Jean-philippe.collet@psl.aphp.frInstitut de Cardiologie – Inserm 937Institut de Cardiologie – Inserm 937Pitié-Salpêtrière University HospitalPitié-Salpêtrière University Hospital

75013 Paris75013 Paris

Nouveaux Antiplaquettaires, Nouveaux Risques?

Poitiers le 19 septembre 2009

0

0,5

1

1,5

2

2,5

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Rapport AFSSAPS juillet 2005, Données GERS

Aspirine à faible doseClopidogrel

Traitement-années (millions)

2 200 000 traitements-années

840 000 traitements-années

Traitements antiagrégants en France

Platelet Activation Mechanisms

ThrombinThrombin

ThromboxaneThromboxaneAA22

5HT5HT

P2Y12

ADPADP ADPADPADPADP5HT5HT

PLATELETPLATELETACTIVATIONACTIVATION

P2Y15HT2A

PAR1

PAR4

Densegranule

ThrombinThrombingenerationgeneration

ShapeShapechangechange

IIb3

IIb3

FibrinogenFibrinogenIIb3

AggregationAggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsCoagulation factorsInflammatory mediatorsInflammatory mediators

TPa

CoagulationCoagulation

GPVI

CollagenCollagen

ATPATPATPATP

P2X1

ASPIRINASPIRIN

x TICLOPIDINETICLOPIDINECLOPIDOGRELCLOPIDOGRELPRASUGRELPRASUGREL

ACTIVE ACTIVE METABOLITEMETABOLITE

x AZD6140 AZD6140 CANGRELORCANGRELOR

GP IIb/IIIa ANTAGONISTSGP IIb/IIIa ANTAGONISTS

xxStorey RF. Curr Pharm Des. 2006;12:1255-59.

C18886C18886

xSCH530348SCH530348

Une success Story

CClopidogrel vs lopidogrel vs TTiclopidine on 30-day MACEiclopidine on 30-day MACE

Bhatt DL et al. J Am Coll Cardiol 2002;39:9–14

Odds ratios & 95% CITrial n

Overall

N. Memorial

Mayo

Lenox Hill

CCF

Müller

TOPPS

CLASSICS

13,880

1,378

2,827

2,565

2,369

700

941

1,020

Wash. Hosp. 844

0.50 (0.40, 0.61)p = 0.001

S. Illinois 875

Ticlopidine betterClopidogrel better

0.1 1 10

Wessex 361

Clop. Ticl.

2.0%

0.8%

0.6%

2.4%

5.7%

3.1%

2.6%

1.3%

4.0%

2.2%

1.6%

3.8%

8.9%

2.0%

3.5%

0.9%

2.0% 0.5%

2.1% 1.4%

2.3% 5.3%

PPlavix lavix RRobust obust CClinical linical RResearch esearch PProgramrogram

More than 100,000 patients in the clinical program…More than 100,000 patients in the clinical program….... and more than 70 million of patients treated to date.... and more than 70 million of patients treated to date

Published Trials

Ongoing Trials

Publication Date Expected Date of Results

CAPRIE

1996

CAPRIE CAPRIECAPRIE

CLASSICS CLASSICS CLASSICS

CURE(PCI-CURE)

CURE(PCI-CURE)

CREDO

2000 2001 2002

CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE

CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS

CURE(PCI-CURE)

CURE(PCI-CURE)

CURE(PCI-CURE)

CURE(PCI-CURE)

CURE(PCI-CURE)

CURE(PCI-CURE)

CREDO CREDO CREDO CREDO CREDO CREDO

20042004 2007200620052005

MATCH MATCH MATCH MATCH MATCH MATCH

CLARITY CLARITY CLARITY CLARITY CLARITY

COMMITCCS2

COMMITCCS2

COMMITCCS2

COMMITCCS2

CHARISMA CHARISMA CHARISMA

CASPAR CASPAR

CARESS

2009

CARESS CARESS CARESS CARESS CARESS

MATCH

CREDO

CURE(PCI-CURE)

CLASSICS

CAPRIE CAPRIE

CLASSICS

CURE(PCI-CURE)

CREDO

MATCH

CLARITY

COMMITCCS2

CHARISMA

CASPAR

2009

CARESS

CURRENT

ACTIVEACTIVE

Indication in Indication in patients after patients after MI, IS, or with MI, IS, or with established established

