The genetic basis of platelet responsiveness to clopidogrel

Summary

Clopidogrel reduces ischaemic complications in a wide range of patients with coronary artery disease. However, there is much inter-individual variation in clopidogrel-induced platelet inhibition, and a substantial proportion of patients will exhibit non-responsiveness to clopidogrel. Multiple studies have demonstrated an association between the presence of genetic polymorphisms associated with suboptimal clopidogrel-active metabolite generation, decreased platelet responsiveness, and adverse clinical outcomes. However, it is not clear to what extent the genetic polymorphisms account for the observed variability in response to clopidogrel. In this review we provide a critical summary of the available evidence linking genetic factors with response to clopidogrel, and discuss the clinical implications of this association.

Keywords

Antiplatelet agents - polymorphisms - platelet pharmacology

• References

• 1 Lange RA, Hillis LD. Antiplatelet therapy for ischemic heart disease. N Engl J Med 2004; 350: 277-280.
• 2 Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004; 113: 340-345.
• 3 Mehta SR, Yusuf S, Peters RJ. et al. ; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
• 4 Steinhubl SR, Berger PB, Mann JT. Ill et al. ; 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. J Am Med Assoc 2002; 288: 2411-2420.
• 5 Patrono C, Baigent C, Hirsh J. et al. ; on behalf of the American College of Chest Physicians. Antiplatelet drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133 (Suppl. 06) 199S-233S.
• 6 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effects of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
• 7 Gurbel PA, Bliden KP, Hayes KM. et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45: 1392-1396.
• 8 Angiolillo DJ, Fernández-Ortiz A, Bernardo E. et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2004; 25: 1903-1910.
• 9 Gurbel PA, Tantry US. Drug insight: clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 2006; 3: 387-395.
• 10 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: 916-922.
• 11 Bonello L, Tantry US, Marucci R. et al. Consensus and future directions on the definition of high-on treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
• 12 Simon T, Verstuyft C, Mary-Krause M. et al. ; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
• 13 Paré G, Mehta SR, Yusuf S. et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704-1714.
• 14 CHARISMA genomics substudy. Paper presented at: Transcatheter Cardiovascular Therapeutics 2009 Meeting. September 30 San Fransisco, California.:
• 15 Hagihara K, Kazui M, Kurihara A. et al. A possible mechanism for the differences in efficiency and variability of active metabolite formation from thienopyridine antiplatelet agents, prasugrel and clopidogrel. Drug Metab Dispos 2009; 37: 2145-2152.
• 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: 92-99.
• 17 Pereillo JM, Maftouh M, Andrieu A. et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 2002; 30: 1288-1295.
• 18 Savi P, Zachayus JL, Delesque-Touchard N. 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.
• 19 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
• 20 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: 1744-1752.
• 21 Hulot JS, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-2247.
• 22 Brandt JT, Close SL, Iturria SJ. 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.
• 23 Fontana P, Hulot JS, De Moerloose P. et al. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. J Thromb Haemost 2007; 5: 2153-2155.
• 24 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: 236-242.
• 25 Giusti B, Gori AM, Marcucci 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.
• 26 Jeong YH, Kim IS, Park Y. et al. Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study. J Am Coll Cardiol Intv 2010; 3: 731-741.
• 27 Gladding P, Webster M, Zeng I. et al. The pharmacogenetics and pharmacodynamics of clopidogrel response. J Am Coll Cardiol Intv 2008; 1: 620-627.
• 28 Frere C, Cuisset T, Morange PE. et al. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008; 101: 1088-1093.
• 29 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: 806-811.
• 30 Trenk D, Hochholzer W, Fromm MF. 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.
• 31 Shuldiner AR, O’Connell JR, Bliden KP. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J Am Med Assoc 2009; 302: 849-857.
• 32 Cutlip DE, Windecker S, Mehran R. et al. ; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
• 33 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: 309-317.
• 34 Wallentin L, James S, Storey RF. 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: 1320-1328.
• 35 CURRENT-OASIS 7 Investigators. Mehta SR, Bassand JP, Chrolavicius S. et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930-942.
• 36 Hulot JS, Collet JP, Silvain J. et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 2010; 56: 134-143.
• 37 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: 512-518.
• 38 Bouman HJ, Schomig E, van Werkum JW. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 2011; 17: 110-116.
• 39 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 Epub ahead of print.
• 40 Taubert D, von Beckerath N, Grimberg G. et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501.
• 41 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376: 1312-1319.
• 42 Harmsze AM, van Werkum JW, Ten Berg JM. et al. CYP2C19*2 and CYP2C19*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J 2010; 31: 3046-3053.
• 43 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: 506-512.
• 44 Lau WC, Gurbel PA, Watkins PB. et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004; 109: 166-171.
• 45 Bliden KP, Dichiara J, Lawal L. et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 2008; 52: 531-533.
• 46 Gurbel PA, Antonino MJ, Tantry US. Recent developments in clopidogrel pharmacology and their relation to clinical outcomes. Expert Opin Drug Metab Toxicol 2009; 5: 989-1004.
• 47 Gilard M, Arnaud B, Cornily JC. et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51: 256-260.
• 48 Harmsze AM, Robijns K, van Werkum JW. et al. The use of amlodipine, but not of p-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response. Thrombosis and Haemostasis 2010; 103: 875-1108.
• 49 Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care 2009; 32: 531-540.
• 50 Park SH, Kim W, Park CS. et al. A comparison of clopidogrel responsiveness in patients with versus without chronic renal failure. Am J Cardiol 2009; 104: 1292-1295.
• 51 Cuisset T, Frere C, Quilici J. et al. Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response. Thromb Res 2009; 123: 597-603.
• 52 Bliden KP, Dichiara J, Lawal L. et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 2008; 52: 531-533.
• 53 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
• 54 Mega JL, Close SL, Wiviott SD. et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: Relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119: 2553-2560.