Modern aspects of clopidogrel pharmacogenetics and its clinical relevance
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Company: A.N. Bakoulev Scientific Center for Cardiovascular Surgery, Rublevskoe shosse, 135, Moscow, 121552, Russian Federation
Keywords: antiplatelet therapy clopidogrel CYP2C19 polymorphisms pharmacogenetics
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2. Chen Z.M., Jiang L.X., Chen Y.P., Xie J.X., Pan H.C., Peto R. et al. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005; 366 (9497): 1607–21.
3. Steinhubl S.R., Berger P.B., Mann J.T. 3rd, Fry E.T., DeLago A., Wilmer C., Topol E.J.; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288 (19): 2411–20.
4. Sabatine M.S., Cannon C.P., Gibson C.M., López- Sendón J.L., Montalescot G., Theroux P. et al. Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCICLARITY study. JAMA. 2005; 294 (10): 1224–32.
5. Kuliczkowski W., Witkowski A., Polonski L., Watala C., Filipiak K., Budaj A. et al. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur. Heart J. 2009; 30 (4): 426–35.
6. Breet N.J., van Werkum J.W., Bouman H.J., Kelder J.C., Harmsze A.M., Hackeng C.M., ten Berg J.M. High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention. Heart. 2011; 97 (12): 983–90.
7. Tantry U.S., Bliden K.P., Gurbel P.A. Resistance to antiplatelet drugs: current status and future research. Expert Opin. Pharmacother. 2005; 6 (12): 2027–45.
8. Geisler T., Kapp M., Göhring-Frischholz K., Daub K., Dösch C., Bigalke B. et al. Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease. Heart. 2008; 94 (6): 743–7.
9. Frelinger A.L. 3rd, Michelson A.D., Wiviott S.D., Trenk D., Neumann F.J., Miller D.L. et al. Intrinsic platelet reactivity before P2Y12 blockade con- highlevel P2Y12 blockade by prasugrel or high-dose clopidogrel. Results from PRINCIPLE-TIMI 44. Thromb. Haemost. 2011; 106 (2): 219–26.
10. Price M.J., Angiolillo D.J., Teirstein P.S., Lillie E., Manoukian S.V., Berger P.B. et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation. 2011; 124 (10): 1132–7.
11. Trenk D., Stone G.W., Gawaz M., Kastrati A., Angiolillo D.J., Müller U. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGERPCI (38. Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J. Am. Coll. Cardiol. 2012; 59 (24): 2159–64.
12. Trenk D., Zolk O., Fromm M.F. et al. Personalizing antiplatelet therapy with clopidogrel. Clin. Pharmacol. Ther. 2012; 92: 476–85.
13. FDA Drug Safety Communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformat ionforPatientsandProviders/ucm203888.htm
14. Savi P., Pereillo J.M., Uzabiaga M.F., Combalbert J., Picard C., Maffrand J.P. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb. Haemost. 2000; 84 (5): 891–6.
15. Kazui M., Nishiya Y., Ishizuka T., Hagihara K., Farid N.A., 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.
16. Scott S.A., Sangkuhl K., Shuldiner A.R., Hulot J.S., Thorn C.F., Altman R.B., Klein T.E. PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19. Pharmacogenet. Genomics. 2012; 22 (2): 159–65.
17. Scott S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin. Pharmacol. Therap. 2011; 90 (2): 328.
18. Сычев Д.А., Раменская Г.В., Игнатьев И.В., Кукес В.Г. Клиническая фармакогенетика. Под ред. Кукес В.Г., Бочкова Н.П. М.; 2007.
19. Lewis J.P., Stephens S.H., Horenstein R.B., O’Connell J.R., Ryan K., Peer C.J. et al. The CYP2C19*17 variant is not independently associated with clopidogrel response. J. Thromb. Haemost. 2013; 11 (9): 1640–6.
20. Hulot J.S., Bura A., Villard E., Azizi M., Remones V., Goyenvalle C. et al. Cytochrome P450 2C19 loss-offunction polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006; 108: 2244–7.
21. Umemura K., Furuta T., Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J. Thromb. Haemost. 2008; 6: 1439–41.
22. 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: 354–62.
23. Brandt J.T., Close S.L., Iturria S.J., Payne C.D., Farid N.A., Ernest C.S. 2nd et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J. Thromb. Haemost. 2007; 5: 2429–36.
24. Simon T., Bhatt D.L., Bergougnan 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. Ther. 2011; 90: 287–95.
25. Varenhorst C., James S., Erlinge D. et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur. Heart J. 2009; 30: 1744–52.
