Effects of P2Y12 receptor antagonists beyond platelet inhibition - Comparison of ticagrelor with thienopyridines

British Journal of Pharmacology

Volumn 173, Issue 7, 2016, Pages 1163-1178

  Nylander, Sven ^a   Schulz, Rainer ^b  

^a ASTRAZENECA R AND D   (Sweden)

^b JUSTUS LIEBIG UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE; ANTITHROMBOCYTIC AGENT; CARDIOTONIC AGENT; EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1; PURINERGIC P2Y RECEPTOR ANTAGONIST; PURINERGIC P2Y12 RECEPTOR; THIENOPYRIDINE DERIVATIVE; TICAGRELOR;

ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; ATHEROSCLEROSIS; BLOOD; CARDIOVASCULAR FUNCTION; COMPARATIVE STUDY; DRUG EFFECTS; HUMAN; INFLAMMATION; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY; THROMBOCYTE;

ADENOSINE; ANIMALS; ATHEROSCLEROSIS; BLOOD PLATELETS; CARDIOTONIC AGENTS; CARDIOVASCULAR PHYSIOLOGICAL PHENOMENA; EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1; HUMANS; INFLAMMATION; PLATELET AGGREGATION INHIBITORS; PURINERGIC P2Y RECEPTOR ANTAGONISTS; RECEPTORS, PURINERGIC P2Y12; THIENOPYRIDINES;

EID: 84959387081     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.13429     Document Type: Review

References (159)

1. Afek A, Kogan E, Maysel-Auslender S, Mor A, Regev E, Rubinstein A, et al., (2009). Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice. Microvasc Res 77: 364-369.
2. Akbulut M, Ozbay Y, Karaca I, Ilkay E, Gundogdu O, Arslan N, (2004). The effect of long-term clopidogrel use on neointimal formation after percutaneous coronary intervention. Coron Artery Dis 15: 347-352.
3. Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C, (2005). Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 3: 85-92.
4. Alexander SPH, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE, et al., (2015a). The Concise Guide to PHARMACOLOGY 2015/16: G Protein-Coupled Receptors. Br J Pharmacol 172: 5744-5869.
5. Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, et al., (2015b). The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 172: 6024-6109.
6. Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, et al., (2012). Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 5: 797-804.
7. Alexopoulos D, Moulias A, Koutsogiannis N, Xanthopoulou I, Kakkavas A, Mavronasiou E, et al., (2013). Differential effect of ticagrelor versus prasugrel on coronary blood flow velocity in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: an exploratory study. Circ Cardiovasc Interv 6: 277-283.
8. Alsharif KF, Thomas MR, Judge HM, Khan H, Prince LR, Sabroe I, et al., (2015). Ticagrelor potentiates adenosine-induced stimulation of neutrophil chemotaxis and phagocytosis. Vascul Pharmacol 71: 201-207.
9. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Jimenez-Quevedo P, et al., (2006). Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 55: 780-784.
10. Antonino MJ, Mahla E, Bliden KP, Tantry US, Gurbel PA, (2009). Effect of long-term clopidogrel treatment on platelet function and inflammation in patients undergoing coronary arterial stenting. Am J Cardiol 103: 1546-1550.
11. Armstrong D, Summers C, Ewart L, Nylander S, Sidaway JE, van Giezen JJ, (2014). Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther 19: 209-219.
12. Aslam M, Schluter KD, Rohrbach S, Rafiq A, Nazli S, Piper HM, et al., (2013). Hypoxia-reoxygenation-induced endothelial barrier failure: role of RhoA, Rac1 and myosin light chain kinase. J Physiol 591: 461-473.
13. Aslam M, Tanislav C, Troidl C, Schulz R, Hamm C, Gündüz D, (2014). cAMP controls the restoration of endothelial barrier function after thrombin-induced hyperpermeability via Rac1 activation. Physiol Rep 2 pii: e12175.
14. Azar RR, Kassab R, Zoghbi A, Aboujaoudé S, El-Osta H, Ghorra P, et al., (2006). Effects of clopidogrel on soluble CD40 ligand and on high-sensitivity C-reactive protein in patients with stable coronary artery disease. Am Heart J 151: e1-521.
15. Baaten CC, Veenstra LF, Wetzels R, van Geffen JP, Swieringa F, de Witt SM, et al., (2015). Gradual increase in thrombogenicity of juvenile platelets formed upon offset of prasugrel medication. Haematologica 100: 1131-1138.
