Abstract
Several polymorphisms in genes that encode platelet components (receptors or enzymes), or cytochrome P450 enzyme isoforms, involved in clopidogrel metabolism, have been proposed as possible mechanisms for nonresponsiveness to clopidogrel. Among them, a great deal of attention has been focused on the loss-of-function CYP2C19*2 (or 681 G>A) polymorphism. We performed a meta-analysis of all the prospective studies that have been published, which analyze the role of such a polymorphism in recurrent cardiovascular events in patients with coronary artery disease (CAD) being treated with clopidogrel. Studies were searched in MedLine, Embase, Web of Science, The Cochrane Systematic Review Database, Google Scholar and bibliographies of retrieved articles up to January 2010. The principal underlying hypothesis was that the presence of the *2 variant allele of the polymorphism would be associated with an increased risk of clinical recurrence. Data were available for a total of 8043 patients from seven cohort prospective studies, who were followed for a period of time ranging from 6 months to 8.3 years. The summary risk ratios (RRs) for the prospective cohort studies included showed a significant association between the CYP2C19*2 polymorphism and an increased risk of major adverse cardiovascular events in the follow-up (RR: 1.96 (1.14–3.37); P=0.02). When studies evaluating stent thrombosis (n=4) for a total of 4975 patients were considered, the presence of the variant allele was associated with an increased risk of stent thrombosis (RR: 3.82 (2.23–6.54); P=0.0001). The current meta-analysis, carried out on nearly 8000 patients with CAD undergoing clopidogrel treatment, shows that the CYP2C19*2 polymorphism is associated with an increased risk of major adverse cardiovascular events and stent thrombosis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) investigators: effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527–533.
Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ . Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246–251.
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49: 1505–1516.
Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM . Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pre-treatment platelet reactivity. Circulation 2003; 107: 2908–2913.
Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312–2317.
Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009; 119: 237–242.
Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 2007; 17: 1057–1064.
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Cavallari U, Trabetti 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: 1895–1900.
Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest II CS et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 2429–2436.
Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244–2247.
Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM 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: 1925–1934.
Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Menevau N et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 411–413.
Collet JP, Hulot JS, Villard E, Esteve JB, Silvain J, Payot L et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309–317.
Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354–362.
Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dorrler K et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30: 916–922.
Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia 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: 806–811.
Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009; 302: 849–858.
Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 2002; 30: 1288–1295.
Savi P, Zachayus JL, Delesque-Touchard N, Labouret C, Herve C, Uzabiaga MF et al. The active metabolite of clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci USA 2006; 103: 11069–11074.
Taubert D, Bouman HJ, van Werkum JW . Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 2249–2250.
COGENT: No CV events but significant GI benefits of PPI omeprazole. Available at http://www.theheart.org/article/1007145/print.do.
Kazui M, Nishiya Y, Ishizuka T, Hagihara H, Farid NA, 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: 92–99.
von Beckerath N, Taubert D, Pogatsa-Murray G, Wieczorek A, Schomig E, Schomig A et al. A patient with stent thrombosis, clopidogrel-resistance and failure to metabolize clopidogrel to its active metabolite. Thromb Haemost 2005; 93: 789–791.
Sibbing D, Taubert D, Schomig A, Kastrati A, von Beckerath N . Pharmacokinetics of clopidogrel in patients with stent thrombosis. J Thromb Haemost 2008; 6: 1230–1232.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict to interest.
Rights and permissions
About this article
Cite this article
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 11, 199–206 (2011). https://doi.org/10.1038/tpj.2010.21
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2010.21
Keywords
This article is cited by
-
The Impact of CYP2C19 Genotype on the Platelet Reactivity Index (PRI) among Chronic Coronary Syndromes (CCS) Patients Undergoing Percutaneous Coronary Intervention (PCI): Affectability of Rapid Genetic Testing
Cardiovascular Drugs and Therapy (2024)
-
Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis
BMC Cardiovascular Disorders (2022)
-
Association between cytochrome P450 2C19 polymorphism and clinical outcomes in clopidogrel-treated Uygur population with acute coronary syndrome: a retrospective study
BMC Cardiovascular Disorders (2021)
-
The effects of polymorphisms in CYP2C19, ATP-binding cassette transporter B1, and paraoxonase-1 on clopidogrel treatment of Uygur patients following percutaneous coronary intervention
European Journal of Clinical Pharmacology (2021)
-
Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI—the POPular Risk Score study
European Journal of Clinical Pharmacology (2019)