Nuevos antiagregantes Nuevos antiagregantes plaquetariosplaquetarios
XII Curso de Formación Continuada XII Curso de Formación Continuada
26-28 marzo 2014 Hotel El Montanyà. Seva, Barcelona 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 SCASEST
ICP1ªICP1ª ICPICPTto.Tto.
médicomédicoCirugíaCirugía
AASAAS
P2Y12 antg.P2Y12 antg. ?
Clopidogrel pretreatment and early risk
PCI-CURE CREDO
30-day death, MI & urg. TVR (%)
p=0.01 p=0.05
300 mg + 75 mg for median of 10 days
300 mg<6 hrs 6–24 hrs
No pretreatmentPretreatment
Clopidogrel: ¿Cúal es la dosis óptima?Clopidogrel: ¿Cúal es la dosis óptima?
0
20
40
60
80
100p<0.0001
p=0.009p=0.005
p=0.001 (MANOVA)
Basal 4h 24h 48h PostACTP
Activación GPIIb/IIIa (ADP2M)
% C
el. p
ositiv
as
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. Eur Heart J 2004;25(21):1903-10
300 mg ( n=20)
600 mg ( n=20)
PCI 600 mgPreloadN= 204
Primaryend point:
cardiac death, MI, TVR
536 Patients with
•Stable angina
or
•NSTE-ACS
undergoingcoronary
angiography
30 days
Clopidogrel600 mg given
4-8 hrs before angio
N= 267
Clopidogrel600 mg at the time of PCI N= 269
PCI 600 mg in-lab
N= 205
Medical RxN= 72
CABGN= 55
N= 409
• CKa-MB
• Troponin-I
• PRU
1st blood sample
Baseline
2nd, 3rd, 4th and 5th blood samples
At the time of PCI
2 hrs after PCI
8 and 24 hrsafter PCI
• PRU • CK-MB
• Troponin-I
• PRU
• PRU
ARMYDA-5 PRELOAD: Study design
R
an
do
miz
atio
n
Angiography
Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557
0
4
8
12
16
20
In-lab load Preload
p=0.72
5 10 15 20 25 30
Days after PCI
Cum
ulat
ive
inci
denc
e of
MA
CE
(%
)
ARMYDA-5 PRELOAD: Primary endpoint
Adverse events at 30 days(Clopidogrel in-lab load vs preload)
Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557
0
4
8
12
16
20
Majorbleeding
In-lab loadPreload
% o
f pat
ient
s%
of p
atie
nts
0
7.8
5.4
p=0.42
Minorbleeding
0
ARMYDA-5 PRELOAD: Safety secondary end point
Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557
1. Wiviott SD et al. Am Heart J. 2006;152:627-635.2. Payne CD et al. Am J Cardiol. 2006;98:S8.
New P2Y12 AntagonistsEarly onset and high inhibition
mean ± SEM 20 μM ADP
Time after loading dose (hrs)
Inh
ibit
ion
of
pla
tele
t a
gg
reg
atio
n (
%)
0
20
40
60
80
100
Clop 300 mg LD
0.25 0.5 1 2 4 6 24
Loading dose
†p<0.001 vs. Clop 300 mg
† †
!†
!p<0.05 vs. Clop 300 mg!
Clop 600 mg LD
*
*
** * *
p<0.001 vs. Clop 300 mgor 600 mg LD*Pras 60 mg LD
0
LD, Loading dose
• Pre-treatment with aspirin and a P2Y12 antagonist is a class I recommendation and is common practice for the treatment of NSTE-ACS
• In CURE, patients were managed conservatively
• In TRITON, patients were not pretreated before cath
• In PLATO, patients were pretreated before cath
• No trial had ever randomized patients presenting with NSTE-ACS, invasively managed, to pre-treatment with clopidogrel, prasugrel or ticagrelor vs. no pre-treatment …… ACCOAST
ACCOAST design
Prasugrel 30 mg
Prasugrel 60 mg Prasugrel 30 mg
Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days
PCI
1° Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa inh. Bailout, at 7 days
Placebo
CoronaryAngiography
n~4100 (event driven)
CoronaryAngiography
PCI
CABG or
MedicalManagement
(no prasugrel)
CABG or
MedicalManagement
(no more prasugrel)
Montalescot G et al. Am Heart J 2011;161:650-656
Randomize 1:1Double-blind
NSTEMI + Troponin ≥ 1.5 times ULN local lab valueClopidogrel naive or on long term clopidogrel 75 mg
Pharmacodynamic Sub-Study
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
Hours (post LD2)
P2Y
12
Rea
ctio
n U
nit
s
0
50
100
150
200
250
300
350Pre-treatment (30/30)No Pre-treatment (0/60)
Pre LD1(baseline)
Pre LD2 0.5 2 3 41 24
Approximatetime of PCI
*
*
30 mgLD1
PlaceboLD1
60 mgLD2
30 mgLD2
*P<0.05
Days From First Dose
0 5 10 15 20 25 30
En
dp
oin
t (%
)
0
5
10
15
1996
20371788
1821
1775
1809
1769
1802
1762
17971752
1791
CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout
1621
1616
No. at Risk, Primary
Efficacy End Point:
No pre-treatment
Pre-treatment
Pre-treatment10.810.0
Pre-treatment
Hazard Ratio, 0.997 (95% 0.83, 1.20)P=0.98P=0.81
(95% 0.84, 1.25) Hazard Ratio, 1.02
No Pre-treatment10.8
9.8No Pre-treatment
1° Efficacy End Point @ 7 + 30 days (All Patients)
All TIMI (CABG or non-CABG) Major Bleeding
(All Treated patients)
Days From First Dose0 5 10 15 20 25 30
En
dp
oin
t (%
)
0
1
2
3
4
5
All TIMI Major Bleeding
Pre-treatment2.9
Pre-treatment2.6
No Pre-treatment1.5
No Pre-treatment1.4
19962037
19471972
13281339
12971310
12881299
12841297
12631280
No. at Risk, All TIMI Major Bleeding:No pre-treatmentPre-treatment
Hazard Ratio, 1.97 (95% 1.26, 3.08)P=0.002
Hazard Ratio, 1.90(95% 1.19, 3.02) P=0.006
*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.
Overall (pre-treatment vs. no pre-treatment)
PCICABG
SexMaleFemale
Age<75 years>75 years
RegionEastern Europe/IsraelWestern Europe/Canada
DiabetesYesNo
52 (2.55)
Hazard Ratio(95% CI)
1.90 (1.19, 3.02)
TotalPatients
4033
2781
Medical Management*
GRACE score<140>140
Weight<60 kg*>60 kg
22 (1.57) 1.98 (0.96, 4.09)238 25 (20.66) 1.59 (0.85, 2.98)
1014 5 (0.97)
Pre-tx(%)
1990 28 (2.75) 1.50 (0.83, 2.71)2008 24 (2.40) 2.70 (1.25, 5.80)
1998 27 (2.72) 2.28 (1.16, 4.51)2003 24 (2.35) 1.54 (0.81, 2.93)
3079 34 (2.22) 1.92 (1.09, 3.41)852 16 (3.54) 1.76 (0.75, 4.12)
2923 31 (2.09) 1.43 (0.82, 2.49)1110 21 (3.80) 3.61 (1.46, 8.95)
3318 36 (2.16) 1.64 (0.96, 2.78)715 16 (4.29) 2.95 (1.08, 8.05)
205 5 (4.85)3824 47 (2.43) 1.78 (1.10, 2.87)
1692
2341
820 6 (1.45) 0.98 (0.32, 3.05)3213 46 (2.83) 2.16 (1.29, 3.62)
InteractionP-value†
0.74
0.23
0.41
0.31
0.09
0.35
0.22
0.87
27 (1.35)
No Pre-tx(%)
11 (0.80)16 (13.68)
0 (0.00)
18 (1.86)9 (0.89)
12 (1.20)15 (1.53)
18 (1.16)8 (2.00)
21 (1.46)6 (1.08)
22 (1.33)5 (1.46)
1 (0.98)26 (1.37)
6 (1.47)21 (1.32)
AccessFemoralRadial
2276 29 (2.54) 1.62 (0.90, 2.91)1711 22 (2.53) 2.67 (1.19, 6.00)
0.6618 (1.58)8 (0.95)
14 (1.62) 2.69 (0.97, 7.47)5 (0.60)
38 (3.24) 1.74 (1.03, 2.94)22 (1.89)
0.46
Pre-treatment better No pre-treatment better
Time from Sx to LD <median>median
Time from first LD to angio/PCI <median>median
NE
NE
CRUSADE score‡<median>median
2051 23 (2.23) 2.29 (1.09, 4.81)1789 27 (2.97) 1.75 (0.93, 3.28)
0.5910 (0.98)15 (1.71)
0.2 0.5 1 2 5 10 15
All TIMI Major Bleeding for Prespecified Subgroups Through 7 days (All Treated Patients)
¿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?
Pretratamiento en SCASCEST: preguntas
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