Prasugrel au SMUR / Urgences ?

Frédéric Munoz / Thierry Carrères Argenteuil

Conflits d’intérêts

Je ne suis pas un garçon intéressé…

Ma femme ne travaille plus chez Lilly !

Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events--a novel insight into plaque rupture by scanning electron microscopy.

Abela GS et al. Scanning 2006;28:1-10.

0 200 400 600 8000

20

40

60

80

100FibrinRed CellsPlateletsWhite CellsMixed Cells-FibrinCholesterol Crystals

Ischemic Time (min)

Thro

mbu

s Co

mpo

sitio

n (%

)

Dynamic thrombus formationInfluence of Time

Fibrin r=0.38, p=0.01

Platelets r=-0.34, p=0.02

Silvain J et al. JACC In press

Avis de recherche: AAP idéal

Effet rapide

Effet puissant

Effet constant

Sans effet secondaire délétère

Clopidogrel and Prasugrel: active metabolite plasma concentrations following oral loading dose

Time From Dose (hours)

Pla

sm

a C

on

cen

trati

on

(n

g/m

L)

Clopidogrel300 mg LD

Prasugrel60 mg LD

0 6 12 18 24

0

100

200

300

400

500

600

Payne C et al. Thromb Haemost 2005;3(Supplement 1):P0952 AM=Active metabolite; LD=Loading dose

Inhibition of Platelet Aggregation in Healthy Volunteers

• Data are expressed as mean ± SEM. Arrows (↓) indicate day of dose administration

Payne CD et al. J Cardiovasc Pharmacol 2007;50(5):555-562

IPA

% (

20 m

M A

DP

)

Loading Dose Maintenance Doses

Time

-10

0

10

20

30

40

50

60

70

80

90

100

2 3 4 5 6 7 8 90.25 0.5 1 2 4 6

‡

*

* * * * ** * * * * *

†

†

‡ ‡‡

*

Pre-doseIPA

Day 1, Hours Days

Clopidogrel 600 mg/75 mg

Clopidogrel 300 mg/75 mg

Prasugrel 60 mg/10 mg

IPA=Inhibition of platelet aggregation; ADP=Adenosine diphosphate

* p<0.001 Prasugrel vs Clopidogrel† p<0.05 Clopidogrel 600 mg vs 300 mg‡ p<0.001 Clopidogrel 600 mg vs 300 mg

Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI

Hours

IPA

% (

20 µ

M A

DP

)

Prasugrel 60 mg

***p<0.0001 Prasugrel vs. Clopidogrel

Clopidogrel 600 mg

*********

***

0.5 4 8 12 16 20 24

0

20

40

60

80

100

62

IPA=inhibition of platelet aggregation; PCI=Percutaneous coronary intervention Wiviott SD et al. Circulation 2007;116(25):2923-2932

Crossover Study in Healthy Subjects

Relationship between individual responses to prasugrel and clopidogrel, (administered in crossover fashion) as measured by IPA at 24 h postdose

IPA

% (

20 m

M

AD

P) In

hib

itio

n o

f P

late

let

Ag

gre

ga

tio

n (

%)

-20

-10

0

10

20

30

40

50

60

70

80

90

100

Clop 300 mg Pras 60 mg

20 μM ADP

Background Variability

Background Variability

Clopidogrel300 mg LD

Prasugrel60 mg LD

Brandt JT et al. Am Heart J 2007;153(1):66.e9-16

0

2

4

6

8

0 1 2 3

1

0

3060 90 180 270 360 450

HR 0.82(0.71-0.96)P=0.01

HR 0.80(0.70-0.93)P=0.003

5.6

4.7

6.9

5.6

Days

Pri

mary

En

dp

oin

t (%

)

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance Dose

TRITON TIMI 38: Timing of Benefit(Landmark Analysis)

