Prasugrel samu
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Transcript of Prasugrel samu
Prasugrel au SMUR / Urgences ?
Frédéric Munoz / Thierry Carrères Argenteuil
Conflits d’intérêts
Je ne suis pas un garçon intéressé…
Ma femme ne travaille plus chez Lilly !
Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events--a novel insight into plaque rupture by scanning electron microscopy.
Abela GS et al. Scanning 2006;28:1-10.
0 200 400 600 8000
20
40
60
80
100FibrinRed CellsPlateletsWhite CellsMixed Cells-FibrinCholesterol Crystals
Ischemic Time (min)
Thro
mbu
s Co
mpo
sitio
n (%
)
Dynamic thrombus formationInfluence of Time
Fibrin r=0.38, p=0.01
Platelets r=-0.34, p=0.02
Silvain J et al. JACC In press
Avis de recherche: AAP idéal
Effet rapide
Effet puissant
Effet constant
Sans effet secondaire délétère
Clopidogrel and Prasugrel: active metabolite plasma concentrations following oral loading dose
Time From Dose (hours)
Pla
sm
a C
on
cen
trati
on
(n
g/m
L)
Clopidogrel300 mg LD
Prasugrel60 mg LD
0 6 12 18 24
0
100
200
300
400
500
600
Payne C et al. Thromb Haemost 2005;3(Supplement 1):P0952 AM=Active metabolite; LD=Loading dose
Inhibition of Platelet Aggregation in Healthy Volunteers
• Data are expressed as mean ± SEM. Arrows (↓) indicate day of dose administration
Payne CD et al. J Cardiovasc Pharmacol 2007;50(5):555-562
IPA
% (
20 m
M A
DP
)
Loading Dose Maintenance Doses
Time
-10
0
10
20
30
40
50
60
70
80
90
100
2 3 4 5 6 7 8 90.25 0.5 1 2 4 6
‡
*
* * * * ** * * * * *
†
†
‡ ‡‡
*
Pre-doseIPA
Day 1, Hours Days
Clopidogrel 600 mg/75 mg
Clopidogrel 300 mg/75 mg
Prasugrel 60 mg/10 mg
IPA=Inhibition of platelet aggregation; ADP=Adenosine diphosphate
* p<0.001 Prasugrel vs Clopidogrel† p<0.05 Clopidogrel 600 mg vs 300 mg‡ p<0.001 Clopidogrel 600 mg vs 300 mg
Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI
Hours
IPA
% (
20 µ
M A
DP
)
Prasugrel 60 mg
***p<0.0001 Prasugrel vs. Clopidogrel
Clopidogrel 600 mg
*********
***
0.5 4 8 12 16 20 24
0
20
40
60
80
100
62
IPA=inhibition of platelet aggregation; PCI=Percutaneous coronary intervention Wiviott SD et al. Circulation 2007;116(25):2923-2932
Crossover Study in Healthy Subjects
Relationship between individual responses to prasugrel and clopidogrel, (administered in crossover fashion) as measured by IPA at 24 h postdose
IPA
% (
20 m
M
AD
P) In
hib
itio
n o
f P
late
let
Ag
gre
ga
tio
n (
%)
-20
-10
0
10
20
30
40
50
60
70
80
90
100
Clop 300 mg Pras 60 mg
20 μM ADP
Background Variability
Background Variability
Clopidogrel300 mg LD
Prasugrel60 mg LD
Brandt JT et al. Am Heart J 2007;153(1):66.e9-16
0
2
4
6
8
0 1 2 3
1
0
3060 90 180 270 360 450
HR 0.82(0.71-0.96)P=0.01
HR 0.80(0.70-0.93)P=0.003
5.6
4.7
6.9
5.6
Days
Pri
mary
En
dp
oin
t (%
)
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance Dose
TRITON TIMI 38: Timing of Benefit(Landmark Analysis)
Avis de recherche: AAP idéal
Effet rapide
Effet puissant
Effet constant
Sans effet secondaire délétère
TRITON-TIMI 38: Efficacy / Safety
TIMI major bleed
Life threaten-
ing
TIMI major or minor
0
1
2
3
4
5
6
clopidogrel
prasugrel
2,4
0,9
1,4
3,8P=0.03
P=0.01
P=0.002
Wiviott et al. New Engl J Med 2007;357:2001-2015
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)
Days
CV
Death
, M
I, S
troke (%
)
12.1
9.9
NNT= 46
Prasugrel
Clopidogrel
P<0.001
1,8
5,0
p=0.03* p=0.025*
9K
-M e
stim
ated
rat
e
8
7
6
5
4
3
2
1
0
2.8
2.2
SAFETY: TIMI Major Non-CABG Bleeds (12-15 months)
1.8
2.4
p=0.001*
2.7
3.7
450 days
AS
A o
nly
360 days360 days
+27% +25% +22%
TicagrelorClopidogrel 150Clopidogrel 75
Prasugrel
1.04 0.95
30 days !
