novel antithrombotic agents in acute coronary syndromes: better or worse than p2y12 inhibitors...
TRANSCRIPT
Novel antithrombotic agents in acute coronary syndromes: better or worse than P2Y12
inhibitors
Giuseppe Biondi Zoccai
Sapienza Università di [email protected]
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
The platelet: our common foe<- Aspirin
<-
<-
PAR inhibitors
<-
P2Y12inhibitors
<-Anticoagulants
IIb/IIIainhibitors
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 trialD
eath
, MI,
stro
ke, T
VR, o
r 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
Endp
oint
(%)
HR=0.91 (0.79-1.05), p=0.21
CV death, MI, or stroke
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
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 trialVascular death, MI or stroke Major bleeding
Months Months
Wallentin et al, New Engl J Med 2009
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
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
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 trialCardiovascular death, MI or stroke GUSTO moderate/severe bleeding
Months Months
Tricoci et al, New Engl J Med 2012
The TRACER trialCardiovascular death, MI or stroke GUSTO moderate/severe bleeding
Months 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 trialSt
ent t
hrom
bosi
s (%
)
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 2011
81% 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 2011
99.2% 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 2012
93% 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.
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: