Impact of <i>CYP2C19*17</i> Gene Polymorphisms on the Clinical Efficacy of Clopidogrel: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

XIEJing ^1,2 , HUXin ¹ , YANGLi-ping ¹

1. Department of Pharmacy, Beijing Hospital, Ministry of Public Health, Beijing 100730, China;
2. Department of Pharmacy, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China;

Corresponding author：

Keywords：

Clopidogrel; CYP2C19; Polymorphism; Systematic review; Meta-analysis; Cohort study

DOI：

10.7507/1672-2531.20140048

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Objective To evaluate anti-platelet effect of clopidogrel influenced by CYP2C19*17 polymorphism in patients with cardiovascular disease. Methods We electronically searched EMbase, PubMed, The Cochrane Library, ClinicalTrials.gov, CNKI, CBM, WanFang Data and VIP databases for cohort studies about the anti-platelet effect of clopidogrel influenced by CYP2C19*17 polymorphism in patients with cardiovascular disease from inception to October 2012. Two reviewers independently screened studies according to the inclusion and exclusion criteria, extracted data and evaluated the methodological quality of the included studies. Then meta-analysis was performed using the software Rev-Man 5.2. Results A total of seven studies involving 12 116 patients were finally included. Three were 5 579 CYP2C19*17 carriers and 6 538 non-carriers. The results of meta-analyses showed that, compared with the CYP2C19*17 non-carriers, lower rate of cardiovascular events (OR=0.85, 95%CI 0.73 to 0.99, P=0.03) and higher bleeding events (OR=1.25, 95%CI 1.05 to 1.50, P=0.01) were found in the CYP2C19*17 carriers. Conclusion CYP2C19*17 carriers is with lower cardiovascular events and higher bleeding events than the CYP2C19*17 non-carriers.

Citation： XIEJing, HUXin, YANGLi-ping. Impact of CYP2C19*17 Gene Polymorphisms on the Clinical Efficacy of Clopidogrel: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2014, 14(3): 271-276. doi: 10.7507/1672-2531.20140048 Copy

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2.	Yusuf S, Ôunpuu S, Anand S. The global epidemic of atherosclerotic cardiovascular disease. Med Principles Pract, 2002, 11(suppl 2):3-8.
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8.	Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 lossof-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol, 2010, 56(2): 134-143.
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11.	Paré 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.
12.	Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation, 2010, 121(4):512-518.
13.	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.
14.	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.
15.	戴泽龙, 陈慧, 吴小盈.冠心病血瘀证患者细胞色素P4502C19*17基因型分布与氯吡格雷治疗后血小板聚集率及出血风险的关系(英文).中西医结合学报, 2012, (6): 647-654.
16.	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 Metab Dispos, 2010, 38(1):92-99.
17.	Geiger J, Brich J, Honig-Liedl P, et al. Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol, 1999, 19(8):2007-2011.
18.	Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P4502C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA, 2009, 302(8):849-857.
19.	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, 2012, 98(2):100-108.
20.	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, 343:d4588.

1. Linsel-Nitschke P, Tall AR. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov, 2005, 4(3):193-205.
2. Yusuf S, Ôunpuu S, Anand S. The global epidemic of atherosclerotic cardiovascular disease. Med Principles Pract, 2002, 11(suppl 2):3-8.
3. Gasparyan AY. Aspirin and clopidogrel resistance:methodological challenges and opportunities. Vasc Health Risk Manag, 2010, 6:109-112.
4. 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.):2143-2150.
5. Sofi F, Giusti B, Marcucci R, et al. Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J, 2011, 11(3): 199-206.
6. Wells G, Shea B, O'Connell D, et al. New Castle-Ottawa Quality Assessment Scale--Cohort Studies. Available at: http://www.ohri.ca/ programs/clinical_epidemiology/oxford.asp. Assessed on June 15, 2012.
7. 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.
8. Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 lossof-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol, 2010, 56(2): 134-143.
9. Higgins JPT, Green S. The Cochrane Collaboration's tool for assessing risk of bias. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0: Section 8. The Cochrane Collaboration. Available at: www.cochrane-handbook.org. Assessed on September 1, 2013.
10. Bhatt DL, Pare G, Eikelboom JW, et al. The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study. Eur Heart J, 2012, 33(17): 2143-2150.
11. Paré 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.
12. Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation, 2010, 121(4):512-518.
13. 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.
14. 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.
15. 戴泽龙, 陈慧, 吴小盈.冠心病血瘀证患者细胞色素P4502C19*17基因型分布与氯吡格雷治疗后血小板聚集率及出血风险的关系(英文).中西医结合学报, 2012, (6): 647-654.
16. 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 Metab Dispos, 2010, 38(1):92-99.
17. Geiger J, Brich J, Honig-Liedl P, et al. Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol, 1999, 19(8):2007-2011.
18. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P4502C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA, 2009, 302(8):849-857.
19. 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, 2012, 98(2):100-108.
20. 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, 343:d4588.

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Impact of CYP2C1917* Gene Polymorphisms on the Clinical Efficacy of Clopidogrel: A Systematic Review

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Impact of CYP2C19*17 Gene Polymorphisms on the Clinical Efficacy of Clopidogrel: A Systematic Review

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Impact of CYP2C1917* Gene Polymorphisms on the Clinical Efficacy of Clopidogrel: A Systematic Review