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Pharmacology of the New P2Y12 Receptor Inhibitors: Insights on Pharmacokinetic and Pharmacodynamic Properties

Abstract

The P2Y12 receptor is a key player in platelet activation and represents an effective pharmacological target for the inhibition of platelet aggregation and prevention of atherothrombotic events. Indeed, the clinical use of the P2Y12 receptor inhibitor clopidogrel is an effective strategy for inhibiting platelet activity in patients with acute coronary syndrome, and for preventing thrombotic events in those undergoing percutaneous coronary intervention with stenting. However, clopidogrel has several drawbacks, which include delayed onset of action, large inter-individual variability in platelet response, genetic polymorphism of the metabolizing enzyme, drug–drug interactions (DDIs), and the two-step activation process catalyzed by a series of cytochrome P450 (CYP) isoenzymes. For these reasons, new P2Y12 receptor inhibitors have been developed in an attempt to improve on the pharmacological and clinical profile of clopidogrel. Three new P2Y12 receptor inhibitors—prasugrel, cangrelor, and ticagrelor—have arrived, and more are coming into clinical use. Each of these antagonists has individual properties and, according to their mechanism of inhibition, can be divided into irreversible (prasugrel) and reversible inhibitors (ticagrelor, cangrelor). These agents also have different metabolic pathways: prasugrel is a prodrug that requires metabolic activation through a cytochrome-dependent pathway, while ticagrelor and cangrelor do not require metabolic conversion. However, ticagrelor is a CYP3A4 substrate/inhibitor and thus it can be involved in DDIs. Indeed, ticagrelor significantly increases the plasma levels of CYP3A4 substrates such as statins. Moreover, concomitant use with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, clarithromycin, ritonavir, telithromycin, etc.) is contraindicated, while the co-administration of ticagrelor with potent CYP3A inducers (carbamazepine, rifampicin, phenytoin, phenobarbital) is discouraged. Prasugrel and ticagrelor determine a faster, greater, and more consistent adenosine diphosphate (ADP)-receptor inhibition than clopidogrel, with a near complete inhibition of platelet aggregation between 1–2 h after administration of an oral loading dose, while cangrelor shows a rapid and potent platelet inhibitory effect with intravenous infusion. Thus, the different pharmacokinetic and pharmacodynamic characteristics of the P2Y12 receptor inhibitors enable clinicians to personalize therapy according to patient-specific medical requirements for better prevention of atherothrombotic events. In the present review, we describe the pharmacological properties, the pharmacokinetic and pharmacodynamic differences, and the clinical efficacy of the currently available P2Y12 receptor inhibitors.

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References

  1. 1.

    Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost. 2009;102(2):248–57.

    PubMed  CAS  Google Scholar 

  2. 2.

    Steinhubl SR, Moliterno DJ. The role of the platelet in the pathogenesis of atherothrombosis. Am J Cardiovasc Drugs. 2005;5(6):399–408.

    PubMed  CAS  Google Scholar 

  3. 3.

    Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):2574–609.

    PubMed  Google Scholar 

  4. 4.

    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(7):494–502.

    PubMed  CAS  Google Scholar 

  5. 5.

    Angiolillo DJ, Capranzano P. Pharmacology of emerging novel platelet inhibitors. Am Heart J. 2008;156(2 Suppl):S10–5.

    PubMed  Google Scholar 

  6. 6.

    Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J. 2010;31(20):2501–55.

    PubMed  Google Scholar 

  7. 7.

    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(23):2908–13.

    PubMed  Google Scholar 

  8. 8.

    Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54(23):2205–41.

    PubMed  Google Scholar 

  9. 9.

    Burnstock G. Purinergic signaling and vascular cell proliferation and death. Arterioscler Thromb Vasc Biol. 2002;22(3):364–73.

    PubMed  Google Scholar 

  10. 10.

    Evans AM, Wyatt CN, Kinnear NP, et al. Pyridine nucleotides and calcium signalling in arterial smooth muscle: from cell physiology to pharmacology. Pharmacol Ther. 2005;107(3):286–313.

    PubMed  CAS  Google Scholar 

  11. 11.

    Kunapuli SP, Daniel JL. P2 receptor subtypes in the cardiovascular system. Biochem J. 1998; 336 (Pt 3):513–23.

    Google Scholar 

  12. 12.

    Born GV. Adenosine diphosphate as a mediator of platelet aggregation in vivo: an editorial view. Circulation. 1985;72(4):741–6.

    PubMed  CAS  Google Scholar 

  13. 13.

    Gachet C. P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal. 2012;8(3):609–19.

    PubMed  CAS  Google Scholar 

  14. 14.

    Fredholm BB, Abbracchio MP, Burnstock G, et al. Nomenclature and classification of purinoceptors. Pharmacol Rev. 1994;46(2):143–56.

    PubMed  CAS  Google Scholar 

  15. 15.

    Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci. 2007;64(12):1471–83.

    PubMed  CAS  Google Scholar 

  16. 16.

    Harden TK, Sesma JI, Fricks IP, et al. Signalling and pharmacological properties of the P2Y receptor. Acta Physiol (Oxf). 2010;199(2):149–60.

