Genetic variability in response to clopidogrel therapy and its clinical implications

Summary

This article concentrates on individual genetic differences responsible for variations of action of clopidogrel, which have been found to be partially responsible for increased cardiovascular events in patients with coronary artery disease under dual antiplatelet therapy. According to these results, genotyping for the relevant gene polymorphisms, especially for the CYP2C19 loss-of-function alleles, has been discussed to be an effective method of individualising and optimising clopidogrel treatment. However, due to the facts that 1) there are no prospective studies demonstrating a clinical benefit of personalising antiplatelet therapy based on genotyping; 2) CYP2C19 polymorphisms account for only approximately 12% of variability in clopidogrel platelet response; 3) the positive predictive value of CYP2C19 loss-of-function polymorphisms for cardiovascular events in patients with acute coronary syndrome undergoing percutaneous coronary intervention is only approximately 12% – 20%; 4) it is likely that other clinical factors and risk constellations might be of greater clinical importance; and 5) it is unknown whether a specific genetic polymorphism is capable of influencing outcome for the individual patient; genetic profiling cannot be recommended for routine use at present but will remain of considerable scientific interest.

Keywords

Antiplatelet agents - coronary syndrome - gene mutations - thrombosis

• References

• 1 Yusuf S, Zhao F, Mehta SR. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
• 2 Chen ZM, Jiang LX, Chen YP. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
• 3 Mehta SR, Yusuf S, Peters RJ. et al. 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 Kuliczkowski W, Witkowski A, Polonski L. 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: 426-435.
• 5 Sharma RK, Reddy HK, Singh VN. et al. Aspirin and clopidogrel hyporesponsiveness and nonresponsiveness in patients with coronary artery stenting. Vasc Health Risk Manag 2009; 5: 965-972.
• 6 Gurbel PA, Antonio MJ, Tantry US. Recent developments in clopidogrel pharmacology and their relation to clinical outcomes. Expert Opin Drug Metab Toxicol 2009; 5: 989-1004.
• 7 Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007; 100: 1261-1275.
• 8 Tavassoli N, Voisin S, Carrie D. et al. High maintenance dosage of clopidogrel is associated with a reduced risk of stent thrombosis in clopidogrel-resistant patients. Am J Cardiovasc Drugs 2010; 10: 29-35.
• 9 Kumar A, Kao J. Platelet resistance to antiplatelet drugs. Recent Pat Cardiovasc Drug Discov 2009; 4: 98-108.
• 10 Campo G, Fileti L, Valgimigli M. et al. Poor response to clopidogrel: current and future options for its management. . J Thromb Thrombolysis 2010; 30: 319-331.
• 11 Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction?. Lancet 2009; 374: 952-953.
• 12 Sibbing D, Morath T, Braun S. et al. Clopidogrel response status assessed with multiplate point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost 2010; 103: 151-159.
• 13 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
• 14 Simon T, Verstuyft C, Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
• 15 Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J 2010; 31: 17-28.
• 16 Ellis KJ, Stouffer GA, McLeod HL. et al. Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations. Pharmacogenomics 2009; 10: 1799-1817.
• 17 Wiviott SD, Braunwald E, McCabe CH. et al. TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008; 19: 1353-1363.
• 18 Steinhubl SR. Genotyping, clopidogrel metabolism, and the search for the therapeutic window of thienopyridines. Circulation 2010; 121: 481-483.
• 19 Mega J, Close S, Wiviott S. et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119: 2553-25560.
• 20 Ford NF. Clopidogrel resistance: pharmacokinetic or pharmacogenetic?. J Clin Pharmacol 2009; 49: 506-512.
• 21 Gladding P, Webster M, Zeng I. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv 2008; 1: 620-627.
• 22 Trenk D, Hochholzer W, Fromm MF. et al. Cytochrome P450 2C19 681G>A ploymorphism 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.
• 23 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.
• 24 Freedman J, Hylek E. Clopidogrel, genetic, and drug responsiveness. N Engl J Med 2009; 360: 411-413.
