy: A meta-analysis. JACC Cardiovasc Interv. 2021;14(7):739-50. https://doi.org/10.1016/J.JCIN.2021.01.024 PMid:33744207 DOI: https://doi.org/10.1016/j.jcin.2021.01.024

Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-9. https://doi.org/10.1056/NEJMoa1215340 PMid:23803136 DOI: https://doi.org/10.1056/NEJMoa1215340

Johnston SC, Easton JD, Farrant M, Barsan W, Battenhouse H, Conwit R, et al. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: Rationale and design. Int J Stroke. 2013;8(6):479-83. https://doi.org/10.1111/IJS.12129 PMid:23879752 DOI: https://doi.org/10.1111/ijs.12129

Gent M, Beaumont D, Blanchard J, Bousser MG, Coffman J, Easton JD. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE steering committee. Lancet. 1996;348(9038):1329-39. https://doi.org/10.1016/S0140-6736(96)09457-3 PMid:8918275 DOI: https://doi.org/10.1016/S0140-6736(96)09457-3

Cho H, Kang J, Kim HS, Park KW. Ethnic differences in oral antithrombotic therapy. Korean Circ J. 2020;50(8):645-57. https://doi.org/10.4070/KCJ.2020.0098 PMid:32725974 DOI: https://doi.org/10.4070/kcj.2020.0098

Kang J, Park KW, Palmerini T, Stone GW, Lee MS, Colombo A, et al. Racial differences in ischaemia/bleeding risk trade-off during anti-platelet therapy: Individual patient level landmark meta-analysis from seven RCTs. Thromb Haemost. 2019;119(1):149-62. https://doi.org/10.1055/S-0038-1676545 PMid:30597509 DOI: https://doi.org/10.1055/s-0038-1676545

Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart disease and stroke statistics-2021 Update. Circulation. 2021;143(8):e254-743. https://doi.org/10.1161/CIR.0000000000000950 PMid:33501848 DOI: https://doi.org/10.1161/CIR.0000000000000950

Chang CS, Chen HJ, Liao CH. Patients with cerebral stroke have an increased risk of gastroesophageal reflux disease: A population-based cohort study. J Stroke Cerebrovasc Dis. 2018;27(5):1267-74. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.12.001 PMid:29325919 DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.12.001

MacMahon S, Baigent C, Duffy S, Whitlock G, Lewington S, Sherliker P, et al. Body-mass index and cause-specific mortality in 900 000 adults: Collaborative analyses of 57 prospective studies. Lancet. 2009;373(9669):1083-96. https:///doi.org/10.1016/S0140-6736(09)60318-4 PMid:19299006 DOI: https://doi.org/10.1016/S0140-6736(09)60318-4

Shiozawa M, Kaneko H, Itoh H, Morita K, Okada A, Matsuoka S, et al. Association of body mass index with ischemic and hemorrhagic stroke. Nutrients. 2021;13(7):2343. https://doi.org/10.3390/NU13072343 PMid:34371853 DOI: https://doi.org/10.3390/nu13072343

Mitchell AB, Cole JW, McArdle PF, Cheng YC, Ryan KA, Sparks MJ, et al. Obesity increases risk of ischemic stroke in young adults. Stroke. 2015;46(6):1690-2. https://doi.org/10.1161/STROKEAHA.115.008940 PMid:25944320 DOI: https://doi.org/10.1161/STROKEAHA.115.008940

Sartika RA, Rosiyati E. Body mass index of adults, pre-elderly and elderly in Indonesia (Indonesian Family Life Survey 2014). Malays J Nutr. 2020;26(2):157-64. https://doi.org/10.31246/mjn-2019-0045 DOI: https://doi.org/10.31246/mjn-2019-0045

Panwar B, Judd SE, Warnock DG, McClellan WM, Booth JN 3rd, Muntner P, et al. Hemoglobin concentration and risk of incident stroke in community-living adults. Stroke. 2016;47(8):2017-24. https://doi.org/10.1161/STROKEAHA.116.013077 PMid:27382006 DOI: https://doi.org/10.1161/STROKEAHA.116.013077