16. Badrnya S, Schrottmaier WC, Kral JB, Yaiw KC, Volf I, Schabbauer G, et al., (2014). Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation. Arterioscler Thromb Vasc Biol 34: 571-580.
17. Ben Addi A, Cammarata D, Conley PB, Boeynaems JM, Robaye B, (2010). Role of the P2Y12 receptor in the modulation of murine dendritic cell function by ADP. J Immunol 185: 5900-5906.
18. Bernlochner I, Goedel A, Plischke C, Schüpke S, Haller B, Schulz C, et al., (2015). Impact of immature platelets on platelet response to ticagrelor and prasugrel in patients with acute coronary syndrome. Eur Heart J 36: 3202-3210.
19. Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G, et al., (2009). Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 361: 2330-2341.
20. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, et al., (2013). Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 368: 1303-1313.
21. Bingham TC, Fisher EA, Parathath S, Reiss AB, Chan ES, Cronstein BN, (2010). A2A adenosine receptor stimulation decreases foam cell formation by enhancing ABCA1-dependent cholesterol efflux. J Leukoc Biol 87: 683-690.
22. Björkman JA, Zachrisson H, Forsberg GB, von Bahr H, Hansson GI, Warner TD, et al., (2013). High-dose aspirin in dogs increases vascular resistance with limited additional anti-platelet effect when combined with potent P2Y12 inhibition. Thromb Res 131: 313-319.
23. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al., (2015). Long-Term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 372: 1791-1800.
24. Bonello L, Harhouri K, Sabatier F, Camoin-Jau L, Arnaud L, Baumstarck-Barrau K, et al., (2010). Level of adenosine diphosphate receptor P2Y12 blockade during percutaneous coronary intervention predicts the extent of endothelial injury, assessed by circulating endothelial cell measurement. J Am Coll Cardiol 56: 1024-1031.
25. Bonello L, Laine M, Kipson N, Mancini J, Helal O, Fromonot J, et al., (2013). Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 63: 872-877.
26. Bonello L, Frere C, Cointe S, Laine M, Mancini J, Thuny F, et al., (2015). Ticagrelor increases endothelial progenitor cell level compared to clopidogrel in acute coronary syndromes: A prospective randomized study. Int J Cardiol 187: 502-507.
27. Braun OO, Johnell M, Varenhorst C, James S, Brandt JT, Jakubowski JA, et al., (2008). Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease. Thromb Haemost 100: 626-633.
28. Buchheiser A, Ebner A, Burghoff S, Ding Z, Romio M, Viethen C, et al., (2011). Inactivation of CD73 promotes atherogenesis in apolipoprotein E-deficient mice. Cardiovasc Res 92: 338-347.
29. Burki NK, Dale WJ, Lee LY, (2005). Intravenous adenosine and dyspnea in humans. J Appl Physiol 98: 180-185.
30. Cattaneo M, Faioni EM, (2012). Why does ticagrelor induce dyspnea? Thromb Haemost 108: 1031-1036.
31. Cattaneo M, Schulz R, Nylander S, (2014). Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol 63: 2503-2509.
32. Cesari F, Marcucci R, Gori AM, Caporale R, Fanelli A, Casola G, et al., (2013). Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 Study. Thromb Haemost 109: 846-853.
33. Chen YG, Xu F, Zhang Y, Ji QS, Sun Y, Lü RJ, et al., (2006). Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J (Engl) 119: 32-36.
34. Chirumamilla AP, Maehara A, Mintz GS, Mehran R, Kanwal S, Weisz G, et al., (2012). High platelet reactivity on clopidogrel therapy correlates with increased coronary atherosclerosis and calcification: a volumetric intravascular ultrasound study. JACC Cardiovasc Imaging 5: 540-549.
35. Diehl P, Olivier C, Halscheid C, Helbing T, Bode C, Moser M, (2010). Clopidogrel affects leukocyte dependent platelet aggregation by P2Y12 expressing leukocytes. Basic Res Cardiol 105: 379-387.
36. Dong ZM, Brown AA, Wagner DD, (2000). Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation 101: 2290-2295.
37. Evangelista V, Manarini S, Dell'Elba G, Martelli N, Napoleone E, Di Santo A, et al., (2005). Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost 94: 568-577.
