Novel antithrombotic agents in acute coronary syndromes: better or worse than P2Y12 inhibitors Giuseppe Biondi Zoccai Sapienza Università di Roma

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

The platelet: our common foe <- Aspirin <- PAR inhibitors <- P2Y12 inhibitors <- Anticoagulants IIb/IIIa inhibitors Jackson et al, Nat Rev Drug Discov 2003

The past

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

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

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

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

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

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

The WOEST trial Dewilde et al, Lancet 2013

The WOEST trial Dewilde et al, Lancet 2013

The WOEST trial Dewilde et al, Lancet 2013

The present

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

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

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

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

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

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

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

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

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

The future

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

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

The LANCELOT trial Wiviott et al, Circulation 2011

The LANCELOT trial Wiviott et al, Circulation 2011

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

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

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

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

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

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

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

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

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

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

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

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

The RE-DEEM trial Oldgren et al, Eur Heart J % on DAPT

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

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

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

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

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

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

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

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

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.

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.

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