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Novel antithrombotic agents in acute coronary syndromes: better or worse tha n P2Y12 inhibitors

Novel antithrombotic agents in acute coronary syndromes: better or worse tha n P2Y12 inhibitors. Giuseppe Biondi Zoccai Sapienza Università di Roma giuseppe.biondizoccai@uniroma1.it. Learning goals. State-of-the-art antithrombotic therapy in acute coronary syndromes (ACS):

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Novel antithrombotic agents in acute coronary syndromes: better or worse tha n P2Y12 inhibitors

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  1. Novel antithrombotic agents in acute coronary syndromes: better or worse than P2Y12 inhibitors Giuseppe Biondi Zoccai Sapienza Università di Roma giuseppe.biondizoccai@uniroma1.it

  2. Learninggoals State-of-the-artantithrombotictherapy in acute coronarysyndromes (ACS): • The past: aspirin, clopidogrel, and warfarin • The present: prasugrel and ticagrelor • The future: atopaxar, vorapaxar, cangrelor, apixaban, dabigatran, and rivaroxaban

  3. The platelet: our common foe PAR inhibitors Anticoagulants <- <- Aspirin <- P2Y12 inhibitors <- <- IIb/IIIa inhibitors Jackson et al, NatRevDrugDiscov 2003

  4. The past

  5. Aspirin • Oraldrug • Irreversibly inactivates cyclooxygenase • Inhibits production of thromboxane A2 (TXA) • Limits TXA-mediated platelet activation and aggregation • Does not impact on other activation pathways and has variable response

  6. Aspirin • Oraldrug • Irreversibly inactivates cyclooxygenase • Inhibits production of thromboxane A2 (TXA) • Limits TXA-mediated platelet activation and aggregation • Does not impact on other activation pathways and has variable response

  7. Clopidogrel • Oraldrug • Irreversiblyinactivates the P2Y12 plateletreceptorfor ADP • Limits P2Y12-mediated plateletactivation and aggregation • Does not impact on other activation pathways and has variable response

  8. Clopidogrel • Oraldrug • Irreversiblyinactivates the P2Y12 plateletreceptorfor ADP • Limits P2Y12-mediated plateletactivation and aggregation • Does not impact on other activation pathways and has variable response

  9. Warfarin • Oralanticoagulant • Inhibits the synthesisoffactors II, VII, IX, and X, aswellasprotein C, S, and • Hasverylimitedtherapeuticindex and requiresfrequentmonitoring and adjustments

  10. The WOEST trial Death, MI, stroke, TVR, or ST (%) Dewildeet al, Lancet 2013

  11. The WOEST trial Dewildeet al, Lancet 2013

  12. The WOEST trial Dewildeet al, Lancet 2013

  13. The WOEST trial Dewildeet al, Lancet 2013

  14. The present

  15. Prasugrel • Oraldrug • Irreversiblyinactivates the P2Y12 plateletreceptorfor ADP (more potently and predictablythan clopidogrel) • Limits P2Y12-mediated plateletactivation and aggregation • Does not impact on other activation pathways

  16. The TRITON-TIMI 38 trial Cardiovasculardeath, MI or stroke Non-CABG-related TIMI major bleeding Wiviottet al, New Engl J Med 2008

  17. The TRILOGY ACS trial CV death, MI, or stroke Endpoint (%) HR=0.91 (0.79-1.05), p=0.21 Wiviottet al, Circulation 2008

  18. The TRILOGY ACS trial CV death, MI, or stroke Endpoint (%) HR=0.91 (0.79-1.05), p=0.21 Wiviottet al, Circulation 2008

  19. Ticagrelor • Oraldrug • Reversiblyantagonizes the P2Y12 plateletreceptorfor ADP • Thuslimits P2Y12-mediated plateletactivation and aggregation • Does not impact on other activation pathways

