Platelet Function Monitoring and Clopidogrel

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Bedside evaluation of thienopyridine antiplatelet therapy. Circulation. 2009;119:2625–32. This article summarizes the different platelet function tests that can be used to measure the antiplatelet effect of P2Y12 antagonists. Tang M, Mukundan M, Yang J, Charpentier N, LeCluyse EL, Black C, et al. Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J Pharmacol Exp Ther. 2006;319:1467–76. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, 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;38:92–9. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007;153(66):e69–16. Payne CD, Li YG, Small DS, Ernest CS, 2nd, Farid NA, Jakubowski JA, et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared with high-dose clopidogrel. J Cardiovasc Pharmacol. 2007;50:555–62. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5:2428–36. Varenhorst C, James S, Erlinge D, Brandt JT, Braun OO, Man M, 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;30:1744–52. Hulot J-S, 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;108:2244–7. •• Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849–57. A seminal study using genome wide association study to demonstrate that the CYPC19 locus is the key genetic determinant of clopidogrel response variability. Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL, et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) Study. J Am Coll Cardiol. 2012;59:1928–37. Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost. 2010;8:1685–93. 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Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA. 2011;306:1765–74. Bliden KP, Dichiara J, Lawal L, Singla A, Antonino MJ, Baker BA, et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol. 2008;52:531–3. Ueno M, Ferreiro JL, Desai B, Tomasello SD, Tello-Montoliu A, Capodanno D, et al. Cigarette smoking is associated with a dose–response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study. JACC Cardiovasc Interv. 2012;5:293–300. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908–13. Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol. 2008;52:1557–63. Price MJ, Nayak KR, Barker CM, Kandzari DE, Teirstein PS. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2009;103:1339–43. 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;49:1505–16. Born G. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962;194:927–9. Toth O, Calatzis A, Penz S, Losonczy H, Siess W. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost. 2006;96:781–8. van Werkum JW, Kleibeuker M, Postma S, Bouman HJ, Elsenberg EH, Ten Berg JM, et al. A comparison between the Plateletworks-assay and light transmittance aggregometry for monitoring the inhibitory effects of clopidogrel. Int J Cardiol. 2008;140:123–6. Malinin A, Pokov A, Swaim L, Kotob M, Serebruany V. Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel. Methods Find Exp Clin Pharmacol. 2006;28:315–22. 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. Golanski J, Pluta J, Baraniak J, Watala C. Limited usefulness of the PFA-100 for the monitoring of ADP receptor antagonists–in vitro experience. Clin Chem Lab Med. 2004;42:25–9. Paniccia R, Antonucci E, Gori AM, Marcucci R, Giglioli C, Antoniucci D, et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost. 2007;5:1839–47. Varenhorst C, James S, Erlinge D, Braun OO, Brandt JT, Winters KJ, et al. Assessment of P2Y12 inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin. Am Heart J. 2009;0:e1–9. •• Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker 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(12):919–33. This article summarizes the observational studies linking clopidogrel response variability to clinical outcomes after PCI, and proposes specific cut-offs for the clinical identification of at-risk patients. • Brar SS, ten Berg J, Marcucci R, Price MJ, Valgimigli M, Kim H-S, et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: a collaborative meta-analysis of individual participant data. J Am Coll Cardiol. 2011;58:1945–54. This study presents the largest sample size of patient-level data yet reported to examine the relationship between on-treatment reactivity and outcomes after PCI. Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the gauging responsiveness with a verifynow P2Y12 assay: impact on thrombosis and safety (GRAVITAS) trial. Circulation. 2011;124:1132–7. Stone GW. Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents (ADAPT-DES): a large-scale, prospective, multicenter registry examining the relationship between platelet responsiveness and stent thrombosis after des implantation. Proceedings of the Transcatheter Cardiovascular Therapeutics; San Francisco, CA. 2011. Ferreiro JL, Sibbing D, Angiolillo DJ. Platelet function testing and risk of bleeding complications. Thromb Haemost. 2010;103:1128–35. • Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol. 2008;51:1404–11. This is the first, proof-of-principle, randomized study to demonstrate a potential benefit of platelet function-guided antiplatelet therapy in PCI patients. Bonello L, Camoin-Jau L, Armero S, Com O, Arques S, Burignat-Bonello C, 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. Valgimigli M, Campo G, de Cesare N, Meliga E, Vranckx P, Furgieri A, et al. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel study. Circulation. 2009;119:3215–22. Campo G, Fileti L, de Cesare N, Meliga E, Furgieri A, Russo F, et al. Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3 T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy. J Am Coll Cardiol. 2010;56:1447–55. •• Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305:1097–105. This article presents the results of the first large, multicenter, randomized trial of platelet function testing in patients undergoing PCI. Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Muller U, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) Study. J Am Coll Cardiol. 2012;59:2159–64. Aradi D, Komocsi A, Price MJ, Cuisset T, Ari H, Hazarbasanov D, et al. Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: systematic review and meta-analysis. Int J Cardiol. 2012. doi:10.1016/j.ijcard.2012.05.100. 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Recovery of platelet function after discontinuation of prasugrel or clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease: the Recovery Trial. J Am Coll Cardiol. 2012;59:2338–43. This randomized multicenter pharmacodynamic study describes the time course of platelet recovery after clopidogrel discontinuation. Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944–82. Mahla E, Suarez TA, Bliden KP, Rehak P, Metzler H, Sequeira AJ, et al. Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to cabg (target-cabg) study. Circ Cardiovasc Interv. 2012;5:261–9. 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