Transcript Les antithrombotiques aujourd'hui

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Séminaire
thromboses
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antithrombotiques
Les
antiplaquettaires
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12-13 Mai 2006
Ludovic DROUET
(Angio-Hématologie, Hôpital Lariboisière-Paris)
TX
ADP
AA
ASA
Cox
thienopyridines
ADP
AA
thienopyridines ASA
ADP
Cox
GPIIb
GPIIIa
Fibrinogène
PAR
Thrombine
IIa
Prévenir les thromboses

Lutter contre
les facteurs
de risque

Agir sur le
principal
mécanisme
en cause
Artère
Veine
Athérosclérose
HTA, Hyper
cholestérolémie,
Tabac,…
Immobilisation +++
ANTI-AGREGANTS
PLAQUETTAIRES
ANTICOAGULANTS
A vie
Tant que le risque persiste
Traiter les thromboses

Désobstruer le
vaisseau
(si risque vital ou
organique majeur)

Empêcher
l’extension,
prévenir la
récidive
Artère
Veine
Angioplastie
(Thrombectomie)
THROMBOLYTIQUES
Antiagrégants
ANTICOAGULANTS
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)
IIb
IIIa
IIb
IIIa
Calcium
IIb IIIa
FVIIIc
IIb IIIa
Fbg
vWF
IIb IIIa
IIb IIIa
pS
vWF
COX1
Calcium
FcgRII
V
Ia IIa
Collagène
Ib IX
vWF
TISSU CONJONCTIF
pS
TX
ADP
Catella-Lawson F, Fitzgerald GA & al, NEJM, 2001
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 trials
in high risk patients f(disease) –ATC BMJ 2002-
1.00 0.99 0.98 0.97 0.96 0.95 0.94 -
0.93 0.92 0.91 -
Aspirin No Diabetes
No Aspirin No Diabetes
Aspirin Diabetes
No Aspirin Diabetes
Log-Rank Test No Diabetes x’=4.98 p-value = 0.03
Log-Rank Test Diabetes x’=0.13 p-value = 0.71
0.90
0
1
2
3
Time (years)
4
5
Primary Prevention of Cardiovascular Events With Low-Dose aspirin and Vitamin E in
Type 2 Diabetic Patients, Results of the Primary Prevention Project (PPP) trial
M. SACCO,et al Diabetes Care 26:3264–3272, 2003
Antiagrégants plaquettaires

L’aspirine a-t-elle une place en prévention
de la thrombose veineuse
Aspirine &
Thrombose veineuse
PEP Study Lancet 2000; 355:1295
Anti 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 dosages
on 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’aspirine
Définition de la résistance : clinique /
biologique
 Observance
 Interactions médicamenteuses
 Dose(s)

Catella-Lawson F, Fitzgerald GA & al, NEJM, 2001
Résistance à l’aspirine
Le modèle exemplaire des assistances cardiocirculatoires chroniques
Nombre de patients
présentant une agrégation plaquettaire
- activation par l'AA6
Doses d'aspirine par jour
500
Dose de départ : 250 mg
5
400
4
300
3
3
2
2
200
1 1
1
0
2
0
1
2
3
100
4
5
6
7
8
9 10
0
0
2
4
Semaines de suivi post implantation
6
8
10
12
Aspirine: les effets secondaires

Toxicité digestive



Gastralgies
Hémorragies digestives
Allergie
CAPRIE : safety
events incidence (%)
Aspirin
325 mg/j
(n = 9 586)
Hemorrhages (all bleedings)
GI
other
intra-cranial
Plavix
75 mg/j
(n = 9 599)
P
9,3
2,7
6,5
0,5
9,3
2,0
7,3
0,4
0,976
0,002
0,024
0,146
GI symptoms (all events)
GI ulcers
diarrheas
severe diarrheas
29,8
1,2
3,4
0,1
27,8
0,7
4,5
0,2
 0,001
Blood count abnormalities
severe Neutropenia(<0,45 x 10 9)
severe Thrombopenia (<80 x 10 9)
0,02
0,1
0,04
0,2
 0,4
 0,255
Other adverse effects
headaches, vertigos
skin
severe rashes
severe itching
23,8
13,1
0,07
0
22,3
15,8
0,13
0,13
0,016
 0,001
 0,05
 0,05
0,001
 0,001
 0,05
Eur Heart J 1998
Clopidogrel



