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Ludovic DROUET(Angio-Hématologie, Hôpital Lariboisière-Paris)
Ludovic DROUET(Angio-Hématologie, Hôpital Lariboisière-Paris)
Séminaire thromboses etantithrombotiques
12-13 Mai 2006
Les antiplaquettaires
Les antiplaquettaires
TXADP
AA
Cox
Throm
boxane A 2
ASA
ADP
thienopyridines
ADP
AA
Cox
Thro
mboxa
ne A 2
ASAthienopyridines
FibrinogèneGPIIbGPIIIa
ThrombineIIa
PAR
Prévenir les thromboses Prévenir les thromboses
Lutter contre les facteurs de risque
Agir sur le principal mécanisme en cause
Veine
Immobilisation +++
ANTICOAGULANTS
Tant que le risque persiste
Artère
Athérosclérose
HTA, Hyper cholestérolémie, Tabac,…
ANTI-AGREGANTS PLAQUETTAIRES
A vie
Traiter les thromboses Traiter les thromboses
Désobstruer le vaisseau(si risque vital ou organique majeur)
Empêcher l’extension, prévenir la récidive
Veine
(Thrombectomie)
Artère
Angioplastie
Antiagrégants
ANTICOAGULANTS
THROMBOLYTIQUES
AAP : principales indications
Prévention artérielle ++ prévention au long cours des complications ischémiques
(thrombotiques) « l’athérothrombose » prévention primaire, prévention secondaire et prévention primo-secondaire
après un premier accident (IDM, angor instable, AVC,etc...) ASPIRINE, (TICLID), PLAVIX : administration orale
Phase aiguë des syndromes coronaires Angor instable Angioplasties
ASPIRINE, (TICLID) PLAVIX (+ASPIRINE) : administration orale Anti GPIIb IIIa : perfusion IV
Post angioplastie + stenting coronaire Autres territoires
ASPIRINE, (TICLID) PLAVIX (+ASPIRINE) : administration orale Durée < 12 mois (Plavix+aspirine)
IIIa
IIIa
FbgvWFFVIIIc
pS
IIb
IIb IIIaIIb IIIa
IIb IIIa
TISSU CONJONCTIF
vWFIb IX
V
Collagène
IIaIa
IIb
COX1
ADPADP
TXA2
pS
vWFNONO
PGI2PGI2
TMIIIaIIb
NONO Calcium
Calcium
NONO
FcRII
TXADP
Catella-Lawson F, Fitzgerald GA & al, NEJM, 2001
Antiplatelet Therapy on vascular events (MI, stroke or vascular death)Antiplatelet Therapy on vascular events (MI, stroke or vascular death)
Antithrombotic Trialists' Collaboration,Meta.analysis of antiplatelet therapy for prevention of death, MI, stroke, BMJ, 2002
Antiplatelet therapy on vascular events in 195 trialsin high risk patients f(disease) –ATC BMJ 2002-Antiplatelet therapy on vascular events in 195 trialsin high risk patients f(disease) –ATC BMJ 2002-
Primary Prevention of Cardiovascular Events With Low-Dose aspirin and Vitamin E in Type 2 Diabetic Patients, Results of the Primary Prevention Project (PPP) trialM. SACCO,et al Diabetes Care 26:3264–3272, 2003
0 1 2 3 4 5 Time (years)
Log-Rank Test No Diabetes x’=4.98 p-value = 0.03Log-Rank Test Diabetes x’=0.13 p-value = 0.71
1.00 -
0.99 -
0.98 -
0.97 -
0.96 -
0.95 -
0.94 -
0.93 -
0.92 -
0.91 -
0.90
Aspirin No DiabetesNo Aspirin No DiabetesAspirin DiabetesNo Aspirin Diabetes
Antiagrégants plaquettairesAntiagrégants plaquettaires
L’aspirine a-t-elle une place en prévention de la thrombose veineuse
Aspirine &Thrombose veineuseAspirine &Thrombose veineuse
PEP Study Lancet 2000; 355:1295
Anti agrég(e)ant plaquettaireAnti agrég(e)ant plaquettaire
L’aspirine en pathologie artérielle atherothrombotique: « oui » mais quelle(s) dose(s) ? En phase chronique À la phase aiguë
Indirect comparisons of aspirin dosageson vascular events in high risk patients (excluding those with acute stroke)
Indirect comparisons of aspirin dosageson vascular events in high risk patients (excluding those with acute stroke)
Antithrombotic Trialists' Collaboration,Meta.analysis of antiplatelet therapy for prevention of death, MI, stroke, BMJ, 2002
PATHOLOGIE
Dose minimale
d’aspirine (mg)ayant
démontré une efficacité
Hommes à haut risque cardiovasculaire 75
Hypertendus 75
