Journal of Thrombosis and Thrombolysis

, Volume 30, Issue 2, pp 240–249 | Cite as

Antiplatelet therapy for atherothrombotic disease: How can we improve the outcomes?

  • Martin Moser
  • Christoph BodeEmail author


Platelets play a key role in hemostasis but are also responsible for the formation of pathogenic thrombi underlying the acute clinical manifestations of vascular atherothrombotic disease. Platelets are activated by multiple pathways, including adenosine diphosphate (ADP), thromboxane A2 (TXA2), and thrombin, ultimately leading to formation of platelet-rich thrombi that occlude the arterial lumen, resulting in ischemia and cardiovascular events. Current oral antiplatelet agents inhibit the TXA2 (aspirin [ASA]) and ADP platelet activation pathways (P2Y12 ADP receptor antagonists) and have demonstrated clinical efficacy for the reduction of morbidity and mortality in patients with atherothrombotic disease. However, these agents are associated with residual risk for thrombotic events, bleeding risk, and variability in response. Thus, there is a strong clinical need for novel antiplatelet therapies that decrease the risk of thrombotic events without exposing patients to increased risk of bleeding. This review describes the clinical safety and efficacy of ASA and P2Y12 ADP receptor antagonists, the limitations of current antiplatelet therapy, and novel therapies in development, including newer P2Y12 ADP receptor antagonists and protease-activated receptor (PAR-1) inhibitors.


ADP Thromboxane A2 Platelets Residual risk Bleeding PAR-1 



M.M. has received speaker’s honoraria from GlaxoSmithKline, Boehringer Ingelheim, and The Medicines Company. C.B. has received speaker’s honoraria from Merck, Astra-Zeneca, and Sanofi. Editorial assistance was provided by Gina Fusaro, PhD, and Joshua Barbach, MA, of Health Science Communications. This assistance was funded by Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, NJ, USA. The authors did not receive any financial compensation for this work and are fully responsible for the content of the manuscript.