PADPAD

Indication in Indication in UA/NSTEMI UA/NSTEMI

patientspatients

Indication in Indication in STEMI STEMI

patientspatients

PPrimary rimary OOutcome utcome (Stroke, MI, non-CNS Systemic Embolism, Vascular Death)(Stroke, MI, non-CNS Systemic Embolism, Vascular Death)

1000 patients treated for 3 years: – Prevent 28 strokes (17 fatal or disabling) and 6 myocardial infarctions– Cost 20 (non-stroke) major bleeds (3 fatal)

Indications

1. Poursuivre l’aspirine à faibles doses (75 à 162 mg/j)(Grade 1A). Il est suggéré de le poursuivre indéfiniment (Grade 2C)

2. Si maladie coronaire symptomatique= associer aspirine (75–100mg/j) et clopidogrel (75 mg/j) [Grade 2B]

3. Si DES, apirine (75–100mg/j) plus clopidogrel (75 mg/j pour au moins 12 mois) [Grade 1A pour 3 à 4 mois; Grade 1B pour 4 à 12 mois]. Après 1 an, poursuivre l’association indéfiniment en l’absence de saignement et si bonne tolérance (Grade 2C)

Maladie Coronaire Stable

(CHEST 2008; 133:71S–105S)

Aspirine seulTS: 0.5%Décès, IDM, AVC (TS exclus): 4%Saignement majeur: 0.5%

Dual OAT (aspirin and clopidogrel)TS: 0.35%Décès, IDM, AVC (TS exclus): 3%Saignement majeurr: 0.6%

5%5%

BBénéfice énéfice CClinique linique NNet et après 1 an de bithérapie après 1 an de bithérapie

4%4%

LLes es EEnjeux njeux PPratiques non ratiques non RRésolusésolus

La résistance aux AAP

La place des nouveaux

Interruption de la bithérapie

Interruption prématurée

Circulation 2007; 115

1. Chez les patients chez qui on suspecte une mauvaise compliancesuspecte une mauvaise compliance au plavix la première année, éviter le stent actif

2.2. En cas de chirurgie programméeEn cas de chirurgie programmée la première année, éviter le stent actif

3.3. L’éducationL’éducation sur la compliance et le risque d’interruption prématurée est une priorité

4.4. Les tutelles Les tutelles doivent être mises en garde sur le risque d’interruption prématuré, en doivent être mises en garde sur le risque d’interruption prématuré, en particulier le coût ne doit pas être une cause d’arrêt prématuréparticulier le coût ne doit pas être une cause d’arrêt prématuré

5.5. Différer toute intervention Différer toute intervention jusqu’à au moins 1 an après le mise en place d’un stent jusqu’à au moins 1 an après le mise en place d’un stent actif et 1 mois en cas de stent nuactif et 1 mois en cas de stent nu

6.6. En cas de stent actif, poursuivre aspirine et En cas de stent actif, poursuivre aspirine et reprende clopidogrel le plus reprende clopidogrel le plus rapidementrapidement

But : éliminer l’interruption prématurée des AAP But : éliminer l’interruption prématurée des AAP

DDiscontinuation of iscontinuation of SSingle/ingle/DDual OAT ual OAT

• 161 cases of late or very late stent thrombosis (84 articles)

Eisenberg et al. Circulation In press

DDiscontinuation of iscontinuation of SSingle/ingle/DDual OAT ual OAT

Eisenberg et al. Circulation In press

AAspirin spirin CComplianceompliance

Cuisset el al. Am H Journal In Press

Interruption après 1 an

Primary Endpoint (MI/Stroke/CV Death) in Patients with Previous MI, IS, or PAD

“CAPRIE-like Cohort”

RRR: 17.1 % [95% CI: 4.4%, 28.1%]p=0.01

Prim

ary

outc

ome

even

t rat

e (%

)

0

2

4

6

8

10

Months since randomization

0 6 12 18 24 30

Clopidogrel + ASA7.3 %

Placebo + ASA8.8 %

N=9,478

Bhatt DL et Al., JACC 2007.

Long-term Bleeding Risk?

Bhatt DL et al. J Am Coll Cardiol 2007;49:1982–1988.