Angor stable 75
Angor instable 75
Infarctus aigu du myocarde 160
Accidents vasculaires cérébraux ischémiques
(constitués et transitoires)
50
Sténose sévère de la carotide 75
Accidents vasculaires cérébraux ischémiques constitués (période aiguë)
160
Aspirine: une notion nouvelle la résistance à l’aspirineAspirine: une notion nouvelle la résistance à l’aspirine
Définition de la résistance : clinique / biologique
Observance Interactions médicamenteuses Dose(s)
Catella-Lawson F, Fitzgerald GA & al, NEJM, 2001
Résistance à l’aspirineRésistance à l’aspirineLe modèle exemplaire des assistances cardio-Le modèle exemplaire des assistances cardio-
circulatoires chroniquescirculatoires chroniques
Semaines de suivi post implantationSemaines de suivi post implantation
Nombre de patientsprésentant une agrégation plaquettaire
- activation par l'AA-Doses d'aspirine par jour
0 2 4 6 8 10 120
100
200
300
400
500
0 1 2 3 4 5 6 7 8 9 100
1
2
3
4
5
6
Dose de départ : 250 mg
3
1 1
2 2
Aspirine: les effets secondairesAspirine: les effets secondaires
Toxicité digestive Gastralgies Hémorragies digestives
Allergie
CAPRIE : safetyCAPRIE : safetyCAPRIE : safetyCAPRIE : safetyevents incidence (%)
Eur Heart J 1998
Aspirin Plavix 325 mg/j 75 mg/j P (n = 9 586) (n = 9 599)
Hemorrhages (all bleedings)GIother
intra-cranial
9,32,76,50,5
9,32,07,30,4
0,9760,0020,0240,146
GI symptoms (all events)GI ulcersdiarrheas
severe diarrheas
29,81,23,40,1
27,80,74,50,2
0,0010,001
0,001 0,05
Blood count abnormalities severe Neutropenia(<0,45 x 10 9) severe Thrombopenia (<80 x 10 9)
0,020,1
0,040,2
0,4 0,255
Other adverse effects headaches, vertigosskin
severe rashes severe itching
23,813,10,07
0
22,315,80,130,13
0,016 0,001 0,05 0,05
prodrogue active metabolite: Identified , very short half live
Acts by irreversible SS bridges with P2Y12 receptor (one the 3 platelet ADP receptors)
Clopidogrel Plavix®
Platelet ADP pathway
ACAC
ADP binds to its receptorADP binds to its receptor
Adenylate Adenylate cyclase cyclase activity activity down-down-regulated regulated
CaCa2+2+ released from released from intracellular storesintracellular stores
ConformationalConformationalchange activateschange activatesGPIIb IIIa GPIIb IIIa receptorreceptor
P2YP2Y1212
CaCa2+2+
P2XP2X11
calciumcalciumchannelchannel
ADPADP
Densegranule
GGPlCPlC
ADPADP
ADPADP
ADPADP
Secretion
ADPADP
Fibrinogen Fibrinogen binds tobinds to
its receptorits receptor
P2Y1P2Y1
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Deuxième niveauTroisième niveauQuatrième niveauCinquième niveau
Mean ( SEM) inhibition of platelet aggregation induced by 5µM
0
20
40
60
80
-20
-40
% In
hibi
tion
Placebo 50 mg 75 mg 100 mg Ticlopidine
Day 2 Day 3 Day 7 Day 15
+-
***
** ***
*
**
***
*** *** *****
***
***
* p < 0.05; ** p < 0.01; *** p < 0.001
Clopidogrel:
Kinetics of antiplatelet activity
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Kinetics of antiplatelet activity of clopidogrel 75 mg/d for 8d in healthy
volunteers (n=12)
Kinetics of antiplatelet activity of clopidogrel 75 mg/d for 8d in healthy
volunteers (n=12)
Before daily Clopidogrel
intake
3 hours after daily
Clopidogrel intake
Inh
ibit
ion
(%
) p
late
let
ag
gre
ga
tio
n
A
DP
5 µ
M
D1 D2 D3 D5 D8
time
Clopidogrel loading dose
Kleffer G et al. Thromb Haemost 1989;62(1):411 (Abstract)
12
31
3942
17,1
28,4
43,138
0
10
20
30
40
50
100 mg 200 mg 400 mg 600 mg
2hrs 4hrs
* ** *
300 mg
Ble
edin
g tim
e
% p
late
let i
nhib
ition
1
2Bleeding time
0
20
40
60
80
100
0 1,5h 3h 6h 24h 27h 48h 8j
Clopidogrel: loading doseClopidogrel: loading doseIn
hib
itio
n (
%)
pla
tele
t a
gg
reg
ati
on
AD
P 5
µM
75 mg 75 mg n=20n=20
300 mg 300 mg n=20n=20