38. Evans DJ, Jackman LE, Chamberlain J, Crosdale DJ, Judge HM, Jetha K, et al., (2009). Platelet P2Y(12) receptor influences the vessel wall response to arterial injury and thrombosis. Circulation 119: 116-122.
39. Freedman JE, (2008). Oxidative stress and platelets. Arterioscler Thromb Vasc Biol 28: s11-s16.
40. Frelinger AL 3rd, Jakubowski JA, Li Y, Barnard MR, Fox ML, Linden MD, et al., (2007). The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin. Thromb Haemost 98: 192-200.
41. Froldi G, Bertin R, Dorigo P, Montopoli M, Caparrotta L, (2011). Endothelium-independent vasorelaxation by ticlopidine and clopidogrel in rat caudal artery. J Pharm Pharmacol 63: 1056-1062.
42. Fuentes E, Palomo I, Alarcón M, (2015). Platelet miRNAs and cardiovascular diseases. Life Sci 133: 29-44.
43. Gachet C, (2012). P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal 8: 609-619.
44. Ge H, Zhou Y, Liu X, Nie X, Wang Z, Guo Y, et al., (2012). Relationship between plasma inflammatory markers and platelet aggregation in patients with clopidogrel resistance after angioplasty. Angiology 63: 62-66.
45. Gent M, Beaumont D, Blanchard J, Bousser MG, Coffman J, Easton JD, et al., (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348: 1329-1339.
46. Giachini FR, Leite R, Osmond DA, Lima VV, Inscho EW, Webb RC, et al., (2014). Anti-platelet therapy with clopidogrel prevents endothelial dysfunction and vascular remodeling in aortas from hypertensive rats. PLoS One 9: e91890.
47. Gremmel T, Eslam RB, Koppensteiner R, Lang IM, Panzer S, (2013). Prasugrel reduces agonists' inducible platelet activation and leukocyte-platelet interaction more efficiently than clopidogrel. Cardiovasc Ther 31: e40-e45.
48. Gros A, Ollivier V, Ho-Tin-Noé B, (2015). Platelets in inflammation: regulation of leukocyte activities and vascular repair. Front Immunol 5: 678.
49. Grzesk G, Kozinski M, Navarese EP, Krzyzanowski M, Grzesk E, Kubica A, et al., (2012). Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: a placebo-controlled study in rats. Thromb Res 130: 65-69.
50. Gurbel PA, Bliden KP, Tantry US, (2006). Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting: results from the CLEAR PLATELETS 1b study. J Am Coll Cardiol 48: 2186-2191.
51. Gurbel PA, Tantry US, (2015). Inhibited and Uninhibited Platelet Deposition Within a Thrombus: Does It Depend on the Antiplatelet Drug? Arterioscler Thromb Vasc Biol 35: 2081-2082.
52. Hadi NR, Mohammad BI, Ajeena IM, Sahib HH, (2013). Antiatherosclerotic potential of clopidogrel: antioxidant and anti-inflammatory approaches. Biomed Res Int 2013: 790263.
53. Hamilos M, Muller O, Ntalianis A, Trana C, Bartunek J, Sarno G, et al., (2011). Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel. J Thromb Thrombolysis 32: 64-71.
54. Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM, et al., (2009). Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 361: 2318-2329.
55. Heitzer T, Rudolph V, Schwedhelm E, Karstens M, Sydow K, Ortak M, et al., (2006). Clopidogrel improves systemic endothelial nitric oxide bioavailability in patients with coronary artery disease: evidence for antioxidant and antiinflammatory effects. Arterioscler Thromb Vasc Biol 26: 1648-1652.
56. Held C, Asenblad N, Bassand JP, Becker RC, Cannon CP, Claeys MJ, et al., (2011). 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 57: 672-684.
57. Hoefer T, Armstrong PC, Finsterbusch M, Chan MV, Kirkby NS, Warner TD, (2015). Drug-Free Platelets Can Act as Seeds for Aggregate Formation During Antiplatelet Therapy. Arterioscler Thromb Vasc Biol 35: 2122-2133.
58. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, et al., (2001). Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409: 202-207.
59. Högberg C, Svensson H, Gustafsson R, Eyjolfsson A, Erlinge D, (2010). The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature. Int J Cardiol 142: 187-192.
