Antiplatelet agents in cardiology: A report on aspirin, clopidogrel, prasugrel, and ticagrelor

Current Pharmaceutical Design

Volumn 22, Issue 13, 2016, Pages 1918-1932

  Dobesh, Paul P ^a   Varnado, Sara ^b   Doyle, Meagan ^a  

^a UNIVERSITY OF NEBRASKA MEDICAL CENTER   (United States)

^b UNIVERSITY OF NEBRASKA MEDICAL CENTER   (United States)

Author keywords

Antiplatelet agents; Aspirin; Clopidogrel; P2Y12 inhibitors; Prasugrel; Ticagrelor

Indexed keywords

ACETYLSALICYLIC ACID; CLOPIDOGREL; PRASUGREL; PURINERGIC P2Y12 RECEPTOR; TICAGRELOR; TICLOPIDINE; ADENOSINE; ANTITHROMBOCYTIC AGENT;

ACUTE CORONARY SYNDROME; ANTICOAGULANT THERAPY; ARTICLE; BARE METAL STENT; BLEEDING; BRAIN ISCHEMIA; CARBOXYLATION; CARDIOLOGY; CORONARY ARTERY DISEASE; CORONARY STENT; CORONARY STENTING; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG ELUTING STENT; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG STRUCTURE; DYSPNEA; GENETIC POLYMORPHISM; HUMAN; MONOTHERAPY; PATIENT CARE; PERCUTANEOUS CORONARY INTERVENTION; PHASE 3 CLINICAL TRIAL (TOPIC); PLATELET REACTIVITY; POSTOPERATIVE HEMORRHAGE; PRIORITY JOURNAL; PROTEIN FUNCTION; THROMBOCYTE ACTIVATION; THROMBOCYTE AGGREGATION; THROMBOCYTE FUNCTION; THROMBOCYTOPENIC PURPURA; TIME TO MAXIMUM PLASMA CONCENTRATION; TRANSCATHETER AORTIC VALVE IMPLANTATION; TREATMENT RESPONSE; ADVERSE EFFECTS; ANALOGS AND DERIVATIVES; CARDIOVASCULAR DISEASES; CHEMISTRY; SYNTHESIS;

ADENOSINE; ASPIRIN; CARDIOVASCULAR DISEASES; HUMANS; PLATELET AGGREGATION INHIBITORS; PRASUGREL HYDROCHLORIDE; TICLOPIDINE; TRANSCATHETER AORTIC VALVE REPLACEMENT;

EID: 84964303662     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612822666151208120106     Document Type: Article

References (139)

1. Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA 2008 guideline update on valvular heart disease: focused update on infective endocarditis: a report of the american college of cardiology/ american heart association task force on practice guidelines: endorsed by the society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, and society of thoracic surgeons. Circulation 2008; 118: 887-96.
2. Iung B, Cachier A, Baron G, et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005; 26: 2714-20.
3. Coller BS. The role of platelets in arterial thrombosis and the rationale for blockade of platelet GP IIb/IIIa receptors as antithrombotic therapy. Eur Heart J 1995; 16(suppl L): 11-5.
4. Frishman WH, Burns B, Atac B, Alturk N, Altajar B, Lerrick K. Novel antiplatelet therapies for treatment of patients with ischemic heart disease: Inhibitors of the platelet glycoprotein IIb/IIIa integrin receptor. Am Heart J 1995; 130: 877-92.
5. Hawiger J. Mechanisms involved in platelet vessel wall interaction. Thromb Haemost 1995; 74: 369-72.
6. Le Breton H, Plow EF, Topol EJ. Role of platelets in restenosis after percutaneous coronary revascularization. J Am Coll Cardiol 1996; 28: 1643-51.
7. Coller BS. Platelet GPIIb-IIIa antagonists: the first anti-integrin receptor therapeutics. J Clin Invest 1997; 99: 1467-71.
8. Nurden AT. Polymorphisms of human platelet membrane glycoproteins: structure and clinical significance. Thromb Haemost 1995; 74: 345-51.
9. Ferguson JJ. Conventional antithrombotic approaches. Am Heart J 1995; 130: 651-57.
10. Oestreich JH, Steinhubl SR. Cangrelor in percutaneous coronary intervention. Expert Rev Clin Pharmacol 2009; 2: 137-45.
11. Ginsberg MH, Du X, O’Toole TE, Loftus JC. Platelet integrins. Thromb Haemost 1995; 74: 352-9.
12. Born GV. Adenosine diphosphate as a mediator of platelet aggregation in vivo: an editorial view. Circulation 1985; 72: 741-6.
13. Hollopeter G, Jantzen HM, Vincent D, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-7.
14. Fredholm BB, Abbracchio MP, Burnstock G, et al. Nomenclature and classification of purinoceptors. Pharmacol Rev 1994; 46: 143-56.
15. Ferri N, Corsini A, Bellosta S. Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties. Drugs 2013; 73: 1681-709.
16. Mahaut-Smith MP, Tolhurst G, Evans RJ. Emerging roles for P2X1 receptors in platelet activation. Platelets 2004; 15: 131-44.
17. 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: 303-8.
18. Kunapuli SP, Ding Z, Dorsam RT, Kim S, Murugappan S, Quinton TM. ADP receptors -targets for developing antithrombotic agents. Curr Pharm Des 2003; 9: 2303-16.
19. 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: 1810-5.
20. Nylander S, Mattsson C, Ramstrom S, et al. Synergistic action between inhibition of P2Y12/P2Y1 and P2Y12/thrombin in ADPand thrombin-induced human platelet activation. Br J Pharmacol 2004; 142: 1325-31.
21. Hechler B, Leon C, Vial C, et al. The P2Y1 receptor is necessary for adenosine 5’ -diphosphate-induced platelet aggregation. Blood 1998; 92: 152-9.
22. Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004; 113: 340-5.
23. Gachet C. Regulation of platelet functions by P2 receptors. Annu Rev Pharmacol Toxicol 2006; 46: 277-300.
24. Dangelmaier C, Jin J, Smith JB, et al. Potentiation of thromboxane A2-induced platelet secretion by Gi singnaling through the phosphoinositide-3 kinase pathway. Thromb Haemost 2001; 85: 341-8.
25. Frishman WH, Burns B, Atac B, Alturk N, Altajar B, Lerrick K. Novel antiplatelet therapies for treatment of patients with ischemic heart disease: inhibitors of the platelet glycoprotein IIb-IIIa integrin receptor. Am Heart J 1995; 130: 877-92.
26. Weisel J, Nagaswami C, Vilaire G, Bennett JS. Examination of the platelet membrane glycoprotein IIb/IIIa complex and its interaction with fibrinogen and other ligands by electron microscopy. J Biol Chem 1992; 267: 1663-7
27. Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: the responsive integrin. Cell 1991; 65: 359-62.
28. Plow EF, McEver RP, Coller BS, et al. Related binding mechanisms for fibrinogen, fibronectin, von Willebrand factor, and thrombospondin on thrombin-stimulated human platelets. Blood 1985; 66: 724-7.
29. Wagner CL, Mascelli MA, Neblock DS, Weisman HF, Coller BS, Jordan RE. Analysis of GP IIb-IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 1996; 88: 907-14.
30. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50.
31. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. J Clin Invest 1975; 56: 624-32.
32. Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest 1978; 61: 314-9.
33. Saravana K, Gandhimathi R. Autopharmacology-a review. IJPR 2012; 22: 88-108.
34. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res 2003; 110: 255-8.
35. Dovizio M, Tacconelli S, Sostres C, Ricciotti E, Patrignani P. Mechanistic and pharmacological issues of aspirin as an anticancer agent. Pharmaceuticals (Basel) 2012; 5: 1346-71.
36. Awtry EH, Loscalzo J. Aspirin. Circulation 2000; 101: 1206-18.
37. Pairet M, Engelhardt G. Distinct isoforms (COX-1 and COX-2) of cyclooxygenase: possible physiological and therapeutic implications. Fundam Clin Pharmacol 1996; 10: 1-17.
38. Lopez-Farre A, Caramelo C, Esteban A, et al. Effects of aspirin on platelet-neutrophil interactions. Role of nitric oxide and endothelin-1. Circulation 1995; 91: 2080-8.
39. Levy G. Clinical pharmacokinetics of salicylates: a re-assessment. Br J Clin Pharmacol 1980; 10 (Suppl 2): 285S-90.
40. Koch PA, Schultz CA, Wills RJ, Hallquist SL, Welling PG. Influence of food and fluid ingestion on aspirin bioavailability. J Pharm Sci 1978; 67: 1533-5.
41. Pearson HA. Comparative effects of aspirin and acetaminophen on hemostasis. Pediatrics 1978; 62(5 Pt 2 Suppl): 926-9.
42. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-72.
43. Antithrombotic Trialists' Collaboration. 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.
44. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010; 376: 1233-43.
45. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med 2001; 345: 494-502.
46. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141(2 Suppl): e637S-68S.
47. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the american college of cardiology/american heart association task force on practice guidelines. J Am Coll Cardiol 2014; 64: e139-228.
48. Saltiel E, Ward A. Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in plateletdependent disease states. Drugs 1987; 34: 222-62.
49. McTavish D, Faulds D, Goa KL. Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs 1990; 40: 238-59.
50. 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: 527-33.
51. Steinhubl SR, Berger PB, Mann JT, 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288(19): 2411-20.
52. 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: 1607-21.
53. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-89.
54. Sabatine MS, Morrow DA, Montalescot G, et al. Angiographic and clinical outcomes in patients receiving low-molecular-weight heparin versus unfractionated heparin in ST-elevation myocardial infarction treated with fibrinolytics in the CLARITY-TIMI 28 Trial. Circulation 2005; 112: 3846-54.
55. Farid NA, Payne CD, Ernest CS, 2nd, et al. Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol 2008; 48: 53-9.
56. Gent M, Blakely JA, Easton JD, et al. The canadian american ticlopidine study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215-20.
57. Page Y, Tardy B, Zeni F, Comtet C, Terrana R, Bertrand JC. Thrombotic thrombocytopenic purpura related to ticlopidine. Lancet 1991; 337: 774-6.
58. Steinhubl SR, Tan WA, Foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. JAMA 1999; 281: 806-10.
59. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667-72.
60. Jiang, X; Samant, S; Lesko, L. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet 2015; 54: 147-66.
61. Dobesh PP. Pharmacokinetics and pharmacodynamics of prasugrel, a thienopyridine P2Y12 inhibitor. Pharmacotherapy 2009; 29: 1089-102.
62. Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy 2014; 34: 1077-90.
63. Sangkuhl, K; Klein, T; Altman, R. Clopidogrel pathway. Pharmacogen Genom 2010; 20: 463-65.
64. 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 Div 2010; 38: 92-9.
65. Farid NA, Small DS, Payne CD, et al. Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy subjects. Pharmacother 2008; 28: 1483-94.
66. Norgard NB, Mathews KD, Wall GC. Drug-drug interaction between clopidogrel and the proton pump inhibitors. Ann Pharmacother 2009; 43: 1266-74.
67. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. The randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51: 256-60.
68. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363: 1909-17.
69. Sanofi Pharmaceuticals. Plavix US Prescribing Information [CLOFPLR-SL-DEC13]. 2013. http://products.sanofi.us/plavix/plavix.html. Accessed 15 August 2015.
70. Ernest CS, Small DS, Rohatagi S, et. al. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirintreated patients with stable coronary artery disease. J Pharmacokiet Pharmacodyn 2008; 35: 593-618.
71. von Beckerath N, Taubert D, Pogatsa-Murray, G. Absorption, metabolism, and antiplatelet effects of 300-, 600-and 900 mg doses of clopidogrel. Results of the ISAR-CHOICE trial. Circulation 2005; 112: 2946-50.
72. Price MJ, Coleman JL, Steinhubl SR. Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers. Am J Cardiol 2006; 98: 681-4.
73. Steinhubl SR, Berger PB, Brennan DM, Topol EJ, for the CREDO Investigators. Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006; 47: 939-43.
74. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600 mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006; 48: 1339-45.
75. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.
76. Kastrati A, von Beckerath N, Joost A, Pogatsa-Murry G, Gorchakova O, Schömig A. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation 2004; 110: 1916-9.
77. Wismann PP, Roest M, Asselbergs FW. Platelet-reactivity tests identify patients at secondary risk of secondary cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost 2014; 12: 736-47
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: 919-33.
79. Price MJ, Berger PB, Teirstein, PS, et al, for the GRAVITAS Investigators. Standard-vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. The GRAVITAS randomized trial. JAMA 2011; 305: 1097-105.
80. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implementation 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.
81. Frelilnger A, Bhatt D, Lee R, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existant variability in platelet function. J Am Coll Cardiol 2013; 61: 872-9.
82. CAPRIE Steering Committee. A randomised, blinided, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.
83. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013 61: 485-510.
84. Zakarija A, Bandarenko N, Pandey DK, et al. Clopidogrelassociated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the food and drug administration. Stroke 2004; 35: 533-7.
85. Sugidachi A, Asai F, Ogawa T, Inoue T, Koike H. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 2000; 129: 1439-46.
86. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30.
87. Hasegawa M, Sugidachi A, Ogawa T, Isobe T, Jakubowski JA, Asai F. 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: 593-8.
88. Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos 2007; 35: 1096-104.
89. Williams ET, Jones KO, Ponsler GD, et al. The biotransformation of prasugrel, a new thienopyridine prodrug, by the human carboxylesterases 1 and 2. Drug Metab Dispos 2008; 36: 1227-32.
90. 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: 600-7.
91. Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 429-36.
92. Jakubowski JA, Payne CD, Brandt JT, et al. The platelet inhibitory effects and pharmacokinetics of prasugrel after administration of loading and maintenance doses in healthy subjects. J Cardiovasc Pharmacol 2006; 47: 377-84.