CURRENT TRITON PLATOCURE
Net Clinical Benefit: Death, MI, Stroke, Major Bleed (non CABG)
0
5
10
15
0 30 60 90 180 270 360 450Days
En
dp
oin
t (%
)
HR 0.87(0.79-0.95)
P=0.004
13.9
12.2
Prasugrel
ClopidogrelITT= 13,608
Events per 1000 pts
MIMajor Bleed(non CABG)
+
Net Clinical Benefit: Bleeding Risk Subgroups
OVERALL
>=60 kg
< 60 kg
< 75
>=75
No
Yes
0.5 1 2
Prior Stroke / TIA
Age
Wgt
Risk (%)
+ 54
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel Better
HR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysis
Wiviott SD, Braunwald E, McCabe CH et al NEJM 2007
All ACS/PCI patientsN=13608
UA/NSTEMI patients
N=10074
STEMI patientsN=3534
Primary PCIN=2438 (69%)
Secondary PCI
N=1094 (31%)*
Clopidogrel
N=1235
PrasugrelN=1203
Clopidogrel
N=530
PrasugrelN=564
Montalescot et al. ESC 2008
TRITON-TIMI 38 STEMI
* 2 patients were missing data for primary or secondaryBefore knowledge of coronary anatomy
TRITON STEMI :Primary EP (CV death, MI and stroke at 15 months)
Montalescot et al. ESC 2008
Time (Days)
5
10
15
00 50 100 150 200 250 300 350 400 450
Pro
port
ion
of
pati
en
ts (
%)
9.5
6.5
12.4
10.0
HR=0.79 (0.65–0.97) NNT=42
p=0.02RRR=21
%p=0.002
RRR=32%
ClopidogrelPrasugrel
Age-adjusted HR=0.81 (0.66-0.99)
TIMI major or minor non-CABG bleeding
Montalescot et al. ESC 2008
2
5.1
4.74
6
HR=1.07 (0.79–1.47) NNH=250
0 100 200 300 4000
Time (Days)
Pro
port
ion
of
pati
en
ts (
%)
50 150 250 350 450
p=0.65
ClopidogrelPrasugrel
Age-adjusted HR=1.14 (0.83-1.55)
TRITON: Efficacy for IIb/IIIa use. Prasugrel triple AP therapy more effective and as safe as Clopidogrel triple AP Therapy
ALL NEVER IIb/IIIA IIb/IIIaPRASUGREL 9.9% 9.3% 10.4%CLOPIDOGRE
L12.2% 11.0% 12.9%
Percentage of subjects reaching the Primary Endpoint
The trial was not randomized against GP IIb/IIIa inhibitors. As its use was left to the discretion of the physicians, patients receiving GPI were likely to be at higher risk for ischemic events.
En résumé…
Effet rapide >> clopidogrel
Effet puissant >> clopidogrel
Effet constant >> clopidogrel
Risque hémorragique > clopidogrel Population à risque identifiée
GP IIbIIIa possibles dans le STEMI / souhaitables ?