300 mg 300 mg n=20n=20
75 mg75 mg
300 mg 300 mg n=20n=20
CAPRIE : safetyCAPRIE : safetyCAPRIE : safetyCAPRIE : safetyevents incidence (%)
Eur Heart J 1998
Aspirin Plavix325 mg/j 75 mg/j P(n = 9 586) (n = 9 599)
Hemorrhages (all bleedings)GIother
intra-cranial
9,32,76,50,5
9,32,07,30,4
0,9760,0020,0240,146
GI symptoms (all events)GI ulcersdiarrheas
severe diarrheas
29,81,23,40,1
27,80,74,50,2
0,0010,001
0,001 0,05
Blood count abnormalities severe Neutropenia(<0,45 x 10 9) severe Thrombopenia (<80 x 10 9)
0,020,1
0,040,2
0,4 0,255
Other adverse effects headaches, vertigosskin
severe rashes severe itching
23,813,10,07
0
22,315,80,130,13
0,016 0,001 0,05 0,05
TTP : clinical Experience since beginning of commercialization
Incidence supposée : 1 / 235 000
20 TTP cases reported on more than 4,7 millions patients treated with PLAVIX.
Incidence similar to that of general populationIncidence similar to that of general population Incidence similar to that of general populationIncidence similar to that of general population
Causality to be establishedCausality to be established Causality to be establishedCausality to be established
No need for systematic blood count monitoringNo need for systematic blood count monitoring No need for systematic blood count monitoringNo need for systematic blood count monitoring
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Atherothrombose
Evolution des traitementsantiplaquettaires
Atherothrombose
Evolution des traitementsantiplaquettaires
Time since randomisation (mois)Time since randomisation (mois)
nb
eve
nts
/100
0 p
atie
nts
/yea
rn
b e
ven
ts/1
000
pat
ien
ts/y
ear
00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636
PlaceboPlacebo
AspirinAspirin
00
4040
8080
120120
161600
25%25%
Aspirin prevents ¼ of ischemic cardio-vascular events
Can an antiplatelet agent be more efficacious?Can an antiplatelet agent be more efficacious?
Placebo arm extrapolated from APTC meta-analysis. Placebo arm extrapolated from APTC meta-analysis. Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106, .Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106, .
CHDCHDn = 6302
CerebrovascularCerebrovascularDiseaseDisease n = 6431
PAD PAD n = 6452
24.7%24.7%
3.8%3.8% 11.8%11.8%
19.2%19.2%
7.4%7.4%
29.9%29.9%
3.3%3.3%
Coccheri. Eur Heart J 1998;19(suppl):P1268.Coccheri. Eur Heart J 1998;19(suppl):P1268.
CAPRIE’s patients CAPRIE’s patients n = 19 185
AtherothrombosisAtherothrombosisA unique disease A unique disease
with multiple with multiple localizationslocalizations
CAPRIE Steering Committee. Lancet 1996;348:1329-1339Gent M. Benefit of clopidogrel in patients with coronary disease Circulation 1997, 96(8) suppltRupprecht HJ. Consistency of the benefit of clopidogrel across a range of vascular related endpoints: results from CAPRIE.European Society of Cardiology, 1998, Vienne (abstract 53116)
CAPRIE : Results analysis CAPRIE : Results analysis CAPRIE : Results analysis CAPRIE : Results analysis
Ischemic stroke
MI
PAD
20
8,4
22,4
8.7
10 0 10 20 30
All patients
Plavix betterPlavix better
As real medical history :As real medical history :
Ischemic stroke
MI
PAD
20
-3,7
7,3
23,8
n = 19 1858.7
10 0 10 20 30
All patients
As inclusion criteria:As inclusion criteria:
Plavix betterPlavix better
7.4
n = 6452
n = 6302
n = 6431 n = 6953
n = 8446
n = 7325
n = 19 185
CAPRIE Study: MI Paradox
Relative Risk Reduction* byQualifying Entry Criteria1
Relative Risk Reduction* byQualifying Entry Criteria1
*Cluster of IS, MI, or vascular death. 1CAPRIE Steering Committee. Lancet 1996;348:1329-1339.2Easton. Neurology 1998;50(suppl 4):A157. 3Gent. Circulation. 1997;96(suppl):I-467.