0.00008

0.00007

0.00006

0.00005

0.00004

0.00003

0.00002

0.00001

015 60 135 270 450 630 810

Days since randomization

Haz

ard

func

tion

per d

ay

Placebo + ASAClopidogrel + ASA

KM from from Time of ime of Discontinuation to iscontinuation to first irst Event* vent* Placebo vs Clopidogrel

0 180 360 540 720 900

100

90

80

70

60

*Primary Efficacy Endpoint (death/MI/Stroke)*Primary Efficacy Endpoint (death/MI/Stroke)

----Clopidogrel Placebo

log-rank test, p=0.029

Average time from drug discontinuation to primary endpoint was 228 days (95% CI 197-258)

clopidogrel was an independent correlate for survival (HR 0.75; 95% CI 0.59-0.95, p=0.016)

Arch Cardiovasc Dis. 2009 Jun-Jul;102(6-7):485-96

Conlcusions1. Bithérapie indéfiniment chez tous (principe de précaution)

2. Monothérapie après 1an chez la majorité − Arrêt clopidogrel ? (principe économique)− Arrêt aspirine ? (principe de réalisme)

3. « A la carte » (principe de bon sens)− Multitronculaires − Multistentés− Petites artères− Post infarctus− Diabètiques− SAT ou nouvel évènement ischémique− Polyvasculaires− …

4. Aide à la décision ARCTIC; ISAR-SAFE

La résistance: un enjeu

EEffect of 900mg of ffect of 900mg of CClopidogrel LDlopidogrel LD

0

20

40

60

80

100

120

IRPA

(20

µMol

AD

P, %

)

900 mg600 mg300 mg

p=0.34

p=0.0008

p=0.017

First reloading dose

RELOAD Study RELOAD Study ((“REload with cLOpidogrel before coronary Angioplasty in subjects

treated long term with Dual antiplatelet therapy”)”

Inhibition of RPA 4 hours after the Inhibition of RPA 4 hours after the first reloading dosefirst reloading dose

P<.05 vs 300 mg LD

0

5

10

15

20

25

30

35

40

(%) I

nhib

ition

1 2 3 4 5 6

300 mg LD 600 mg LD 900 mg LD

Time (hours)The ALBION study (J ACC 2006;48:931– 8)

24

The ALBION trial(Assessment of the Best Loading Dose of Clopidogrel

to Blunt Platelet Activation, Inflammation and Ongoing Necrosis)

Maximum Inhibition of Platelet Maximum Inhibition of Platelet Aggregation Aggregation

(ADP 20 µmol/L(ADP 20 µmol/L))

Circulation. 2008 ;118(12):1225-33

2,4%3,1% 3,5%

1,4%2,4% 2,7%

8,6% 8,6%

10,5%

Cardiac Death Stent Thrombosis Cardiac Death andST

Overall (n=804) Responders (n=699) Non-Responders (n=105)

p<0.001p<0.001

p<0.001

Buonamici, J Am Coll Cardiol 2007;49:2312-7

The RECLOSE Study: 6 Month Outcomes After DES Implantation Stratified By Post-Plavix ADP-

mediated Platelet Reactivity

Non-responders defined as >70% aggregation by LTA 12 hours after 600-mg plavix load

« VASP-Guided » PCI after a first 600mg LD of clopidogrel

J Am Coll Cardiol 2008;51:1404–11

1

0.95

0.90

0.85

0.800 5 10 15 20 25 30days

(10 vs 0%, p=0.004)

1

0.95

0.90

0.85

0.800 5 10 15 20 25 30days

(10 vs 0%, p=0.004)

0 5 10 15 20 25 30days

(10 vs 0%, p=0.004)

MACE: CV death, MI, revasc.

Log rank p =0.007

1

0.95

0.90

0.85

0.800 5 10 15 20 25 30days

(10 vs 0%, p=0.004)

1

0.95

0.90

0.85

0.800 5 10 15 20 25 30days

(10 vs 0%, p=0.004)

0 5 10 15 20 25 30days

(10 vs 0%, p=0.004)

MACE: CV death, MI, revasc.