Plavix®
prodrogue
active metabolite: Identified , very short half live
Acts by irreversible SS bridges with P2Y12 receptor
(one the 3 platelet ADP receptors)
Platelet ADP pathway
ADP binds to its receptor
P2Y12
Adenylate
AC
cyclase
activity
downregulated
P2Y1
G
Ca2+
a
P2X1
PlC
calcium
channel
Dense
ADP granule
Secretion
ADP
Ca2+ released from
intracellular stores
Conformational
change activates
GPIIb IIIa
Fibrinogen
receptor
binds to
its receptor
Clopidogrel:
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Kinetics of antiplatelet
activity
% Inhibition
Mean ( +- SEM) inhibition of platelet aggregation induced by 5µM
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80
***
masque
***
** ***
***
60
*** ***
**
**
**
* Deuxième niveau **
40
*
*
Troisième niveau
20
Quatrième niveau
0
Cinquième niveau
-20
-40
Placebo
50 mg
Day 2
* p < 0.05; ** p < 0.01; *** p < 0.001
75 mg
Day 3
100 mg
Day 7
Ticlopidine
Day 15
Kinetics
of antiplatelet
activity
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leof
clopidogrel 75 mg/d for 8d in healthy
style
volunteers (n=12)
100
%
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80
masque
Deuxième niveau
60
Troisième niveau
40
Quatrième niveauBefore daily Clopidogrel
intake
Cinquième niveau
3 hours after daily
Clopidogrel intake
20
0
0 D1
D2
20
D3 40
time
D5
60
80D8
Clopidogrel loading dose
% platelet inhibition
2hrs
43,1
4hrs
42
39
40
31
Bleeding time
30
28,4
2
12
1
*
*
10
*
*
17,1
20
38
Bleeding time
50
0
100 mg
200 mg
400 mg
600 mg
300 mg
Kleffer G et al. Thromb Haemost 1989;62(1):411 (Abstract)
Clopidogrel: loading dose
300 mg n=20
100
75 mg
80
75 mg n=20
300 mg n=20
300 mg n=20
60
40
20
0
0
1,5h
3h
6h
24h
27h
48h
8j
CAPRIE : safety
events incidence (%)
Aspirin
325 mg/j
(n = 9 586)
Hemorrhages (all bleedings)
GI
other
intra-cranial
Plavix
75 mg/j
(n = 9 599)
P
9,3
2,7
6,5
0,5
9,3
2,0
7,3
0,4
0,976
0,002
0,024
0,146
GI symptoms (all events)
GI ulcers
diarrheas
severe diarrheas
29,8
1,2
3,4
0,1
27,8
0,7
4,5
0,2
 0,001
Blood count abnormalities
severe Neutropenia(<0,45 x 10 9)
severe Thrombopenia (<80 x 10 9)
0,02
0,1
0,04
0,2
 0,4
 0,255
Other adverse effects
headaches, vertigos
skin
severe rashes
severe itching
23,8
13,1
0,07
0
22,3
15,8
0,13
0,13
0,016
 0,001
 0,05
 0,05
0,001
 0,001
 0,05
Eur Heart J 1998
TTP : clinical Experience since
beginning of commercialization
20 TTP cases reported on more than 4,7
millions patients treated with PLAVIX.
Incidence supposée : 1 / 235 000
 Incidence
similar to that of general population
 Causality
to be established
 No
need for systematic blood count monitoring
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Atherothrombose
style
Evolution
deslestraitements
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Aspirin prevents ¼ of ischemic
cardio-vascular events
nb events/1000 patients/year
16
0
Placebo
120
Aspirin
80
25%
Placebo arm extrapolated from APTC meta-analysis.
Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106, .
40
0
0
3
6
9 12 15 18 21 24 27 30 33 36
Time since randomisation (mois)
