Antithrombotiques

• Antiagrégants plaquettaires

• Anticoagulants

Les Antiagrégants Plaquettaires

P2Y12

Plateletactivatio

n

TXA2

Aspirin -

Ticlopidine

Clopidogrel

Prasugel

-ADP

Antiplaquettaires

Activemetabolit

e

-

Ticagrelor

Cangrelor

Elinogrel

Les indications

• Toutes les localisations de l’athérosclérose

– Maladie coronaire stable– Syndrome coronarien aigu (SCA) (infarctus –

angor instable)– Angioplastie coronaire percutanée– Artériopathie– AVC/AIT (si Absence indication à

l’anticoagulation)

Les preuves pour l’aspirine en prévention secondaire

Antithrombotic Trialist Collaboration

Antithrombotic Trialist Collaboration. BMJ2002;324:71–86

% Odds ReductionAcute MIAcute CVA Prior MIPrior CVA/TIA

Other high riskCVD (e.g. unstable angina, heart failure)PAD (e.g. intermittent claudication)High risk of embolism (e.g. Afib)Other (e.g. DM)

All trials1.0

0.5

0.0

1.5

2.0Control betterAntiplatelet better

Effect of aspirin on Death, MI and stroke

Les associations d’AAP

• Indication des associations de plusieurs antiagrégants plaquettaires

– SCA pendant 1 an avec ou sans angioplastie coronaire

– Angioplastie coronaire percutanée pendant 1 mois à 1 an selon les cas

• Aspirine plus un des Inhibiteurs du récepteur P2Y12 à l’ADP

Aucune indication à ce jour à associer

Clopidogrel + ASA*

3 6 9

Placebo + ASA*

Months of Follow-Up

11.4%

9.3%

0 12

* In combination with standard therapy

Primary End Point - MI/Stroke/CV-DeathCURE

Biological data: Prasugrel

14 Days

IPA (%; 20 µΜ µΜ µΜ µΜ Α∆Π)Α∆Π)Α∆Π)Α∆Π)

P<0.0001

Prasugrel 10 mg

Clopidogrel 150 mg

IPA (%; 20 µΜ µΜ µΜ µΜ Α∆Π)Α∆Π)Α∆Π)Α∆Π)

Hours

P<0.0001 for eachn=201

Prasugrel 60 mg

Clopidogrel 600 mg

DISPERSE 2 Study

Storey RF, et al. J Am Coll Cardiol. 2006;47(suppl A):204A. Abstract 821-3.

Inhibition of Platelet Aggregation Induced by ADP 20 µM (Final Extent, Day 1)

Ticagrelor 90 mgTicagrelor 180 mgTicagrelor 270 mgClopidogrel 300 mg

0 2 4 6 8 10

12

0

25

50

75

100

Time Postdose, h

IPA

, % (

Mea

n ±± ±±

SE

M)

Biological data: Ticagrelor

0

5

10

15

0 30

60

90

180

270

360

450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Temps (Jours)

Evè

nem

ents

(%

)

12.1

9.9

↓↓↓↓138évènements

Primary endpoint

Décès cardiovasculaires / IDM / AVC NNT = 46

Primary Endpoint (composite of CV death, MI or stroke)

No. at risk

ClopidogrelTicagrelor

9,2919,333

8,5218,628

8,3628,460

8,124

Days after randomisation

6,7436,743

5,0965,161

4,0474,147

0 60

120

180

240

300

360

1211109876543210

13

Cum

ulat

ive

inci

denc

e (%

)9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

p=0.03* p=0.025*

7

6

5

4

3

2

1

0

2.8

2.2

Sécurité = Saignements TIMI Majeurs non liés pontage

1.8

2.4

p=0.001*

2.7

3.7

450 days

AS

A o

nly

360 days360 days

+38% +32% +27%

TicagrelorClopidogrel 75

Prasugrel

TRITON PLATOCURE

Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010

Les Risques

Les Anticoagulants(per os)

Les principales indications

� Fibrillation atriale

� Thrombus dans les cavités cardiaques

� Phlébite, embolie pulmonaire et Prévention de TVP

� Prothèses valvulaires mécaniques aortique, mitrale

AVK

� Inhibe les facteurs II, VII, IX et X

� modifient l’INR => mode de surveillance biologique

Temps d’objectif thérapeutique atteint

65%

Les Risques

Le risque hémorragique

Les Risques

Eléments influant sur l’INR

Attention aux interactions médicamenteuses : ATB

Antidote des AVK

• Vitamine K ou les facteurs de coagulation

Nouveaux anticoagulants

• Dabigatran (PRADAXA*) :Inhibiteur directe de la thrombine. Elimination rapide 24h.

• Rivaroxaban (XARELTO*) : Anti Xa per os. Elimination en 24h.

• Apixaban (ELIQUIS*) : Anti Xa per os. Elimination en 24h.

Nouveaux anticoagulants

• Indication : prévention phlébite post-op et traitement de EP

• FA• Pas d’indication dans les valvulopathies• Avantages : pas d’INR, demi-vie courte• Inconvénients : Pas d’antidote pour le

moment, pas de surveillance possible de la prise et de compliance

Nouveaux anticoagulants

NEW ORAL ANTICOAGULANTS VS WARFARIN IN NON-VALVULAR ATRIAL

FIBRILLATION

• All randomized; RE-LY unblinded

• All designed as non-inferiority trials

• Primary outcome was stroke or embolism

• All funded by drug manufacturer

Trial Drug being compared

# subjects CHADS2(mean)

TTR under VKA

(mean)

RE-LY Dabigatran(two doses)

18,113 2.1 64%

ROCKET-AF Rivaroxaban 14,264 3.5 58%

ARISTOTLE Apixaban 18,201 2.1 62%

NEJM 2009; 361: 1139 NEJM 2011; 365:883 NEJM 2011; 365:981

NEW ORAL ANTICOAGULANTS VS WARFARIN: STROKE RISK

NEW ORAL ANTICOAGULANTS VS WARFARIN: BLEEDING RISK

NEW ORAL ANTICOAGULANTS VS WARFARIN: MORTALITY

Dabigatran vs warfarin for acute VTEThe RE-COVER trial

Treatment VTE recurrence Major bleeding Any bleeding

Dabigatran 2.4% 1.6% 16.1%

Warfarin 2.1% 1.9% 21.9%

NEJM 2009; 361: 2342

Conclusion: A fixed dose of dabigatran is as effective and safe as warfarin for treatment of acute venous thromboembolism

Rivaroxaban for acute VTEThe EINSTEIN-DVT trial

Treatment Recurrent VTE Bleeding

Rivaroxaban 2.1% 8.1%

Standard treatment 3.0% 8.1%

NEJM 2010; 363: 2499

Conclusion: rivaroxaban is as effective and safe as standard treatment for acute VTE

Plus• Rapid onset of action – can

use for initial Rx, no bridging

• Fewer drug interactions

• No known food interactions

• Less genetic variation in dose-response

• Less dependent on liver metabolism than VKAs

• No routine monitoring, fixed dose

• Patient convenience

• More cost-effective?

MinusRisk of bleeding in patients with

impaired kidney function

Harder to determine compliance or overdose

Expense (vs VKAs)

Short half-life → greater risk of treatment failure with missed doses?

Rebound effect? (Doubtful)

Antidote or reversing agent?

Potential for overuse?

Les plus et les moins

merci