• 25 Meschia JF. Pharmacogenetics and stroke. Stroke 2009; 40: 3641-3645.
• 26 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
• 27 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: 1409-1411.
• 28 Gori AM, Marcucci R, Migliorini A. et al. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug-eluting stents. J Am Coll Cardiol 2008; 52: 734-739.
• 29 Gurbel PA, Tantry US, Schuldiner AK. et al. Genotyping: one piece of the puzzle to personalize antiplatelet therapy. J Am Coll Cardiol 2010; 56: 112-116.
• 30 Shuldiner AR, Bilden KP, Gandhi A. 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.
• 31 Harmsze A, van Werkum JW, Bouman HJ. et al. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics 2010; 20: 18-25.
• 32 Harmsze AM, van Werkum JW, Ten Berg JM. et al. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J 2010; 31: 3046-3053.
• 33 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: 99-105.
• 34 Lee JM, Park S, Shin DJ. et al. Relation of genetic polymorphisms in the cytoch-rome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. Am J Cardiol 2009; 104: 46-51.
• 35 Sibbing D, Gebhard D, Koch W. et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost 2010; 8: 1685-1693.
• 36 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.
• 37 Gladding P, White H, Voss J. et al. Pharmacogenetic testing for clopidogrel using the rapid INFINITI analyzer: a dose-escalation study. JACC Cardiovasc Interv 2009; 2: 1095-1101.
• 38 Dick RJ, Dear AE, Byron KA. Clopidogrel resistance: Case reports of CYP2C19 gene variants in suspected coronary stent thrombosis. Heart Lung Circ. 2011 prepublished online.
• 39 Sweeny JM, Gorog DA, Fuster V. Antiplatelet drug ‘resistance’. Part 1: mechanisms and clinical measurements. Nat Rev Cardiol 2009; 6: 273-282.
• 40 Bellemain-Appaix A, Montalescot G, Silvain J. et al. ALBION Investigators. Slow response to clopidogrel predicts low response. J Am Coll Cardiol 2010; 55: 815-822.
• 41 Bonello L, Armero S, Ait Mokhtar O. et al. Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism. J Am Coll Cardiol 2010; 56: 1630-1636.
• 42 Bonello L, Camoin-Jau L, Armero S. et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009; 103: 5-10.
• 43 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.
• 44 Taubert D, Bouman HJ, van Werkum JW. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 2249-2250 author reply 2251.
• 45 Cannon C, Harrington R, James S. et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375: 283-293.
• 46 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. JACC Cardiovasc Interv 2010; 3: 731-741.
• 47 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.
• 48 Momary KM, Dorsch MP, Bates ER. Genetic causes of clopidogrel nonresponsiveness: which ones really count?. Pharmacotherapy 2010; 30: 265-274.
• 49 Wiviott SD, Braunwald E, McCabe CH. et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008; 371: 1353-1363.
• 50 Gurbel P, Bliden K, Butler K. et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120: 2577-2585.
• 51 Wiviott SD, Trenk D, Frelinger AL. et al. Prasugrel compared with high loading-and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923-2932.
• 52 Petersen KU. Relevance of metabolic activation pathways: the example of clopidogrel and prasugrel. Arzneimittelforschung 2009; 59: 213-227.
• 53 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.
• 54 Kowalczyk M, Banach M, Mikhailidis DP. et al. Ticagrelor--a new platelet aggregation inhibitor in patients with acute coronary syndromes. An improvement of other inhibitors? Med Sci Monit 2009; 15: 24-30.
• 55 Gurbel P, Bliden K, Butler K. et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010; 121: 1188-1199.
• 56 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: 1320-1328.
• 57 Huber K. Genetic variability in response to clopidogrel therapy: clinical implications. Eur Heart J 2010; 31: 2974-2976.
• 58 Hochholzer W, Trenk D, Fromm MF. 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: 2427-2434.
• 59 Aleil B, Leon C, Cazenave JP. et al. CYP2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring. J Thromb Haemost 2009; 7: 1747-1749.
• 60 Gaborit B, Frere C, Cuisset T. et al. Enhanced post-clopidogrel platelet reactivity in diabetic patients is independently related to plasma fibrinogen level but not to glycemic control. J Thromb Haemost 2009; 7: 1939-1941.