elalamy diabète et aap sfa 2009
TRANSCRIPT
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ANTIPLAQUETTAIRES ET DIABETEANTIPLAQUETTAIRES ET DIABETE
INTERETS ET LIMITESINTERETS ET LIMITES
I. ELALAMYI. ELALAMY
UNITE HEMOSTASE-THROMBOSEUNITE HEMOSTASE-THROMBOSE
HOPITAL TENONHOPITAL TENON
PARISPARIS
1947 _ 2010 1947 _ 2010
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DIABETE MALADIE VASCULAIRE
3 à 5% de la population «occidentale»
170 M => 350 M en 2030
athérosclérose accélérée
micro et macro-angiopathie +++
co-morbidité avec d’autres facteurs de risque
vasculaires
risque d’AVC, d’IDM, décès cardio-vasculaire x 2 à 4
maladie coronarienne : principale cause de
mortalité
Moreno & Fuster, J Am Coll Cardiol 2004
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DIABETE ET THROMBOSE
athérothrombose : 1ère cause de mortalité
fréquence de l’ischémie silencieuse +++
atteinte plus sévère : pluri-tronculaire (DID)
sténoses multiples
réserve fonctionnelle
coronaire
fragilité des plaques +++
atteinte pariétale +++ : vascoconstriction et
hyperglycémie
hyperplasie néointimale
Moreno & Fuster, J Am Coll Cardiol 2004
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DIABETE ET HYPERAGREGABILITE
adhésivité (récepteurs, willebrand, CD62…)
réponse aux agonistes (ADP, AA, collagène,
thrombine…)
génération de TxA2
turn-over, hyperploïdie des mégacaryocytes
sécrétion granulaire (PDGF, TG, PECAM-1…)
interactions cellulaires (endothélium,
leucocytes…)
Sobel & Schneider, Cur Opin Pharmacol 2005
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dysfonction endothéliale : profil
«vasoconstricteur»
défaut de réponse au NO ( NO circulant)
activité procoagulante plaquettaire
(prothrombinase)
libération accrue de microparticules
complexes TAT, F1+2, FPA
facteur tissulaire, VIIa, VIII…
hypofibrinolyse : PAI, tPA
DIABETE ET HYPERCOAGULABILITE
Cola et al, Vascular Health and Risk Management 2009
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0
0,5
1
1,5
2
2,5
3
3,5
PM
P/m
l
Controls Diabetics Diabetics withatherosclerosis
Platelet microparticles and markers of platelet activation in diabetic patientsPlatelet microparticles and markers of platelet activation in diabetic patients
sCD40L (ng/ml)
43(31-65)
885(139-1282)
643(106-1172)
p<0,001
p<0,046
n=18 n=21n=18
Tan KT and Lip GYH. Diabet Med 2005
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Polynucléaire Polynucléaire neutrophileneutrophile
Polynucléaire Polynucléaire neutrophileneutrophile MonocyteMonocyteMonocyteMonocyte
CD62CD62
PSGL-1RANTES
Plaquette Plaquette activéeactivée
Plaquette Plaquette activéeactivée
EndotheliumEndotheliumEndotheliumEndothelium
CD62CD62
PSGL-1PAF
ActivationActivation ActivationActivation
COMPLEXES LEUCO-PLAQUETTAIRES
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COMPLEXES LP ET DIABETE
*p < 0.01
*
0
10
20
30
40
50
Controls Patients Type 1 Type 2
PPA
PMA
*
**
*
*
Perc
en
tag
e %
Elalamy et al, Thromb Res 2009
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CLP ET LESIONS VASCULAIRES
* p<0,05
** p<0,01
0
10
20
30
40
50
60
Without
lesions
With
lesions
PPA
PMA
**
*
n=27 n=38Perc
en
tag
e %
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CLP=MARQUEURS D’ANGIOPATHIE?
n
PPA
PMA
0
27
18±7(9-33)
38±13(15-68)
1
18
21±11(5-42)
46±18(16-72)
2
11
28±17(10-66)
54±21(25-77)
≥3
9
34±9(13-69)
63±11(39-87)
Number of vascular damaged territories
p<0,05
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CLP ET DIABETE
Circulating PLA = increased cellular reactivityCirculating PLA = increased cellular reactivity
mitogenic factors (PDGF, VEGF), vasoconstrictors (TxAmitogenic factors (PDGF, VEGF), vasoconstrictors (TxA22))
capillary microembolisationscapillary microembolisations
thromboses thromboses PPA≥18% PPA≥18% OR=6 (95%IC:1.6;23) vascular lesions OR=6 (95%IC:1.6;23) vascular lesions PMA≥38%PMA≥38% OR=19 (95%IC:2.3;154) retinopathyOR=19 (95%IC:2.3;154) retinopathy
Markers of inflammatory and prothrombotic phenomenon? Markers of inflammatory and prothrombotic phenomenon?
Potentiel interest in patients risk stratification?Potentiel interest in patients risk stratification?
Potential interest in therapeutic survey?Potential interest in therapeutic survey?