26. Giusti B., Gori A.M., Marcucci R. et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am. J. Cardiol. 2009; 103: 806–11.
27. Shuldiner A.R., O’Connell J.R., Bliden K.P. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J. Am. Med. Assoc. 2009; 302: 849–57.
28. Hochholzer W., Trenk D., Fromm M.F. et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J. Am. Coll. Cardiol. 2010; 55: 2427–34.
29. Sibbing D., Stegherr J., Latz W., Koch W., Mehilli J., Dörrler K. et al. Cytochrome P450 2C19 loss-offunction polymorphism and stent thrombosis following percutaneous coronary intervention. Eur. Heart J. 2009; 30: 916–22.
30. Wallentin L., James S., Storey R.F., Armstrong M., Barratt B.J., Horrow J. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcome of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010; 376: 1320–8.
31. Голухова Е.З., Рябинина М.Н., Булаева Н.И., Григорян М.В., Кубова М.Ч. Реактивность тромбоцитов на фоне двойной антиагрегантной терапии после стентирования коронарных артерий: генетический полиморфизм и клинические варианты. Креативная кардиология. 2013; 2: 15–27.
32. Mega J.L., Simon T., Collet J.P., Anderson J.L., Antman E.M., Bliden K. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010; 304: 1821–30.
33. Holmes M.V., Perel P., Shah T., Hingorani A.D., Casas J.P. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011; 306: 2704–14.
34. Shuldiner A.R., Vesely M.R., Fisch A. CYP2C19 genotype and cardiovascular events. JAMA. 2012; 307: 1482.
35. Mega J.L., Topol E.J., Sabatine M.S. CYP2C19 genotype and cardiovascular events. JAMA. 2012; 307: 1482–3.
36. Siasos G., Tousoulis D., Stefanadis C. CYP2C19 genotype and cardiovascular events. JAMA. 2012; 307: 1483–4.
37. Sim S.C., Risinger C., Dahl M.L., Aklillu E., Christensen M., Bertilsson L., Ingelman-Sundberg M. 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.
38. Frére C., Cuisset T., Gaborit B., Alessi M.C., Hulot J.S. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J. Thromb. Haemost. 2009; 7 (8): 1409–11.
39. Sibbing D., Gebhard D., Koch W., Braun S., Stegherr J., Morath T. et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J. Thromb. Haemost. 2010; 8 (8): 1685–93.
40. Harmsze A.M., van Werkum J.W., Hackeng C.M., Ruven H.J., Kelder J.C., Bouman H.J. et al. The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting. Pharmacogenet. Genomics. 2012; 22 (3): 169–75.
41. Li Y., Tang H.L., Hu Y.F., Xie H.G. The gain-offunction variant allele CYP2C19*17: a doubleedged sword between thrombosis and bleeding in clopidogrel-treated patients. J. Thromb. Haemost. 2012; 10 (2): 199–206.
42. Taubert D., von Beckerath N., Grimberg G. et al. Impact of p-glycoprotein on clopidogrel absorption. Clin. Pharmacol. Ther. 2006; 80: 486–501.
43. Simon T., Verstuyft C., Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N. Engl. J. Med. 2009; 360: 363–75.
44. Luo M., Li J., Xu X. et al. ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: A meta-analysis. Thromb. Res. 2012; 129: 754–9.
45. Bouman H.J., Schoömig E., van Werkum J.W. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat. Med. 2011; 17: 110–6.
46. Sibbing D., Koch W., Massberg S. et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur. Heart J. 2011; 32: 1605–13.
47. Trenk D., Hochholzer W., Fromm M.F. et al. Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. Circ. Cardiovasc. Genet. 2011; 4: 429–36.
48. Reny J.L., Combescure C., Daali Y. et al. Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: A systematic review and meta-analysis. J. Thrombos. Haemostas. 2012; 10: 1242–51.
49. Levine G.N., Bates E.R., Blankenship J.C., Bailey S.R., Bittl J.A., Cercek B. et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. Catheter. Cardiovasc. Interv. 2011; 82 (4): E266–E355.
50. Hamm C.W., Bassand J.-P., Agewall S., Bax J., Boersma E., Bueno H. et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 2011; 32: 2999–3054.
51. Steg P.G., James S.K., Atar D., Badano L.P., Lundqvist C.B., Borger M.A. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur. Heart J. 2012; 33 (20): 2569–619.
52. Scott S.A., Sangkuhl K., Stein C.M., Hulot J.S., Mega J.L., Roden D.M. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin. Pharmacol. Ther. 2013; 94 (3): 317–23.
53. Roberts J.D., Wells G.A., Le May M.R., Labinaz M., Glover C., Froeschl M. et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proofof- concept trial. Lancet. 2012; 379 (9827): 1705–11.
