Skip to main content
SpringerLink
Log in

Promises of PAR-1 Inhibition in Acute Coronary Syndrome

  • New Therapies for Cardiovascular Disease (KW Mahaffey, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Platelet activation is a key process in the pathogenesis of acute coronary syndromes (ACS). Of the many triggers involved in this process, three are presumed to be critical: thromboxane A2 (TBXA2) via the TBXA2 receptor, adenosine diphosphate via the P2Y12 receptor, and thrombin via the protease-activated receptor (PAR)-1. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y12 inhibitors, the incidence of recurrent ischemic events remains high after ACS. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preclinical data and phase 2 clinical trials in patients with stable and unstable coronary disease support the potential of these compounds to improve clinical outcome. In this review we discuss the rationale for developing this novel class of agents with a focus on the two compounds in most advanced clinical development, vorapaxar (SCH 530348) and atopaxar (E5555).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CURE:

Clopidogrel in Unstable Angina to Prevent Recurrent Events

LANCELOT:

Lessons from Antagonizing the Cellular Effects of Thrombin Acute Coronary Syndromes

TRA 2 P:

Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50

TRA•CER:

Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome

TRA-PCI:

Thrombin Receptor Antagonist-Percutaneous Coronary Intervention

TRITON-TIMI 38:

Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Naghavi M, Libby P, Falk E, et al. From Vulnerable Plaque to Vulnerable Patient. Circulation. 2003;108:1664–72.

    Article  PubMed  Google Scholar 

  2. • Fuster V, Sweeny JM. Aspirin. Circulation 2011;123:768–78. This is an excellent review on the most widely used antiplatelet agent, aspirin.

    Article  PubMed  Google Scholar 

  3. Thebault JJBC, Blanchard JF, Panak EA. Effects of ticlopidine, a new platelet aggregation inhibitor in man. Clin Pharmacol Ther. 1975;18:485–90.

    PubMed  CAS  Google Scholar 

  4. The 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. 2001;345:494–502.

    Article  Google Scholar 

  5. Mehta SR, Yusuf S, Peters RJG, 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.

    Article  PubMed  CAS  Google Scholar 

  6. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. JAMA. 2002;288:2411–20.

    Article  PubMed  CAS  Google Scholar 

  7. 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.

    Article  PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Leonardi S, Rao SV, Harrington RA, et al. Rationale and design of the randomized, double-blind trial testing INtraveNous and oral administration of elinogrel, a selective and reversible P2Y12-receptor inhibitor, versus clopidogrel to eVAluate tolerability and efficacy in nonurgent percutaneous coronary interventions patients (INNOVATE-PCI). Am Heart J. 2010;160:65–72.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Eikelboom JW, Weitz JI, Budaj A, et al. Clopidogrel does not suppress blood markers of coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary syndromes. Eur Heart J. 2002;23:1771–9.

    Article  PubMed  CAS  Google Scholar 

  14. Hamilton JR, Cornelissen I, Coughlin SR. Impaired hemostasis and protection against thrombosis in protease-activated receptor 4-deficient mice is due to lack of thrombin signaling in platelets. J Thromb Haemost. 2004;2:1429–35.

    Article  PubMed  CAS  Google Scholar 

  15. Chintala MVS, Kurowski S, Sabin C, Reynolds D, Prevete K, Friedrichs G. SCH 530348, a novel oral antiplatelet agent, demonstrated no bleeding risk alone or in combination with aspirin and clopidogrel in cynomolgus monkeys. Atheroscler Thromb Vasc Biol. 2008;28:e32–e149. Abstract P579.

    Article  Google Scholar 

  16. • Gurbel PA, Tantry US. Combination Antithrombotic Therapies. Circulation 2010;121:569–83. This is an important review on the rationale of combining antiplatelet agents and their applications.

    Article  PubMed  Google Scholar 

  17. Chintala M, Strony J, Yang B, Kurowski S, Li Q. SCH 602539, a protease-activated receptor-1 antagonist, inhibits thrombosis alone and in combination with cangrelor in a folts model of arterial thrombosis in cynomolgus monkeys. Arterioscler Thromb Vasc Biol. 2010;30:2143–9.

    Article  PubMed  CAS  Google Scholar 

  18. Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482–94.