Can an antiplatelet agent be more efficacious?
CAPRIE’s patients n = 19 185
Cerebrovascular
Disease
n = 6431
CHD
n = 6302
24.7%
7.4%
29.9%
3.3%
3.8%
Atherothrombosis
A unique disease
with multiple
localizations
11.8%
19.2%
PAD
Coccheri. Eur Heart J 1998;19(suppl):P1268.n = 6452
CAPRIE : Results analysis
As inclusion criteria:
7,3
Ischemic stroke
n = 6431
-3,7
MI
n = 6302
23,8
PAD
n = 6452
10
0
10
Ischemic stroke
n = 6953
8,4
MI
n = 8446
7.4
22,4
PAD
n = 7325
8.7
All patients
n = 19 185
20
As real medical history :
8.7
All patients
n = 19 185
20
Plavix better
30
20
10
0
10
20
Plavix better
CAPRIE Steering Committee. Lancet 1996;348:1329-1339
Gent M. Benefit of clopidogrel in patients with coronary disease Circulation 1997, 96(8) supplt
Rupprecht 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)
30
CAPRIE Study: MI Paradox
Relative Risk Reduction* by
Qualifying Entry Criteria1
Relative Risk Reduction of
Individual End Points
5.2
7.3
IS
n=6431
-3.7
MI n=6302
IS (fatal or
non-fatal)2
19.2
MI (fatal or
non-fatal)3
23.8
PAD
n=6452
8.7
Total n=19185
20
10
0
10
20
30
clopidogrel better
n=19,185
7.6
Vascular
death1
IS, MI, vascular8.7
death1
20
10
0
10
20
30
clopidogrel better
*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.
Incidence/1000 patients (average follow-up, 2 years)
CAPRIE: Amplified Benefit of Clopidogrel
in Patients with Higher Vascular Risk1–3
Incidence of MI, IschemicStroke,
or Vascular Death
300
250
200
152
150
1
1
200
2
8
238
3
4
204
172
141
100
50
0
All CAPRIE patients¹
(n=19,825)
Events
Prevented/1000
Patients/Year
over ASA
Prior history of any
Prior history of major
ischemic event²
acute event (MI or stroke) 3
(n=8,854)
(n=4,496)
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.
ASA
Clopidogrel
*
Annual event rate (%)
CAPRIE: Amplified Benefit of Clopidogrel
in Patients with Hypercholesterolemia1
Incidence of Myocardial Infarction, Stroke, Vascular Death or
Hospitalization for Ischemic Events or Bleeding
Events
2
Prevented/1000
15.1%
16
2
14.6%
Patients/Year
9
14
7
over ASA
12.2%
11.9%
12
10
ASA
Clopidogrel
8
6
4
2
0
On any lipid-lowering agent
On statin
Overall benefit: p = 0.026; multivariate analysis
1. Bhatt DL et al. J Am Coll Cardiol 2000; 35(suppl A): 326.
CAPRIE: Amplified Benefit of Clopidogrel in
Patients with Additional Risk Factors1, 2
Incidence/1000 patients/year
Incidence of Myocardial Infarction, Stroke, Vascular Death or
Hospitalization for Ischemic Events or Bleeding
Events
3
Prevented/1000
250
8
215
Patients/Year
2
over ASA
200
1
150
137
1
1
177
177
156
ASA
Clopidogrel
126
100
50
0
All CAPRIE patients¹
Diabetes²
Diabetes treated with
insulin²
1. Bhatt DL et al. Am Heart J 2000; 140: 67–73. 2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.
Atherothrombosis is a Generalized Disease
PLAQUE
RUPTURE /
erosion
Symptomatic
occlusion
Acute Syndromes
 coronaries
 cerebrovascular
 peripheral
Occlusive thrombus
± permanent
Silent
occlusion
Fatty
streak
Plaque
Asymptomatic
PLAQUE
RUPTURE /
erosion
Parietal
thrombus
EVOLUTION
Progressive destruction of
the downstream capillary
bed
 myocardium
 brain
 peripheral tissues
Event Rates (% Death, MI, Revasc.)
Ticlid + aspirin for prevention of
subacute thrombosis on coronary
stents
ASA
12
Coumadin + ASA
Ticlopidine + ASA
11
P=0.01
P=0.07
8.3
8
P=0.01
6.2
5.6
5.7
P<0.001
4
3.6
0
2.7
1.6
ISAR
1
0.5
FANTASTIC
N=517
N=485
1
2
MATTIS
N=350
3
STARS
4
N=1653
Schömig et al. (1996), 2 Bertrand et al. (1998), 3 Urban (1998), 4 Leon et al. (1998)
Patient Randomization
Clopidogrel
Patients with
Acute Coronary
Syndrome
(UA or MI Without ST
elevation)
Aspirin 75-325mg
R
75mg o.d.
(6259 patients)
3 months  double-blind treatment  12 months
Aspirin 75-325mg
Placebo
1 tab o.d.
(6303 patients)
R=Randomization
N Engl J Med. 2001
0.14
Cure : Cumulative Hazard Rates for CV Death/MI/Stroke
0.12
0.10
+ASA
0.08
Clopidogrel
0.06
9.3%
+ ASA
0.02
0.04
20% RRR
P < 0.001
N = 12,562
P < 0.001
0.0
Hazard Rates
Cumulative
Rates
Hazard
Cumulative
11.4%
Placebo
00
No of Pts
3
3
66
99
12
12
Months of Follow-up
Months
of Follow-up
Plac 6303
5780
4664
3600
2388
Clop 6259
5866
4779
3644
2418
N Engl J Med. 2001
PCI-CURE:
Study Design
CURE
PCI-CURE
Pretreatment N=2,658 patients undergoing PCI
Open-label thienopyridine
PLACEBO
+ ASA
R
N = 1345
PCI
30 d. post PCI*
Follow-up
(to 12 m
after rand.)
Open-label thienopyridine
CLOPIDOGREL
N = 1313
+ ASA
Pretreatment
*1o Outcome: CV Death, MI, Urg Revasc.
Mehta SR et al. Lancet 2001:358:527-33
12.6%
0.10
Placebo
8.8%
0.05
Clopidogrel + ASA
RR 0.69
95% CI 0.54-0.87
P=0.002
0.0
Cumulative Hazard Rate
0.15
PCI-Cure : Overall Results: CV Death or MI
010 40
A=median time to PCI
B=30 days after PCI
A B
100
200
300
400
Days following PCI
Mehta SR et al. Lancet 2001:358:527-33
PCI-Cure : CV Death or MI at Various Intervals
RRR: 31%
CV death or MI (%)
14
12
32%
34%
21%
12,6
Placebo
Clopidogrel
*
10
8
8,8
6
5,1
4
4,4
3,9
3,6
2
2,9
3,1
0
Overall Before
PCI
*P=0.002
PCI to 30 d. to
30 d.
1 yr
Mehta SR et al. Lancet 2001:358:527-33
CHARISMA - Design
Clopidogrel
75mg o.d.
(n = 7,600)
Patients
aged 45 years or older
R
Double-blind treatment up to 1,040 primary efficacy events*
at high-risk
of atherothrombotic event
Placebo
1 tab o.d.
(n = 7,600)
All patients receiving ASA 75–162 mg o.d.
* event driven trial, approximately 15,000 patients
R = Randomization
Distribution of Responsiveness to Clopidogrel in 544
Individuals
A Normal Distribution: Consistent with a Poly-Genetic
and Poly-Environmental Influence
112
96
Number of
patients
Who is a
Non-Responder?
80
64
48
32
16
0
<= -20
[-10,0] [11,20] [31,40] [51,60] [71,80] [91,100]
Change in Aggregation to 5µM ADP
Serebruany V. JACC 2004; In press
FT
Plaquette
Plaquette
FIX
FVII
FIXa
FVIIIa
FVIIa
Inhibiteurs
FX
Plaquette
FXa
FVIII
FVa
FII
FV
Thrombine
Fibrinogène
Plaquette
Fibrine
Coagulation
Les antiagrégants plaquettaires dans la fibrillation auriculai
FT
Plaquette
Plaquette
FIX
FVII
FIXa
FVIIIa
FVIIa
Inhibiteurs
FX
Plaquette
FXa
FVIII
FVa
FII
FV
Thrombine
Fibrinogène
Plaquette
Fibrine
Coagulation
Les antiagrégants plaquettaires dans la fibrillation auriculaire