References
1. Pena A., Collet J.P., Hulot J.S. et al. Can we override clopidogrel resistance? Circulation. 2009; 119 (21): 2854–7.2. Chen Z.M., Jiang L.X., Chen Y.P., Xie J.X., Pan H.C., Peto R. et al. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005; 366 (9497): 1607–21.
3. Steinhubl S.R., Berger P.B., Mann J.T. 3rd, Fry E.T., DeLago A., Wilmer C., Topol E.J.; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288 (19): 2411–20.
4. Sabatine M.S., Cannon C.P., Gibson C.M., López- Sendón J.L., Montalescot G., Theroux P. et al. Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCICLARITY study. JAMA. 2005; 294 (10): 1224–32.
5. Kuliczkowski W., Witkowski A., Polonski L., Watala C., Filipiak K., Budaj A. et al. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur. Heart J. 2009; 30 (4): 426–35.
6. Breet N.J., van Werkum J.W., Bouman H.J., Kelder J.C., Harmsze A.M., Hackeng C.M., ten Berg J.M. High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention. Heart. 2011; 97 (12): 983–90.
7. Tantry U.S., Bliden K.P., Gurbel P.A. Resistance to antiplatelet drugs: current status and future research. Expert Opin. Pharmacother. 2005; 6 (12): 2027–45.
8. Geisler T., Kapp M., Göhring-Frischholz K., Daub K., Dösch C., Bigalke B. et al. Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease. Heart. 2008; 94 (6): 743–7.
9. Frelinger A.L. 3rd, Michelson A.D., Wiviott S.D., Trenk D., Neumann F.J., Miller D.L. et al. Intrinsic platelet reactivity before P2Y12 blockade con- highlevel P2Y12 blockade by prasugrel or high-dose clopidogrel. Results from PRINCIPLE-TIMI 44. Thromb. Haemost. 2011; 106 (2): 219–26.
10. Price M.J., Angiolillo D.J., Teirstein P.S., Lillie E., Manoukian S.V., Berger P.B. et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation. 2011; 124 (10): 1132–7.
11. Trenk D., Stone G.W., Gawaz M., Kastrati A., Angiolillo D.J., Müller U. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGERPCI (38. Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J. Am. Coll. Cardiol. 2012; 59 (24): 2159–64.
12. Trenk D., Zolk O., Fromm M.F. et al. Personalizing antiplatelet therapy with clopidogrel. Clin. Pharmacol. Ther. 2012; 92: 476–85.
13. FDA Drug Safety Communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformat ionforPatientsandProviders/ucm203888.htm
14. Savi P., Pereillo J.M., Uzabiaga M.F., Combalbert J., Picard C., Maffrand J.P. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb. Haemost. 2000; 84 (5): 891–6.
15. Kazui M., Nishiya Y., Ishizuka T., Hagihara K., Farid N.A., 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.
16. Scott S.A., Sangkuhl K., Shuldiner A.R., Hulot J.S., Thorn C.F., Altman R.B., Klein T.E. PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19. Pharmacogenet. Genomics. 2012; 22 (2): 159–65.
17. Scott S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin. Pharmacol. Therap. 2011; 90 (2): 328.
18. Сычев Д.А., Раменская Г.В., Игнатьев И.В., Кукес В.Г. Клиническая фармакогенетика. Под ред. Кукес В.Г., Бочкова Н.П. М.; 2007.
19. Lewis J.P., Stephens S.H., Horenstein R.B., O’Connell J.R., Ryan K., Peer C.J. et al. The CYP2C19*17 variant is not independently associated with clopidogrel response. J. Thromb. Haemost. 2013; 11 (9): 1640–6.
20. Hulot J.S., Bura A., Villard E., Azizi M., Remones V., Goyenvalle C. et al. Cytochrome P450 2C19 loss-offunction polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006; 108: 2244–7.
21. Umemura K., Furuta T., Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J. Thromb. Haemost. 2008; 6: 1439–41.
22. 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: 354–62.
23. Brandt J.T., Close S.L., Iturria S.J., Payne C.D., Farid N.A., Ernest C.S. 2nd et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J. Thromb. Haemost. 2007; 5: 2429–36.
24. Simon T., Bhatt D.L., Bergougnan 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. Ther. 2011; 90: 287–95.
25. Varenhorst C., James S., Erlinge D. et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur. Heart J. 2009; 30: 1744–52.
26. Giusti B., Gori A.M., Marcucci R. et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am. J. Cardiol. 2009; 103: 806–11.
