XII Curso de Formación Continuada
Nuevos antiagregantes
plaquetarios
26-28 marzo 2014
Hotel El Montanyà. Seva, Barcelona
¿Sigue siendo importante el
pretratamiento
con los nuevos
antiagregantes plaquetarios?
Concepto de pretratamiento en SCA
SCACEST
AAS
SCASEST
?
P2Y12 antg.
ICP1ª
ICP
Cirugía
Tto.
médico
Clopidogrel pretreatment and early risk
No pretreatment
Pretreatment
30-day death, MI & urg. TVR (%)
PCI-CURE
p=0.01
300 mg + 75 mg for
median of 10 days
CREDO
p=0.05
300 mg
<6 hrs
6–24 hrs
Clopidogrel: ¿Cúal es la dosis óptima?
100
Activación GPIIb/IIIa (ADP2M)
300 mg ( n=20)
p<0.0001
600 mg ( n=20)
% Cel. positivas
80
p=0.009
p=0.005
60
40
p=0.001 (MANOVA)
20
0
Basal
4h
24h
48h PostACTP
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. Eur Heart J 2004;25(21):1903-10
ARMYDA-5 PRELOAD: Study design
30 days
• Stable angina
or
• NSTE-ACS
undergoing
coronary
angiography
Randomization
536 Patients with
Clopidogrel
600 mg given
4-8 hrs
before angio
N= 267
Medical Rx
N= 72
N= 409
PCI 600 mg
Preload
N= 204
Angiography
Clopidogrel
600 mg at
the time
of PCI
N= 269
PCI 600 mg
in-lab
N= 205
CABG
N= 55
1st blood sample
Baseline
Primary
end point:
cardiac death,
MI, TVR
2nd, 3rd, 4th and 5th blood samples
At the time
of PCI
2 hrs
8 and 24 hrs
after PCI
after PCI
• CKa-MB
• Troponin-I
• PRU
• PRU • PRU • CK-MB
• Troponin-I
• PRU
Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557
ARMYDA-5 PRELOAD: Primary endpoint
Adverse events at 30 days
(Clopidogrel in-lab load vs preload)
Cumulative incidence of MACE (%)
In-lab load
Preload
20
16
p=0.72
12
8
4
0
5
10
15
20
Days after PCI
Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557
25
30
ARMYDA-5 PRELOAD:
Safety secondary end point
20
16
p=0.42
12
7.8
8
5.4
4
0
0
0
Major
bleeding
Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557
Minor
bleeding
In-lab load
Preload
New P2Y12 Antagonists
Early onset and high inhibition
Loading dose
•
•
•
•
Inhibition of platelet aggregation (%)
• Pre-treatment
with aspirin and a P2Y12 antagonist is
100
*
*
*
a class I recommendation and is common practice
80
for the treatment of NSTE-ACS
60
In CURE, patients were managed conservatively
40
In TRITON,
patients were not pretreated before cath
In PLATO,20patients were pretreated before cath
No trial had0 ever randomized patients presenting
0
0.25
0.5
1
2
4
6 24
with NSTE-ACS,
invasively
managed,
to preTime after loading dose (hrs)
treatment with clopidogrel,
prasugrel or ticagrelor vs.
1. Wiviott SD et al. Am Heart J. 2006;152:627-635.
no pre-treatment …… ACCOAST
2. Payne CD et al. Am J Cardiol. 2006;98:S8.
LD, Loading dose
*
*
Pras 60 mg LD
†
†
†
†p<0.001
!
*
p<0.001 vs. Clop 300 mg
or 600 mg LD*
vs. Clop 300 mg
Clop 600 mg LD
!p<0.05
!
Clop 300 mg LD
mean ± SEM
20 μM ADP
vs. Clop 300 mg
ACCOAST design
NSTEMI + Troponin ≥ 1.5 times ULN local lab value
Clopidogrel naive or on long term clopidogrel 75 mg
Randomize 1:1
n~4100 (event driven)
Double-blind
CABG
or
Medical
Management
(no more prasugrel)
Prasugrel 30 mg
Placebo
Coronary
Angiography
Coronary
Angiography
Prasugrel 30 mg
Prasugrel 60 mg
PCI
PCI
CABG
or
Medical
Management
(no prasugrel)
Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days
1° Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa inh. Bailout, at 7 days
Montalescot G et al. Am Heart J 2011;161:650-656
Pharmacodynamic Sub-Study
350
Placebo
LD1
Pre-treatment (30/30)
No Pre-treatment (0/60)
60 mg
LD2
*P<0.05
P2Y12 Reaction Units
300
250
Approximate
time of PCI
200
150
100
30 mg
LD1
*
*
50
0
30 mg
LD2
Pre LD1 Pre LD2
(baseline)
0.5
1
2
3
Hours (post LD2)
Data presented as median ± SEM. * p<0.05 relative to the No pre-treatment group. LD = loading dose.
Pretreatment=Prasugrel 30 mg/Prasugrel 30 mg; No Pre-treatment=Placebo/Prasugrel 60 mg
4
24
1° Efficacy End Point @ 7 + 30 days
(All Patients)
15
CV Death, MI, Stroke,
UR, GPIIb/IIIa Bailout
Pre-treatment
10.8
Endpoint (%)
Pre-treatment
10.0
10
No Pre-treatment
10.8
No Pre-treatment
9.8
5
Hazard Ratio, 1.02
(95% 0.84, 1.25)
P=0.81
Hazard Ratio, 0.997
(95% 0.83, 1.20)
P=0.98
0
0
No. at Risk, Primary
Efficacy End Point:
No pre-treatment
Pre-treatment
5
10
15
20
25
30
1752
1791
1621
1616
Days From First Dose
1996
2037
1788
1821
1775
1809
1769
1802
1762
1797
All TIMI (CABG or non-CABG) Major Bleeding
(All Treated patients)
5
Hazard Ratio, 1.90
(95% 1.19, 3.02)
P=0.006
Hazard Ratio, 1.97
(95% 1.26, 3.08)
P=0.002
Endpoint (%)
4
Pre-treatment
2.9
3
Pre-treatment
2.6
2
All TIMI Major Bleeding
1
No Pre-treatment
1.5
0
No Pre-treatment
1.4
0
No. at Risk, All TIMI
Major Bleeding:
No pre-treatment
Pre-treatment
5
10
15
20
25
30
1284
1297
1263
1280
Days From First Dose
1996
2037
1947
1972
1328
1339
1297
1310
1288
1299
All TIMI Major Bleeding for Prespecified
Subgroups Through 7 days (All Treated Patients)
Total
Patients
Pre-tx
(%)
No Pre-tx
(%)
Overall (pre-treatment vs. no pre-treatment)
Age
Hazard Ratio Interaction
(95% CI)
P-value†
4033
52 (2.55)
27 (1.35)
1.90 (1.19, 3.02)
PCI
CABG
Medical Management*
2781
238
1014
22 (1.57) 11 (0.80)
25 (20.66) 16 (13.68)
5 (0.97)
0 (0.00)
1.98 (0.96, 4.09)
1.59 (0.85, 2.98)
NE
0.74
<75 years
>75 years
3318
715
36 (2.16)
16 (4.29)
22 (1.33)
5 (1.46)
1.64 (0.96, 2.78)
2.95 (1.08, 8.05)
0.31
2923
1110
31 (2.09)
21 (3.80)
21 (1.46)
6 (1.08)
1.43 (0.82, 2.49)
3.61 (1.46, 8.95)
0.09
205
3824
5 (4.85)
47 (2.43)
1 (0.98)
26 (1.37)
NE
1.78 (1.10, 2.87)
0.35
820
3213
6 (1.45)
46 (2.83)
6 (1.47)
21 (1.32)
0.98 (0.32, 3.05)
2.16 (1.29, 3.62)
0.22
1990
2008
28 (2.75)
24 (2.40)
18 (1.86)
9 (0.89)
1.50 (0.83, 2.71)
2.70 (1.25, 5.80)
0.23
1998
2003
27 (2.72)
24 (2.35)
12 (1.20)
15 (1.53)
2.28 (1.16, 4.51)
1.54 (0.81, 2.93)
0.41
2051
1789
23 (2.23)
27 (2.97)
10 (0.98) 2.29 (1.09, 4.81)
15 (1.71) 1.75 (0.93, 3.28)
0.59
3079
852
34 (2.22)
16 (3.54)
18 (1.16)
8 (2.00)
1.92 (1.09, 3.41)
1.76 (0.75, 4.12)
0.87
2276
1711
29 (2.54)
22 (2.53)
18 (1.58)
8 (0.95)
1.62 (0.90, 2.91)
2.67 (1.19, 6.00)
0.66
1692
2341
14 (1.62)
38 (3.24)
5 (0.60)
22 (1.89)
2.69 (0.97, 7.47)
1.74 (1.03, 2.94)
0.46
Sex
Male
Female
Weight
<60 kg*
>60 kg
Diabetes
Yes
No
Time from Sx to LD
<median
>median
Time from first LD to angio/PCI
<median
>median
CRUSADE score‡
<median
>median
GRACE score
<140
>140
Access
Femoral
Radial
Region
Eastern Europe/Israel
Western Europe/Canada
0.2
0.5
Pre-treatment better
1
2
5
10
15
No pre-treatment better
*Hazard ratio not evaluated for <10 events.
†Interaction p-value is from a Cox proportional hazards model with treatment, subgroup, and the treatment-by-subgroup interaction as fixed
effects; ‡CRUSADE score is a post-hoc analysis; PCI includes 11 patients with PCI + CABG.
Pretratamiento en SCASCEST: preguntas
 ¿Existe evidencia del beneficio del pretatamiento con
clopidogrel?
 ¿Necesitan todos los pacientes pretratamiento?
 Con los nuevos antiagregantes, ¿es importante el
pretratamiento?
 ¿Es igual con prasugrel que con tricagrelor?
 ¿Influye la precocidad en realizar la coronariografía?
 ¿ Dónde iniciar el tratamiento de los nuevos
antiagregantes?, ¿ambulancia?, ¿urgencias?, ¿lab.
hemodinámica?