CYP2C19*2、*3基因多态性与氯吡格雷临床疗效相关性的系统评价△_《中国循证医学杂志》

作者：

杨莉萍 ¹ , 谢婧 ^1,2 , 刘瑶 ¹ ,  胡欣 ¹

1. 卫生部北京医院药学部（北京 100730）；2. 沈阳药科大学药学院（沈阳 110016）;

关键词：

氯吡格雷心血管疾病 CYP2C19 基因多态性 Meta分析安全用药

DOI：

10.7507/1672-2531.20120166

视频：

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摘要 全文 图表 视频 参考文献 施引文献 补充材料

目的　系统评价心血管疾病患者中植入支架后服用氯吡格雷抗血小板作用效果受CYP2C192、3基因多态性的影响程度，以期为其安全使用提供证据。
方法　计算机检索EMbase、PubMed、The Cochrane Library、Clinical Trial、CBM以及CNKI数据库，查找有关心血管疾病患者携带CYP2C192、3基因与氯吡格雷疗效关系的观察性研究和临床试验，检索时限均从建库截至2011年11月。对符合条件的研究，由2位研究者按照纳入和排除标准，独立筛选文献、提取资料、评价质量，并交叉核对后，采用RevMan 5.1软件进行Meta 分析。
结果　共纳入13篇文献，包含14个研究（n=36 855）。Meta分析结果显示：植入支架后服用氯吡格雷，CYP2C192、3和CYP2C191基因携带者的心血管事件及出血事件发生率差异均无统计学意义，但CYP2C192、3基因携带者植入支架后发生血栓的危险较CYP2C191基因携带者明显增加（P lt;0.000 1），其在1个月内发生支架植入后血栓的相对危险度较CYP2C191基因携带者增加了92%（P lt;0.000 1）。
结论　在植入支架后使用氯吡格雷的心血管疾病患者中，CYP2C192、3基因携带者比CYP2C191基因携带者更易发生支架后血栓，但心血管事件和出血事件发生率相当。鉴于CYP2C192、3基因携带者在植入支架后1个月内形成血栓的风险更大，因此，对拟行PCI手术并用氯吡格雷的患者，我们建议先测CYP2C19基因型，再考虑是否应用氯吡格雷抗血小板预防血栓。

引用本文： 杨莉萍,谢婧,刘瑶,胡欣. CYP2C19*2、*3基因多态性与氯吡格雷临床疗效相关性的系统评价△. 中国循证医学杂志, 2012, 12(9): 1063-1070. doi: 10.7507/1672-2531.20120166 复制

1. Uchiyama S. Clopidogrel Resistance: Identifying and overcoming a barrier to effective antiplatelet treatment. Cardiovascular Therapeutics, 2011, 29(6): e100-e11.

2. Plosker GL, Lyseng-Williamson KA. Clopidogrel: A review of its use in the prevention of thrombosis. Drugs, 2007, 67(4): 613-646.

3. Singh M, Thapa B, Arora R. Clopidogrel pharmacogenetics and its clinical implications. American Journal of Therapeutics, 2010, 17(3): e66-e73.

4. Sofi F, Marcucci R, Gori AM, et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost, 2010, 103(4): 841-848.

5. Gurbel PA, Tantry US. Drug Insight: Clopidogrel nonresponsiveness. Nature Clinical Practice Cardiovascular Medicine, 2006, 3(7): 387-395.

6. van Werkum JW, Heestermans AACM, Deneer VHM, et al. Clopidogrel resistance: Fact and fiction. Future Cardiology, 2006, 2(2): 215-228.

7. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: A review of the evidence. Journal of the American College of Cardiology, 2005, 45(8): 1157-1164.

8. Park KW, Park JJ, Jeon KH, et al. Enhanced clopidogrel responsiveness in smokers, nullsmokers’ paradoxnull is dependent on cytochrome P450 CYP1A2 status. Journal of the American College of Cardiology, 2010, 56(13): B1.

9. Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. Journal of the American College of Cardiology, 2011, 57(11): 1251-1263.

10. Ford NF. Clopidogrel resistance: Pharmacokinetic or pharmacogenetic? Journal of Clinical Pharmacology, 2009, 49(5): 506-512.

11. Achar S. Pharmacokinetics, drug metabolism, and safety of prasugrel and clopidogrel. Postgraduate Medicine, 2011, 123(1): 73-79.

12. Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther, 2008, 84(2): 236-242.

13. Pettersen AA, Arnesen H, Opstad TB, et al. The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel. Thromb J, 2011, 94.

14. Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: The ONSET/OFFSET and RESPOND genotype studies. Circulation: Cardiovascular Genetics, 2010, 3(6): 556-566.

15. Frere C, Cuisset T, Gaborit B, et al. 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): 1409-1411.

16. Scott SA, Sangkuhl K, Gardner EE, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clinical Pharmacology and Therapeutics, 2011, 90(2): 328-332.

17. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther, 2011, 89(5): 662-673.

18. Swen JJ, Wilting I, de Goede AL, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther, 2008, 83(5): 781-787.

19. Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med, 2010, 363(18): 1704-1714.

20. Administration. FaD. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug.: U.S. Food and Drug Administration; 2010 [cited 2011 Nov17]; [4 screen]. Available from: http: //www.fda.gov/Drugs/DrugSafety/.

21. Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nature medicine, 2011, 17(1): 110-116.

22. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet, 2009, 373(9660): 309-317.

23. Giusti B, Gori AM, 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(6): 806-811.

24. Malek LA, Kisiel B, Spiewak M, et al. Coexisting polymorphisms of P2Y12 and CYP2C19 genes as a risk factor for persistent platelet activation with clopidogrel. Circ J, 2008, 72(7): 1165-1169.

25. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med, 2009, 360(4): 354-362.

26. Sawada T, Shinke T, Shite J, et al. Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel. Circ J, 2010, 75(1): 99-105.

27. Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J, 2009, 30(8): 916-922.

28. 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(13): 1605-1613.

29. 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): 363-375.

30. Tiroch KA, Sibbing D, Koch W, et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J, 2010, 160(3): 506-512.

31. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet, 2010, 376(9749): 1320-1328.

32. Yamamoto K, Hokimoto S, Chitose T, et al. Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol, 2011, 57(2): 194-201.

33. Karunakaran A, Judge H, Morton A, et al. Cytochrome P450 2C19 loss-of-function genetic variants but not paraoxonase-1 activity modulate P2Y12 blockade in response to clopidogrel therapy. Journal of the American College of Cardiology, 2011, 58(20): B45.

34. Kazui M, Nishiya Y, Ishizuka T, 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 metabolism and disposition: the biological fate of chemicals, 2010, 38(1): 92-99.

35. Simon T, Bhatt DL, Bergougnan L, et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clinical Pharmacology and Therapeutics, 2011, 90(2): 287-295.

36. Harmsze AM, Van Werkum JW, Ten Berg JM, et al. Effect of genetic variants on the effectiveness of clopidogrel. Pharmaceutisch Weekblad, 2011, 146(20): 79-84.

37. Mo SL, Liu YH, Duan W, et al. Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6. Current Drug Metabolism, 2009, 10(7): 730-753.

38. PharmGKB. Variant in CYP2C19. Stanford University; 2012 [cited 2012 April. 19]; [2 screen]. Available from: https: //www.pharmgkb.org.

39. Beitelshees AL, Horenstein RB, Vesely MR, et al. Pharmacogenetics and clopidogrel response in patients undergoing percutaneous coronary interventions. Clinical Pharmacology and Therapeutics, 2011, 89(3): 455-459.

40. Luo Y, Zhao YT, Verdo A, et al. Relationship between cytochrome P450 2C19*2 polymorphism and stent thrombosis following percutaneous coronary intervention in Chinese patients receiving clopidogrel. Journal of International Medical Research, 2011, 39(5): 2012-2019.

41. Zabalza M, Subirana I, Sala J, et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart, 2011, 98(2): 100-108.

42. Mega JL, Simon T, Collet JP, 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(16): 1821-1830.

43. Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ, 2011, 343d4588.

1. Uchiyama S. Clopidogrel Resistance: Identifying and overcoming a barrier to effective antiplatelet treatment. Cardiovascular Therapeutics, 2011, 29(6): e100-e11.

2. Plosker GL, Lyseng-Williamson KA. Clopidogrel: A review of its use in the prevention of thrombosis. Drugs, 2007, 67(4): 613-646.

3. Singh M, Thapa B, Arora R. Clopidogrel pharmacogenetics and its clinical implications. American Journal of Therapeutics, 2010, 17(3): e66-e73.

4. Sofi F, Marcucci R, Gori AM, et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost, 2010, 103(4): 841-848.

5. Gurbel PA, Tantry US. Drug Insight: Clopidogrel nonresponsiveness. Nature Clinical Practice Cardiovascular Medicine, 2006, 3(7): 387-395.

