Rational Pharmacotherapy in Cardiology

Advanced search


Full Text:


Platelets play an important role in the pathogenesis of atherosclerosis. They are involved in atherosclerosis progression and thrombotic complications. That is why antiplatelet therapy is a necessary element of these complications prevention in patients with coronary heart disease. One of the most commonly used antiplatelet agents all over the world is clopidogrel, R2Y12-receptor blocker. It is shown that clopidogrel has insufficient effect in some patients, ie they are resistant to clopidogrel. Genetic causes of resistance to clopidogrel are considered in this review. It is shown that genetic factors related to the metabolism of clopidogrel play an important role in the resistance development. Allel variants of the gene cytochrome CYP2C19 are the main among them. The role of other genes is less studied.

About the Author

A. N. Meshkov
Russian Cardiology Research and Production Complex
Russian Federation
Tretya Cherepkovskaya ul. 15a, Moscow, 121552


1. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994;308(6921):81106.

2. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86.

3. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348(9038): 1329-1339.

4. Fox K.A., Mehta S.R., Peters R. et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110(10):1202-8.

5. Steinhubl S.R., Berger P.B., Mann J.T. 3rd et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288(19):2411-20.

6. 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): 783-787.

7. Geisler T., Langer H., Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27(20): 2420–2425

8. Combescure C., Fontana P., Mallouk N. et al. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis.J ThrombHaemost 2010; 8(5): 923–933

9. Aleil B., Jacquemin L., De Poli F. et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc Interv 2008;1(6):631-8.

10. Cuisset T., Frere C., Quilici J. et al. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study. JACC Cardiovasc Interv 2008;1(6):649-53.

11. Zuern C.S., Schwab M., Gawaz M., Geisler T. Platelet Pharmacogenomics. J Thromb Haemost 2010;8(6):1147-58.

12. Simon T., Verstuyft C., Mary-Krause M. et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. N Engl J Med 2009;360(4):363-75.

13. Kim K.A., Park P.W., Hong S.J., Park J.Y. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther 2008; 84(2): 236-42.

14. Mega J.L., Close S.L., Wiviott S.D. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360(4): 354-62.

15. Trenk D., Hochholzer W., Fromm M.F. et al. Cytochrome P450 2C19 681G>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(10):1925-1934

16. Brandt J.T., Close S.L., Iturria S.J. 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.

17. HarmszeA., vanWerkumJ.W.,BoumanH.J. et al.BesidesCYP2C19*2,the variant alleleCYP2C9*3 is associatedwithhigheron-clopidogrelplateletreactivity inpatientsondual antiplatelettherapyun￾dergoing elective coronary stent implantation. Pharmacogenet Genomics 2010;20(1):18-25.

18. Lau W.C., Gurbel P.A., Watkins P.B. et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrelresistance. Circulation 2004; 109(21): 166-71.

19. Angiolillo D.J., Fernandez-Ortiz A., Bernardo E. et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 2006; 26(8): 1895-900.

20. Fontana P., Dupont A., Gandrille S. et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 2003; 108(8): 989-995.

21. Ziegler S., SchillingerM., FunkM. et al.Association of a functional polymorphism in the clopidogrel targetreceptor gene, P2Y12, and the risk forischemic cerebrovascular events in patientswith peripheral artery disease. Stroke 2005: 36(7): 1394–1399.

22. Rudez G., BoumanH.J., vanWerkum J.W. et al. Common variation in the plateletreceptor P2RY12 gene is associated with residual on-clopidogrel platelet reactivity in patients undergoing elective percutaneous coronary interventions. Circ Cardiovasc Genet 2009;2(5):515-21.

23. Сироткина О.В., Богданова Е.В., Боганькова Н.А. и др. Эффективность антиагрегантной терапии клопидогрелом у пациентов, перенесших инфаркт миокарда с подъемом сегмента ST. Кардиоваскулярная терапия и профилактика 2009; 8(1): 51-55.

24. А.Б. Сумароков, Л.И. Бурячковская, М.В. Ежов, И.А. Учитель, Ю.В. Доценко. Особенности дезагрегантной терапии у больных ишемической болезнью сердца в сочетании с язвенной болезнью. Кардиоваскулярная терапия и профилактика, 2010; 9(51) 28-36.

For citation:

Meshkov A.N. CLOPIDOGREL PHARMACOGENETICS. Rational Pharmacotherapy in Cardiology. 2010;6(4):569-572. (In Russ.)

Views: 505

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

ISSN 1819-6446 (Print)
ISSN 2225-3653 (Online)