60. Hulsmans M, Holvoet P, (2013). MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc Res 100: 7-18.
61. Husted S, Storey RF, Harrington RA, Emanuelsson H, Cannon CP, (2010). Changes in inflammatory biomarkers in patients treated with ticagrelor or clopidogrel. Clin Cardiol 33: 206-212.
62. Husted SE, Storey RF, Bliden K, Tantry US, Høimark L, Butler K, et al., (2012). Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET-OFFSET and RESPOND studies. Clin Pharmacokinet 51: 397-409.
63. Ibrahim H, Schutt RC, Hannawi B, DeLao T, Barker CM, Kleiman NS, (2014). Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol 64: 2122-2129.
64. Ibrahim H, Nadipalli S, DeLao T, Guthikonda S, Kleiman NS, (2012). Immature platelet fraction (IPF) determined with an automated method predicts clopidogrel hyporesponsiveness. J Thromb Thrombolysis 33: 137-142.
65. Jakubowski A, Chlopicki S, Olszanecki R, Jawien J, Lomnicka M, Dupin JP, et al., (2005). Endothelial action of thienopyridines and thienopyrimidinones in the isolated guinea pig heart. Prostaglandins Leukot Essent Fatty Acids 72: 139-145.
66. Jakubowski JA, Zhou C, Winters KJ, Lachno DR, Howard J, Payne CD, et al., (2014). The effect of prasugrel on ADP-stimulated markers of platelet activation in patients with sickle cell disease. Platelets 20: 1-6.
67. Jalkanen J, Yegutkin GG, Hollmén M, Aalto K, Kiviniemi T, Salomaa V, et al., (2015). Aberrant circulating levels of purinergic signaling markers are associated with several key aspects of peripheral atherosclerosis and thrombosis. Circ Res 116: 1206-1215.
68. Järemo P, Lindahl TL, Fransson SG, Richter A, (2002). Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 252: 233-238.
69. Johnston LR, La Flamme AC, Larsen PD, Harding SA, (2015). Prasugrel inhibits platelet-enhanced pro-inflammatory CD4+ T cell responses in humans. Atherosclerosis 239: 283-286.
70. Jones MR, Zhao Z, Sullivan CP, Schreiber BM, Stone PJ, Toselli PA, et al., (2004). A(3) adenosine receptor deficiency does not influence atherogenesis. J Cell Biochem 92: 1034-1043.
71. Judge HM, Buckland RJ, Sugidachi A, Jakubowski JA, Storey RF, (2008). The active metabolite of prasugrel effectively blocks the platelet P2Y12 receptor and inhibits procoagulant and pro-inflammatory platelet responses. Platelets 19: 125-133.
72. Kawaguchi A, Sato M, Kimura M, Ichinohe T, Tazaki M, Shibukawa Y, (2015). Expression and function of purinergic P2Y12 receptors in rat trigeminal ganglion neurons. Neurosci Res 98: 17-27.
73. Kirkby NS, Leadbeater PD, Chan MV, Nylander S, Mitchell JA, Warner TD, (2011). Antiplatelet effects of aspirin vary with level of P2Y receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost 9: 2103-2105.
74. Kirkby NS, Lundberg MH, Chan MV, Vojnovic I, Solomon AB, Emerson M, et al., (2013). Blockade of the purinergic P2Y12 receptor greatly increases the platelet inhibitory actions of nitric oxide. Proc Natl Acad Sci U S A 110: 15782-15787.
75. Koupenova M, Johnston-Cox H, Vezeridis A, Gavras H, Yang D, Zannis V, et al., (2012). A2b adenosine receptor regulates hyperlipidemia and atherosclerosis. Circulation 125: 354-363.
76. Kuijpers MJ, Megens RT, Nikookhesal E, Feijge MA, De Mey JG, Oude Egbrink MG, et al., (2011). Role of newly formed platelets in thrombus formation in rat after clopidogrel treatment: comparison to the reversible binding P2Y antagonist ticagrelor. Thromb Haemost 106: 1179-1188.
77. Kunadian V, James SK, Wojdyla DM, Zorkun C, Wu J, Storey RF, et al., (2013). Angiographic outcomes in the PLATO Trial (Platelet Inhibition and Patient Outcomes). JACC Cardiovasc Interv 6: 671-683.
78. Lhermusier T, Baker NC, Waksman R, (2015). Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting regarding cangrelor. Am J Cardiol 115: 1154-1161.