93. 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: 209-17.
94. Matsushima N, Jakubowski JA, Asai F, et al. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a multiple-dose study in healthy humans. Platelets 2006; 17: 218-26.
95. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30.
96. 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: 66 e9-16.
97. Payne CD, Li YG, Small DS, et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007; 50: 555-62.
98. Jakubowski JA, Matsushima N, Asai F, et al. A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharmacol 2007; 63: 421-30.
99. Weerakkody GJ, Jakubowski JA, Brandt JT, et al. Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status. Am J Cardiol 2007; 100: 331-6.
100. Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-73.
101. Sugidachi A, Ogawa T, Kurihara A, et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite. J Thromb Haemost 2007; 5: 1545-51.
102. Wiviott SD, Trenk K, 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: 2923-32.
103. Wiviott SD, Braunwald E, McCabe CH, et al, for the TRITONTIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-15.
104. Wiviott SD, Braunwald E, Angiolillo DJ, et al, for the TRITONTIMI 38 Investigators. Greater clinical benefit of more intense oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by opti mizing platelet inhibition with prasugrel -Thrombolysis in Myocardial Infarction 38. Circulation 2008; 118: 1626-36.
105. 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: 6013-18.
106. Sillén H, Cook M, Davis P. Determination of unbound ticagrelor and its active metabolite (AR-C124910XX) in human plasma by equilibrium dialysis and LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2011; 879: 2315-22.
107. van Giezen JJ, Nilsson L, Berntsson P, et al. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADPinduced receptor signaling and platelet aggregation. J Thromb Haemost 2009; 7: 1556-65.
108. van Giezen JJ, Berntsson P, Zachrisson H, Björkman JA. Comparison of ticagrelor and thienopyridine P2Y(12) binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis. Thromb Res 2009; 124: 565-71.
109. van Giezen JJ, Sidaway J, Glaves P, Kirk I, Björkman JA. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosinemediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther 2012; 17: 164-72.
110. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 2013; 61: 723-7.
111. Armstrong D, Summers C, Ewart L, Nylander S, Sidaway JE, van Giezen JJ. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther 2014; 19: 209-19.
112. Scirica BM, Cannon CP, Emanuelsson H, et al. The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiographic assessment substudy. J Am Coll Cardiol 2011; 57: 1908-16.
113. Camm AJ, Garratt CJ. Adenosine and supraventricular tachycardia. N Engl J Med 1991; 325: 1621-9.
114. Teng R, Oliver S, Hayes MA, Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 2010; 38: 1514-21.
115. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 2010; 70: 65-77.
116. Giorgi MA, Cohen Arazi H, Gonzalez CD, Di Girolamo G. Beyond efficacy: pharmacokinetic differences between clopidogrel, prasugrel and ticagrelor. Expert Opin Pharmacother 2011; 12: 1285-95.
117. Teng R, Butler K. Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers. J Drug Asses 2013; 2: 30-9.
118. Teng R, Mitchell PD, Butler KA. Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers. Eur J Clin Pharmacol 2013; 69: 477-87.
119. Teng R, Butler K. A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers. Eur J Clin Pharmacol 2013; 69: 1801-8.
120. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-47.
121. 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: 487-96.
122. Storey RF, Husted S, Harrington RA, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50: 1852-6.
123. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment. J Clin Pharmacol 2012; 52: 1388-98.
124. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment. J Clin Pharmacol 2011; 51: 978-87.
125. 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: 2577-85.
126. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010; 121: 1188-99.
127. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-57.
128. Mahaffey KW, Wojdyla DM, Carroll K, et al, for the PLATO Investigators. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2011; 124: 544-54.
129. Cannon CP, Husted S, Harrington RA, et al, for the DISPERSE-2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007; 50: 1844-51.
130. Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011; 32: 2945-53.
131. Nashimura, RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease. J Am Coll Cardiol 2014; 63: e570185.
132. Durand E, Blanchard D, Chassaing S, et al. Comparison of two antiplatelet therapy strategies in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2014; 113: 355-60.
133. Poliacikova P, Cockburn J, de Belder A, Trivedi U, Hildick-Smith D. Antiplatelet and antithrombotic treatment after transcatheter aortic valve implantation -comparison of regimes. J Invasive Cardiol 2013; 25: 544-8.
134. Aryal MR, Karmacharya P, Pandit A, et al. Dual versus single antiplatelet therapy in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis. Heart Lung Circ 2015; 24: 185-92.
135. Smith CR, Leon MB, Mack MJ, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2011; 363; 1597-607.
136. Linke A, Wenaweser P, Gerckens U, et al. Treatment of aortic stenosis with a self-expanding transcatheter valve: the international multi-centre ADVANCE study. Eur Heart Journal 2014; 35: 2672-84.
137. Adams DH, Popma JJ, Reardon MJ, et. al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014; 370: 1790-8.
138. Mauri L, Kereiakas DJ, Yeh RW, et al, for the DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371: 2155-66.
139. Bonaca MP, Bhatt DL, Cohen M, et al for the PEGASUS-TIMI 54 Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: 1791-800.