  1. 1.
    Wasserman EJ, Shipley NM (2006) Atherothrombosis in acute coronary syndromes: mechanisms, markers, and mediators of vulnerability. Mt Sinai J Med 73:431–439PubMedGoogle Scholar
  2. 2.
    Davì G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494CrossRefPubMedGoogle Scholar
  3. 3.
    Furie B, Furie BC (2008) Mechanisms of thrombus formation. N Engl J Med 359:938–949CrossRefPubMedGoogle Scholar
  4. 4.
    Storey RF (2001) The P2Y12 receptor as a therapeutic target in cardiovascular disease. Platelets 12:197–209CrossRefPubMedGoogle Scholar
  5. 5.
    Varga-Szabo D, Pleines I, Nieswandt B (2008) Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol 28:403–412CrossRefPubMedGoogle Scholar
  6. 6.
    Brass LF (2003) Thrombin and platelet activation. Chest 124:18S–25SCrossRefPubMedGoogle Scholar
  7. 7.
    Offermanns S (2006) Activation of platelet function through G protein-coupled receptors. Circ Res 99:1293–1304CrossRefPubMedGoogle Scholar
  8. 8.
    Meadows TA, Bhatt DL (2007) Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 100:1261–1275CrossRefPubMedGoogle Scholar
  9. 9.
    Coughlin SR (2005) Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 3:1800–1814CrossRefPubMedGoogle Scholar
  10. 10.
    Cohen M (2009) Oral antiplatelet therapy for acute and chronic management of NSTE ACS: residual ischemic risk and opportunities for improvement. Cardiovasc Drugs Ther 23:489–499CrossRefPubMedGoogle Scholar
  11. 11.
    Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsén M (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057CrossRefPubMedGoogle Scholar
  12. 12.
    Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015CrossRefPubMedGoogle Scholar
  13. 13.
    Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502CrossRefPubMedGoogle Scholar
  14. 14.
    Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR (2008) Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 336:195–198CrossRefPubMedGoogle Scholar
  15. 15.
    Angiolillo DJ, Fernández-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49:1505–1516CrossRefPubMedGoogle Scholar
  16. 16.
    Schulman SP (2004) Antiplatelet therapy in non-ST-segment elevation acute coronary syndromes. JAMA 292:1875–1882CrossRefPubMedGoogle Scholar
  17. 17.
    Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE III, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H (1983) Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 309:396–403PubMedGoogle Scholar
  18. 18.
    AntithromboticTrialists’ Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324:71–86CrossRefGoogle Scholar
  19. 19.
    Antithrombotic Trialists’ Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A (2009) Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373:1849–1860CrossRefPubMedGoogle Scholar
  20. 20.
    Schwartz L, Bourassa MG, Lespérance J, Aldridge HE, Kazim F, Salvatori VA, Henderson M, Bonan R, David PR (1988) Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 318:1714–1719PubMedCrossRefGoogle Scholar
  21. 21.
    Raju NC, Eikelboom JW, Hirsh J (2008) Platelet ADP-receptor antagonists for cardiovascular disease: past, present and future. Nat Clin Pract Cardiovasc Med 5:766–780CrossRefPubMedGoogle Scholar
  22. 22.
    CAPRIE Steering Committee (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348:1329–1339Google Scholar
  23. 23.
    Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E (2005) Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 352:1179–1189CrossRefPubMedGoogle Scholar
  24. 24.
    Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS (2005) Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366:1607–1621CrossRefPubMedGoogle Scholar
  25. 25.
    Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358:527–533CrossRefPubMedGoogle Scholar
  26. 26.
    Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C, Topol EJ (2002) Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288:2411–2420CrossRefPubMedGoogle Scholar
  27. 27.
    Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ (2006) Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354:1706–1717CrossRefPubMedGoogle Scholar
  28. 28.
