Role of Cytochrome p450 in Clopidogrel Resistance in Indonesian Stroke Patients

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

doi:10.3889/oamjms.2023.11557

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, Jakarta, 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 https://orcid.org/0000-0002-7924-5419
Melva Louisa Department of Neurology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia https://orcid.org/0000-0002-9451-0380
Erlin Listyaningsih Department of Biomedical Laboratory, Harapan Kita Hospital, Jakarta, Indonesia https://orcid.org/0000-0003-3966-6857
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, West Jakarta, Indonesia https://orcid.org/0000-0002-7503-2395

DOI:

https://doi.org/10.3889/oamjms.2023.11557

Keywords:

antiplatelet, clopidogrel resistance, CYP450, CYP2C19, stroke

Abstract

BACKGROUND: Stroke is the second leading cause of death in the world. Clopidogrel is one of the recommended therapies for it. Disturbances in the metabolic stages of clopidogrel, such as dysregulation of cytochrome p450 (CYP450) and cytochrome P450 2C19 (CYP2C19), can cause unresponsiveness or resistance. However, studies on clopidogrel resistance related to CYP450 and CYP2C19 in Indonesia are limited.

METHODS: This cross-sectional study was conducted in two hospitals over a 1-year period. All patients had a minimum of one episode of ischemic stroke. Data on demographics, clopidogrel resistance, CYP450 concentration, and CYP2C19 polymorphism were collected. In total, 112 participants were enrolled in this study.

RESULTS: We found that the incidence of clopidogrel resistance was 14.3% and the bleeding risk was high (40.3 %). The number of mutations in the CYP2C19 allele *17 was 96.0%. We also found that sex, hemoglobin, and CYP450 were significantly correlated with clopidogrel resistance, and with hemoglobin and CYP450 as independent factors. Fasting blood glucose and CYP2C19 allele *3 were independent factors for CYP450.

CONCLUSION: The incidence of clopidogrel resistance in the Indonesian population is low; therefore, it is not an urgent issue. An important issue in this population is the high risk for bleeding. Patient treatment should be adjusted by considering this risk.

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References

The Top 10 Causes of Death. Available from: https:/ANww.who. int/en/news-roomlfaet-sheets/detaiIIth e-t op-10-causes-of-death [Last accessed on 2022 July 05].

Hackam DG, Hegele RA Cholesterol lowering and prevention of stroke. Stroke. 2019;50(2):537-41. https://doi.org/10.1161/strokeaha.118.023167 PMid:30602355 DOI: https://doi.org/10.1161/STROKEAHA.118.023167

Gladstone DJ, Lindsay MP, Douketis J, Smith EE, Dowlatshahi D, Wein T, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke update 2020. Can J Neurol Sci. 2022;49(3):315-37. https://doi.org/10.1017/CJN.2021.127 PMid 34140063 DOI: https://doi.org/10.1017/cjn.2021.127

Gent M, Beaumont D. Blanchard J. Bousser MG, Coffman J, Easton JD, et al. 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

Hidayat R, Nabilah RA, Rasyid A Harris S, Harahap AR, Herqutanto H, et al. Clopidogrel resistance among ischemic stroke patients and its risk factors in Indonesia. Acta Med Acad. 2022;51(1):29-34. https://doi.org/10.5644/AMA2006-124.367 PMid 35695400 DOI: https://doi.org/10.5644/ama2006-124.367

Hasan MS, Basri HB, Hin LP, Stanslas J. Genetic polymorphisms and drug interactions leading to clopidogrel resistance: Why the Asian population requires special attention. lnt J Neurosci. 2013;123(3) 143-54. https://doi.org/10.3109100207454.2012.7 4 4308 PMid23110469 DOI: https://doi.org/10.3109/00207454.2012.744308

WangY, ZhaoX, Lin J, Li H, Johnston SC, Lin Y, 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(1):70-8. https://doi.org/10.1001/ama.2016.8662 PMid 27348249 DOI: https://doi.org/10.1001/jama.2016.8662

Akkaif MA. Daud NA, Sha'aban A. Ng ML, Kader MA, Noor DA, et al. The role of genetic polymorphism and other factors on clopidogrel resistance (CR) in an Asian population with coronary heart disease (CHD). Molecules. 2021;26(7):1987. https://doi.org/10.3390/molecules26071987 PMid:33915807 DOI: https://doi.org/10.3390/molecules26071987

