The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel

Alf-Aage R Pettersen, Harald Arnesen, Trine B Opstad, Ingebjorg Seljeflot, Alf-Aage R Pettersen, Harald Arnesen, Trine B Opstad, Ingebjorg Seljeflot

Abstract

Background: Different platelet function tests can be used to evaluate the degree of achieved platelet inhibition in patients treated with clopidogrel. The presence of CYP 2C19*2 polymorphism can reduce the formation of the active metabolite of clopidogrel, resulting in less platelet inhibition.

Patients and methods: Patients with symptomatic coronary artery disease, all on chronic single aspirin treatment were randomized to continue on aspirin or change to clopidogrel. In 219 randomly selected clopidogrel treated patients, platelet reactivity was evaluated by VASP-PRI determination and by use of VerifyNow P2Y12-PRU. The CYP 2C19*2 G/A polymorphism was further determined.

Results: The total frequency of clopidogrel resistance was 29.0% by VASP-PRI and 31.6% by VerifyNow-PRU. The number of patients being hetero- and homozygous combined for the CYP 2C19*2 polymorphism (GA/AA) was 64 (29%). Platelet reactivity was significantly higher in patients with the polymorphism compared to wild-type patients (GG). VASP-PRI was 50.9% (SD19) in patients having the polymorphism compared to 38.3% (SD21) in patients with the GG genotype (p = 0.001). Correspondingly, the mean PRU was 165 (SD67) compared to 124 (SD69) (p < 0.001). The frequency of clopidogrel resistance in patients with the polymorphism was 32% compared to 16% in wild-type patients when defined by VASP-PRI (p = 0.006). When defined by PRU (VerifyNow), the corresponding frequencies were 53% and 22% (p < 0.001).

Conclusions: Clopidogrel treated patients with the CYP 2C19*2 polymorphism have significantly increased platelet reactivity compared to patients with the wild-type, evaluated with the VASP determination, and even more pronounced with the VerifyNow P2Y12 method.

Trial registration: ClinicalTrials.gov: NCT00222261.

Figures

Figure 1
Figure 1
Frequency distribution (in deciles) of VASP-PRI (Panel a) and VerifyNow-PRU (Panel b) in patients on clopidogrel as single antiplatelet therapy. Cut-off levels ≥55 and ≥170, respectively, as indicated.
Figure 2
Figure 2
The correlation between platelet reactivity index, PRI, measured by VASP and platelet reaction unit, PRU, measured by the VerifyNow.
Figure 3
Figure 3
The frequencies of clopidogrel resistance in patients with and without the CYP2C19*2 A-allele, as determined by VASP-PRI and VerifyNow PRU.