  20. The PLATO trial Vasculardeath, MI or stroke Major bleeding Months Months Wallentinet al, New Engl J Med 2009

  21. Benefitsacross the board Wallentinet al, New Engl J Med 2009

  22. Benefitsacross the board Wallentinet al, New Engl J Med 2009

  23. Adjustedindirectcomparison Biondi-Zoccaiet al, Int J Cardiol 2011

  24. The future

  25. Atopaxar • Oraldrug • Reversiblyinhibits the protease-activatedreceptor (PAR)-1 whichbindsthrombin on platelets • Thuslimitsthrombin-mediatedplateletactivation and aggregation

  26. The LANCELOT-ACS trial O’Donoghueet al, Circulation 2011

  27. The LANCELOT trial Wiviottet al, Circulation 2011

  28. The LANCELOT trial Wiviottet al, Circulation 2011

  29. Vorapaxar • Oraldrug • Reversiblyinhibits the protease-activatedreceptor (PAR)-1 whichbindsthrombin on platelets • Thuslimitsthrombin-mediatedplateletactivation and aggregation

  30. The TRACER trial Cardiovasculardeath, MI or stroke GUSTO moderate/severe bleeding Months Months Tricociet al, New Engl J Med 2012

  31. The TRACER trial Cardiovasculardeath, MI or stroke GUSTO moderate/severe bleeding Months Months Tricociet al, New Engl J Med 2012

  32. Cangrelor • IV drug • Reversiblyantagonizes the P2Y12 platelet receptorfor ADP • Thuslimits P2Y12-mediated plateletactivation and aggregation • Does not impact on other activation pathways

  33. The CHAMPION PHOENIX trial Stentthrombosis (%) Bhattet al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI)

  34. The CHAMPION PHOENIX trial Bhattet al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI)

  35. The CHAMPION PHOENIX trial Bhattet al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI)

  36. Apixaban • Oralanticoagulant • FactorXainhibitor • Favorablerisk-benefitprofilealreadyestablished in atrialfibrillation and deepveinthrombosis-pulmonaryembolism

  37. The APPRAISE-2 trial 81% on DAPT Alexander et al, New Engl J Med 2011

  38. The APPRAISE-2 trial Alexander et al, New Engl J Med 2011

  39. The APPRAISE-2 trial Alexander et al, New Engl J Med 2011

  40. Dabigatran • Oralanticoagulant • Directthrombininhibitor • Favorablerisk-benefitprofilealreadyestablished in atrialfibrillation and deepveinthrombosis-pulmonaryembolism

  41. The RE-DEEM trial 99.2% on DAPT Oldgrenet al, Eur Heart J 2011

  42. The RE-DEEM trial Oldgrenet al, Eur Heart J 2011

  43. The RE-DEEM trial Oldgrenet al, Eur Heart J 2011

  44. Rivaroxaban • Oralanticoagulant • FactorXainhibitor • Favorablerisk-benefitprofilealreadyestablished in atrialfibrillation and deepveinthrombosis-pulmonaryembolism

  45. The ATLAS ACS 2-TIMI 51 trial 93% on DAPT Mega et al, New Engl J Med 2012

  46. The ATLAS ACS 2-TIMI 51 trial Mega et al, New Engl J Med 2012

  47. The ATLAS ACS 2-TIMI 51 trial Mega et al, New Engl J Med 2012

  48. The ATLAS ACS 2-TIMI 51 trial Mega et al, New Engl J Med 2012

  49. The ATLAS ACS 2-TIMI 51 trial Mega et al, New Engl J Med 2012

  50. Take home messages • Antithrombotic management of ACS willresemble in a fewyears the treatment ofhypertension, withmanyavailabledrugs and dozensofpossiblecocktails. • Aspirinremains the background therapyofchoiceforitscost-effectiveness (and potentialantineoplasticeffects). • Clopidogrel continuestobeuseful in those at low thromboticrisk or high bleedingrisk. • Prasugrel and ticagrelor are useful in allthosewithout high bleedingrisk, especiallyif at high thromboticrisk.

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