Log rank p =0.007

• Each LD by 35 to 49% suboptimal response

•14% patients remained suboptimal responders

• Average LD 1600 mg

BBenefit of enefit of HHigh igh LLoading oading DDose vs ose vs SStandard tandard LLoading oading DDose ose Death and MI within the first month of PCI Death and MI within the first month of PCI

Study or subcategory High loading Standard loading Peto OR Peto OR

n/N n/N 95% CI 95% CI Year

01 Randomized trials ALBION 2/68 1/35 1.03 [0.09, 11.50] 2006 ARMYDA-2 5/126 15/129 0.35 [0.14, 0.87] 2005 CLEAR PLATELETS 1/60 3/60 0.36 [0.05, 2.61] 2005 Cuisset et al 7/146 15/146 0.46 [0.19, 1.09] 2006 Gurbel et al 0/52 0/138 2005 ISAR-CHOICE 0/40 0/20 2005 Muller et al 0/10 0/10 2001Subtotal (95% CI)Subtotal (95% CI) 502 538502 538 0.42 [0.23, 0.75]Total events: 15 (High loading), 34 (Standard loading)Test for heterogeneity: Chi² = 0.75, df = 3 (P = 0.86), I² = 0%Test for overall effect: Z = 2.93 (P = 0.003)

02 Non-randomized studies Angiolillo et al 0/23 0/27 2004 Seyfarth et al 0/11 0/21 2003 Wolfram et al 13/319 4/126 1.28 [0.44, 3.74] 2006Subtotal (95% CI)Subtotal (95% CI) 353 174353 174 1.28 [0.44, 3.74]Total events: 13 (High loading), 4 (Standard loading)Test for heterogeneity: not applicableTest for overall effect: Z = 0.45 (P = 0.66)

Total (95% CI) 855 712 0.54 [0.32, 0.90]Total events: 28 (High loading), 38 (Standard loading)Test for heterogeneity: Chi² = 3.94, df = 4 (P = 0.41), I² = 0%Test for overall effect: Z = 2.36 (P = 0.02)

0.1 0.2 0.5 1 2 5 10 Favours high loading Favours low loading

Aucune augmentation du risque d’hémorragie majeure ou mineure (p=0.55 et p=0.98). Interaction significative entre le taux d’événement ischémique et le bénéfice clinique des fortes doses de charge

(p=0.005), suggérant que plus le risque est élevé et plus l’intérêt de forte de charge est important

La thrombose de stent : situation complexe

75 150 225 300 10 900 0

20

40

60

80

% R

PA (2

0µM

AD

P)

PrasugrelMD dose (mg)

Clopidogrel RD dose (mg)

Clopidogrel MD dose (mg)

p=0.0032 (Krukal Wallis)

A

Efficacité du Prasugrel

Thombose de stent sous clopidogrel

Facteurs multiplesFacteurs multiples Risque de récidiveRisque de récidive Prévalence de la résistance élevéePrévalence de la résistance élevée

Circulation. 2009 Jun 2;119(21):2854-7

La résistance: les causes

Dose Prescrite

Dose administrée

Concentration au site d’action

Effet

AbsorptionDistributionElimination

RécepteurEffecteur

Pharmacocinétique

Pharmacodynamique

– Non-observance– Erreur d’administration

– Facteurs pathologiques et physiologiques

– Facteurs environnementaux

– Facteurs génétiques

Sources de Variabilité de la Réponse aux Médicaments

Déterminisme génétique du métabolisme des médicaments

N Engl J Med 2008

Clopidogrel metabolism

S

N

Cl

O OCH3

S

N

Cl

O OCH3

O

HS

N

Cl

O OCH3

HOOC

CYP2C19CYP1A2CYP2B6

EsterasesEsterases

~85% Inactive

Metabolites

CYP3A4CYP2C19CYP2C9CYP2B6

CYP2C19*2 CYP2C19*2 681 G 681 G A A

Exon 4 Exon 5Intron 4

*1 (sauvage)

Exon 4 Exon 5Intron 4

*2 (muté)

Épissage aberrant

Exon 4 Exon 5

G681

A681

Protéine complète et fonctionnelle

Exon 4 Exon 5

Perte de 40bp dans l’exon 5

Décalage du cadre de lecture

Codon stop prématuréProtéine tronquée

et non-fonctionnelle

AFIJI Registry (STEMI<45yrs, n=259)death/non fatal MI /urgent revascularization

HR=3.66; 95%CI (1.69-8.05) p=0.0005Stent thrombosis3.31 [1.05-10.47]; p=0.04

CYP 2C19*1/*1*1/*2 or *2/*2

0 1 2 3 4 5 years

1.0

0.0

0.8

0.7

0.6

0.5

0.2

0.1

0.0

*1/*1 *1/*2 *2/*211/186 (5.9%) 13/64 (20.3%) 2/9 (22.2%)

