Preliminary Data from a Study on Polymorphism RS4244285 of P4502c19 Cytochrome Gene in Patients with Acute Coronary Syndrome, Undergoing Treatment with Dual Antiplatelet Therapy With Clopidogrel and Aspirin

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Summary

Administration of antiplatelet therapy Aspirin and Clopidogrel (CLP) is a corner stone inpatients with Acute Coronary Syndrome (ACS) undergoing Percutaneous Coronary Intervention (PCI) with/without stent implantation. The CYP2C19*2 allele is the most important genetic variant determining response to CLP. We aim to investigate frequency of CYP2C19*2 polymorphism in patients with ACS and significance for the individual response to CLP therapy. The preliminary data of a study including a total of 120 patients with ACS undergoing PCI with stent placement and treated with dual antiplatelet therapy (CLP and Aspirin) are presented. So far 18 patients (41-81 year age) are tested for CYP2C19*l/*2 polymorphisms. The genotype CYP2C19*1/*1; CYP2C19*l/*2 and CYP2C19*2/*2 is demonstrated in 50%, 33%, 17% respectively, of the patients. The established frequency of CYP2C 19*2 allele (33%) is significantly higher (x2=5.220; p=0.022) than in healthy Bulgarian individuals (16%). In-stent thrombosis have developed 3 (17%) of patients: 2 are C YP2C19* l/*2 carriers, and 1 - homozygous CYP2C19*2/*2. The preliminary data demonstrate high prevalence of CYP2C19*2 polymorphism in patients with ACS and point to significance of the variant for CLP therapy. Further extension of the study with larger samples and monitoring of the patients are required to determine the effects of the polymorphism on the prognosis for major adverse cardiovascular events.

1. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreoti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2016;(37):267-315.

2. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg G, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;(33):2569-2619.

3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox K.K. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl JMed. 2001 ;(345):494-502.

4. Mega JL, Close SL, Wiviott SD, Shen L, Hocket RD, Brandt JT, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;(360):354-62.

5. Shuldiner AR, Vesely MR, Fisch A. CYP2C19 genotype and cardiovascular events. JAMA. 2012;307( 14): 1482; author reply 1484-5.

6. Hulot JS, Collet JP, Cayla G, Silvain J, Allanic F, Bellemain-Appaix A, et al. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv. 2011;(4):422-8.

7. Mega JL, Topol EJ, Sabatine MS. CYP2C19 genotype and cardiovascular events. JAMA. 2012;307( 14): 1482-3; author reply 1484-5.

8. Lanham KJ,()estreichJH,DunnSP, Steinhubl SR. Impact of genetic polymorphisms on clinical response to antithrombotics. Pharmacogenomics Pers Med.2010;(3):87-99.

9. Tzveova R, Mitkova A, Paskaleva I, Kaneva R, Mitev V. [The role of genetic factors in determining the clinical efficacy of Clopidogrel]. Cardivascular diseases. 2013;44( 1): 16-29. Bulgarian.

10. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Mafffand JP, et al. Identification and biological activity of the active metabolite of clopidogrel.Thromb Haemost. 2000;(84):891-6.

11. Kazui M,Nishiya Y, IshizukaT,HagiharaK, Farid NA, Okazaki O, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38( 1 ):92-9.

12. Taubert D, von Beckerath N, Grimbeig G, Lazar A, Jung N, Goeser T, et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Then 2006;80(5):486-501.

13. Gladding P, Webster M, Zeng I, Farrell H, Stewart J, Ruygrok Ret al. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv. 2008; 1 (6):620-7.

14. Hulot JS, Bura A, Vi Hard E, Azizi M, Remones V, Goyenvalle C, et al. Cytochrome P4502C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006; 108(7):2244-7.

15. Brandt JT, Close SL, Itunria SJ, Payne CD, Farid NA, Ernest II CS, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5( 12):2429-36.

16. Harmsze A, van Werkum JW, Bouman HJ, Ruven HJ, Breet NJ, Ten Berg JM, et al. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics. 2010;20( 1): 18-25.

17. Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM et al. Cytochrome P450 2C19 681 G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51(20): 1925-34.

18. Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302(8):849-57.

19. Simon T, Bhatt DL, Beigougnan L, Farenc C, Pearson K, Perrin L et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin Pharmacol Then 2011;90(2):287-95.

20. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for cytochrome CYP2C19 genotype and clopidogrel therapy: 2013 Update. Clin Pharmacol Then 2013;94(3):317-323.

21. Pcndichcva D, Tzvcova R, Dimitrova-KaramfOova A, Naydcnova G, Atanasov P, Mitkova A, ct al. Genetic polymorphisms in Clopidogrel and Accnocoumarol related genes and their frequencies in South-Hastem European populatioa ClinThcr. 2014;36(8 Suppl):c7.

22. Akhlaghi A, Shirani S, Ziaic N, Pirhaji O, Yaran M, Shahverdi G, ct al. Cytochrome P450 2C19 Polymorphism in Iranian patients with Coronary Artery Disease. ARYA Athcrosclcr. 2011;7(3): 106-10.

23. Namazi S, Kojuri J, Khalili A, Azarpira N. The impact of genetic polymorphisms of P2Y12, CYP3A5 and CYP2C19 on Clopidogrel response variability in Iranian patients. Biochcm Pharmacol 2012;83(7):903-8.

24. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, ct al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after [treatment with clopidogrel and prasugrcl in the TRITON-T1MI 38 trial: a pharmacogcnctic analysis. Lancet. 2010;376(9749):1312-9.

25. Simon T, Verstuyft C, Mary-Krause M, Qutcinch L, Drouct E, Mcncvcau N, ct al. Genetic determinants of response to Clopidogrel and cardiovascular Events. N Engl J Med. 2009;(360):363-75.

26. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J,ct al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009;373(9660):309-l 7.

27. Sibbing D, Morath T, Braun S, Stegherr J, Mchilli J, Vogt W, ct al. Clopidogrel response status assessed with Multiplatc point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost. 2010;103( 1): 151-9.

28. Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mchilli J, ct al. Antiplatclct effects ofclopidogrcl and bleeding in patients undergoing coronary stent placement. Thromb Haemost. 2010;8(2):250-6.

29. Sibbing D, Stegherr J, LatzW, Koch W, Mchilli J, Dorrlcr K, ct al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J. 2009;30{8):916-22.

30. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, ct al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a metaanalysis. JAMA. 2010;304(16): 1821 -30.

31. Hulot JS, Collet JP, Silva in J, Pena A, Bellemain-Appaix A, Barthelemy O, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-tunction allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010;56(2): 134-43.

32. Hulot JS, Hajjar R, Montalescot G. Clopidogrel and CYP2C19 testing: ready for clinical prime time? Clin Chem. 2012;58( 1): 154-7.

33. Wallentin L, James S, Storey RF, Armstrong M, BarrattBJ, Borrow J,etal. Effect ofCYP2C 19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelol versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376(9749): 1320-8.

34. Pare G, Mehta SR, YusufS, Anand SS, Connolly SJ, Hirsh J et al. Effects ofCYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010;363(18): 1704-14.

35. Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM,Taubert D et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ. 201 l;(343):d4588.

36. Angiolillo DJ, Bernardo E, Sabate M, Jimenez-Quevedo P, Costa MA, Palazuelos J, et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol. 2007;50( 16): 1541-7.

37. Cuisset T, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol. 2009;54{ 13): 1149-53.

38. Gilard M, Amaud B, Comily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the anti platelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008;51 (3):256-60.

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