    Article  PubMed  Google Scholar 

  19. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407:258–64.

    Article  PubMed  CAS  Google Scholar 

  20. 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;103:879–87.

    Article  PubMed  CAS  Google Scholar 

  21. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet. 2009;373:919–28.

    Article  PubMed  CAS  Google Scholar 

  22. Ghosal A, Lu X, Penner N, et al. Identification of human liver cytochrome p450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist. Drug Metab Dispos. 2011;39:30–8.

    Article  PubMed  CAS  Google Scholar 

  23. Doc ID 3303095. SCH 530348: influence of chronic renal disease and hemodialysis on the single-dose pharmacokinetics and pharmacodynamics of SCH 530348 [study report for protocol P03464]. Kenilworth (NJ): Schering-Plough Research Institute. 2005.

  24. Goto SYT, Ikeda Y, Kato K, Yamaguchi H, Jensen P. 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. 2010;17:156–64.

    Article  PubMed  CAS  Google Scholar 

  25. Shinohara Y, Goto S, Doi M, Jensen P. Safety of the Novel Protease-Activated Receptor-1 Antagonist Vorapaxar in Japanese Patients with a History of Ischemic Stroke. Journal of Stroke and Cerebrovascular Diseases;In Press, Corrected Proof.

  26. The TRACER. Executive steering C. The thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA-CER) trial: study design and rationale. Am Heart J. 2009;158:327–34.

    Article  Google Scholar 

  27. Morrow DA, Scirica BM, Fox KAA, et al. 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°P)-TIMI 50 trial. Am Heart J. 2009;158:335–341.e3.

    Article  PubMed  CAS  Google Scholar 

  28. Kogushi M, Matsuoka T, Kawata T, et al. The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs. Eur J Pharmacol. 2011;657:131–7.

    Article  PubMed  CAS  Google Scholar 

  29. Kogushi M, Matsuoka T, Kuramochi H, et al. Oral administration of the thrombin receptor antagonist E5555 (atopaxar) attenuates intimal thickening following balloon injury in rats. Eur J Pharmacol. 2011;666:158–64.

    Article  PubMed  CAS  Google Scholar 

  30. Serebruany VL KM, Dastros-Pitei D, Flather M, Bhatt DL. he 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. 2009;102:111–9.

    PubMed  Google Scholar 

  31. Tello-Montoliu A, Tomasello SD, Ueno M, Angiolillo DJ. Antiplatelet therapy: thrombin receptor antagonists. Br J Clin Pharmacol. 2011;72:658–71.

    Article  PubMed  CAS  Google Scholar 

  32. Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur Heart J. 2010;3:2601–13.

    Article  Google Scholar 

  33. O’Donoghue ML, Bhatt DL, Wiviott SD, et al. Safety and tolerability of atopaxar in the treatment of patients with acute cronary syndromes/clinical perspective. Circulation. 2011;123:1843–53.

    Article  PubMed  Google Scholar 

  34. Wiviott SD, Flather MD, O’Donoghue ML, et al. Randomized trial of atopaxar in the treatment of patients with coronary artery disease/clinical perspective. Circulation. 2011;123:1854–63.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Conflicts of interest: S. Leonardi: none; P. Tricoci: has been a consultant for Merck; and has received grant support from Merck through the Duke Clinical Research Institute; K.W. Mahaffey: has been a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers, Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Ortho-McNeil, Pfizer, Polymedix, Sanofi-Aventis, and Schering-Plough; and has received grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers, Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Portola, Pozen, Regado Biotechnologies, Sanofi-Aventis, Schering-Plough, and The Medicines Company.

Author information

Authors and Affiliations

  1. Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Room 0311 Terrace Level, Durham, NC, 27705, USA

    Sergio Leonardi, Pierluigi Tricoci & Kenneth W. Mahaffey

  2. Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Sergio Leonardi

Authors
  1. Sergio Leonardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierluigi Tricoci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth W. Mahaffey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth W. Mahaffey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leonardi, S., Tricoci, P. & Mahaffey, K.W. Promises of PAR-1 Inhibition in Acute Coronary Syndrome. Curr Cardiol Rep 14, 32–39 (2012). https://doi.org/10.1007/s11886-011-0232-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-011-0232-z

Keywords

Search

Navigation