Odds Ratio, fixed modelBilateral CI, 95% for trials, 95% for MA

events / size0 1 2 3 4 5 10 20Odds Ratio

Mega et al. (0.26)

Collet et al. (0.15)

Giusti et al. (0.34)

Sibbing et al. (0.24)

2C19*2 2C19*1

10/375 8/1014

8/73 4/186

13/247 11/525

10/680 7/1805

41/1375 30/3530

OR 3.45 95% CI: 2.14-5.57, p<0.001, phet=0.78

Total

STENT THROMBOSIS (n=4905)

2C19*2 better 2C19*2 worse

Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump

Inhibitors Following Acute Coronary Syndrome

JAMA. 2009;301(9):937-944

AOR=1.25; 95% CI (1.11-1.41)

Neither clopi nor PPIPPI without clopiClopi+PPIClopi without PPI

0 90 180 270 360 450 540 630 810 900 900 Period since discharge in days

0.7

0.6

0.5

0.4

0.3

0.3

0.1

0

Deat

h or

Reh

osp

for A

CS %

What We Do Not Know, Precisely

Clinical ResistanceClinical Resistance(thrombotic event)

Platelet resistancePlatelet resistance(low response on a functional test)

Genetic resistanceGenetic resistance(2C19*2)(2C19*2)

PHAO 2008 ARCTIC (Essai n° P080403)- Promoteur AP-HP

36

Evaluation du critère primaire de jugement tous les 6 mois (6 jusqu’à 18 mois)

1. Toute cause de mortalité 2. Infarctus du myocard3. Toute revascularisation urgente4. Thrombose de stent nécessitant une revascularisation ou non5. AVC ischémique nécessitant une nouvelle hospilisation

Groupe 2 : Bras Conventionnel

1- Pas d’évaluation de la réponse biologique au traitement antiplaquettaire

2- La stratégie antiplaquettaire orale est laissée à la discrétion de l’investigateur en fonction des pratiques habituelles

Groupe 1 : Bras Monitoré

1-Evaluation systématique de la réponse biologique à l’aspirine et au clopidogrel avant la mise en place de l’endoprothèse active.

2-Adaptation du traitement antiplaquettaire chez les hypo-répondeurs au moment de l’angioplastie

3-Réévaluation chez tous les patients à J30±3 de la réponse au traitement antiplaquettaire oral et ajustement du de la dose d’entretien

Randomisation avant implantation d’un stent actif

AAssessment with a double ssessment with a double RRandomization of 1) a monitoring-adjusted antiplatelet treatment andomization of 1) a monitoring-adjusted antiplatelet treatment vs.vs. a a CCommon antiplatelet ommon antiplatelet TTreatment for DES implantation, and 2) reatment for DES implantation, and 2) IInterruption nterruption vs. vs. CContinuation of double antiplatelet therapy one year after stentingontinuation of double antiplatelet therapy one year after stenting

Algorithme d’ajustement de la dose

ARU≥550 (cartouche ASA) %inh≤15% ou PRU≥235 ( cartouche P2Y12)

Recharge avec 500 mg ASAdoses d’entretien au choix

Inhibiteurs de la GPIIb/IIIa + recharge en clopidogrel (300-900mg) et dose d’entretien à 150

mg

Aspirine à 200 mg et fractionner clopidogrel sans limite supérieure

Patient prévu pour angioplastie élective avec DES et prétraité par aspirine et clopidogrel (pratiques

locales) et randomisés dans le “bras monitoring”

VerifyNow avant PCI : TM-Aspirin &Clopidogrel

VerifyNow @ J30 TM-Aspirin & Clopidogrel tous les patients

ARU≥550 (cartouche ASA) %inh≤15% ou PRU≥235(cartouche P2Y12)

Les nouveaux

Biotransformation and mode of action Biotransformation and mode of action

Platelet Aggregation at 4 hoursPlatelet Aggregation at 4 hours

90

80

70

60

50

40

30

20

10

0

300mg300mg

100

600mg600mg

900mg900mg

90mg90mg

10mg10mg

60mg60mg

ISAR-CHOICE – Von Beckerhat et al .Circulation 2005 ALBION – