Skip to main content
SpringerLink
Log in

State of the art of new P2Y12 antagonists

  • IM - Review
  • Published:
Internal and Emergency Medicine Aims and scope Submit manuscript

Abstract

The interaction of ADP with its platelet receptor P2Y12 plays a crucial role in platelet activation and thrombogenesis. This article reviews the pharmacology and clinical trials of specific antagonists of P2Y12. Clopidogrel is a thienopyridine with proven antithrombotic efficacy, but it has some important drawbacks: (a) it is a pro-drug that needs to be metabolized to its active metabolite; (b) it has a delayed onset and offset of action and (c) there is high inter-individual variability in pharmacological response. Prasugrel is also a thienopyridine, with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel, accounting for lower incidence of ischemic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and higher incidence of both non-CABG-related bleeding complications. Two direct and reversible P2Y12 antagonists, Cangrelor and ticagrelor, are characterized by rapid onset and reversal of platelet inhibition. Cangrelor is not superior to clopidogrel in preventing thrombotic events in patients undergoing PCI. Ticagrelor is superior to clopidogrel in preventing major adverse cardiac events in ACS patients, but, like prasugrel, is associated with a higher frequency of non-CABG-related bleeding complications. A shorter period of drug discontinuation before surgery is necessary in ticagrelor-treated patients compared to clopiodgrel-treated patients to limit the severity of post-surgical bleeding.

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
Fig. 3

Similar content being viewed by others

References

  1. Cattaneo M (2006) ADP receptors antagonists. In: Michelson AD (ed) Platelets. Academic Press, San Diego, pp 1127–1144

    Google Scholar 

  2. Cattaneo M, Lecchi A (2007) Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin. J Thromb Haemost 5:577–582

    Article  CAS  PubMed  Google Scholar 

  3. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV (2007) Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 154:221–231

    Article  CAS  PubMed  Google Scholar 

  4. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ (2007) Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 5:2429–2436

    Article  CAS  PubMed  Google Scholar 

  5. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108:2244–2247

    Article  CAS  PubMed  Google Scholar 

  6. Norgard NB, Mathews KD, Wall GC (2009) Drug-drug interaction between clopidogrel and the proton pump inhibitors. Ann Pharmacother 43:1266–1274

    Article  CAS  PubMed  Google Scholar 

  7. Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O, Simeoni MC, Barragan P, Dignat-George F, Paganelli F (2008) Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 51:1404–1411

    Article  CAS  PubMed  Google Scholar 

  8. Bonello L, Camoin-Jau L, Armero S, Com O, Arques S, Burignat-Bonello C, Giacomoni MP, Bonello R, Collet F, Rossi P, Barragan P, Dignat-George F, Paganelli F (2009) Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 103:5–10

    Article  CAS  PubMed  Google Scholar 

  9. Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA (2007) Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 115(6):708–716

    Article  CAS  PubMed  Google Scholar 

  10. Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT, Darstein C, Jakubowski JA, Salazar DE (2007) Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 81:735–741

    Article  CAS  PubMed  Google Scholar 

  11. 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) TRITON-TIMI 38 Investigators Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015

    Article  CAS  PubMed  Google Scholar 

  12. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Antman EM, Walker R, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362

    Article  CAS  PubMed  Google Scholar 

  13. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS (2009) Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 119:2553–2560

    Article  CAS  PubMed  Google Scholar 

  14. Ajani AE, Lefkovits J (2008) Approaching an age of reason with antiplatelet therapy. Lancet 371:1315–1316

    Article  PubMed  Google Scholar 

  15. Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA, Sugidachi A, Winters KJ, Siegbahn A (2008) 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 29:21–30

    Article  CAS  PubMed  Google Scholar 

  16. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, Asai F (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 5:1545–1551

    Article  CAS  PubMed  Google Scholar 

  17. Price M (2009) Bedside evaluation of thienopyridine antiplatelet therapy. Circulation 119:2625–2632

    Article  PubMed  Google Scholar 

  18. Sibbing D, Braun S, Morath T, Mehilli J, Vogt W, Schömig A, Kastrati A, von Beckerath N (2009) Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 53:849–856

    Article  CAS  PubMed  Google Scholar 

  19. van Giezen JJJ, Humphries RG (2005) Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Sem Thromb Hemost 31:195–204