27. Shuldiner A.R., O’Connell J.R., Bliden K.P. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J. Am. Med. Assoc. 2009; 302: 849–57.
28. Hochholzer W., Trenk D., Fromm M.F. et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J. Am. Coll. Cardiol. 2010; 55: 2427–34.
29. Sibbing D., Stegherr J., Latz W., Koch W., Mehilli J., Dörrler K. et al. Cytochrome P450 2C19 loss-offunction polymorphism and stent thrombosis following percutaneous coronary intervention. Eur. Heart J. 2009; 30: 916–22.
30. Wallentin L., James S., Storey R.F., Armstrong M., Barratt B.J., Horrow J. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcome of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010; 376: 1320–8.
31. Голухова Е.З., Рябинина М.Н., Булаева Н.И., Григорян М.В., Кубова М.Ч. Реактивность тромбоцитов на фоне двойной антиагрегантной терапии после стентирования коронарных артерий: генетический полиморфизм и клинические варианты. Креативная кардиология. 2013; 2: 15–27.
32. Mega J.L., Simon T., Collet J.P., Anderson J.L., Antman E.M., Bliden K. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010; 304: 1821–30.
33. Holmes M.V., Perel P., Shah T., Hingorani A.D., Casas J.P. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011; 306: 2704–14.
34. Shuldiner A.R., Vesely M.R., Fisch A. CYP2C19 genotype and cardiovascular events. JAMA. 2012; 307: 1482.
35. Mega J.L., Topol E.J., Sabatine M.S. CYP2C19 genotype and cardiovascular events. JAMA. 2012; 307: 1482–3.
36. Siasos G., Tousoulis D., Stefanadis C. CYP2C19 genotype and cardiovascular events. JAMA. 2012; 307: 1483–4.
37. Sim S.C., Risinger C., Dahl M.L., Aklillu E., Christensen M., Bertilsson L., Ingelman-Sundberg M. 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.
38. Frére C., Cuisset T., Gaborit B., Alessi M.C., Hulot J.S. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J. Thromb. Haemost. 2009; 7 (8): 1409–11.
39. Sibbing D., Gebhard D., Koch W., Braun S., Stegherr J., Morath T. et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J. Thromb. Haemost. 2010; 8 (8): 1685–93.
40. Harmsze A.M., van Werkum J.W., Hackeng C.M., Ruven H.J., Kelder J.C., Bouman H.J. et al. The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting. Pharmacogenet. Genomics. 2012; 22 (3): 169–75.
41. Li Y., Tang H.L., Hu Y.F., Xie H.G. The gain-offunction variant allele CYP2C19*17: a doubleedged sword between thrombosis and bleeding in clopidogrel-treated patients. J. Thromb. Haemost. 2012; 10 (2): 199–206.
42. Taubert D., von Beckerath N., Grimberg G. et al. Impact of p-glycoprotein on clopidogrel absorption. Clin. Pharmacol. Ther. 2006; 80: 486–501.
43. Simon T., Verstuyft C., Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N. Engl. J. Med. 2009; 360: 363–75.
44. Luo M., Li J., Xu X. et al. ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: A meta-analysis. Thromb. Res. 2012; 129: 754–9.
45. Bouman H.J., Schoömig E., van Werkum J.W. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat. Med. 2011; 17: 110–6.
46. Sibbing D., Koch W., Massberg S. et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur. Heart J. 2011; 32: 1605–13.
47. Trenk D., Hochholzer W., Fromm M.F. et al. Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. Circ. Cardiovasc. Genet. 2011; 4: 429–36.
48. Reny J.L., Combescure C., Daali Y. et al. Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: A systematic review and meta-analysis. J. Thrombos. Haemostas. 2012; 10: 1242–51.
49. Levine G.N., Bates E.R., Blankenship J.C., Bailey S.R., Bittl J.A., Cercek B. et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. Catheter. Cardiovasc. Interv. 2011; 82 (4): E266–E355.
50. Hamm C.W., Bassand J.-P., Agewall S., Bax J., Boersma E., Bueno H. et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 2011; 32: 2999–3054.
51. Steg P.G., James S.K., Atar D., Badano L.P., Lundqvist C.B., Borger M.A. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur. Heart J. 2012; 33 (20): 2569–619.
52. Scott S.A., Sangkuhl K., Stein C.M., Hulot J.S., Mega J.L., Roden D.M. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin. Pharmacol. Ther. 2013; 94 (3): 317–23.
53. Roberts J.D., Wells G.A., Le May M.R., Labinaz M., Glover C., Froeschl M. et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proofof- concept trial. Lancet. 2012; 379 (9827): 1705–11.