6. van Werkum JW, Heestermans AACM, Deneer VHM, et al. Clopidogrel resistance: Fact and fiction. Future Cardiology, 2006, 2(2): 215-228.

7. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: A review of the evidence. Journal of the American College of Cardiology, 2005, 45(8): 1157-1164.

8. Park KW, Park JJ, Jeon KH, et al. Enhanced clopidogrel responsiveness in smokers, nullsmokers’ paradoxnull is dependent on cytochrome P450 CYP1A2 status. Journal of the American College of Cardiology, 2010, 56(13): B1.

9. Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. Journal of the American College of Cardiology, 2011, 57(11): 1251-1263.

10. Ford NF. Clopidogrel resistance: Pharmacokinetic or pharmacogenetic? Journal of Clinical Pharmacology, 2009, 49(5): 506-512.

11. Achar S. Pharmacokinetics, drug metabolism, and safety of prasugrel and clopidogrel. Postgraduate Medicine, 2011, 123(1): 73-79.

12. Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther, 2008, 84(2): 236-242.

13. Pettersen AA, Arnesen H, Opstad TB, et al. The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel. Thromb J, 2011, 94.

14. Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: The ONSET/OFFSET and RESPOND genotype studies. Circulation: Cardiovascular Genetics, 2010, 3(6): 556-566.

15. Frere C, Cuisset T, Gaborit B, et al. 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): 1409-1411.

16. Scott SA, Sangkuhl K, Gardner EE, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clinical Pharmacology and Therapeutics, 2011, 90(2): 328-332.

17. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther, 2011, 89(5): 662-673.

18. Swen JJ, Wilting I, de Goede AL, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther, 2008, 83(5): 781-787.

19. Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med, 2010, 363(18): 1704-1714.

20. Administration. FaD. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug.: U.S. Food and Drug Administration; 2010 [cited 2011 Nov17]; [4 screen]. Available from: http: //www.fda.gov/Drugs/DrugSafety/.

21. Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nature medicine, 2011, 17(1): 110-116.

22. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet, 2009, 373(9660): 309-317.

23. Giusti B, Gori AM, 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(6): 806-811.

24. Malek LA, Kisiel B, Spiewak M, et al. Coexisting polymorphisms of P2Y12 and CYP2C19 genes as a risk factor for persistent platelet activation with clopidogrel. Circ J, 2008, 72(7): 1165-1169.

25. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med, 2009, 360(4): 354-362.

26. Sawada T, Shinke T, Shite J, et al. Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel. Circ J, 2010, 75(1): 99-105.

27. Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J, 2009, 30(8): 916-922.

28. 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(13): 1605-1613.

29. 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): 363-375.

30. Tiroch KA, Sibbing D, Koch W, et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J, 2010, 160(3): 506-512.

31. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet, 2010, 376(9749): 1320-1328.

32. Yamamoto K, Hokimoto S, Chitose T, et al. Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol, 2011, 57(2): 194-201.

33. Karunakaran A, Judge H, Morton A, et al. Cytochrome P450 2C19 loss-of-function genetic variants but not paraoxonase-1 activity modulate P2Y12 blockade in response to clopidogrel therapy. Journal of the American College of Cardiology, 2011, 58(20): B45.

34. Kazui M, Nishiya Y, Ishizuka T, 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 metabolism and disposition: the biological fate of chemicals, 2010, 38(1): 92-99.

35. Simon T, Bhatt DL, Bergougnan L, et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clinical Pharmacology and Therapeutics, 2011, 90(2): 287-295.

36. Harmsze AM, Van Werkum JW, Ten Berg JM, et al. Effect of genetic variants on the effectiveness of clopidogrel. Pharmaceutisch Weekblad, 2011, 146(20): 79-84.

37. Mo SL, Liu YH, Duan W, et al. Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6. Current Drug Metabolism, 2009, 10(7): 730-753.

38. PharmGKB. Variant in CYP2C19. Stanford University; 2012 [cited 2012 April. 19]; [2 screen]. Available from: https: //www.pharmgkb.org.

39. Beitelshees AL, Horenstein RB, Vesely MR, et al. Pharmacogenetics and clopidogrel response in patients undergoing percutaneous coronary interventions. Clinical Pharmacology and Therapeutics, 2011, 89(3): 455-459.

40. Luo Y, Zhao YT, Verdo A, et al. Relationship between cytochrome P450 2C19*2 polymorphism and stent thrombosis following percutaneous coronary intervention in Chinese patients receiving clopidogrel. Journal of International Medical Research, 2011, 39(5): 2012-2019.

