American Journal of Cardiology
Volume 103, Issue 3, Supplement , Pages 40A-51A , 2 February 2009

Advances in Antiplatelet Therapy: Agents in Clinical Development

  • Dominick J. Angiolillo, MD, PhD

      Affiliations

    • Division of Cardiology, University of Florida College of Medicine–Jacksonville, Jacksonville, Florida, USA
    • Corresponding Author InformationAddress for reprints: Dominick J. Angiolillo, MD, PhD, Division of Cardiology, University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209
    • ,
  • Deepak L. Bhatt, MD, MPH

      Affiliations

    • Veterans Affairs Boston Healthcare System, Brigham and Women's Hospital, Boston, Massachusetts, USA
    • ,
  • Paul A. Gurbel, MD

      Affiliations

    • Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Cardiac Catheterization Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    • ,
  • Lisa K. Jennings, PhD

      Affiliations

    • Vascular Biology Center of Excellence, Departments of Internal Medicine, Molecular Sciences and Surgery, and Biomedical Engineering, University of Memphis; and Tennessee–Arkansas–Mississippi (TAM) Cardiovascular Clinical Research Consortium, University of Tennessee Health Science Center, Memphis, Tennessee, USA

References 

  1. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost. 2000;84:891–896
  2. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502
  3. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Barrera-Ramirez C, Sabate M, et al Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res. 2005;115:101–108
  4. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49:1505–1516
  5. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908–2913
  6. Gurbel PA, Bliden KP. Durability of platelet inhibition by clopidogrel. Am J Cardiol. 2003;91:1123–1125
  7. Müller I, Besta F, Schulz C, Massberg S, Schönig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost. 2003;89:783–787
  8. 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;129:1439–1446
  9. Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA, et al. Prasugrel achieves greater and faster P2Y12 receptor-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
  10. Weerakkody GJ, Jakubowski JA, Brandt JT, Farid NA, Payne CD, Zhu J, 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;100:331–336
  11. Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos. 2006;34:600–607
  12. Farid NA, Smith RL, Gillespie TA, Rash TJ, Blair PE, Kurihara A, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos. 2007;35:1096–1104
  13. Niitsu Y, Jakubowski JA, Sugidachi A, Asai F. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost. 2005;31:184–194
  14. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, 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:e9–e16
  15. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, 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;5:1545–1551
  16. Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, 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;27:1166–1173
  17. Wiviott SD, Trenk D, Frelinger AL, O'Donoghue M, Neumann FJ, Michelson AD, 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;116:2923–2932
  18. Wiviott SD, Antman EM, Winters KJ, Weerakkody G, Murphy SA, Behounek BD, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation. 2005;111:3366–3373
  19. Wiviott SD, Antman EM, Gibson CM, Montalescot G, Riesmeyer J, Weerakkody G, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet Inhibition with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006;152:627–635
  20. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015
  21. Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, et al. 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. 2008;371:1353–1363
  22. Ingall AH, Dixon J, Bailey A, Coombs ME, Cox D, McInally JI, et al Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy. J Med Chem. 1999;42:213–220
  23. Wang K, Zhou X, Zhou Z, Tarakji K, Carneiro M, Penn MS, et al Blockade of the platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanalization and improves the myocardial tissue perfusion in a canine thrombosis model. Arterioscler Thromb Vasc Biol. 2003;23:357–362
  24. Storey RF, Judge HM, Wilcox RG, Heptinstall S. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin. Thromb Haemost. 2002;88:488–494
  25. Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol. 2000;110:925–934
  26. Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets. 2002;13:407–413
  27. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res. 2007;100:1261–1275
  28. Steinhubl SR, Oh JJ, Oestreich JH, Ferraris S, Nessel CC, Schwabe KD, et al. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res. 2007;121:527–534
  29. van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost. 2005;31:195–204
  30. 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;27:1038–1047
  31. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, et al. 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;50:1844–1851
  32. Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest. 1999;103:879–887
  33. Holinstat M, Voss B, Bilodeau ML, Hamm HE. Protease-activated receptors differentially regulate human platelet activation through a phosphatidic acid-dependent pathway. Mol Pharmacol. 2007;71:686–694
  34. Wu CC, Teng CM. Comparison of the effects of PAR1 antagonists, PAR4 antagonists, and their combinations on thrombin-induced human platelet activation. Eur J Pharmacol. 2006;546:142–147
  35. Keuren JF, Wielders SJ, Ulrichts H, Hackeng T, Heemskerk JW, Deckmyn H, et al. Synergistic effect of thrombin on collagen-induced platelet procoagulant activity is mediated through protease-activated receptor-1. Arterioscler Thromb Vasc Biol. 2005;25:1499–1505
  36. Colognato R, Slupsky JR, Jendrach M, Burysek L, Syrovets T, Simmet T. Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells. Blood. 2003;102:2645–2652
  37. Moliterno DJ, Becker RC, Jennings LK, Berman G, Yang B, Strony J, et al. Results of a multinational randomized, double-blind, placebo-controlled study of a novel thrombin receptor antagonist (SCH 530348) in percutaneous coronary intervention. [Abstract]. Last update: 2007 http://www.spectrumscience.com/assets/files/acc07/i2%20LBCT%20Sat%2012%20pm/Moliterno%20Abstract.pdfAccessed June 27, 2007.
  38. Jennings LK, Earhart A, Becker RC. Thrombin receptor antagonist (TRA; SCH530348) is a selective, potent inhibitor of PAR1 activity with predictable pharmacokinetics. [abstract] Circulation. 2007;116:674

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9149(08)02032-8

doi: 10.1016/j.amjcard.2008.11.023

American Journal of Cardiology
Volume 103, Issue 3, Supplement , Pages 40A-51A , 2 February 2009

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