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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





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





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





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


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


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

Documents

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