79. Li M, Zhang Y, Ren H, Zhang Y, Zhu X, (2007). Effect of clopidogrel on the inflammatory progression of early atherosclerosis in rabbits model. Atherosclerosis 194: 348-356.
80. Li D, Wang Y, Zhang L, Luo X, Li J, Chen X, et al., (2012). Roles of purinergic receptor P2Y, G protein-coupled 12 in the development of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 32: e81-e89.
81. Lindholm D, Storey RF, Christersson C, Halvorsen S, Grove EL, Braun OÖ, et al., (2015). Design and rationale of TROCADERO: A TRial Of Caffeine to Alleviate DyspnEa Related to ticagrelOr. Am Heart J 170: 465-470.
82. Liverani E, Rico MC, Garcia AE, Kilpatrick LE, Kunapuli SP, (2013). Prasugrel metabolites inhibit neutrophil functions. J Pharmacol Exp Ther 344: 231-243.
83. Lum H, Jaffe HA, Schulz IT, Masood A, RayChaudhury A, Green RD, (1999). Expression of PKA inhibitor (PKI) gene abolishes cAMP-mediated protection to endothelial barrier dysfunction. Am J Physiol 277: C580-C588.
84. Lussana F, Di Marco F, Terraneo S, Parati M, Razzari C, Scavone M, et al., (2015). Effect of prasugrel in patients with asthma: results of PRINA, a randomized, double-blind, placebo-controlled, cross-over study. J Thromb Haemost 13: 136-141.
85. Mahaffey KW, Wojdyla DM, Carroll K, Becker RC, Storey RF, Angiolillo DJ, et al., (2011). Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 124: 544-554.
86. Malek LA, Grabowski M, Spiewak M, Filipiak KJ, Szpotanska M, Imiela T, et al., (2007). Relation between impaired antiplatelet response to clopidogrel and possible pleiotropic effects. J Thromb Thrombolysis 24: 301-305.
87. Martin-Ventura JL, Madrigal-Matute J, Martinez-Pinna R, Ramos-Mozo P, Blanco-Colio LM, Moreno JA, et al., (2012). Erythrocytes, leukocytes and platelets as a source of oxidative stress in chronic vascular diseases: detoxifying mechanisms and potential therapeutic options. Thromb Haemost 108: 435-442.
88. Massberg S, Brand K, Grüner S, Page S, Müller E, Müller I, et al., (2002). A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 196: 887-896.
89. Molero L, López-Farré A, Mateos-Cácere PJ, Fernández-Sánchez R, Luisa Maestro M, Silva J, et al., (2005). Effect of clopidogrel on the expression of inflammatory markers in rabbit ischemic coronary artery. Br J Pharmacol 146: 419-424.
90. Montalescot G, Sideris G, Meuleman C, Baldit-Sollier C, Lellouche N, Steg PG, et al., (2006). A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 48: 931-938.
91. Montalescot G, van 't Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, et al., ATLANTIC Investigators(2014). Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 371: 1016-1027.
92. Muhlestein JB, (2010). Effect of antiplatelet therapy on inflammatory markers in atherothrombotic patients. Thromb Haemost 103: 71-82.
93. Nanhwan MK, Ling S, Kodakandla M, Nylander S, Ye Y, Birnbaum Y, (2014). Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect. Arterioscler Thromb Vasc Biol 34: 2078-2085.
94. Nording HM, Seizer P, Langer HF, (2015). Platelets in inflammation and atherogenesis. Front Immunol 6: 98.
95. Nylander S, Femia EA, Scavone M, Berntsson P, Asztély AK, Nelander K, et al., (2013). Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism. J Thromb Haemost 11: 1867-1876.
96. Öhman J, Kudira R, Albinsson S, Olde B, Erlinge D, (2012). Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun 418: 754-758.
97. Ostad MA, Nick E, Paixao-Gatinho V, Schnorbus B, Schiewe R, Tschentscher P, et al., (2011). Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study. Clin Res Cardiol 100: 29-36.
98. Palmerini T, Barozzi C, Tomasi L, Sangiorgi D, Marzocchi A, De Servi S, et al., (2010). A randomised study comparing the antiplatelet and antiinflammatory effect of clopidogrel 150 mg/day versus 75 mg/day in patients with ST-segment elevation acute myocardial infarction and poor responsiveness to clopidogrel: results from the DOUBLE study. Thromb Res 125: 309-314.
