Transcript Prasugrel in all ACS Patients!

Novel antithrombotic agents
in acute coronary syndromes:
better or worse than P2Y12
inhibitors
Giuseppe Biondi Zoccai
Sapienza Università di Roma
[email protected]
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
Anticoagulants
PAR inhibitors
<- Aspirin
P2Y12
inhibitors
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
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
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
Death, MI, stroke, TVR, or ST (%)
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 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
Cardiovascular death, MI or stroke
Non-CABG-related TIMI major bleeding
Wiviott et al, New Engl J Med 2008
The TRILOGY ACS trial
Endpoint (%)
CV death, MI,
or stroke
HR=0.91 (0.79-1.05), p=0.21
Wiviott et al, Circulation 2008
The TRILOGY ACS trial
Endpoint (%)
CV death, MI,
or stroke
HR=0.91 (0.79-1.05), p=0.21
Wiviott et al, Circulation 2008
Ticagrelor
• Oral drug
• Reversibly antagonizes the
P2Y12 platelet receptor
for ADP
• Thus limits P2Y12mediated platelet
activation and
aggregation
• Does not impact on other
activation pathways
The PLATO trial
Vascular death, MI or stroke
Major bleeding
Months
Months
Wallentin et al, New Engl J Med 2009
Benefits across the board
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
901 (10.2)
1,065 (12.3)
0.84 (0.77–0.92)
<0.001
1,290 (14.6) 1,456 (16.7)
0.88 (0.81–0.95)
<0.001
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Myocardial infarction
504 (5.8)
593 (6.9)
0.84 (0.75–0.95)
0.005
CV death
353 (4.0)
442 (5.1)
0.79 (0.69–0.91)
0.001
Stroke
125 (1.5)
106 (1.3)
1.17 (0.91–1.52)
0.22
Total death
399 (4.5)
506 (5.9)
0.78 (0.69–0.89)
<0.001
Wallentin et al, New Engl J Med 2009
Benefits across the board
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
901 (10.2)
1,065 (12.3)
0.84 (0.77–0.92)
<0.001
1,290 (14.6) 1,456 (16.7)
0.88 (0.81–0.95)
<0.001
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Myocardial infarction
504 (5.8)
593 (6.9)
0.84 (0.75–0.95)
0.005
CV death
353 (4.0)
442 (5.1)
0.79 (0.69–0.91)
0.001
Stroke
125 (1.5)
106 (1.3)
1.17 (0.91–1.52)
0.22
Total death
399 (4.5)
506 (5.9)
0.78 (0.69–0.89)
<0.001
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 thrombinmediated 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 thrombinmediated platelet activation
and aggregation
The TRACER trial
Cardiovascular death, MI or stroke
GUSTO moderate/severe bleeding
Months
Months
Tricoci et al, New Engl J Med 2012
The TRACER trial
Cardiovascular 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
Stent thrombosis (%)
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)
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 thrombosispulmonary embolism
The APPRAISE-2 trial
81% on DAPT
Alexander et al, New Engl J Med 2011
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 riskbenefit profile
already established
in atrial fibrillation
and deep vein
thrombosispulmonary embolism
The RE-DEEM trial
99.2% on DAPT
Oldgren et al, Eur Heart J 2011
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 thrombosispulmonary embolism
The ATLAS ACS 2-TIMI 51 trial
93% on DAPT
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
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 WOESTlike 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
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