The platelet reactivity after percutaneous coronary intervention in patients with double antiplatelet therapy: impact of genetic polymorphisms

Authors: E.Z. Golukhova, M.N. Ryabinina, N.I. Bulaeva, M.V. Grigoryan, M.Ch. Kubova


For citation: Golukhova EZ, Ryabinina MN, Bulaeva NI, at al. The platelet reactivity after percutaneous coronary intervention in patients with double antiplatelet therapy: impact of genetic polymorphisms. Kreativnaya kardiologiya. 2013; 2: 15-27 (in Russian).

Keywords: ischemic heart disease genetic polymorphism antiplatelet therapy platelet aggregation

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Abstract

Objective. To assess antiplatelet therapy efficacy considering the CYP2C19*2 and CYP2C19*3 genetic testing before percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (SCAD).

Material and methods. 55 SCAD-patients aged 36 to 75 years (mean age 59±9.68 years) were studied pre- and postoperatively, mean follow-up was 2 years. Beside conventional investigations, antiplatelet therapy efficacy was assessed by Thromboelastogrphy (TEG) and panel Рlаtеlеt Мaррing with arachidonic acid and ADP-induced platelet aggregation and light transmission aggregometry. Detecting a genetic polymorphism in CYP2C19*2 and CYP2C19*3 were held using allele-specific polymerase chain reaction at the end of follow-up period.

Results. Among study group – 11 patients had MACE (major adverse cardiac events). According to the study, high levels of ADPinduced platelet aggregation (more than 48%, p=0,027) and PRU (more than 225, p=0,00046) influenced on the development of complications. Our analysis revealed a normal genotype (GG) in 39 patients, heterozygous polymorphisms CYP2C19 (GA) G681A allele were detected in 14 patients, and 2 patients has homozygous polymorphisms CYP2C19 (AA) G681A allele. All 55 patients in our study had normal CYP2C19*3 (Trp212Ter) genotype of CYP2C19 gene. We revealed a statistically significant influence of various genotypes of CYP2C19*2 (GG, GA, AA) on the average values of platelet aggregation (F (1,51)=5,75, p=0,02). Also a reliable relationship between MACE and the platelet aggregation according to the LTA (F (1,51)=10,52, p=0,002) was obtained. The interaction of these two factors was significant (F (1,51)=5,57, p=0,022). In our study there was no significant relationship between the different genotypes CYP2C19*2 and the average values of PRU (p=0,057), however, their joint impact on MACE was statistically significant (p=0,041).

Conclusion. Patients with high on-treatment platelet reactivity had a significantly increased risk of having MACE. The platelet reactivity was higher in patients with heterozygous and homozygous carriers of CYP2C19*2 versus normal genotype.

References

1. Trenk D., Kristensen S.D., Hochholzer W., Neumann F.-J. High on-treatment platelet reactivity and P2Y12 antagonist in clinical trials. Thromb. Haemost. 2013; 109 (2): 1–11. 2. Gum P.A., Kottke-Marchant K., Welsh P.A. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J. Am. Coll. Cardiol. 2003; 41: 961–5. 3. Muller I., Besta F., Schulz C. et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb. Haemost. 2003; 89 (5): 783–7. 4. Gurbel P., Bliden K., Hiatt B., O’Connor C. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003. 107 (23): 2908–13. 5. Herlitz J., Toth P.P., Naesdal J. Low-dose aspirin therapy for cardiovascular prevention: quantification and consequences of poorcomliance or discontinuation. Am. J. Cardiovasc. Drugs. 2010; 2: 125–41. 6. Barragan P., Bouvier J.L., Roquebert P.Q. et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter. Cardivasc. Interv. 2003; 59: 295–302. 7. Воробьева И.И., Рыжкова Е.В., Васильева Е.Ю., Шпектор А.В. Влияние системного воспаления на эффект антиагрегантной терапии у больных с острым коронарным синдромом. Креативная кардиология. 2012; 1: 5–14. 8. Церетели Н.В., Иошина В.И. Актуальная проблемы: антиагрегантная терапия при чрескожных коронарных вмешательствах. Бюллетень НЦССХ им. А.Н. Бакулева РАМН. 2009; 10: 203–14. 9. Mobley J., Bress S., Wortham D. et al. Frequency of nonresponce antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am. J. Cardiol. 2004; 93 (4): 456–8. 10. Muller I., Besta F., Schuz C. et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb. Haemost. 2003; 89 (5): 783–7. 11. Herlitz J., Toth P.P., Naesdal J. Low-dose aspirin therapy for cardiovascular prevention: quantification and consequences of poorcomliance or discontinuation. Am. J. Cardiovasc. Drugs. 2010; 2: 125–41. 12. Boggon R., van Staa T.P., Timmis A. et al. Clopidogrel discontinuation after acute coronary syndromes: frequency, predictors and associations with death and myocardial infarction – a hospital registry-primary care linked cohort (MINAP – GPRD). Eur. Heart J. 2011; 32 (19): 2376–86. 13. Gurbel P.A., Tantry U.S. Platelet function testing and genotyping improve outcome in patients treated with antithrombotic agents. Circulation. 2012; 125: 1276–87. 14. Sangkuhl K., Shuldiner A.R., Klein T.E., Altman R.B. Clopidogrel pathway. Pharmacogenet. Genomics. 2010; 20 (7): 463–5. 15. Clarke T.A., Waskell L.A. The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug. Metab. Dispos. 2003; 31: 53–9. 16. Kazul M., Nishiya Y., Ishizuka T., Hagihara K., Farid N.A., Okazaki O., Ikeda T., Kurihara A. 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. 2003; 31: 53–9. 17. Сычев Д.А. Фармакогенетическое тестирование: клиническая интерпретация результатов. М.; 2011: 1–84. 18. ESC Guidelines for themanagement of acute coronary syndromes in patient’s presenting without persistent ST-segment elevation: The Task Force for themanagement of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 2011; doi:10.1093/eurheartj/ehr236.

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, President of Bakoulev National Medical Research Center for Cardiovascular Surgery