geometrie variabili nella scelta della terapia ... · timing of administration with respect to...
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ALMA MATER STUDIORUM
UNIVERSITA’ DI BOLOGNA
Geometrie variabili nella scelta della
terapia antiaggregante nelle SCA
Francesco SaiaIstituto di Cardiologia – Università di Bologna
Policlinico S. Orsola – MalpighiBologna
Lucca, 28 Novembre 2013
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1. Adhesion
2. Activation
3. Aggregation
Resting platelet
The Role of Platelets in AtherothrombosisThe Role of Platelets in Atherothrombosis
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The Role of Platelets in AtherothrombosisThe Role of Platelets in Atherothrombosis
Coagulation cascade
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Molecular targets of antiplatelet agentsMolecular targets of antiplatelet agents
Michelson AD. Nature Reviews Drug Discovery 2010; 9:154-169
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(Incomplete) List of hot topics on antiplatelet Rx(Incomplete) List of hot topics on antiplatelet Rx
� Type of agent, characteristics, evidence for use (old and new drugs)
� Dosage (e.g. bolus dose for oral agents, GPI bolus vs. bolus+infusion)
� Way of administration (e.g. GPI i.c. vs i.v.)
� Combination of drugs (e.g. antiplatelet+anticoagulant)
� Timing of administration with respect to diagnosis (e.g. pre-treatment vs. no
pre-tx in ACS)
� Drug-drug interaction (e.g. clopidogrel and PPI)
� Length of prescription
� Tailored treatment:
� Baseline clinical parameters (e.g. high risk ACS, DM,coronary anatomy..)
� Treatment strategy (e.g. conservative vs. invasive)
� Laboratory parameters (e.g. bedside monitoring of on-treatment
antiplatelet reactivity and dose-adjustement)
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ISIS-2: Lancet 1988;2:349-60
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Antiplatelet Trialists' Collaboration BMJ 1994;308: 81-106
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High- vs. low-dose ASA in ACS: CURRENT OASIS 7High- vs. low-dose ASA in ACS: CURRENT OASIS 7
CURRENT-OASIS 7 Investigators. N EJM 2010; 363:930-42
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ASA
75-100 mg
ASA
300-325 mg
HR 95% CI P
CV Death/MI/Stroke
PCI (2N=17,232) 4.2 4.1 0.98 0.84-1.13 0.76
No PCI (2N=7855) 4.7 4.4 0.92 0.75-1.14 0.44
Overall (2N=25,087) 4.4 4.2 0.96 0.85-1.08 0.47
Stent Thrombosis 2.1 1.9 0.91 0.73-1.12 0.37
TIMI Major Bleed 1.03 0.97 0.94 0.73-1.21 0.71
CURRENT Major Bleed
2.3 2.3 0.99 0.84-1.17 0.90
CURRENT Severe Bleed
1.7 1.7 1.00 0.83-1.21 1.00
GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051
Primary Outcome and BleedingPrimary Outcome and Bleeding
CURRENT-OASIS 7 Investigators. N EJM 2010; 363:930-42
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Mahaffey KW, et al. Circulation 2010; 124: 544-54
Aspirin dose and ticagrelor: insights from PLATOAspirin dose and ticagrelor: insights from PLATO
• Median aspirin dose ≥300 mg/d 53.6% US vs. 1.7% in the rest of the world
• No similar observation with prasugrel � Drug-specific? Play of chance?
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A future without ASA? A future without ASA?
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New P2Y12 inhibitors vs. clopidogrelNew P2Y12 inhibitors vs. clopidogrel
Wiviott SD, et al. N Engl J Med 2007;357: 2001-15Wallentin L, et al. N Engl J Med 2009; 361: 1045-57
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Hamm CW et al. Eur Heart J. 2011;32:2999-3054
STEMI Guidelines 2012
NSTE-ACS Guidelines 2011
ESC GuidelinesESC Guidelines
Steg G, et al. Eur Heart J .2012;33, 2569–2619
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Which drug after ASA?Which drug after ASA?
