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
1. Adhesion
2. Activation
3. Aggregation
Resting platelet
The Role of Platelets in AtherothrombosisThe Role of Platelets in Atherothrombosis
The Role of Platelets in AtherothrombosisThe Role of Platelets in Atherothrombosis
Coagulation cascade
Molecular targets of antiplatelet agentsMolecular targets of antiplatelet agents
Michelson AD. Nature Reviews Drug Discovery 2010; 9:154-169
(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)
ISIS-2: Lancet 1988;2:349-60
Antiplatelet Trialists' Collaboration BMJ 1994;308: 81-106
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
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
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?
A future without ASA? A future without ASA?
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
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
Which drug after ASA?Which drug after ASA?
Clopidogrel Ticagrelor Prasugrel
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
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
Reduction of stent thrombosisReduction of stent thrombosis
Ferreiro JL and Angiolillo DJ. Circ Cardiovasc Intvn 2012; 2012;5:433-445
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
Average daily event rates after PPCI: HORIZONS AMIAverage daily event rates after PPCI: HORIZONS AMI
G. Stone. TCT 2013
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
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
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
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
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
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
Is there still a role for GPIs ? Is there still a role for GPIs ?
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
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
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
Valgimigli M et al, J Am Coll Cardiol Intv 2012;5:268–77
GPI bolus + prasugrel: FABOLUS PROGPI bolus + prasugrel: FABOLUS PRO
P for interaction = 0.0254
p = 0.03 p = 0.34
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
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
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
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
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.
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
Genereux P, et al. JACC 2013; in press
Insights from the CHAMPION PHOENIX
Impact of intra-procedural Stent ThrombosisImpact of intra-procedural Stent Thrombosis
Impact of intra-procedural Stent ThrombosisImpact of intra-procedural Stent Thrombosis
Genereux P, et al. JACC 2013; in press
Insights from the CHAMPION PHOENIX
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
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)