IS n=6431
MI n=6302
PAD n=6452
Total n=19185
clopidogrel better
0 10 201020 30
8.7
7.3
-3.7
23.8
Relative Risk Reduction ofIndividual End Points
Relative Risk Reduction ofIndividual End Points
IS (fatal or non-fatal)2
MI (fatal or non-fatal)3
Vascular death1
IS, MI, vascular death1
clopidogrel better
0 10 201020 30
19.2
5.2
7.6
n=19,185
8.7
CAPRIE: Amplified Benefit of Clopidogrel in Patients with Higher Vascular Risk1–3
CAPRIE: Amplified Benefit of Clopidogrel in Patients with Higher Vascular Risk1–3
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77. 3. Ringleb PA et al. Eur Heart J 1999; 20: 666.
Incidence of MI, IschemicStroke, or Vascular Death
152
200
238
141
172
204
0
50
100
150
200
250
300
All CAPRIE patients¹(n=19,825)
Prior history of anyischemic event²
(n=8,854)
Prior history of majoracute event (MI or stroke)
(n=4,496)
Inc
ide
nc
e/1
00
0 p
ati
en
ts (
av
era
ge
fo
llo
w-u
p,
2 y
ea
rs)
ASAClopidogrel
11
28
34
3
Events Prevented/1000 Patients/Year
over ASA
CAPRIE: Amplified Benefit of Clopidogrel in Patients with Hypercholesterolemia1 CAPRIE: Amplified Benefit of Clopidogrel in Patients with Hypercholesterolemia1
1. Bhatt DL et al. J Am Coll Cardiol 2000; 35(suppl A): 326.
Overall benefit: p = 0.026; multivariate analysis
15.1%14.6%
12.2%11.9%
0
2
4
6
8
10
12
14
16
On any lipid-lowering agent On statin
* An
nu
al e
ven
t ra
te (
%)
ASAClopidogrel
29
27
Events Prevented/1000 Patients/Year
over ASA
Incidence of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Ischemic Events or Bleeding
CAPRIE: Amplified Benefit of Clopidogrel in Patients with Additional Risk Factors1, 2
CAPRIE: Amplified Benefit of Clopidogrel in Patients with Additional Risk Factors1, 2
1. Bhatt DL et al. Am Heart J 2000; 140: 67–73. 2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.
Incidence of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Ischemic Events or Bleeding
137
177
215
126
156177
0
50
100
150
200
250
All CAPRIE patients¹ Diabetes² Diabetes treated withinsulin²
Inc
ide
nc
e/1
00
0 p
ati
en
ts/y
ea
r
ASA
Clopidogrel
11
21
38
Events Prevented/1000 Patients/Year
over ASA
Atherothrombosis is a Generalized Disease Atherothrombosis is a Generalized Disease
Progressive destruction of the downstream capillary bed
myocardium brain peripheral tissues
Symptomatic Symptomatic occlusionocclusion
Acute Syndromes coronaries cerebrovascular peripheral
Occlusive thrombus ± permanent
PLAQUE PLAQUE RUPTURE /RUPTURE /
erosion erosion
Asymptomatic
Fattystreak
PlaquePLAQUE PLAQUE RUPTURE /RUPTURE /erosionerosion
LOCALLOCAL
Silent Silent occlusionocclusion
DISTALDISTALParietal
thrombus EVOLUTIONEVOLUTION
Ticlid + aspirin for prevention of subacute thrombosis on coronary stents
1 Schömig et al. (1996), 2 Bertrand et al. (1998), 3 Urban (1998), 4 Leon et al. (1998)
Eve
nt
Rat
es (
% D
eath
, MI,
Rev
asc.
)
0
4
8
12
ISAR 1
N=517FANTASTIC 2
N=485STARS 4
N=1653MATTIS 3
N=350
Ticlopidine + ASACoumadin + ASA
6.2
1.6
8.3
5.7
2.7
0.5
11
5.6
3.6
ASA
P=0.01
P=0.01P=0.07
P<0.001
Patient Randomization Patient Randomization
3 months double-blind treatment 12 months
Aspirin 75-325mg
Clopidogrel75mg o.d.
(6259 patients)
Placebo1 tab o.d.