Avis de recherche: AAP idéal

Effet rapide

Effet puissant

Effet constant

Sans effet secondaire délétère

TRITON-TIMI 38: Efficacy / Safety

TIMI major bleed

Life threaten-

ing

TIMI major or minor

0

1

2

3

4

5

6

clopidogrel

prasugrel

2,4

0,9

1,4

3,8P=0.03

P=0.01

P=0.002

Wiviott et al. New Engl J Med 2007;357:2001-2015

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)

Days

CV

Death

, M

I, S

troke (%

)

12.1

9.9

NNT= 46

Prasugrel

Clopidogrel

P<0.001

1,8

5,0

p=0.03* p=0.025*

9K

-M e

stim

ated

rat

e

8

7

6

5

4

3

2

1

0

2.8

2.2

SAFETY: TIMI Major Non-CABG Bleeds (12-15 months)

1.8

2.4

p=0.001*

2.7

3.7

450 days

AS

A o

nly

360 days360 days

+27% +25% +22%

TicagrelorClopidogrel 150Clopidogrel 75

Prasugrel

1.04 0.95

30 days !

CURRENT TRITON PLATOCURE

Net Clinical Benefit: Death, MI, Stroke, Major Bleed (non CABG)

0

5

10

15

0 30 60 90 180 270 360 450Days

En

dp

oin

t (%

)

HR 0.87(0.79-0.95)

P=0.004

13.9

12.2

Prasugrel

ClopidogrelITT= 13,608

Events per 1000 pts

MIMajor Bleed(non CABG)

+

Net Clinical Benefit: Bleeding Risk Subgroups

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)

+ 54

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel Better

HR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysis

Wiviott SD, Braunwald E, McCabe CH et al NEJM 2007

All ACS/PCI patientsN=13608

UA/NSTEMI patients

N=10074

STEMI patientsN=3534

Primary PCIN=2438 (69%)

Secondary PCI

N=1094 (31%)*

Clopidogrel

N=1235

PrasugrelN=1203

Clopidogrel

N=530

PrasugrelN=564

Montalescot et al. ESC 2008

TRITON-TIMI 38 STEMI

* 2 patients were missing data for primary or secondaryBefore knowledge of coronary anatomy

TRITON STEMI :Primary EP (CV death, MI and stroke at 15 months)

Montalescot et al. ESC 2008

Time (Days)

5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

port

ion

of

pati

en

ts (

%)

9.5

6.5

12.4

10.0

HR=0.79 (0.65–0.97) NNT=42

p=0.02RRR=21

%p=0.002

RRR=32%

ClopidogrelPrasugrel

Age-adjusted HR=0.81 (0.66-0.99)

TIMI major or minor non-CABG bleeding

Montalescot et al. ESC 2008

2

5.1

4.74

6

HR=1.07 (0.79–1.47) NNH=250

0 100 200 300 4000

Time (Days)

Pro

port

ion

of

pati

en

ts (

%)

50 150 250 350 450

p=0.65

ClopidogrelPrasugrel

Age-adjusted HR=1.14 (0.83-1.55)

TRITON: Efficacy for IIb/IIIa use. Prasugrel triple AP therapy more effective and as safe as Clopidogrel triple AP Therapy

ALL NEVER IIb/IIIA IIb/IIIaPRASUGREL 9.9% 9.3% 10.4%CLOPIDOGRE

L12.2% 11.0% 12.9%

Percentage of subjects reaching the Primary Endpoint

The trial was not randomized against GP IIb/IIIa inhibitors. As its use was left to the discretion of the physicians, patients receiving GPI were likely to be at higher risk for ischemic events.

En résumé…

Effet rapide >> clopidogrel

Effet puissant >> clopidogrel

Effet constant >> clopidogrel

Risque hémorragique > clopidogrel Population à risque identifiée

GP IIbIIIa possibles dans le STEMI / souhaitables ?