Furlan JC, Fang J, Silver FL. Acute ischemic stroke and abnormal blood hemoglobin concentration. Acta Neurol Scand. 2016;134(2):123-30. https://doi.org/10.1111/ANE.12521 PMid:26487325 DOI: https://doi.org/10.1111/ane.12521

Kuperman A, López-Reyes R, Bosco LS, Lorenzo A, José B, Bancel DF, et al. Anemia and bleeding in patients receiving anticoagulant therapy for venous thromboembolism. J Thromb Thrombolysis. 2018;45(3):360-8. https://doi.org/10.1007/s11239-018-1610-9 PMid:29383557 DOI: https://doi.org/10.1007/s11239-018-1610-9

Nguyen KA, Eadon MT, Yoo R, Milway E, Kenneally A, Fekete K, et al. Risk factors for bleeding and clinical ineffectiveness associated with clopidogrel therapy: A comprehensive meta-analysis. Clin Transl Sci. 2021;14(2):645-55. https://doi.org/10.1111/CTS.12926 PMid:33202084 DOI: https://doi.org/10.1111/cts.12926

Lemesle G, Meurice T, Tricot O, Lamblin N, Bauters C. Association of diabetic status and glycemic control with ischemic and bleeding outcomes in patients with stable coronary artery disease: The 5-year CORONOR registry. J Am Heart Assoc. 2018;7(10):e008354. https://doi.org/10.1161/JAHA.117.008354 PMid:29728374 DOI: https://doi.org/10.1161/JAHA.117.008354

Pol T, Held C, Westerbergh J, Lindbäck J, Alexander JH, Alings M, et al. Dyslipidemia and risk of cardiovascular events in patients with atrial fibrillation treated with oral anticoagulation therapy: Insights from the ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) Trial. J Am Heart Assoc. 2018;7(3):e007444. https://doi.org/10.1161/JAHA.117.007444 PMid:29419390 DOI: https://doi.org/10.1161/JAHA.117.007444

Xu J, Dai L, Zhang Y, Wang A, Li H, Wang Y, et al. Severity of nonalcoholic fatty liver disease and risk of future ischemic stroke events. Stroke. 2021;52(1):103-10. https://doi.org/10.1161/STROKEAHA.120.030433 PMid:33272125 DOI: https://doi.org/10.1161/STROKEAHA.120.030433

Spinosa M, Stine JG. Nonalcoholic fatty liver disease-evidence for a thrombophilic state? Curr Pharm Des. 2020;26(10):1036-44. https://doi.org/10.2174/1381612826666200131101553 PMid:32003679 DOI: https://doi.org/10.2174/1381612826666200131101553

Cresci S, Depta JP, Lenzini PA, Li AY, Lanfear DE, Province MA, et al. Cytochrome p450 gene variants, race, and mortality among clopidogrel-treated patients after acute myocardial infarction. Circ Cardiovasc Genet. 2014;7(3):277-86. https://doi.org/10.1161/CIRCGENETICS.113.000303/-/DC1 PMid:24762860 DOI: https://doi.org/10.1161/CIRCGENETICS.113.000303

Huo Y, Jeong YH, Gong Y, Wang D, He B, Chen J, et al. 2018 update of expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Sci Bull (Beijing). 2019;64(3):166-79. https://doi.org/10.1016/J.SCIB.2018.12.020 PMid:36659616 DOI: https://doi.org/10.1016/j.scib.2018.12.020

Gurbel PA, Shuldiner AR, Bliden KP, Ryan K, Pakyz RE, Tantry US. The relation between CYP2C19 genotype and phenotype in stented patients on maintenance dual antiplatelet therapy. Am Heart J. 2011;161(3):598-604. https://doi.org/10.1016/J.AHJ.2010.12.011 PMid:21392617 DOI: https://doi.org/10.1016/j.ahj.2010.12.011