(6303 patients)
Aspirin 75-325mgD
ay 1
6 m
. Vis
it
9 m
. Vis
it
12 m
.
or F
inal
Vis
it
Clopid
ogrel
300m
g load
ing
dose
3 m
. Vis
it
Dis
char
ge V
isit
1 m
. Vis
it
Patients withAcute Coronary
Syndrome
(UA or MI Without STelevation)
R
Plac
ebo
load
ing
dose
R=Randomization
N Engl J Med. 2001N Engl J Med. 2001
Months of Follow-up
Cum
ulat
ive
Haz
ard
Rat
es
0.0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0 3 6 9 12
Cure : Cumulative Hazard Rates for CV Death/MI/StrokeCure : Cumulative Hazard Rates for CV Death/MI/Stroke
P < 0.001
Clopidogrel
+ ASA
Placebo
+ASA
Cum
ulat
ive
Haz
ard
Rat
es
Months of Follow-up0 3 6 9 12
6303
6259
5780
5866
4664
4779
3600
3644
2388
2418
Plac
Clop
No of Pts
N Engl J Med. 2001N Engl J Med. 2001
20% RRR20% RRRPP < 0.001 < 0.001
N = 12,562N = 12,562
11.4%11.4%
9.3%9.3%
PCI-CURE: Study DesignPCI-CURE: Study Design
RPCIPCIPCIPCI
PLACEBOPLACEBO + ASA+ ASA
CLOPIDOGRELCLOPIDOGREL+ ASA+ ASA
30 d. post PCI*30 d. post PCI*30 d. post PCI*30 d. post PCI*Follow-up Follow-up (to 12 m(to 12 mafter rand.)after rand.)
Follow-up Follow-up (to 12 m(to 12 mafter rand.)after rand.)
Open-label thienopyridineOpen-label thienopyridine
Pretreatment
Open-label thienopyridineOpen-label thienopyridine
Pretreatment N=2,658 patients undergoing PCI
N = 1345
N = 1313
CURE PCI-CURE
*1o Outcome: CV Death, MI, Urg Revasc. Mehta SR et al. Lancet 2001:358:527-33
0.0
0.0
50
.10
0.1
5
0 40 100 200 300 40010 100 200 300 400
A BDays following PCI
Cu
mu
lati
ve H
aza
rd R
ate
RR 0.69RR 0.6995% CI 0.54-0.8795% CI 0.54-0.87P=0.002P=0.002
Clopidogrel + ASAClopidogrel + ASA
PlaceboPlacebo
A=median time to PCIB=30 days after PCI
PCI-Cure : Overall Results: CV Death or MIPCI-Cure : Overall Results: CV Death or MI
Mehta SR et al. Lancet 2001:358:527-33
12.6%12.6%
8.8%8.8%
PCI-Cure : CV Death or MI at Various IntervalsPCI-Cure : CV Death or MI at Various Intervals
0
2
4
6
8
10
12
14
CV
de
ath
or
MI (
%)
PlaceboClopidogrel
12,6
8,8
Overall
RRR: 31%
*
*P=0.002 Mehta SR et al. Lancet 2001:358:527-33
5,1
3,6
BeforePCI
32%
4,4
2,9
PCI to30 d.
34%
3,93,1
30 d. to1 yr
21%
CHARISMA - Design CHARISMA - Design
Double-blind treatment up to 1,040 primary efficacy events*
All patients receiving ASA 75–162 mg o.d.
Clopidogrel75mg o.d.(n = 7,600)
Placebo1 tab o.d.(n = 7,600)
42 m
onth
or fi
nal v
isit
1 m
onth
vis
it
3 m
onth
vis
it
Patients aged 45 years or older
at high-risk of atherothrombotic event
R = Randomization
R
* event driven trial, approximately 15,000 patients
Distribution of Responsiveness to Clopidogrel in 544 IndividualsDistribution of Responsiveness to Clopidogrel in 544 Individuals
Change in Aggregation to 5µM ADP
Number of patients
0
16
32
48
64
80
96
112
<= -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100]
Serebruany V. JACC 2004; In press
Who is a Who is a Non-Responder?Non-Responder?
Who is a Who is a Non-Responder?Non-Responder?
A Normal Distribution: Consistent with a Poly-Genetic and Poly-Environmental Influence
Inhibiteurs
Coagulation
FTPlaquette
Plaquette
FVIII
Plaquette
FVa
Fibrinogène Fibrine
FVII FVIIaFIX FIXa
FVIIIa
FV
FXa
FII
FX
PlaquetteThrombine
Les antiagrégants plaquettaires dans la fibrillation auriculaire
Inhibiteurs
Coagulation
FTPlaquette
Plaquette
FVIII
Plaquette
FVa
Fibrinogène Fibrine
FVII FVIIaFIX FIXa
FVIIIa
FV
FXa
FII
FX
PlaquetteThrombine
Les antiagrégants plaquettaires dans la fibrillation auriculaire