41. Zabalza M, Subirana I, Sala J, et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart, 2011, 98(2): 100-108.

42. Mega JL, Simon T, Collet JP, 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(16): 1821-1830.

43. Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ, 2011, 343d4588.

上一篇
消化医师循证医学实践情况及其相关因素调查

下一篇
血管紧张素转换酶基因多态性与2型糖尿病肾病相关性的Meta分析

1资料与方法

1.1一般资料

1.2方法

1.3察指标和判定标准

1.4统计学方法

2结果

2.1两组患者疗效比较

2.2两组患者换药次数、导管留置时间、治愈时间比较

2.3两组患者治疗前后血清PCT、CRP、WBC水平比较

3讨论

《中国循证医学杂志》

CYP2C192、3基因多态性与氯吡格雷临床疗效相关性的系统评价△

摘要 全文 图表 视频 参考文献 施引文献 补充材料

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Content

1.	Uchiyama S. Clopidogrel Resistance: Identifying and overcoming a barrier to effective antiplatelet treatment. Cardiovascular Therapeutics, 2011, 29(6): e100-e11.
2.	Plosker GL, Lyseng-Williamson KA. Clopidogrel: A review of its use in the prevention of thrombosis. Drugs, 2007, 67(4): 613-646.
3.	Singh M, Thapa B, Arora R. Clopidogrel pharmacogenetics and its clinical implications. American Journal of Therapeutics, 2010, 17(3): e66-e73.
4.	Sofi F, Marcucci R, Gori AM, et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost, 2010, 103(4): 841-848.
5.	Gurbel PA, Tantry US. Drug Insight: Clopidogrel nonresponsiveness. Nature Clinical Practice Cardiovascular Medicine, 2006, 3(7): 387-395.
6.	van Werkum JW, Heestermans AACM, Deneer VHM, et al. Clopidogrel resistance: Fact and fiction. Future Cardiology, 2006, 2(2): 215-228.
7.	Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: A review of the evidence. Journal of the American College of Cardiology, 2005, 45(8): 1157-1164.
8.	Park KW, Park JJ, Jeon KH, et al. Enhanced clopidogrel responsiveness in smokers, nullsmokers’ paradoxnull is dependent on cytochrome P450 CYP1A2 status. Journal of the American College of Cardiology, 2010, 56(13): B1.
9.	Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. Journal of the American College of Cardiology, 2011, 57(11): 1251-1263.
10.	Ford NF. Clopidogrel resistance: Pharmacokinetic or pharmacogenetic? Journal of Clinical Pharmacology, 2009, 49(5): 506-512.
11.	Achar S. Pharmacokinetics, drug metabolism, and safety of prasugrel and clopidogrel. Postgraduate Medicine, 2011, 123(1): 73-79.
12.	Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther, 2008, 84(2): 236-242.
13.	Pettersen AA, Arnesen H, Opstad TB, et al. The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel. Thromb J, 2011, 94.
14.	Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: The ONSET/OFFSET and RESPOND genotype studies. Circulation: Cardiovascular Genetics, 2010, 3(6): 556-566.
15.	Frere C, Cuisset T, Gaborit B, et al. 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): 1409-1411.
16.	Scott SA, Sangkuhl K, Gardner EE, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clinical Pharmacology and Therapeutics, 2011, 90(2): 328-332.
17.	Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther, 2011, 89(5): 662-673.
18.	Swen JJ, Wilting I, de Goede AL, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther, 2008, 83(5): 781-787.
19.	Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med, 2010, 363(18): 1704-1714.
20.	Administration. FaD. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug.: U.S. Food and Drug Administration; 2010 [cited 2011 Nov17]; [4 screen]. Available from: http: //www.fda.gov/Drugs/DrugSafety/.
21.	Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nature medicine, 2011, 17(1): 110-116.
22.	Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet, 2009, 373(9660): 309-317.
23.	Giusti B, Gori AM, 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(6): 806-811.
24.	Malek LA, Kisiel B, Spiewak M, et al. Coexisting polymorphisms of P2Y12 and CYP2C19 genes as a risk factor for persistent platelet activation with clopidogrel. Circ J, 2008, 72(7): 1165-1169.
25.	Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med, 2009, 360(4): 354-362.
26.	Sawada T, Shinke T, Shite J, et al. Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel. Circ J, 2010, 75(1): 99-105.
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CYP2C192、3基因多态性与氯吡格雷临床疗效相关性的系统评价△

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