Osnabrugge RL, Head SJ, Zijlstra F, Berg JM. Hunink MG. Kappetein AP, et al. A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users. Genet Med. 2015:17(1):3-11. https://doi.org/10.1038/gim.2014.76 PMid:24946154 DOI: https://doi.org/10.1038/gim.2014.76

Holmes MV. Perel P, Shah T. Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: A systematic revievv and meta analysis. JAMA 2011;306(24):2704-14 https://doi.org/10.1001/JAMA.2011.1880 PMid:22203539 DOI: https://doi.org/10.1001/jama.2011.1880

Bauer T. Bouman HJ, van Werkum JW. Ford NF. ten Berg JM. Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: Systematic review and meta-analysis. BMJ. 2011:343(7819):d4588. https://doi.org/10.1136/bmi.d4588 PMid:21816733 DOI: https://doi.org/10.1136/bmj.d4588

Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006:79(1):103-13. https://doi.org/10.1016/J.CLPT2005 10 002 PMid:16413245 DOI: https://doi.org/10.1016/j.clpt.2005.10.002

Trenk D, Hochholzer W. Genetics of platelet inhibitor treatment. BrJ Clin Pharmacol. 2014:77(4):642-53. https://doi.org/10.1111/BCP.12230 PMid:23981082 DOI: https://doi.org/10.1111/bcp.12230

Shiozawa M, Kaneko H, ltoh H, Morita K, OkadaA, 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

Legrand D, Barbato E, Chenu P, Magne J. Vrolix M, Wijns W. et al. The STIB score: A simple clinical test to predict clopidogrel resistance. Acta Cardiol. 2015;70(5):516-21. https://doi.org/10.2143/AC.70.5.3110511 PMid 26567810 DOI: https://doi.org/10.1080/AC.70.5.3110511

Price MJ. Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D. et al. Standard-vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: The GRAVITAS randomized trial. JAMA. 2011;305(11):1097-105. https://doi.org/10.1001/ama.2011.290 PMid:21406646 DOI: https://doi.org/10.1001/jama.2011.290

Hulot JS, Bura A, Villard E. Azizi M, Remones V, Goyenvalle C. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244-7. https://doi.org/10.1182/blood-2006-04-013052 PMid:16772608 DOI: https://doi.org/10.1182/blood-2006-04-013052

Hagihara K, Kazui M, Kurihara A. Yoshiike M. Honda K. Okazaki 0, et al. A possible mechanism for the diferences in ef'iciency and variability of active metabolite formation from thienopyridine antiplatelet agents, prasugrel and clopidogrel. Drug Met ab Dispos. 2009;37(11):2145-52. https://doi.org/10.1124/DMD.109.028498 PMid 19704027 DOI: https://doi.org/10.1124/dmd.109.028498

Cavallari LH. Lee CR, Beitelshees AL, Cooper-DeHofi' 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 lnterv. 2018;11{2):181-91. https://doi.org/10.1016/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 lnterv. 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

Gurbel PA, Bliden KP, Etherington A. Tantry US. Assessment of clopidogrel responsiveness: Measurements of maximum platelet aggregation, final platelet aggregation and their correlation with vasodilator-stimulated phosphoprotein in resistant patients. Thromb Res. 2007;121(1):107-15. https://doi.org/10.1016/thromres.2007.02.007 PMid:17400283 DOI: https://doi.org/10.1016/j.thromres.2007.02.007

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

Zhong Z, Hou J, li 8, Zhang 0, liu S, li C, et al. Analysis of CYP2C19 genetic polymorphism in a large ethnic Hakka population in Southern China. Med Sci Monit. 2017:23:6186-92. https://doi.org/10.12659/MSM.905337 PMid:29288619 DOI: https://doi.org/10.12659/MSM.905337

Scott SA, Sangkuhl K. Gardner EE, Stein CM, Hulot JS, Johnson JA. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacal Ther. 2011;90(2):328-32. https://doi.org/10.1038/clpt.2011.132 PMid:21716271 DOI: https://doi.org/10.1038/clpt.2011.132

Pan Y, Elm JJ, li H, Easton JD, Wang Y, Farrant M. et al. Outcomes associated with clopidogrel-aspirin use in minor stroke or transient ischemic attack: A pooled analysis of clopidogrel in high-risk patients with acute non-disabling cerebrovascular events (CHANCE) and platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trials. JAMA Neurol. 2019;76(12):1466-73. https://doi.org/10.1001/jamaneurol.2019.2531 PMid:31424481 DOI: https://doi.org/10.1001/jamaneurol.2019.2531

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