References

    1. Collaboration AT. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86. doi: 10.1136/bmj.324.7329.71.
    1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation; the CURE trial. N Engl J Med. 2001;345:494–502. doi: 10.1056/NEJMoa010746.
    1. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA. 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. doi: 10.1016/S0140-6736(01)05701-4.
    1. Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED, Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159–168. doi: 10.1001/jama.297.2.joc60179.
    1. 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. doi: 10.1016/j.jacc.2004.09.067.
    1. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol. 2005;45:1157–1164. doi: 10.1016/j.jacc.2005.01.034.
    1. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109:3171–3175. doi: 10.1161/01.CIR.0000130846.46168.03.
    1. Frere C, Cuisset T, Morange PE, Quilici J, Camoin-Jau L, Saut N, Faille D, Lambert M, Juhan-Vague I, Bonnet JL, Alessi MC. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol. 2008;101:1088–1093. doi: 10.1016/j.amjcard.2007.11.065.
    1. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360:363–375. doi: 10.1056/NEJMoa0808227.
    1. Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dörrler K, Morath T, Schömig A, Kastrati A, von Beckerath N. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J. 2009;30:916–922. doi: 10.1093/eurheartj/ehp041.
    1. Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849–857. doi: 10.1001/jama.2009.1232.
    1. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354–362. doi: 10.1056/NEJMoa0809171.
    1. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373:309–317. doi: 10.1016/S0140-6736(08)61845-0.
    1. Harrison P, Frelinger ALr, Furman MI, Michelson AD. Measuring antiplatelet drug effects in the laboratory. Thromb Res. 2007;120:323–336. doi: 10.1016/j.thromres.2006.11.012.
    1. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49:1505–1516. doi: 10.1016/j.jacc.2006.11.044.
    1. Bonello L, Bonello-Palot N, Armero S, Bonello C, Mokhtar OA, Arques S, Dignat-George F, Camoin-Jau L, Paganelli F. Impact of P2Y12-ADP receptor polymorphism on the efficacy of clopidogrel dose-adjustment according to platelet reactivity monitoring in coronary artery disease patients. Thromb Res. 2010;125:e167–70. doi: 10.1016/j.thromres.2009.10.014.
    1. Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost. 2005;3:85–92. doi: 10.1111/j.1538-7836.2004.01063.x.
    1. Gurbel PA, Bliden KP, Tantry US. Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting: results from the CLEAR PLATELETS 1b study. J Am Coll Cardiol. 2006;48:2186–2191. doi: 10.1016/j.jacc.2005.12.084.
    1. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation. 2005;111:1153–1159. doi: 10.1161/01.CIR.0000157138.02645.11.
    1. Pettersen AA, Seljeflot I, Abdelnoor M, Arnesen H. Unstable angina, stroke, myocardial infarction and death in aspirin non-responders. A prospective, randomized trial. The ASCET (ASpirin non-responsiveness and Clopidogrel Endpoint Trial) design. Scand Cardiovasc J. 2004;38:353–356. doi: 10.1080/14017430410024324.
    1. Schwarz UR, Geiger J, Walter U, Eigenthaler M. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets--definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost. 1999;82:1145–1152.
    1. Bidet A, Jais C, Puymirat E, Coste P, Nurden A, Jakubowski J, Nurden P. VerifyNow and VASP phosphorylation assays give similar results for patients receiving clopidogrel, but they do not always correlate with platelet aggregation. Platelets. 2010;21:94–100. doi: 10.3109/09537100903437206.
    1. Harmsze AM, van Werkum JW, Ten Berg JM, Zwart B, Bouman HJ, Breet NJ, van 't Hof AW, Ruven HJ, Hackeng CM, Klungel OH, de Boer A, Deneer VH. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J. 2010;31:3046–3053. doi: 10.1093/eurheartj/ehq321.
    1. Lee JM, Park S, Shin DJ, Choi D, Shim CY, Ko YG, Kim JS, Shin ES, Chang CW, Lee JE, Jang Y. Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. Am J Cardiol. 2009;104:46–51. doi: 10.1016/j.amjcard.2009.02.045.
    1. Bonello L, Palot-Bonello N, Armero S, Camoin-Jau L, Paganelli F. Impact of loading dose adjustment on platelet reactivity in homozygotes of the 2C19 2* loss of function polymorphism. Int J Cardiol. 2010;145(1):165–166. doi: 10.1016/j.ijcard.2009.07.033.
    1. Bonello L, Armero S, Ait Mokhtar O, Mancini J, Aldebert P, Saut N, Bonello N, Barragan P, Arques S, Giacomoni MP, Bonello-Burignat C, Bartholomei MN, Dignat-George F, Camoin-Jau L, Paganelli F. 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. doi: 10.1016/j.jacc.2010.07.004.
    1. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schömig A, von Beckerath N, Kastrati A. 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. doi: 10.1161/CIRCULATIONAHA.109.885194.
    1. Grove EL, Hvas AM, Mortensen SB, Larsen SB, Kristensen SD. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost. 2011;9:185–191. doi: 10.1111/j.1538-7836.2010.04115.x.
    1. Kim KA, Park PW, Hong SJ, Park JY. 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. doi: 10.1038/clpt.2008.20.
    1. Paniccia R, Antonucci E, Gori AM, Marcucci R, Giglioli C, Antoniucci D, Gensini GF, Abbate R, Prisco D. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost. 2007;5:1839–1847. doi: 10.1111/j.1538-7836.2007.02656.x.
    1. Huber K. Genetic variability in response to clopidogrel therapy: clinical implications. Eur Heart J. 2010;31:2974–2976. doi: 10.1093/eurheartj/ehq329.
    1. Storey RF. Clopidogrel in acute coronary syndrome: to genotype or not? Lancet. 2009;373:276–278. doi: 10.1016/S0140-6736(08)61846-2.
    1. Farid NA, Small DS, Payne CD, Jakubowski JA, Brandt JT, Li YG, Ernest CS, Salazar DE, Konkoy CS, Winters KJ. Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects. Pharmacotherapy. 2008;28:1483–1494. doi: 10.1592/phco.28.12.1483.
    1. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J. 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. doi: 10.1016/j.jacc.2007.06.064.
    1. Hwang SJ, Jeong YH, Kim IS, Park KS, Kang MK, Koh JS, Park JR, Park Y, Koh EH, Kwak CH, Hwang JY, Kim S. Cytochrome 2C19 polymorphism and response to adjunctive cilostazol versus high maintenance-dose clopidogrel in patients undergoing percutaneous coronary intervention. Circ Cardiovasc Interv. 2010;3:450–459. doi: 10.1161/CIRCINTERVENTIONS.110.949859.
    1. Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE, Tait AR, Bates ER. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004;109:166–171. doi: 10.1161/01.CIR.0000112378.09325.F9.
    1. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180:699–700. doi: 10.1503/cmaj.090251.
    1. Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol. 2008;52:1557–1563. doi: 10.1016/j.jacc.2008.07.055.
    1. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2009;157:148.e1–148.e5. doi: 10.1016/j.ahj.2008.09.017.
    1. Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition. Heart. 2010;96:186–189. doi: 10.1136/hrt.2009.171488.
    1. Ang L, Palakodeti V, Khalid A, Tsimikas S, Idrees Z, Tran P, Clopton P, Zafar N, Bromberg-Marin G, Keramati S, Mahmud E. Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel. J Am Coll Cardiol. 2008;52:1052–1059. doi: 10.1016/j.jacc.2008.05.054.
    1. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Barrera Ramirez C, Sabate M, Fernandez C, Hernandez-Antolin R, Escaned J, Alfonso F, Macaya C. Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted? J Invasive Cardiol. 2004;16:169–174.
    1. Kelly RV, Hsu A, Topol E, Steinhubl S. The influence of body mass index on outcomes and the benefit of antiplatelet therapy following percutaneous coronary intervention. J Invasive Cardiol. 2006;18:115–119.
    1. Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Smoking promotes clopidogrel-mediated platelet inhibition in patients receiving dual antiplatelet therapy. Thromb Res. 2009;124:588–591. doi: 10.1016/j.thromres.2009.06.012.
    1. Desai NR, Mega JL, Jiang S, Cannon CP, Sabatine MS. Interaction between cigarette smoking and clinical benefit of clopidogrel. J Am Coll Cardiol. 2009;53:1273–1278. doi: 10.1016/j.jacc.2008.12.044.

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