    Article  Google Scholar 

  20. Jacobsson F, Swahn E, Wallentin L, Ellborg M (2002) Safety profile and tolerability of intravenous ARC69931MX, a new antiplatelet drug, in unstable angina pectoris and non-Q-wave myocardial infarction. Clin Ther 24:752–765

    Article  CAS  PubMed  Google Scholar 

  21. Greenbaum AB, Grines CL, Bittl JA, Becker RC, Kereiakes DJ, Gilchrist IC, Clegg J, Stankowski JE, Grogan DR, Harrington RA, Emanuelsson H, Weaver WD (2006) Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J 151:689.e1–689.e10

    Google Scholar 

  22. Storey RF, Wilcox RG, Heptinstall S (2002) Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets 13:407–413

    Article  CAS  PubMed  Google Scholar 

  23. Greenbaum AB, Ohman EM, Gibson CM, Borzak S, Stebbins AL, Lu M, Le May MR, Stankowski JE, Emanuelsson H, Weaver WD (2007) Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction STEP-AMI) angiographic trial. Am Heart J 154:702–709

    Article  CAS  PubMed  Google Scholar 

  24. Steinhubl SR, Oh JJ, Oestreich JH, Ferraris S, Charnigo R, Akers WS (2008) Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res 121:527–534

    Article  CAS  PubMed  Google Scholar 

  25. Harrington RA, Stone GW, McNulty S et al (2009) Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 361:2318–2329

    Article  CAS  PubMed  Google Scholar 

  26. Bhatt DL, Lincoff AM, Gibson CM et al (2009) Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 361:2330–2341

    Article  CAS  PubMed  Google Scholar 

  27. Husted S, van Giezen JJ (2009) Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 27(4):259–274

    Article  CAS  PubMed  Google Scholar 

  28. Nilsson L, van Giezen JJJ, Greasley PJ (2006) Evidence for distinct ligand binding sites on recombinant human P2Y12 receptors. Circulation 114:II_248–II_249 (abstract)

    Google Scholar 

  29. van Giezen JJ, Nilsson L, Berntsson P, Wissing BM, Giordanetto F, Tomlinson W, Greasley PJ (2009) Ticagrelor binds to the human P2Y receptor independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 7:1556–1565

    Article  Google Scholar 

  30. 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 27:1038–1047

    Article  CAS  PubMed  Google Scholar 

  31. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G (2007) Storey RF; 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 50:1844–1851

    Article  CAS  PubMed  Google Scholar 

  32. Serebruany VL, Stebbing J, Atar D (2007) Dyspnoea after antiplatelet agents: the AZD6140 controversy. Int J Clin Pract 61:529–533

    Article  CAS  PubMed  Google Scholar 

  33. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P, Cannon CP (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

    Article  CAS  PubMed  Google Scholar 

  34. James S, Akerblom A, Cannon CP, Emanuelsson H, Husted S, Katus H, Skene A, Steg PG, Storey RF, Harrington R, Becker R, Wallentin L (2009) Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 157:599–605

    Article  CAS  PubMed  Google Scholar 

  35. 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, PLATO Investigators (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057

    Article  CAS  PubMed  Google Scholar 

  36. Cattaneo M (2010) New P2Y12 inhibitors. Circulation 121:171–179

    Article  PubMed  Google Scholar 

  37. Gurbel PA, Bliden KP, Antonino MJ, Stephens G, Gretler DD, Jurek MM, Pakyz RE, Shuldiner AR, Conley PB, Tantry US (2009) The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to cyp 2c19*2 genotype: first experience in patients. J Thromb Haemost 8:43–53

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

M. Cattaneo received honoraria and consulting fees (<10,000$, total) from the following Companies: Lilly-Daiichi Sankyo, AstraZeneca, The Medicines Company.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Unità di Medicina III, Ospedale San Paolo, Dipartimento di Medicina, Chirurgia e Odonotoiatria, Università degli Studi di Milano, Via di Rudinì 8, 20142, Milan, Italy

    Marco Cattaneo & Gian Marco Podda

Authors
  1. Marco Cattaneo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gian Marco Podda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco Cattaneo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cattaneo, M., Podda, G.M. State of the art of new P2Y12 antagonists. Intern Emerg Med 5, 385–391 (2010). https://doi.org/10.1007/s11739-010-0363-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11739-010-0363-z

Keywords

Search

Navigation