    Mehta S (2009) CURRENT OASIS 7: a 2 × 2 factorial randomized trial of optimal clopidogrel and aspirin dosing in patients with ACS undergoing an early invasive strategy with intent for PCI. Presented at European Society of Cardiology (ESC) 2009 congress, Barcelona, Spain, August 29–September 2, 2009Google Scholar
  29. 29.
    Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, Goodman SG, Corbalan R, Purdy DA, Murphy SA, McCabe CH, Antman EM (2008) 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 118:1626–1636CrossRefPubMedGoogle Scholar
  30. 30.
    Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA, Sugidachi A, Winters KJ, Siegbahn A (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 29:21–30CrossRefPubMedGoogle Scholar
  31. 31.
    Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L (2006) 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 27:1166–1173CrossRefPubMedGoogle Scholar
  32. 32.
    Bhatt DL (2009) Intravenous platelet blockade with cangrelor during PCI. New Engl J Med 361. E-pub ahead of printGoogle Scholar
  33. 33.
    Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, Antman EM (2009) Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 373:723–731CrossRefPubMedGoogle Scholar
  34. 34.
    Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM (2008) Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 371:1353–1363CrossRefPubMedGoogle Scholar
  35. 35.
    Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G (2006) 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 27:1038–1047CrossRefPubMedGoogle Scholar
  36. 36.
    Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Fabry-Ribaudo L, Hu T, Topol EJ, Fox KA (2007) Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 49:1982–1988CrossRefPubMedGoogle Scholar
  37. 37.
    Jennings LK (2009) Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 102:248–257PubMedGoogle Scholar
  38. 38.
    Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, Diaz R, Commerford PJ, Valentin V, Yusuf S (2003) Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 108:1682–1687CrossRefPubMedGoogle Scholar
  39. 39.
    Budaj A, Eikelboom JW, Mehta SR, Afzal R, Chrolavicius S, Bassand JP, Fox KA, Wallentin L, Peters RJ, Granger CB, Joyner CD, Yusuf S (2009) Improving clinical outcomes by reducing bleeding in patients with non-ST-elevation acute coronary syndromes. Eur Heart J 30:655–661CrossRefPubMedGoogle Scholar
  40. 40.
    Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S (2006) Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 114:774–782CrossRefPubMedGoogle Scholar
  41. 41.
    Kinnaird TD, Stabile E, Mintz GS, Lee CW, Canos DA, Gevorkian N, Pinnow EE, Kent KM, Pichard AD, Satler LF, Weissman NJ, Lindsay J, Fuchs S (2003) Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 92:930–935CrossRefPubMedGoogle Scholar
  42. 42.
    Moscucci M, Fox KA, Cannon CP, Klein W, Lopez-Sendon J, Montalescot G, White K, Goldberg RJ (2003) Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 24:1815–1823CrossRefPubMedGoogle Scholar
  43. 43.
    Rao SV, O’Grady K, Pieper KS, Granger CB, Newby LK, Van de Werf F, Mahaffey KW, Califf RM, Harrington RA (2005) Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 96:1200–1206CrossRefPubMedGoogle Scholar
  44. 44.
    Segev A, Strauss BH, Tan M, Constance C, Langer A, Goodman SG (2005) Predictors and 1-year outcome of major bleeding in patients with non-ST-elevation acute coronary syndromes: insights from the Canadian Acute Coronary Syndrome Registries. Am Heart J 150:690–694CrossRefPubMedGoogle Scholar
  45. 45.
    Subherwal S, Bach RG, Chen AY, Gage BF, Rao SV, Newby LK, Wang TY, Gibler WB, Ohman EM, Roe MT, Pollack CV Jr, Peterson ED, Alexander KP (2009) Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation 119:1873–1882CrossRefPubMedGoogle Scholar
  46. 46.
    Rao SV, Jollis JG, Harrington RA, Granger CB, Newby LK, Armstrong PW, Moliterno DJ, Lindblad L, Pieper K, Topol EJ, Stamler JS, Califf RM (2004) Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 292:1555–1562CrossRefPubMedGoogle Scholar
  47. 47.
    O’Donnell MJ, Kapral MK, Fang J, Saposnik G, Eikelboom JW, Oczkowski W, Silva J, Gould L, D’Uva C, Silver FL (2008) Gastrointestinal bleeding after acute ischemic stroke. Neurology 71:650–655CrossRefPubMedGoogle Scholar