23

ESC Guidelines 2010Drug COR LOE

NSTE-ACSAspirin I C

Clopidogrel (600mg ASAP) I C

Clopidogrel (for 9-12mo after PCI)

I B

Prasugrel IIa B

Ticagrelor I B

STEMIAspirin I B

Clopidogrel (600mg ASAP) I C

Prasugrel I B

Ticagrelor I B

European Heart Journal 2010

Prasugrel dans le camion ?

Aucun data avec le clopidogrel…

SCA ST+ Fibrinolyse Risque hémorragique élevé ATCD AVC / AIT, âge > 75 ans (?), poids < 60 kg (?) Pas de Prasugrel

SCA ST+ Pas d’ATCD hémorragique récent Pas d’ATCD d’AVC / AIT Âge < 75 ans, poids > 60 kg (?) Prasugrel

SCA ST- : Prasugrel ?

SCA ST- : stratifier Risque thrombotique élevé

Score GRACE

Risque hémorragique bas Score CRUSADE

Pas d’ATCD hémorragique récent Pas d’ATCD d’AVC / AIT Âge > 75 ans, poids > 60 kg (?) Prasugrel

…merci de votre attention !

Score de risque dérivé de GRACE

26http://www.outcomes-umassmed.org/externalwindow.cfm?URL=http://www.outcomes.org/grace/acs_risk/acs_risk.html&Link=http://www.outcomes-umassmed.org/GRACE/index.cfm&DeptName=Center%20for%20Outcomes%20Research

Classification saignement TIMI

Majeur Hémorragie intracrânienne, saignement cliniquement évident (y compris visualisation par imagerie) avec chute de l’hémoglobine ≥ 5 g/dl

Mineur Saignement cliniquement évident (y compris visualisation par imagerie) avec chute de 3 à 5 g/dl de l’hémoglobine

Minime Saignement cliniquement évident (y compris visualisation par imagerie) avec chute de l’hémoglobine < 3 g/dl

Classification saignement GUSTOSévère ou mettant en jeu le pronostic vital

Hémorragie intracrânienne ou saignement provoquant une instabilité hémodynamique nécessitant une intervention

Modéré Saignement nécessitant une transfusion sanguine, mais n’entraînant pas d’instabilité hémodynamique

Faible Saignement ne répondant pas aux critères des saignements sévères ou modérés

27Bassand JP, et al. The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. European Heart Journal 2007, 28:1598-1660

STEMI PatientsSubgroup analysis by time of LD relative to

PCI

TRITON STEMI: TIMI major non-CABG bleeding

Montalescot et al. ESC 2008

0.5

1.0

2.0

2.5

1.5

2.1

2.4

HR=1.11 (0.70–1.77) NNH=333

Pro

port

ion

of

pati

en

ts (

%)

Time (Days)

p=0.65

0 100 200 300 4000

ClopidogrelPrasugrel

Age-adjusted HR=1.19 (0.75-1.89)

TIMI life-threatening non-CABG bleeding

Montalescot et al. ESC 2008

HR=1.11 (0.59–2.10) NNH=500

Lif

e t

hre

ate

nin

g b

leed

ing

(%

)

Time (Days)

p=0.75

ClopidogrelPrasugrel

Age-adjusted HR=1.20 (0.63-2.26)

TRITON: Safety for IIb/IIIa use: No differences between Prasugrel and Clopidogrel at 3 days.

ALL ACS UA/NSTEMI STEMIIIb/IIIa

No Use

IIb/IIIa

Any Use

IIb/IIIa

No Use

IIb/IIIa

Any Use

IIb/IIIa

No Use

IIb/IIIa

Any Use

PRASUGREL 0.84 1.64 0.9 1.37 0.62 2.29

CLOPIDOGREL 0.46 1.65 0.54 1.20 0.16 2.71

The Co-Administration of a GP IIb/IIIa inhibitor with the loading dose increased the risk of instrumentation related TIMI major bleeding in both

prasugrel- and clopidogrel-treated subjects, particularly in the STEMI population.

Prasugrel dans le camion ?