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. Learning goals State-of-the-art antithrombotic therapy in acute coronary syndromes (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 <- Aspirin <- PAR inhibitors <- P2Y12 inhibitors <- Anticoagulants IIb/IIIa inhibitors Jackson et al, Nat Rev Drug Discov 2003

4. The past

5. Aspirin Oral drug 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. Oral drug 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 Aspirin

7. Clopidogrel Oral drug Irreversibly inactivates the P2Y12 platelet receptor for ADP Limits P2Y12-mediated platelet activation and aggregation Does not impact on other activation pathways and has variable response

8. Clopidogrel Oral drug Irreversibly inactivates the P2Y12 platelet receptor for ADP Limits P2Y12-mediated platelet activation and aggregation Does not impact on other activation pathways and has variable response

9. Warfarin Oral anticoagulant Inhibits the synthesis of factors II, VII, IX, and X, as well as protein C, S, and Has very limited therapeutic index and requires frequent monitoring and adjustments

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

11. The WOEST trial Dewilde et al, Lancet 2013

12. The WOEST trial Dewilde et al, Lancet 2013

13. The WOEST trial Dewilde et al, Lancet 2013

14. The present

15. Prasugrel Oral drug Irreversibly inactivates the P2Y12 platelet receptor for ADP (more potently and predictably than clopidogrel) Limits P2Y12-mediated platelet activation and aggregation Does not impact on other activation pathways

16. The TRITON-TIMI 38 trial Wiviott et al, New Engl J Med 2008 Cardiovascular death, MI or stroke Non-CABG-related TIMI major bleeding

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

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

19. Ticagrelor Oral drug Reversibly antagonizes the P2Y12 platelet receptor for ADP Thus limits P2Y12- mediated platelet activation and aggregation Does not impact on other activation pathways

20. The PLATO trial Vascular death, MI or strokeMajor bleeding Months Wallentin et al, New Engl J Med 2009

21. Benefits across the board Wallentin et al, New Engl J Med 2009

22. Benefits across the board Wallentin et al, New Engl J Med 2009

23. Adjusted indirect comparison Biondi-Zoccai et al, Int J Cardiol 2011

24. The future

25. Atopaxar Oral drug Reversibly inhibits the protease-activated receptor (PAR)-1 which binds thrombin on platelets Thus limits thrombin- mediated platelet activation and aggregation

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

27. The LANCELOT trial Wiviott et al, Circulation 2011

28. The LANCELOT trial Wiviott et al, Circulation 2011

29. Vorapaxar Oral drug Reversibly inhibits the protease-activated receptor (PAR)-1 which binds thrombin on platelets Thus limits thrombin- mediated platelet activation and aggregation

30. The TRACER trial Cardiovascular death, MI or strokeGUSTO moderate/severe bleeding Months Tricoci et al, New Engl J Med 2012

31. The TRACER trial Cardiovascular death, MI or strokeGUSTO moderate/severe bleeding Months Tricoci et al, New Engl J Med 2012

32. Cangrelor IV drug Reversibly antagonizes the P2Y12 platelet receptor for ADP Thus limits P2Y12-mediated platelet activation and aggregation Does not impact on other activation pathways

33. The CHAMPION PHOENIX trial Stent thrombosis (%) Bhatt et al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI )

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

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

36. Apixaban Oral anticoagulant Factor Xa inhibitor Favorable risk-benefit profile already established in atrial fibrillation and deep vein thrombosis- pulmonary embolism

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

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 Oral anticoagulant Direct thrombin inhibitor Favorable risk- benefit profile already established in atrial fibrillation and deep vein thrombosis- pulmonary embolism

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

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

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

44. Rivaroxaban Oral anticoagulant Factor Xa inhibitor Favorable risk-benefit profile already established in atrial fibrillation and deep vein thrombosis- pulmonary embolism

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

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 will resemble in a few years the treatment of hypertension, with many available drugs and dozens of possible cocktails. Aspirin remains the background therapy of choice for its cost-effectiveness (and potential antineoplastic effects). Clopidogrel continues to be useful in those at low thrombotic risk or high bleeding risk. Prasugrel and ticagrelor are useful in all those without high bleeding risk, especially if at high thrombotic risk.

51. Take home messages Atopaxar, vorapaxar and cangrelor may have some favorable features in carefully selected patients, but the evidence base is still incomplete. Apixaban and dabigatran do not seem beneficial on top of dual antiplatelet therapy. Conversely, rivaroxaban may appear beneficial even within a triple therapy regimen, as long as bleeding risk is not high, with a 2.5 mg bid regimen possibly reducing mortality. Only further trials will clarify whether a WOEST- like dual-agent new-generation P2Y12-factor Xa inhibitor combo (e.g. ticagrelor plus rivaroxaban) may be the best possible option.

52. Many thanks for your attention For these slides and further ones on similar topics feel free to visit: www.metcardio.org/slides.html For additional details or queries feel free to contact me directly: giuseppe.biondizoccai@uniroma1.it