Clopidogrel Ticagrelor Prasugrel
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Prasugrel in STEMI: TRITON-TIMI 38Prasugrel in STEMI: TRITON-TIMI 38
Montalescot G, et al. Lancet. 2009;373: 723-31
• Rapid efficacy
• 31% of the patients pre-treated
• No significative interaction between primary and secondary PCI
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Ticagrelor in STEMI: PLATOTicagrelor in STEMI: PLATO
Steg PG, et al. Circulation 2010;122:2131-41
• Delayed efficacy
• Worrisome findings on stroke
• Possible problems with AV blocks and interpretation of dyspnea
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Reduction of stent thrombosisReduction of stent thrombosis
Ferreiro JL and Angiolillo DJ. Circ Cardiovasc Intvn 2012; 2012;5:433-445
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The tradeoff between efficacy and bleeding is most favorable around day 12, exhibits a
gentle “plateau” through approximately day 30, and declines through day 80, as the
numbers of attributable bleeding events outpace the number of endpoint events
prevented
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Average daily event rates after PPCI: HORIZONS AMIAverage daily event rates after PPCI: HORIZONS AMI
G. Stone. TCT 2013
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Time of enrollment in PLATO and TRITONTime of enrollment in PLATO and TRITON
ACS Patient
UA/NSTEMI
Admission Initial Management
Angiography
Conservative strategy
Conservative strategy or
CABG
Enrollment Enrollment
PCI
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7.9
4.1
Clopidogrel
Ticagrelor
HR=0.52; 95% CI 0.32-0.85; p<0.001
Held C, et al. J Am Coll Cardiol 2011; 57:672–84
Ticagrelor in patients undergoing CABGTicagrelor in patients undergoing CABG
CV death
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Ticagrelor in patients undergoing CABGTicagrelor in patients undergoing CABG
Held C, et al. J Am Coll Cardiol 2011; 57:672–84
59,3
21,0
10,6
43,7
0,8
57,6
21,6
12,2
42,6
1,00,0
10,0
20,0
30,0
40,0
50,0
60,0
70,0
TIMI major
bleed
TIMI minor Gusto severe Life-threat Fatal bleed
Ticagrelor
Clopidogrel
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Ticagrelor in pts intended for non-invasive managem entTicagrelor in pts intended for non-invasive managem ent
James S, et al. BMJ. 2011 Jun 17;342:d3527
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Prasugrel in pre-treatment in ACS: ACCOASTPrasugrel in pre-treatment in ACS: ACCOAST
Montalescot G, et al. N Engl J Med 2013;369:999-1010.
Primary EP: CVD, MI, stroke, urg revasc, or GPI bailout
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Prasugrel in ACS pts without revascularizationPrasugrel in ACS pts without revascularization
Roe MT et al. N Engl J Med. 2012; 367:1297-309
Overall population
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Is there still a role for GPIs ? Is there still a role for GPIs ?
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Bivalirudin vs. Hep+GPI: EUROMAXBivalirudin vs. Hep+GPI: EUROMAX
Steg PG. N Engl J Med. 2013 Oct 30. [Epub ahead of print]
The primary endpoint is driven by bleeding as defin ed in the study
Bivalirudin (N=1089) Heparins with optional GPI (N=1109)
P value
Death 32 (2.9%) 34 (3.1%) 0.86
Bleedings 28 (2.6%) 67 (6.0%) <0.001
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Stent thrombosis in bivalirudin trials in STEMI Stent thrombosis in bivalirudin trials in STEMI
Steg PG. N Engl J Med. 2013 Oct 30. [Epub ahead of print]
p=0.09
p<0.001 p=0.02 P=0.007
Stone G. N Engl J Med. 2008; 358:2218-30
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Parodi G et al. J Am Coll Cardiol 2013; 61:1601–6
Prasugrel vs Ticagrelor in STEMI: RAPID-PCIPrasugrel vs Ticagrelor in STEMI: RAPID-PCI
After 2h around 50% of the patients have insufficient
platelet inhibition
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Valgimigli M et al, J Am Coll Cardiol Intv 2012;5:268–77
GPI bolus + prasugrel: FABOLUS PROGPI bolus + prasugrel: FABOLUS PRO