23
ESC Guidelines 2010Drug COR LOE
NSTE-ACSAspirin I C
Clopidogrel (600mg ASAP) I C
Clopidogrel (for 9-12mo after PCI)
I B
Prasugrel IIa B
Ticagrelor I B
STEMIAspirin I B
Clopidogrel (600mg ASAP) I C
Prasugrel I B
Ticagrelor I B
European Heart Journal 2010
Prasugrel dans le camion ?
Aucun data avec le clopidogrel…
SCA ST+ Fibrinolyse Risque hémorragique élevé ATCD AVC / AIT, âge > 75 ans (?), poids < 60 kg (?) Pas de Prasugrel
SCA ST+ Pas d’ATCD hémorragique récent Pas d’ATCD d’AVC / AIT Âge < 75 ans, poids > 60 kg (?) Prasugrel
SCA ST- : Prasugrel ?
SCA ST- : stratifier Risque thrombotique élevé
Score GRACE
Risque hémorragique bas Score CRUSADE
Pas d’ATCD hémorragique récent Pas d’ATCD d’AVC / AIT Âge > 75 ans, poids > 60 kg (?) Prasugrel
…merci de votre attention !
Score de risque dérivé de GRACE
26http://www.outcomes-umassmed.org/externalwindow.cfm?URL=http://www.outcomes.org/grace/acs_risk/acs_risk.html&Link=http://www.outcomes-umassmed.org/GRACE/index.cfm&DeptName=Center%20for%20Outcomes%20Research
Classification saignement TIMI
Majeur Hémorragie intracrânienne, saignement cliniquement évident (y compris visualisation par imagerie) avec chute de l’hémoglobine ≥ 5 g/dl
Mineur Saignement cliniquement évident (y compris visualisation par imagerie) avec chute de 3 à 5 g/dl de l’hémoglobine
Minime Saignement cliniquement évident (y compris visualisation par imagerie) avec chute de l’hémoglobine < 3 g/dl
Classification saignement GUSTOSévère ou mettant en jeu le pronostic vital
Hémorragie intracrânienne ou saignement provoquant une instabilité hémodynamique nécessitant une intervention
Modéré Saignement nécessitant une transfusion sanguine, mais n’entraînant pas d’instabilité hémodynamique
Faible Saignement ne répondant pas aux critères des saignements sévères ou modérés
27Bassand JP, et al. The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. European Heart Journal 2007, 28:1598-1660
STEMI PatientsSubgroup analysis by time of LD relative to
PCI
TRITON STEMI: TIMI major non-CABG bleeding
Montalescot et al. ESC 2008
0.5
1.0
2.0
2.5
1.5
2.1
2.4
HR=1.11 (0.70–1.77) NNH=333
Pro
port
ion
of
pati
en
ts (
%)
Time (Days)
p=0.65
0 100 200 300 4000
ClopidogrelPrasugrel
Age-adjusted HR=1.19 (0.75-1.89)
TIMI life-threatening non-CABG bleeding
Montalescot et al. ESC 2008
HR=1.11 (0.59–2.10) NNH=500
Lif
e t
hre
ate
nin
g b
leed
ing
(%
)
Time (Days)
p=0.75
ClopidogrelPrasugrel
Age-adjusted HR=1.20 (0.63-2.26)
TRITON: Safety for IIb/IIIa use: No differences between Prasugrel and Clopidogrel at 3 days.
ALL ACS UA/NSTEMI STEMIIIb/IIIa
No Use
IIb/IIIa
Any Use
IIb/IIIa
No Use
IIb/IIIa
Any Use
IIb/IIIa
No Use
IIb/IIIa
Any Use
PRASUGREL 0.84 1.64 0.9 1.37 0.62 2.29
CLOPIDOGREL 0.46 1.65 0.54 1.20 0.16 2.71
The Co-Administration of a GP IIb/IIIa inhibitor with the loading dose increased the risk of instrumentation related TIMI major bleeding in both
prasugrel- and clopidogrel-treated subjects, particularly in the STEMI population.
Prasugrel dans le camion ?