    CAS  Google Scholar 

  17. 17.

    Hollopeter G, Jantzen HM, Vincent D, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001;409(6817):202–7.

    PubMed  CAS  Google Scholar 

  18. 18.

    Wihlborg AK, Wang L, Braun OO, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol. 2004;24(10):1810–5.

    PubMed  CAS  Google Scholar 

  19. 19.

    Hechler B, Leon C, Vial C, et al. The P2Y1 receptor is necessary for adenosine 5’-diphosphate-induced platelet aggregation. Blood. 1998;92(1):152–9.

    PubMed  CAS  Google Scholar 

  20. 20.

    Leon C, Hechler B, Freund M, et al. Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y(1) receptor-null mice. J Clin Invest. 1999;104(12):1731–7.

    PubMed  CAS  Google Scholar 

  21. 21.

    Gachet C. Regulation of platelet functions by P2 receptors. Annu Rev Pharmacol Toxicol. 2006;46:277–300.

    PubMed  CAS  Google Scholar 

  22. 22.

    Conley PB, Delaney SM. Scientific and therapeutic insights into the role of the platelet P2Y12 receptor in thrombosis. Curr Opin Hematol. 2003;10(5):333–8.

    PubMed  CAS  Google Scholar 

  23. 23.

    Cattaneo M, Lecchi A, Lombardi R, et al. Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet ‘primary secretion defect’ are heterozygous for a defect of P2CYC receptors. Arterioscler Thromb Vasc Biol. 2000;20(11):E101–6.

    PubMed  CAS  Google Scholar 

  24. 24.

    Dangelmaier C, Jin J, Smith JB, et al. Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway. Thromb Haemost. 2001;85(2):341–8.

    PubMed  CAS  Google Scholar 

  25. 25.

    Kauffenstein G, Bergmeier W, Eckly A, et al. The P2Y(12) receptor induces platelet aggregation through weak activation of the alpha(IIb)beta(3) integrin—a phosphoinositide 3-kinase-dependent mechanism. FEBS Lett. 2001;505(2):281–90.

    PubMed  CAS  Google Scholar 

  26. 26.

    Savi P, Pflieger AM, Herbert JM. cAMP is not an important messenger for ADP-induced platelet aggregation. Blood Coagul Fibrinolysis. 1996;7(2):249–52.

    PubMed  CAS  Google Scholar 

  27. 27.

    Jackson SP, Yap CL, Anderson KE. Phosphoinositide 3-kinases and the regulation of platelet function. Biochem Soc Trans. 2004;32(Pt 2):387–92.

    PubMed  CAS  Google Scholar 

  28. 28.

    Garcia A, Kim S, Bhavaraju K, et al. Role of phosphoinositide 3-kinase beta in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways. Biochem J. 2010;429(2):369–77.

    PubMed  CAS  Google Scholar 

  29. 29.

    Jin J, Kunapuli SP. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci USA. 1998;95(14):8070–4.

    PubMed  CAS  Google Scholar 

  30. 30.

    Hechler B, Eckly A, Ohlmann P, et al. The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol. 1998;103(3):858–66.

    PubMed  CAS  Google Scholar 

  31. 31.

    Savi P, Beauverger P, Labouret C, et al. Role of P2Y1 purinoceptor in ADP-induced platelet activation. FEBS Lett. 1998;422(3):291–5.

    PubMed  CAS  Google Scholar 

  32. 32.

    Nylander S, Mattsson C, Ramstrom S, et al. Synergistic action between inhibition of P2Y12/P2Y1 and P2Y12/thrombin in ADP- and thrombin-induced human platelet activation. Br J Pharmacol. 2004;142(8):1325–31.

    PubMed  CAS  Google Scholar 

  33. 33.

    Mahaut-Smith MP, Tolhurst G, Evans RJ. Emerging roles for P2X1 receptors in platelet activation. Platelets. 2004;15(3):131–44.

    PubMed  CAS  Google Scholar 

  34. 34.

    Rolf MG, Brearley CA, Mahaut-Smith MP. Platelet shape change evoked by selective activation of P2X1 purinoceptors with alpha, beta-methylene ATP. Thromb Haemost. 2001;85(2):303–8.

    PubMed  CAS  Google Scholar 

  35. 35.

    Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost. 2000;84(5):891–6.

    PubMed  CAS  Google Scholar 

  36. 36.

    Ito MK, Smith AR, Lee ML. Ticlopidine: a new platelet aggregation inhibitor. Clin Pharm. 1992;11(7):603–17.

    PubMed  CAS  Google Scholar 

  37. 37.

    Hasegawa M, Sugidachi A, Ogawa T, et al. Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747 (prasugrel, LY640315), a novel P2Y12 receptor inhibitor. Thromb Haemost. 2005;94(3):593–8.

    PubMed  CAS  Google Scholar 

  38. 38.

    Ding Z, Bynagari YS, Mada SR, et al. Studies on the role of the extracellular cysteines and oligomeric structures of the P2Y12 receptor when interacting with antagonists. J Thromb Haemost. 2009;7(1):232–4.

    PubMed  CAS  Google Scholar 

  39. 39.

