Novel antithrombotic agents in acute coronary syndromes: better or worse tha n P2Y12 inhibitors
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Transcript of Novel antithrombotic agents in acute coronary syndromes: better or worse tha n P2Y12 inhibitors
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Novel antithrombotic agents in acute coronary syndromes: better or worse than P2Y12
inhibitors
Giuseppe Biondi Zoccai
Sapienza Università di [email protected]
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Learning goals
State-of-the-art antithrombotic therapy in acutecoronary syndromes (ACS):• The past: aspirin, clopidogrel, and warfarin• The present: prasugrel and ticagrelor• The future: atopaxar, vorapaxar, cangrelor,
apixaban, dabigatran, and rivaroxaban
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The platelet: our common foe<- Aspirin
<-
<-
PAR inhibitors
<-
P2Y12inhibitors
<-Anticoagulants
IIb/IIIainhibitors
Jackson et al, Nat Rev Drug Discov 2003
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The past
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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
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• 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
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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
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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
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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
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The WOEST trialDe
ath,
MI,
stro
ke, T
VR, o
r ST
(%)
Dewilde et al, Lancet 2013
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The WOEST trial
Dewilde et al, Lancet 2013
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The WOEST trial
Dewilde et al, Lancet 2013
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The WOEST trial
Dewilde et al, Lancet 2013
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The present
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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
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The TRITON-TIMI 38 trial
Wiviott et al, New Engl J Med 2008
Cardiovascular death, MI or stroke
Non-CABG-related TIMI major bleeding
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The TRILOGY ACS trial
Wiviott et al, Circulation 2008
Endp
oint
(%)
HR=0.91 (0.79-1.05), p=0.21
CV death, MI, or stroke
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The TRILOGY ACS trial
Wiviott et al, Circulation 2008
Endp
oint
(%)
HR=0.91 (0.79-1.05), p=0.21
CV death, MI, or stroke
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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
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The PLATO trialVascular death, MI or stroke Major bleeding
Months Months
Wallentin et al, New Engl J Med 2009
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Benefits across the board
Wallentin et al, New Engl J Med 2009
All patients*Ticagrelor(n=9,333)
Clopidogrel(n=9,291)
HR for (95% CI) p value
Primary objective, n (%) CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001
Secondary objectives, n (%) Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events Myocardial infarction CV death Stroke
901 (10.2)
1,290 (14.6)
504 (5.8)353 (4.0)125 (1.5)
1,065 (12.3)
1,456 (16.7)
593 (6.9)442 (5.1)106 (1.3)
0.84 (0.77–0.92)
0.88 (0.81–0.95)
0.84 (0.75–0.95) 0.79 (0.69–0.91)1.17 (0.91–1.52)
<0.001
<0.001
0.005 0.001 0.22
Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001
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Benefits across the board
Wallentin et al, New Engl J Med 2009
All patients*Ticagrelor(n=9,333)
Clopidogrel(n=9,291)
HR for (95% CI) p value
Primary objective, n (%) CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001
Secondary objectives, n (%) Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events Myocardial infarction CV death Stroke
901 (10.2)
1,290 (14.6)
504 (5.8)353 (4.0)125 (1.5)
1,065 (12.3)
1,456 (16.7)
593 (6.9)442 (5.1)106 (1.3)
0.84 (0.77–0.92)
0.88 (0.81–0.95)
0.84 (0.75–0.95) 0.79 (0.69–0.91)1.17 (0.91–1.52)
<0.001
<0.001
0.005 0.001 0.22
Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001
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Adjusted indirect comparison
Biondi-Zoccai et al, Int J Cardiol 2011
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The future
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Atopaxar
• Oral drug• Reversibly inhibits the
protease-activated receptor (PAR)-1 which binds thrombin on platelets
• Thus limits thrombin-mediated platelet activation and aggregation
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The LANCELOT-ACS trial
O’Donoghue et al, Circulation 2011
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The LANCELOT trial
Wiviott et al, Circulation 2011
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The LANCELOT trial
Wiviott et al, Circulation 2011
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Vorapaxar
• Oral drug• Reversibly inhibits the
protease-activated receptor (PAR)-1 which binds thrombin on platelets
• Thus limits thrombin-mediated platelet activation and aggregation
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The TRACER trialCardiovascular death, MI or stroke GUSTO moderate/severe bleeding
Months Months
Tricoci et al, New Engl J Med 2012
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The TRACER trialCardiovascular death, MI or stroke GUSTO moderate/severe bleeding
Months Months
Tricoci et al, New Engl J Med 2012
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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
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The CHAMPION PHOENIX trialSt
ent t
hrom
bosis
(%)
Bhatt et al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI)
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The CHAMPION PHOENIX trial
Bhatt et al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI)
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The CHAMPION PHOENIX trial
Bhatt et al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI)
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Apixaban
• Oral anticoagulant• Factor Xa inhibitor• Favorable risk-benefit
profile already established in atrial fibrillation and deep vein thrombosis-pulmonary embolism
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The APPRAISE-2 trial
Alexander et al, New Engl J Med 2011
81% on DAPT
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The APPRAISE-2 trial
Alexander et al, New Engl J Med 2011
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The APPRAISE-2 trial
Alexander et al, New Engl J Med 2011
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Dabigatran• Oral anticoagulant• Direct thrombin
inhibitor • Favorable risk-benefit
profile already established in atrial fibrillation and deep vein thrombosis-pulmonary embolism
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The RE-DEEM trial
Oldgren et al, Eur Heart J 2011
99.2% on DAPT
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The RE-DEEM trial
Oldgren et al, Eur Heart J 2011
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The RE-DEEM trial
Oldgren et al, Eur Heart J 2011
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Rivaroxaban
• Oral anticoagulant• Factor Xa inhibitor• Favorable risk-benefit
profile already established in atrial fibrillation and deep vein thrombosis-pulmonary embolism
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The ATLAS ACS 2-TIMI 51 trial
Mega et al, New Engl J Med 2012
93% on DAPT
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The ATLAS ACS 2-TIMI 51 trial
Mega et al, New Engl J Med 2012
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The ATLAS ACS 2-TIMI 51 trial
Mega et al, New Engl J Med 2012
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The ATLAS ACS 2-TIMI 51 trial
Mega et al, New Engl J Med 2012
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The ATLAS ACS 2-TIMI 51 trial
Mega et al, New Engl J Med 2012
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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.
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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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Many thanks for your attention
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