  48. 48.
    van Hattum ES, Algra A, Lawson JA, Eikelboom BC, Moll FL, Tangelder MJ (2009) Bleeding increases the risk of ischemic events in patients with peripheral arterial disease. Circulation 120:1569–1576CrossRefPubMedGoogle Scholar
  49. 49.
    Spencer FA, Moscucci M, Granger CB, Gore JM, Goldberg RJ, Steg PG, Goodman SG, Budaj A, FitzGerald G, Fox KA (2007) Does comorbidity account for the excess mortality in patients with major bleeding in acute myocardial infarction? Circulation 116:2793–2801CrossRefPubMedGoogle Scholar
  50. 50.
    Cuisset T, Frere C, Quilici J, Morange PE, Nait-Saidi L, Carvajal J, Lehmann A, Lambert M, Bonnet JL, Alessi MC (2006) 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 48:1339–1345CrossRefPubMedGoogle Scholar
  51. 51.
    Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, Gick M, Caputo A, Buttner HJ, Neumann FJ (2006) Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 48:1742–1750CrossRefPubMedGoogle Scholar
  52. 52.
    Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H (2004) Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 109:3171–3175CrossRefPubMedGoogle Scholar
  53. 53.
    Chen WH, Cheng X, Lee PY, Ng W, Kwok JY, Tse HF, Lau CP (2007) Aspirin resistance and adverse clinical events in patients with coronary artery disease. Am J Med 120:631–635CrossRefPubMedGoogle Scholar
  54. 54.
    Ferreiro JL, Angiolillo DJ (2009) Clopidogrel response variability: current status and future directions. Thromb Haemost 102:7–14PubMedGoogle Scholar
  55. 55.
    Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G (2009) Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373:309–317CrossRefPubMedGoogle Scholar
  56. 56.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362CrossRefPubMedGoogle Scholar
  57. 57.
    Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360:363–375CrossRefPubMedGoogle Scholar
  58. 58.
    Taubert D, Kastrati A, Harlfinger S, Gorchakova O, Lazar A, von Beckerath N, Schomig A, Schomig E (2004) Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost 92:311–316PubMedGoogle Scholar
  59. 59.
    Angiolillo DJ, Bernardo E, Sabaté M, Jimenez-Quevedo P, Costa MA, Palazuelos J, Hernandez-Antolin R, Moreno R, Escaned J, Alfonso F, Banuelos C, Guzman LA, Bass TA, Macaya C, Fernández-Ortiz A (2007) Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 50:1541–1547CrossRefPubMedGoogle Scholar
  60. 60.
    Angiolillo DJ, Fernández-Ortiz A, Bernardo E, Barrera Ramirez C, Sabaté M, Fernandez C, Hernandez-Antolin R, Escaned J, Alfonso F, Macaya C (2004) Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted? J Invasive Cardiol 16:169–174PubMedGoogle Scholar
  61. 61.
    Schwartz KA, Schwartz DE, Ghosheh K, Reeves MJ, Barber K, DeFranco A (2005) Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. Am J Cardiol 95:973–975CrossRefPubMedGoogle Scholar
  62. 62.
    Soffer D, Moussa I, Harjai KJ, Boura JA, Dixon SR, Grines CL, O’Neill WW, Roubin GS, Moses JW (2003) Impact of angina class on inhibition of platelet aggregation following clopidogrel loading in patients undergoing coronary intervention: do we need more aggressive dosing regimens in unstable angina? Catheter Cardiovasc Interv 59:21–25CrossRefPubMedGoogle Scholar
  63. 63.
    Berger JS, Roe MT, Gibson CM, Kilaru R, Green CL, Melton L, Blankenship JD, Metzger DC, Granger CB, Gretler DD, Grines CL, Huber K, Zeymer U, Buszman P, Harrington RA, Armstrong PW (2009) Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid Reversal of Platelet Thrombosis With Intravenous Elinogrel Before PCI to Optimize Reperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J 158:998–1004.e.1Google Scholar
  64. 64.
    A phase 2 safety and efficacy study of PRT 060128 a novel intravenous and oral P2Y12 inhibitor in non-urgent PCI (INNOVATE-PCI) (2010) NCT00751231. Accessed February 23, 2010
  65. 65.
    Harrington RA (2009) Platelet inhibition with cangrelor in patients undergoing PCI. New Engl J Med 361:2318–2329CrossRefPubMedGoogle Scholar
  66. 66.
    Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G, Kleiman NS, Goodman SG, White HD, Mahaffey KW, Pollack CV Jr, Manoukian SV, Widimsky P, Chew DP, Cura F, Manukov I, Tousek F, Jafar MZ, Arneja J, Skerjanec S, Harrington RA (2009) Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 361:2330–2341CrossRefPubMedGoogle Scholar
  67. 67.
    Derian CK, Damiano BP, Addo MF, Darrow AL, D’Andrea MR, Nedelman M, Zhang HC, Maryanoff BE, Andrade-Gordon P (2003) Blockade of the thrombin receptor protease-activated receptor-1 with a small-molecule antagonist prevents thrombus formation and vascular occlusion in nonhuman primates. J Pharmacol Exp Ther 304:855–861CrossRefPubMedGoogle Scholar
  68. 68.
    Kato Y, Kita Y, Hirasawa-Taniyama Y, Nishio M, Mihara K, Ito K, Yamanaka T, Seki J, Miyata S, Mutoh S (2003) Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig. Eur J Pharmacol 473:163–169CrossRefPubMedGoogle Scholar
  69. 69.
    Vandendries ER, Hamilton JR, Coughlin SR, Furie B, Furie BC (2007) Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis. Proc Natl Acad Sci USA 104:288–292CrossRefPubMedGoogle Scholar
  70. 70.
    Chackalamannil S, Ahn HS, Xia Y, Doller D, Foster C (2003) Potent non-peptide thrombin receptor antagonists. Curr Med Chem Cardiovasc Hematol Agents 1:37–45CrossRefPubMedGoogle Scholar
  71. 71.
    Chackalamannil S, Wang Y, Greenlee WJ, Hu Z, Xia Y, Ahn HS, Boykow G, Hsieh Y, Palamanda J, Agans-Fantuzzi J, Kurowski S, Graziano M, Chintala M (2008) Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 51:3061–3064CrossRefPubMedGoogle Scholar
  72. 72.
    Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J, Niederman A, Ziada KM, Berman G, Strony J, Joseph D, Mahaffey KW, Van de Werf F, Veltri E, Harrington RA (2009) Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 373:919–928CrossRefPubMedGoogle Scholar
  73. 73.
    Jennings LK, Earhart A, Becker RC, Reyderman L, Veltri E, Strony J, Harrington RA (2007) Thrombin receptor antagonist (TRA;SCH530348) is a selective, potent inhibitor of PAR1 activity with predictable pharmacokinetics. Circulation 116(Suppl):II 674. Abstract 3010Google Scholar
  74. 74.
    Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P (2010) Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH 530348 for non-ST-segment elevation acute coronary syndrome. J Atheroscler Thromb 26:156–164Google Scholar
  75. 75.
    Shinohara Y, Goto S, Shimizu K, Jensen P (2008) A phase II safety study of novel antiplatelet agent, SCH 530348, in Japanese patients with prior ischemic stroke. Int J Stroke 2008(suppl 1):139. AbstractGoogle Scholar
  76. 76.
    The TRA·CER Executive and Steering Committees (2009) The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA·CER) trial: study design and rationale. Am Heart J 158:327–334.e.4Google Scholar
  77. 77.
    Morrow DA, Scirica BM, Fox KA, Berman G, Strony J, Veltri E, Bonaca MP, Fish P, McCabe CH (2009) Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. Am Heart J 158:335–341.e.3Google Scholar
  78. 78.
    Kogushi M, Kobayashi H, Matsuoka T, Suzuki S, Kawahara T, Kajiwara A, Hishinuma I (2003) Anti-thrombotic and bleeding time effects of E5555, an orally active protease-activated receptor-1 antagonist, in guinea pigs. Circulation 108 (Suppl IV):IV-280. Abstract 1327Google Scholar
  79. 79.
    Serebruany VL, Kogushi M, Dastros-Pitei D, Flather M, Bhatt DL (2009) The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease. Thromb Haemost 102:111–119PubMedGoogle Scholar
  80. 80.
    A Double-Blind Study of E5555 in Japanese Patients With Acute Coronary Syndrome (2009) NCT00619164. Accessed February 17, 2009
  81. 81.
    A Double-Blind Study of E5555 in Japanese Subjects With Coronary Artery Disease (2009) NCT00540670. Accessed February 17, 2009
  82. 82.
    Safety and Tolerability of E5555 and Its Effects on Markers of Intravascular Inflammation in Subjects With Acute Coronary Syndrome (2010) NCT00548587. Accessed March 2010
  83. 83.
    Safety and Tolerability of E5555 and Its Effects on Markers of Intravascular Inflammation in Subjects With Coronary Artery Disease (2010) NCT00312052. Accessed March 2010

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Internal Medicine IIIUniversity Hospital FreiburgFreiburgGermany

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