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P for interaction = 0.0254
p = 0.03 p = 0.34
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Visible thrombus: “Block and Bridge”Visible thrombus: “Block and Bridge”
Christ G, et al. Thrombosis Research 2013; in press
Abciximab bolus only
on top of
Clopidogrel 600 mg or Prasugrel 60 mg
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UFH/En+GPI vs bivalirudin: ACUITYUFH/En+GPI vs bivalirudin: ACUITY
11,7%
7,3%5,7%
3,0%
10,1%7,8%
Net clinicaloutcome
Ischemiccomposite
Major bleeding
30 d
ay e
vent
s (%
)
UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)
Primary endpoint (ITT)
PNI <0.0001PSup = 0.015
PNI = 0.011PSup = 0.32
PNI <0.0001PSup <0.0001
Stone G, et al. N Engl J Med 2006; 355 :2203-16
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Prognostic value of HTPR in the ISAR-REACT 4Prognostic value of HTPR in the ISAR-REACT 4
Sibbing, et al. J Am Coll Cardiol. 2012;60:369-77
OR 5.4; 95% CI 2.4-12.1P<0.0001
OR 1.4P=NS
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Immediate vs delayed PCI: ABOARDImmediate vs delayed PCI: ABOARD
0 20 40 60 80 100
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Troponin I (ng/mL)
Den
sity
in the immediate and delayed groups
immediate groupdelayed group
Primary EP: peak values of troponin I
Median, IQR
2.1 (0.3-7.1)1.7 (0.3-7.2)
p = 0.70
Montalescot G, et al. JAMA 2009; 302;9:947-954
All PCIs on abciximab
• A strategy of
immediate PCI is not
superior to a strategy
of early delayed PCI
• When immediate PCI
is required, full
antiplatelet treatment
may avoid the “early
hazard” related to the
procedure
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CI-37
Cangrelor– Parenteral administration
– Direct platelet P2Y12 receptor antagonist
– ATP analogue (MW=800 Daltons)
– T1/2 ≈ 3 to 6 minutes
– Offset ≈ 60 minutes
– Metabolism not dependent on renal or hepatic function
N N
N N
NH
SCF3
OHOH
OO
PO
O
PP
OO
OClCl
OO
O
S
4Na+
Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012;34:44-55.
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CI-38
Recovery time~60 minutes
dose 30ug/kg bolus + 4ug/kg/min infusion
Con
cent
ratio
n (n
g/m
L)
% P
late
let A
ggre
gatio
n (im
peda
nce)
Time (minutes)0
20
40
60
80
100
120
140
160
0
100
200
300
400
500
600
700
800
0 20 40 60 80 100 120 140 160
Platelet activity
Plasmaconcentration
infusion
bolus
Akers J Clin Pharmacol. 2010;50:27-35
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Genereux P, et al. JACC 2013; in press
Insights from the CHAMPION PHOENIX
Impact of intra-procedural Stent ThrombosisImpact of intra-procedural Stent Thrombosis
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Impact of intra-procedural Stent ThrombosisImpact of intra-procedural Stent Thrombosis
Genereux P, et al. JACC 2013; in press
Insights from the CHAMPION PHOENIX
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Bivalirudin - Cangrelor synergy to avoid early thrombotic hazard
Mortality for STEMI without
cardiogenic shock
Adapted from Capranzano et al. Expert Rev. Cardiovasc. Ther. 2012; 10:411.422
Cangrelor Infusion Stop
Cangrelor Infusion Start Prasugrel or Ticagrelor LD
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ConclusioniConclusioni� ASA low-dose (75-100 mg) after the acute phase in a ll patients
� GPIs (bolus-only) in selected STEMI patients (high- risk, early presenters)
and in high-risk NSTEMI patients not adequately pre -treated, associated
with strategies for bleeding risk reduction
� P2Y12 antagonists
� STEMI ���� Prasugrel (except previous CVA; caveat for weight<60 Kg and
age >75)
� NSTEMI ���� Ticagrelor
� Clopidogrel in patients at high-risk of bleeding (e .g. OAT, age and
multiple comorbidity, previous severe bleeding or a ctive bleeding etc..)
� When bivalirudin is used, more potent P2Y12 antagon ists should be
preferred over clopidogrel. Bridge with Cangrelor h olds a strong rationale
(but costs may be relevant)