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DIABETE type 2, OBESITE ET ACTIVATION PLAQUETTAIRE
Schneider et al, Diabetes Care 2009
Mais pas de corrélation BMI et augmentation de FPA et/ou F1+2
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Angiolillo, Diabetes Care 2009
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Options for antiplatelet treatmentOptions for antiplatelet treatment
• Single antiplatelet agent– Aspirin 75 mg – 325 mg/o.d.– Clopidogrel
• 75 mg o.d.• 300 mg or 600 mg bolus
• Dual antiplatelet treatment– Aspirin (75 mg – 325 mg) + clopidogrel (75 mg) o.d. (CURE)– AAP +Anti-GPIIb-IIIa : mortalité CV de 70%
ATC, BMJ 2002 & ADA , Diabetes Care 2004
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• SYNTHESE PERSISTANTE DE TxA2
- coopération plaquettes-cellules endothéliales : (Karim et al., 1996)
- coopération plaquettes-cellules monocytaires :
(Cippollone et al., 1997)
• ACTIVATION PLAQUETTAIRE INDEPENDANTE DU TXA2
- shear-stress, thrombine…
- coopération plaquettes-érythrocytes(Santos et al., 1997)
LIMITES DE L’ACTION DE L’ASPIRINE
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Cellule endothélialeou monocyte
Plaquette
PGH2
Cox-1
Aspirine faible dose
XAA
AA PGH2Cox-1COX-2
X
Inflammation
PGH2
TxA2
TxA2
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CAPRIE: primary efficacy end-point. Subgroup-analysis
CAPRIE: primary efficacy end-point. Subgroup-analysis
-60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60Aspirin better Clopidogrel better
Relative Risk Reduction (%)
Stroke (p/ys=12033)
AMI (p/ys 11630)
PAD (p/ys 11592)
All patients (p/ys=35155)
p=0,26
p=0,66
p=0,0028
p=0,043
CAPRIE Lancet 1996;348:1329–1339.
19185 patients with atherosclerotic vascular disease (recent stroke, AMI, or symptomatic PAD)
Clopidogrel vs aspirin
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Efficacy of Clopidogrel versus aspirin in high risk patients in the CAPRIE Study
Efficacy of Clopidogrel versus aspirin in high risk patients in the CAPRIE Study
0 50 100 150 200 250
196total CAPRIEpopulation
16
50
41
48
77
previous CABG
history>1 ischemicevent
multiple vascularbeds
diabetes
hypercholesterolemia
number of treated patients to prevent 1 ischemic episode/yearHirsh et al Arch Intern Med, 0ct 2004;164:2106-2110
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BI-THERAPIE CHEZ PATIENTS NSTEMI (n=12562)
OU AVEC ANGIOPLASTIE (n=2658)
Hirsh et al, Arch Intern Med 2004
Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)
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BI-THERAPIE ET PREVENTION ISCHEMIQUEClopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA)
Wang et al, Eur Heart J 2007 & Bhatt et al, JACC 2007
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BI-THERAPIE ET RISQUE HEMORRAGIQUECHARISMA
Wang et al, Eur Heart J 2007
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<44%44% - 52%52% - 62%>62%
months
Event-free survival from cardiovascular events according to platelet response in patients with
diabetes type 2
173 patients with CADChronic dual antiplatelet treatment
Agniolio et al J Am Coll Cardiol 2007
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Wiviott et al, Circulation 2008
(n=3 146)
(n=10 462)
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Wiviott et al, Circulation 2008
PRASUGREL versus CLOPIDOGREL
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Wiviott et al, Circulation 2008
PRASUGREL versus CLOPIDOGREL
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Wiviott et al, Circulation 2008
PRASUGREL versus CLOPIDOGREL
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Wiviott et al, Circulation 2008
PRASUGREL versus CLOPIDOGREL
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cytokines
CD40L
Inflammatory reaction
MMP
TF
COX-1TxA2
Thrombin
ASA-insensitiveplatelet activation
ASA-sensitive TxA2 synthesis
ASA-insensitiveTxA2 synthesis Platelets
AGEs
ROS
Hyperglycemia
Hyperinsulinemia Insulin Resistance
Dyslipidemia
Hypertension
DIA
BE
TE
S
Platelet reactivity Leukocyte adhesion TF expression TF expressing microparticles ROS production
Endothelial dysfunctions Adhesive molecules Chemokines COX-2 TxA2
PgI2
NO PAI-1
Circulating cells dysfunctions
Atheroscleroticplaque
Plaque instability
COX-2
Evangelista V. Thromb Haemost. 2005
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ACTIVATION PLAQUETTAIRE: Clé de voûte de l’athérothrombose
•Sécrétion
•Agrégation
•Inflammation
ActivationAtteinte
Vasculaire
IDM, Stroke ou Décès
Contrôle effectif de la réactivité cellulaire et de l’hypercoagulabilité
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Belch et al, BMJ 2008
Diabetes Type 1 and 2, age ≥ 40, Ankle Brachial Pressure ≤0.99
100 mg/d
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Belch et al, BMJ 2008
Composite end point : death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or amputation above the ankle for critical limb ischaemia
18.2% vs 18.3% HR 0.98 (95% CI 0.76 to 1.26). p=0.86
p=0.36
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Belch et al, BMJ 2008
proportion of patients who died from any cause, compared with proportion expected based on age and sex specific population rates for Scotland, 2002
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PLavix Use for Treatment Of Diabetes (PLUTO-Diabetes) trial
AGRP
AA
AGRP
ADP 5
Verify Now
PRU
PFA-100
CADP
PAC-1
IMF
PAR-1
IMF
Asp 2312 676 15219 21329 101.7 426Asp+cl
op2519 667 14421 21828 101.4 445
Asp 2312 678 14622 21529 101.5 445Asp+cl
op2616 3510
*8223* 25137* 81.8* 455
Serebruany et al Am Heart J 2008
* p<0.001
Diabétiques :- Existence de RPR malgré association d’AAP- Expression des récepteurs à la thrombine non modifiée