99. Park SD, Baek YS, Woo SI, Kim SH, Shin SH, Kim DH, et al., (2014). Comparing the effect of clopidogrel versus ticagrelor on coronary microvascular dysfunction in acute coronary syndrome patients (TIME trial): study protocol for a randomized controlled trial. Trials 15: 151.
100. Patil SB, Jackman LE, Francis SE, Judge HM, Nylander S, Storey RF, (2010). Ticagrelor effectively and reversibly blocks murine platelet P2Y12-mediated thrombosis and demonstrates a requirement for sustained P2Y12 inhibition to prevent subsequent neointima. Arterioscler Thromb Vasc Biol 30: 2385-2391.
101. Patti G, Grieco D, Dicuonzo G, Pasceri V, Nusca A, Di Sciascio G, (2011). High versus standard clopidogrel maintenance dose after percutaneous coronary intervention and effects on platelet inhibition, endothelial function, and inflammation results of the ARMYDA-150 mg (antiplatelet therapy for reduction of myocardial damage during angioplasty) randomized study. J Am Coll Cardiol 57: 771-778.
102. Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SPH, Buneman OP, et al., NC-IUPHAR(2014). The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledge base of drug targets and their ligands. Nucl. Acids Res. 42 (Database Issue): D1098-D1106.
103. Quinn MJ, Bhatt DL, Zidar F, Vivekananthan D, Chew DP, Ellis SG, et al., (2004). Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous coronary intervention. Am J Cardiol 93: 679-684.
104. Rahman M, Gustafsson D, Wang Y, Thorlacius H, Braun OO, (2014). Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis. Platelets 25: 257-263.
105. Ramadan R, Dhawan SS, Syed H, Pohlel FK, Binongo JN, Ghazzal ZB, et al., (2014). Effects of clopidogrel therapy on oxidative stress, inflammation, vascular function, and progenitor cells in stable coronary artery disease. J Cardiovasc Pharmacol 63: 369-374.
106. Rauch BH, Rosenkranz AC, Ermler S, Böhm A, Driessen J, Fischer JW, et al., (2010). 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 30: 2434-2442.
107. Reiner MF, Stivala S, Akhmedov A, Spescha RD, Camici G, Beer JHJ, (2013). Ticagrelor and endothelial dysfunction: platelet independent effects. J Thromb Haemost 11 (S2) Meeting abstract PA 1.01-6.
108. Reiss AB, Rahman MM, Chan ES, Montesinos MC, Awadallah NW, Cronstein BN, (2004). Adenosine A2A receptor occupancy stimulates expression of proteins involved in reverse cholesterol transport and inhibits foam cell formation in macrophages. J Leukoc Biol 76: 727-734.
109. Rosiak M, Postula M, Kaplon-Cieslicka A, Kondracka A, Trzepla E, Czlonkowski A, et al., (2013). Effect of ASA dose doubling versus switching to clopidogrel on plasma inflammatory markers concentration in patients with type 2 diabetes and high platelet reactivity: the AVOCADO study. Cardiol J 20: 545-551.
110. Rusnak J, Mogler C, Buttler A, Bea F, Blessing E, Katus HA, et al., (2014). Ticagrelor promotes atherosclerotic lesion stabilization in advanced lesions of Apolipoprotein E deficient mice. Clin Res Cardiol 103 (S1) Abstract.
111. Satonaka H, Nagata D, Takahashi M, Kiyosue A, Myojo M, Fujita D, et al., (2015). Involvement of P2Y12 receptor in vascular smooth muscle inflammatory changes via MCP-1 upregulation and monocyte adhesion. Am J Physiol Heart Circ Physiol 308: H853-H861.
112. Schäfer A, Fraccarollo D, Pförtsch S, Loch E, Neuser J, Vogt C, et al., (2011). Clopidogrel improves endothelial function and NO bioavailability by sensitizing adenylyl cyclase in rats with congestive heart failure. Basic Res Cardiol 106: 485-494.
113. Schirmer SH, Kratz MT, Kazakov A, Nylander S, Baumhakel M, Laufs U, et al., (2012). Inhibition of the adenosine diphosphate receptor P2Y12 reduces atherosclerotic plaque size in hypercholesterolemic ApoE-/- mice. Eur Heart J 33 (Supplement): A200.
114. Schnorbus B, Daiber A, Jurk K, Warnke S, König J, Krahn U, et al., (2014). Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study. BMJ Open 4: e005268.
115. Schrottmaier WC, Kral JB, Badrnya S, Assinger A, (2015). Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes. Thromb Haemost 114: 478-89.
116. Schulz C, Konrad I, Sauer S, Orschiedt L, Koellnberger M, Lorenz R, et al., (2008). Effect of chronic treatment with acetylsalicylic acid and clopidogrel on atheroprogression and atherothrombosis in ApoE-deficient mice in vivo. Thromb Haemost 99: 190-195.
117. Shanker G, Kontos JL, Eckman DM, Wesley-Farrington D, Sane DC, (2006). Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts. J Thromb Thrombolysis 22: 213-220.
118. Siasos G, Oikonomou E, Zaromitidou M, Kioufis S, Kokkou E, Mourouzis K, et al., (2015). Clopidogrel response variability is associated with endothelial dysfunction in coronary artery disease patients receiving dual antiplatelet therapy. Atherosclerosis 242: 102-108.
119. Simon J, Filippov AK, Göransson S, Wong YH, Frelin C, Michel AD, et al., (2002). Characterization and channel coupling of the P2Y(12) nucleotide receptor of brain capillary endothelial cells. J Biol Chem 277: 31390-31400.
120. Smadja DM, Bura A, Szymezak J, Blanchard A, Remones V, Azizi M, et al., (2012). Effect of clopidogrel on circulating biomarkers of angiogenesis and endothelial activation. J Cardiol 59: 30-35.
121. Solheim S, Pettersen AA, Arnesen H, Seljeflot I, (2006). No difference in the effects of clopidogrel and aspirin on inflammatory markers in patients with coronary heart disease. Thromb Haemost 96: 660-664.
122. Song YB, Hahn JY, Gwon HC, Chang SA, Lee SC, Choe YH, et al., (2012). A high loading dose of clopidogrel reduces myocardial infarct size in patients undergoing primary percutaneous coronary intervention: a magnetic resonance imaging study. Am Heart J 163: 500-507.
123. Springthorpe B, Bailey A, Barton P, Birkinshaw TN, Bonnert RV, Brown RC, et al., (2007). From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett 17: 6013-6018.
124. Steinhubl SR, Badimon JJ, Bhatt DL, Herbert JM, Lüscher TF, (2007). Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 12: 113-122.
125. Stokes KY, Russell JM, Jennings MH, Alexander JS, Granger DN, (2007). Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia. Free Radic Biol Med 43: 22-30.
126. Storey RF, Becker RC, Harrington RA, Husted S, James SK, Cools F, et al., (2011). Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 32: 2945-2953.
127. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, et al., (2007). 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 50: 1852-1856.
128. Storey RF, James SK, Siegbahn A, Varenhorst C, Held C, Ycas J, et al., (2014). Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets 25: 517-525.
129. Sürer S, Toktas F, Ay D, Eris C, Yavuz S, Turk T, et al., (2014). Effect of the P2Y12 antagonist Ticagrelor on neointimal hyperplasia in a rabbit carotid anastomosis model. Interact Cardiovasc Thorac Surg 19: 198-204.
130. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, et al., (2007). 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 7: 1545-1551.
131. Takeda M, Yamashita T, Shinohara M, Sasaki N, Tawa H, Nakajima K, et al., (2012). Beneficial effect of anti-platelet therapies on atherosclerotic lesion formation assessed by phase-contrast X-ray CT imaging. Int J Cardiovasc Imaging 28: 1181-1191.
132. Teng B, Smith JD, Rosenfeld ME, Robinet P, Davis ME, Morrison RR, et al., (2014). A adenosine receptor deficiency or inhibition reduces atherosclerotic lesions in apolipoprotein E deficient mice. Cardiovasc Res 102: 157-165.
133. Thomas M, Judge H, Dockrell D, Sabroe I, Storey R, (2014). Ticagrelor inhibits release of pro-inflammatory cytokines TNF and IL-6 during human endotoxaemia. Heart 100 (S3): A117-A118.
134. Thomas MR, Storey RF, (2015). Effect of P2Y12 inhibitors on inflammation and immunity. Thromb Haemost 114: 449-458.
135. Torngren K, Ohman J, Salmi H, Larsson J, Erlinge D, (2013). Ticagrelor improves peripheral arterial function in patients with a previous acute coronary syndrome. Cardiology 124: 252-258.
136. Totani L, Dell'Elba G, Martelli N, Di Santo A, Piccoli A, Amore C, et al., (2012). Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost 107: 1130-1140.
137. van Giezen JJ, Nilsson L, Berntsson P, Wissing BM, Giordanetto F, Tomlinson W, et al., (2009). Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 7: 1556-1565.
138. Varenhorst C, Alström U, Scirica BM, Hogue CW, Åsenblad N, Storey RF, et al., (2012). Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol 60: 1623-1630.
139. Vivekananthan DP, Bhatt DL, Chew DP, Zidar FJ, Chan AW, Moliterno DJ, et al., (2004). Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol 94: 358-360.
140. Waksman R, Pakala R, Roy P, Baffour R, Hellinga D, Seabron R, et al., (2008). Effect of clopidogrel on neointimal formation and inflammation in balloon-denuded and radiated hypercholesterolemic rabbit iliac arteries. J Interv Cardiol 21: 122-128.
141. Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA, et al., (2008). 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 29: 21-30.
142. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al., (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361: 1045-1057.
143. Wang L, Jacobsen SE, Bengtsson A, Erlinge D, (2004). P2 receptor mRNA expression profiles in human lymphocytes, monocytes and CD34+ stem and progenitor cells. BMC Immunol 5: 16.
144. Wang H, Zhang W, Zhu C, Bucher C, Blazar BR, Zhang C, et al., (2009). Inactivation of the adenosine A2A receptor protects apolipoprotein E-deficient mice from atherosclerosis. Arterioscler Thromb Vasc Biol 29: 1046-1052.
145. Wang K, Zhou X, Huang Y, Khalil M, Wiktor D, van Giezen JJ, et al., (2010). Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model. Thromb Haemost 104: 609-617.
146. Warner TD, Nylander S, Whatling C, (2011). Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. Br. J Clin Pharmacol 72: 619-633.
147. Warnholtz A, Ostad MA, Velich N, Trautmann C, Schinzel R, Walter U, et al., (2008). A single loading dose of clopidogrel causes dose-dependent improvement of endothelial dysfunction in patients with stable coronary artery disease: results of a double-blind, randomized study. Atherosclerosis 196: 689-695.
148. Welsh RC, Rao SV, Zeymer U, Thompson VP, Huber K, Kochman J, et al., (2012). A randomized, double-blind, active-controlled phase 2 trial to evaluate a novel selective and reversible intravenous and oral P2Y12 inhibitor elinogrel versus clopidogrel in patients undergoing nonurgent percutaneous coronary intervention: the INNOVATE-PCI trial. Circ Cardiovasc Interv 5: 336-346.
149. West LE, Steiner T, Judge HM, Francis SE, Storey RF, (2014). Vessel wall, not platelet, P2Y12 potentiates early atherogenesis. Cardiovasc Res 102: 429-435.
150. Wihlborg AK, Wang L, Braun OO, Eyjolfsson A, Gustafsson R, Gudbjartsson T, et al., (2004). ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 24: 1810-1815.
151. Willoughby SR, Luu LJ, Cameron JD, Nelson AJ, Schultz CD, Worthley SG, et al., (2014). Clopidogrel improves microvascular endothelial function in subjects with stable coronary artery disease. Heart Lung Circ 23: 534-541.
152. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, van Giezen JJ, Jonasson J, Nylander S, et al., (2013). Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 61: 723-727.
153. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al., (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357: 2001-2015.
154. Woo JS, Kim W, Jang HH, Kim JB, Kim WS, Kim KS, (2014). Effect of platelet reactivity, endothelial function, and inflammatory status on outcomes in patients with stable angina pectoris on clopidogrel therapy. Am J Cardiol 113: 786-792.
155. Xiao Z, Théroux P, (2004). Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol 43: 1982-1988.
156. Yang XM, Liu Y, Cui L, Yang X, Liu Y, Tandon N, et al., (2013). Platelet P2Y blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther 18: 251-262.
157. Yeh ET, Khan BV, (2006). The potential role of antiplatelet agents in modulating inflammatory markers in atherothrombosis. J Thromb Haemost 4: 2308-2316.
158. Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y, (2015). Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction. Arterioscler Thromb Vasc Biol 35: 1805-1814.
159. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, (2001). Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345: 494-502.