    Algaier I, Jakubowski JA, Asai F, et al. Interaction of the active metabolite of prasugrel, R-138727, with cysteine 97 and cysteine 175 of the human P2Y12 receptor. J Thromb Haemost. 2008;6(11):1908–14.

    PubMed  CAS  Google Scholar 

  40. 40.

    Niitsu Y, Jakubowski JA, Sugidachi A, et al. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost. 2005;31(2):184–94.

    PubMed  CAS  Google Scholar 

  41. 41.

    Sugidachi A, Asai F, Ogawa T, et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol. 2000;129(7):1439–46.

    PubMed  CAS  Google Scholar 

  42. 42.

    Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27(4):259–74.

    PubMed  CAS  Google Scholar 

  43. 43.

    Yoneda K, Iwamura R, Kishi H, et al. Identification of the active metabolite of ticlopidine from rat in vitro metabolites. Br J Pharmacol. 2004;142(3):551–7.

    PubMed  CAS  Google Scholar 

  44. 44.

    Humphries RG, Robertson MJ, Leff P. A novel series of P2T purinoceptor antagonists: definition of the role of ADP in arterial thrombosis. Trends Pharmacol Sci. 1995;16(6):179–81.

    PubMed  CAS  Google Scholar 

  45. 45.

    Cattabeni F, Williams M. Purines 2000: Third International Symposium on Nucleosides and Nucleotides. 9-13 July 2000, Madrid, Spain. IDrugs. 2000;3(10):1182–4.

    PubMed  CAS  Google Scholar 

  46. 46.

    Chattaraj SC. Cangrelor AstraZeneca. Curr Opin Investig Drugs. 2001;2(2):250–5.

    PubMed  CAS  Google Scholar 

  47. 47.

    Springthorpe B, Bailey A, Barton P, et al. From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett. 2007;17(21):6013–8.

    PubMed  CAS  Google Scholar 

  48. 48.

    Wang K, Zhou X, Zhou Z, et al. Sustained coronary artery recanalization with adjunctive infusion of a novel P2T-receptor antagonist AR-C69931 in a canine model [abstract 1111-47]. J Am Coll Cardiol. 2000;35(Suppl.):281A–282A.

    Google Scholar 

  49. 49.

    Huang J, Driscoll EM, Gonzales ML, et al. Prevention of arterial thrombosis by intravenously administered platelet P2T receptor antagonist AR-C69931MX in a canine model. J Pharmacol Exp Ther. 2000;295(2):492–9.

    PubMed  CAS  Google Scholar 

  50. 50.

    Gurbel PA, Bliden KP, 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(25):2577–85.

    PubMed  CAS  Google Scholar 

  51. 51.

    van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost. 2005;31(2):195–204.

    PubMed  Google Scholar 

  52. 52.

    Van Giezen JJ, Zachrisson H, Bjorkman JA. Reduced bleeding time prolongation for the reversible P2Y12 antagonist AZD6140 compared with clopidogrel and AZ11703072, a chemical compound indistinguishable from prasugrel, in both a rat and a dog model of combined thrombosis and hemostasis. Arterioscler Thromb Cardiovasc Dis. 2008;28:e40.

    Google Scholar 

  53. 53.

    Wiviott SD, Antman EM, Gibson CM, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006;152(4):627–35.

    PubMed  CAS  Google Scholar 

  54. 54.

    Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.

    PubMed  CAS  Google Scholar 

  55. 55.

    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(14):1744–52.

    PubMed  CAS  Google Scholar 

  56. 56.

    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(1):92–9.

    PubMed  CAS  Google Scholar 

  57. 57.

    Floyd CN, Passacquale G, Ferro A. Comparative pharmacokinetics and pharmacodynamics of platelet adenosine diphosphate receptor antagonists and their clinical implications. Clin Pharmacokinet. 2012;51(7):429–42.

    PubMed  CAS  Google Scholar 

  58. 58.

    Small DS, Wrishko RE, Ernest CS 2nd, et al. Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease. J Clin Pharm Ther. 2009;34(5):585–94.

    PubMed  CAS  Google Scholar 

  59. 59.

    Farid NA, Small DS, Payne CD, et al. Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects. Pharmacotherapy. 2008;28(12):1483–94.

    PubMed  CAS  Google Scholar 

  60. 60.

    Asai F, Jakubowski JA, Naganuma H, et al. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a single ascending dose study in healthy humans. Platelets. 2006;17(4):209–17.

    PubMed  CAS  Google Scholar 

  61. 61.

    Ernest CS 2nd, Small DS, Rohatagi S, et al. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease. J Pharmacokinet Pharmacodyn. 2008;35(6):593–618.

    PubMed  CAS  Google Scholar 

  62. 62.

    von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation. 2005;112(19):2946–50.

    Google Scholar 

  63. 63.

    Taubert D, von Beckerath N, Grimberg G, et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006;80(5):486–501.

    PubMed  CAS  Google Scholar 

  64. 64.

    Cairns JA, Eikelboom J. Clopidogrel resistance: more grist for the mill. J Am Coll Cardiol. 2008;51(20):1935–7.

    PubMed  CAS  Google Scholar 

  65. 65.

    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(9749):1312–9.

    PubMed  CAS  Google Scholar 

  66. 66.

    Jakubowski JA, Winters KJ, Naganuma H, et al. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev. 2007;25(4):357–74.

    PubMed  CAS  Google Scholar 

  67. 67.

    Farid NA, Kurihara A, Wrighton SA. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol. 2010;50(2):126–42.

    PubMed  CAS  Google Scholar 

  68. 68.

    Rehmel JL, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos. 2006;34(4):600–7.

    PubMed  CAS  Google Scholar 

  69. 69.

    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(19):2553–60.

    PubMed  CAS  Google Scholar 

  70. 70.

    Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J. 2009;30(16):1964–77.

    PubMed  CAS  Google Scholar 

  71. 71.

    Teng R, Oliver S, Hayes MA, et al. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos. 2010;38(9):1514–21.

    PubMed  CAS  Google Scholar 

  72. 72.

    Teng R. Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor. Clin Pharmacokinet. 2012;51(5):305–18.

    PubMed  CAS  Google Scholar 

  73. 73.

    Storey RF. Melissa Thornton S, Lawrance R, et al. Ticagrelor yields consistent dose-dependent inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in P2RY12, P2RY1, and ITGB3. Platelets. 2009;20(5):341–8.

    PubMed  CAS  Google Scholar 

  74. 74.

    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(9749):1320–8.

    PubMed  CAS  Google Scholar 

  75. 75.

    Angiolillo DJ, Bhatt DL, Gurbel PA, et al. Advances in antiplatelet therapy: agents in clinical development. Am J Cardiol. 2009;103(3 Suppl):40A–51A.

    PubMed  CAS  Google Scholar 

  76. 76.

    Akers WS, Oh JJ, Oestreich JH, et al. Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol. 2010;50(1):27–35.

    PubMed  CAS  Google Scholar 

  77. 77.

    Frelinger AL 3rd, Bhatt DL, Lee RD, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;61(8):872–9.

    PubMed  CAS  Google Scholar 

  78. 78.

    Bonello L, Tantry US, Marcucci 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.

    PubMed  CAS  Google Scholar 

  79. 79.

    Bellemain-Appaix A, O’Connor SA, Silvain J, et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. JAMA. 2012;308(23):2507–16.

    PubMed  CAS  Google Scholar 

  80. 80.

    Hochholzer W, Trenk D, Mega JL, et al. Impact of smoking on antiplatelet effect of clopidogrel and prasugrel after loading dose and on maintenance therapy. Am Heart J. 2011;162(3):518–26.e5.

    Google Scholar 

  81. 81.

    Gurbel PA, Bliden KP, Logan DK, et al. The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study. J Am Coll Cardiol. 2013;62(6):505-12.

    Google Scholar 

  82. 82.

    Brandt JT, Payne CD, Wiviott SD, et al. 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(1):66.e9–16.

    Google Scholar 

  83. 83.

    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(25):2923–32.

    PubMed  CAS  Google Scholar 

  84. 84.

    Cheng JW. Ticagrelor: oral reversible P2Y(12) receptor antagonist for the management of acute coronary syndromes. Clin Ther. 2012;34(6):1209–20.

    PubMed  CAS  Google Scholar 

  85. 85.

    Small DS, Farid NA, Payne CD, et al. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of prasugrel. Clin Pharmacokinet. 2010;49(12):777–98.

    PubMed  CAS  Google Scholar 

  86. 86.

    Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol. 2010;66(5):487–96.

    PubMed  CAS  Google Scholar 

  87. 87.

    Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients. J Am Coll Cardiol. 2013;61(15):1601–6.

    PubMed  CAS  Google Scholar 

  88. 88.

    Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2012;5(6):797–804.

    PubMed  CAS  Google Scholar 

  89. 89.

    Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363–75.

    PubMed  CAS  Google Scholar 

  90. 90.

    Cornel JH, Becker RC, Goodman SG, et al. Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-insights from the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2012;164(3):334–42.e1.

    Google Scholar 

  91. 91.

    Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012;307(3):265–74.

    PubMed  CAS  Google Scholar 

  92. 92.

    Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303–13.

    PubMed  CAS  Google Scholar 

  93. 93.

    Steinhubl SR, Oh JJ, Oestreich JH, et al. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res. 2008;121(4):527–34.

    PubMed  CAS  Google Scholar 

  94. 94.

    Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets. 2002;13(7):407–13.

    PubMed  CAS  Google Scholar 

  95. 95.

    Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298(7):765–75.

    PubMed  CAS  Google Scholar 

  96. 96.

    Basra SS, Tsai P, Lakkis NM. Safety and efficacy of antiplatelet and antithrombotic therapy in acute coronary syndrome patients with chronic kidney disease. J Am Coll Cardiol. 2011;58(22):2263–9.

    PubMed  CAS  Google Scholar 

  97. 97.

    Mehran R, Pocock S, Nikolsky E, et al. Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage strategy), and HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trials. JACC Cardiovasc Interv. 2011;4(6):654–64.

    PubMed  Google Scholar 

  98. 98.

    Fuster V, Farkouh ME. Acute coronary syndromes and diabetes mellitus: a winning ticket for prasugrel. Circulation. 2008;118(16):1607–8.

    PubMed  Google Scholar 

  99. 99.

    Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation. 2008;118(16):1626–36.

    PubMed  CAS  Google Scholar 

  100. 100.

    Angiolillo DJ, Bates ER, Bass TA. Clinical profile of prasugrel, a novel thienopyridine. Am Heart J. 2008;156(2 Suppl):S16–22.

    PubMed  Google Scholar 

  101. 101.

    James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2010;31(24):3006–16.

    PubMed  CAS  Google Scholar 

  102. 102.

    Alber HF, Huber K, Pachinger O, et al. Prasugrel vs. ticagrelor in acute coronary syndromes: which one to choose? Wien Klin Wochenschr. 2011;123(15–16):468–76.

    PubMed  Google Scholar 

  103. 103.

    Alexopoulos D, Xanthopoulou I, Mavronasiou E, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with diabetes. Diabetes Care. 2013;36(8):2211–6.

    PubMed  CAS  Google Scholar 

  104. 104.

    Rydén L, Grant PJ, Anker SD, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. Epub 2013 Aug 30.

  105. 105.

    Ferreiro JL, Ueno M, Tello-Montoliu A, et al. Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation. J Thromb Thrombolysis. 2013;35(2):155–64.

    PubMed  CAS  Google Scholar 

  106. 106.

    Wattanakit K, Cushman M, Stehman-Breen C, et al. Chronic kidney disease increases risk for venous thromboembolism. J Am Soc Nephrol. 2008;19(1):135–40.

    PubMed  Google Scholar 

  107. 107.

    Mezzano D, Tagle R, Panes O, et al. Hemostatic disorder of uremia: the platelet defect, main determinant of the prolonged bleeding time, is correlated with indices of activation of coagulation and fibrinolysis. Thromb Haemost. 1996;76(3):312–21.

    PubMed  CAS  Google Scholar 

  108. 108.

    Castillo R, Lozano T, Escolar G, et al. Defective platelet adhesion on vessel subendothelium in uremic patients. Blood. 1986;68(2):337–42.

    PubMed  CAS  Google Scholar 

  109. 109.

    Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351(13):1285–95.

    PubMed  CAS  Google Scholar 

  110. 110.

    Best PJ, Lennon R, Ting HH, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol. 2002;39(7):1113–9.

    PubMed  Google Scholar 

  111. 111.

    Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367(7):625–35.

    PubMed  CAS  Google Scholar 

  112. 112.

    Best PJ, Steinhubl SR, Berger PB, et al. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J. 2008;155(4):687–93.

    PubMed  CAS  Google Scholar 

  113. 113.

    Keltai M, Tonelli M, Mann JF, et al. Renal function and outcomes in acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev Rehabil. 2007;14(2):312–8.

    PubMed  Google Scholar 

  114. 114.

    Wrishko RE, Ernest CS 2nd, Small DS, et al. Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38. J Clin Pharmacol. 2009;49(8):984–98.

    PubMed  CAS  Google Scholar 

  115. 115.

    Alexopoulos D, Panagiotou A, Xanthopoulou I, et al. Antiplatelet effects of prasugrel vs. double clopidogrel in patients on hemodialysis and with high on-treatment platelet reactivity. J Thromb Haemost. 2011;9(12):2379–85.

    PubMed  CAS  Google Scholar 

  116. 116.

    Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment. J Clin Pharmacol. 2012;52(9):1388–98.

    PubMed  CAS  Google Scholar 

  117. 117.

    Alexopoulos D, Xanthopoulou I, Plakomyti TE, et al. Ticagrelor in clopidogrel-resistant patients undergoing maintenance hemodialysis. Am J Kidney Dis. 2012;60(2):332–3.

    PubMed  Google Scholar 

  118. 118.

    James S, Budaj A, Aylward P, et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2010;122(11):1056–67.

    PubMed  Google Scholar 

  119. 119.

    Serebruany VL, Atar D. The PLATO trial: do you believe in magic? Eur Heart J. 2010;31(7):764–7.

    PubMed  Google Scholar 

  120. 120.

    Rajan L, Moliterno DJ. Beyond aspirin and clopidogrel: is there a need for additional antiplatelet therapy in ACS? Curr Cardiol Rep. 2011;13(4):303–11.

    PubMed  Google Scholar 

  121. 121.

    Burki NK, Dale WJ, Lee LY. Intravenous adenosine and dyspnea in humans. J Appl Physiol. 2005;98(1):180–5.

    PubMed  CAS  Google Scholar 

  122. 122.

    Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol. 2013;61(7):723-7.

    Google Scholar 

  123. 123.

    Mehran R, Pocock SJ, Nikolsky E, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol. 2010;55(23):2556–66.

    PubMed  Google Scholar 

  124. 124.

    Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol. 2013;61(7):723–7.

    PubMed  CAS  Google Scholar 

  125. 125.

    Cambou JP, Simon T, Mulak G, et al. The French registry of Acute ST elevation or non-ST-elevation Myocardial Infarction (FAST-MI): study design and baseline characteristics. Arch Mal Coeur Vaiss. 2007;100(6–7):524–34.

    PubMed  Google Scholar 

  126. 126.

    Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009;120(22):2271–306.

    PubMed  Google Scholar 

  127. 127.

    Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15.

    PubMed  CAS  Google Scholar 

  128. 128.

    James SK, Storey RF, Khurmi NS, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes and a history of stroke or transient ischemic attack. Circulation. 2012;125(23):2914–21.

    PubMed  CAS  Google Scholar 

  129. 129.

    Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821–30.

    PubMed  CAS  Google Scholar 

  130. 130.

    FDA. Safety alert. Plavix (clopidogrel): Reduced effectiveness in patients who are poor metabolizers of the drug. 2010. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm204256.htm. Last Accessed 5 Jan 2013.

  131. 131.

    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(8):1409–11.

    PubMed  CAS  Google Scholar 

  132. 132.

    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(4):512–8.

    PubMed  CAS  Google Scholar 

  133. 133.

    Grosdidier C, Quilici J, Loosveld M, et al. Effect of CYP2C19*2 and *17 genetic variants on platelet response to clopidogrel and prasugrel maintenance dose and relation to bleeding complications. Am J Cardiol. 2013;111(7):985–90.

    PubMed  CAS  Google Scholar 

  134. 134.

    Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354–62.

    PubMed  CAS  Google Scholar 

  135. 135.

    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. JAMA. 2009;302(8):849–57.

    PubMed  CAS  Google Scholar 

  136. 136.

    Varenhorst C, James S, Erlinge D, et al. Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin. Am Heart J. 2009;157(3):562.e1–9.

    Google Scholar 

  137. 137.

    Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011;306(24):2704–14.

    PubMed  CAS  Google Scholar 

  138. 138.

    Johnson JA, Roden DM, Lesko LJ, et al. Clopidogrel: a case for indication-specific pharmacogenetics. Clin Pharmacol Ther. 2012;91(5):774–6.

    PubMed  CAS  Google Scholar 

  139. 139.

    Hulot JS, Collet JP, Montalescot G. Thienopyridine-associated drug-drug interactions: pharmacologic mechanisms and clinical relevance. Curr Cardiol Rep. 2011;13(5):451–8.

    PubMed  Google Scholar 

  140. 140.

    Jeong YH, Hwang JY, Kim IS, et al. Adding cilostazol to dual antiplatelet therapy achieves greater platelet inhibition than high maintenance dose clopidogrel in patients with acute myocardial infarction: Results of the adjunctive cilostazol versus high maintenance dose clopidogrel in patients with AMI (ACCEL-AMI) study. Circ Cardiovasc Interv. 2010;3(1):17–26.

    PubMed  CAS  Google Scholar 

  141. 141.

    Kim JY. Strategy for the treatment of clopidogrel low responsiveness in diabetes mellitus and stent implantation. Korean Circ J. 2009;39(11):459–61.

    PubMed  CAS  Google Scholar 

  142. 142.

    Bhindi R, Ormerod O, Newton J, et al. Interaction between statins and clopidogrel: is there anything clinically relevant? QJM. 2008;101(12):915–25.

    PubMed  CAS  Google Scholar 

  143. 143.

    Rolan PE. Plasma protein binding displacement interactions–why are they still regarded as clinically important? Br J Clin Pharmacol. 1994;37(2):125–8.

    PubMed  CAS  Google Scholar 

  144. 144.

    Ganesan S, Williams C, Maslen CL, et al. Clopidogrel variability: role of plasma protein binding alterations. Br J Clin Pharmacol. 2013;75(6):1468–77.

    PubMed  CAS  Google Scholar 

  145. 145.

    Weber AA, Reimann S, Schror K. Specific inhibition of ADP-induced platelet aggregation by clopidogrel in vitro. Br J Pharmacol. 1999;126(2):415–20.

    PubMed  CAS  Google Scholar 

  146. 146.

    Silvain J, Cayla G, Hulot JS, et al. High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study. Eur Heart J. 2012;33(10):1241–9.

    PubMed  CAS  Google Scholar 

  147. 147.

    Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am J Cardiol. 2007;100(9):1364–9.

    PubMed  Google Scholar 

  148. 148.

    MedicineComplete. Stockley’s interaction alerts. 2013. http://www.medicinescomplete.com/mc/alerts/current/interactions.htm?q=clopidogrel&searchButton=Search. Last Accessed 6 Jan 2013.

  149. 149.

    Gibaldi M. Pharmacokinetic variability-drug interactions. 4th ed. Philadelphia: Lea & Febiger; 1991. p. 305–43.

    Google Scholar 

  150. 150.

    Holmes DR Jr, Dehmer GJ, Kaul S, et al. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2010;56(4):321–41.

    PubMed  CAS  Google Scholar 

  151. 151.

    Angiolillo DJ, Gibson CM, Cheng S, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther. 2011;89(1):65–74.

    PubMed  CAS  Google Scholar 

  152. 152.

    FDA. Safety alert. Clopidogrel (marketed as Plavix) and Omeprazole (marketed as Prilosec)—Drug Interaction. 2009. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm190848.htm. Last Accessed 5 Jan 2013.

  153. 153.

    Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–17.

    PubMed  CAS  Google Scholar 

  154. 154.

    Burkard T, Kaiser CA, Brunner-La Rocca H, et al. Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial. J Intern Med. 2012;271(3):257–63.

    PubMed  CAS  Google Scholar 

  155. 155.

    Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol. 2010;56(24):2051–66.

    PubMed  Google Scholar 

  156. 156.

    O’Donoghue M, Antman EM, Braunwald E, et al. The efficacy and safety of prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38) analysis. J Am Coll Cardiol. 2009;54(8):678–85.

    PubMed  Google Scholar 

  157. 157.

    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(2):134–43.

    PubMed  CAS  Google Scholar 

  158. 158.

    Bellosta S, Corsini A. Statin drug interactions and related adverse reactions. Expert Opin Drug Saf. 2012;11(6):933–46.

    PubMed  CAS  Google Scholar 

  159. 159.

    Farid NA, Payne CD, Small DS, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007;81(5):735–41.

    PubMed  CAS  Google Scholar 

  160. 160.

    Siller-Matula JM, Lang I, Christ G, et al. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol. 2008;52(19):1557–63.

    PubMed  CAS  Google Scholar 

  161. 161.

    Jeong YH, Cho JH, Kang MK, et al. Smoking at least 10 cigarettes per day increases platelet inhibition by clopidogrel in patients with ST-segment-elevation myocardial infarction. Thromb Res. 2010;126(4):e334–8.

    PubMed  CAS  Google Scholar 

  162. 162.

    Lev EI, Arikan ME, Vaduganathan M, et al. Effect of caffeine on platelet inhibition by clopidogrel in healthy subjects and patients with coronary artery disease. Am Heart J. 2007;154(4):694.e1–7.

    Google Scholar 

  163. 163.

    Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol. 2008;48(4):475–84.

    PubMed  CAS  Google Scholar 

  164. 164.

    O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374(9694):989–97.

    PubMed  Google Scholar 

  165. 165.

    Schror K, Siller-Matula JM, Huber K. Pharmacokinetic basis of the antiplatelet action of prasugrel. Fundam Clin Pharmacol. 2012;26(1):39–46.

    PubMed  Google Scholar 

  166. 166.

    Dinicolantonio JJ, Serebruany VL. Exploring the ticagrelor-statin interplay in the PLATO trial. Cardiology. 2013;124(2):105–7.

    PubMed  CAS  Google Scholar 

  167. 168.

    Schneider DJ, Tracy PB, Mann KG, et al. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation. 1997;96(9):2877–83.

    PubMed  CAS  Google Scholar 

  168. 168.

    Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol. 2011;57(6):672–84.

    PubMed  CAS  Google Scholar 

  169. 169.

    Biondi-Zoccai G, Lotrionte M, Agostoni P, et al. Adjusted indirect comparison meta-analysis of prasugrel versus ticagrelor for patients with acute coronary syndromes. Int J Cardiol. 2011;150(3):325–31.

    PubMed  Google Scholar 

  170. 170.

    Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009;361(24):2330–41.

    PubMed  CAS  Google Scholar 

  171. 171.

    Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med. 2009;361(24):2318–29.

    PubMed  CAS  Google Scholar 

  172. 172.

    Leonardi S, Mahaffey KW, White HD, et al. Rationale and design of the Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON PHOENIX trial. Am Heart J. 2012;163(5):768–76.e2.

    Google Scholar 

  173. 173.

    Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303-13.

    Google Scholar 

  174. 174.

    Di Virgilio F, Solini A. P2 receptors: new potential players in atherosclerosis. Br J Pharmacol. 2002;135(4):831–42.

    PubMed  Google Scholar 

  175. 175.

    Massberg S, Brand K, Gruner S, et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med. 2002;196(7):887–96.

    PubMed  CAS  Google Scholar 

  176. 176.

    Massberg S, Schurzinger K, Lorenz M, et al. Platelet adhesion via glycoprotein IIb integrin is critical for atheroprogression and focal cerebral ischemia: an in vivo study in mice lacking glycoprotein IIb. Circulation. 2005;112(8):1180–8.

    PubMed  CAS  Google Scholar 

  177. 177.

    Frelinger AL 3rd, Jakubowski JA, Li Y, et al. The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin. Thromb Haemost. 2007;98(1):192–200.

    PubMed  CAS  Google Scholar 

  178. 178.

    Klinkhardt U, Bauersachs R, Adams J, et al. Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Ther. 2003;73(3):232–41.

    PubMed  CAS  Google Scholar 

  179. 179.

    Hagiwara S, Iwasaka H, Hasegawa A, et al. Adenosine diphosphate receptor antagonist clopidogrel sulfate attenuates LPS-induced systemic inflammation in a rat model. Shock. 2011;35(3):289–92.

    PubMed  CAS  Google Scholar 

  180. 180.

    Liu Y, Gao XM, Fang L, et al. Novel role of platelets in mediating inflammatory responses and ventricular rupture or remodeling following myocardial infarction. Arterioscler Thromb Vasc Biol. 2011;31(4):834–41.

    PubMed  CAS  Google Scholar 

  181. 181.

    Totani L, Dell’Elba G, Martelli N, et al. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost. 2012;107(6):1130–40.

    PubMed  CAS  Google Scholar 

  182. 182.

    Evangelista V, Manarini S, Dell’Elba G, et al. Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost. 2005;94(3):568–77.

    PubMed  CAS  Google Scholar 

  183. 183.

    Winning J, Reichel J, Eisenhut Y, et al. Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms. Platelets. 2009;20(1):50–7.

    PubMed  CAS  Google Scholar 

  184. 184.

    Lee CW, Hwang I, Park CS, et al. Comparison of differential expression of P2Y(1)(2) receptor in culprit coronary plaques in patients with acute myocardial infarction versus stable angina pectoris. Am J Cardiol. 2011;108(6):799–803.

    PubMed  CAS  Google Scholar 

  185. 185.

    Rauch BH, Rosenkranz AC, Ermler S, et al. Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions. Arterioscler Thromb Vasc Biol. 2010;30(12):2434–42.

    PubMed  CAS  Google Scholar 

  186. 186.

    Harada K, Matsumoto Y, Umemura K. Adenosine diphosphate receptor P2Y12-mediated migration of host smooth muscle-like cells and leukocytes in the development of transplant arteriosclerosis. Transplantation. 2011;92(2):148–54.

    PubMed  CAS  Google Scholar 

  187. 187.

    Zeiffer U, Schober A, Lietz M, et al. Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines. Circ Res. 2004;94(6):776–84.

    PubMed  CAS  Google Scholar 

  188. 188.

    Chew DP, Bhatt DL, Robbins MA, et al. Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein. Am J Cardiol. 2001;88(6):672–4.

    PubMed  CAS  Google Scholar 

  189. 189.

    Xiao Z, Theroux P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol. 2004;43(11):1982–8.

    PubMed  CAS  Google Scholar 

  190. 190.

    Cha JK, Jeong MH, Lee KM, et al. Changes in platelet P-selectin and in plasma C-reactive protein in acute atherosclerotic ischemic stroke treated with a loading dose of clopidogrel. J Thromb Thrombolysis. 2002;14(2):145–50.

    PubMed  Google Scholar 

  191. 191.

    Hermann A, Rauch BH, Braun M, et al. Platelet CD40 ligand (CD40L)—subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets. 2001;12(2):74–82.

    PubMed  CAS  Google Scholar 

  192. 192.

    Husted S, Storey RF, Harrington RA, et al. Changes in inflammatory biomarkers in patients treated with ticagrelor or clopidogrel. Clin Cardiol. 2010;33(4):206–12.

    PubMed  Google Scholar 

  193. 193.

    Afek A, Kogan E, Maysel-Auslender S, et al. Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice. Microvasc Res. 2009;77(3):364–9.

    PubMed  CAS  Google Scholar 

  194. 194.

    Schulz C, Konrad I, Sauer S, et al. Effect of chronic treatment with acetylsalicylic acid and clopidogrel on atheroprogression and atherothrombosis in ApoE-deficient mice in vivo. Thromb Haemost. 2008;99(1):190–5.

    PubMed  CAS  Google Scholar 

  195. 195.

    Li M, Zhang Y, Ren H, et al. Effect of clopidogrel on the inflammatory progression of early atherosclerosis in rabbits model. Atherosclerosis. 2007;194(2):348–56.

    PubMed  CAS  Google Scholar 

  196. 196.

    Li D, Wang Y, Zhang L, et al. Roles of purinergic receptor P2Y, G protein-coupled 12 in the development of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2012;32(8):e81–9.

    PubMed  CAS  Google Scholar 

  197. 197.

    Sachais BS, Turrentine T, Dawicki McKenna JM, et al. Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE−/− mice. Thromb Haemost. 2007;98(5):1108–13.

    PubMed  CAS  Google Scholar 

  198. 198.

    Sugidachi A, Yamaguchi S, Jakubowski JA, et al. Selective blockade of P2Y12 receptors by prasugrel inhibits myocardial infarction induced by thrombotic coronary artery occlusion in rats. J Cardiovasc Pharmacol. 2011;58(3):329–34.

    PubMed  CAS  Google Scholar 

  199. 199.

    Siller-Matula JM, Krumphuber J, Jilma B. Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases. Br J Pharmacol. 2010;159(3):502–17.

    PubMed  CAS  Google Scholar 

  200. 200.

    Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297–309.

    PubMed  CAS  Google Scholar 

  201. 201.

    Wouter Jukema J, Collet JP, De Luca L. Antiplatelet therapy in patients with ST-elevation myocardial infarction undergoing myocardial revascularisation: beyond clopidogrel. Curr Med Res Opin. 2012;28(2):203–11.

    PubMed  CAS  Google Scholar 

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Correspondence to Stefano Bellosta.

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Ferri, N., Corsini, A. & Bellosta, S. Pharmacology of the New P2Y12 Receptor Inhibitors: Insights on Pharmacokinetic and Pharmacodynamic Properties. Drugs 73, 1681–1709 (2013). https://doi.org/10.1007/s40265-013-0126-z

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Keywords

  • Percutaneous Coronary Intervention
  • Acute Coronary Syndrome
  • Clopidogrel
  • Stent Thrombosis
  • P2Y12 Receptor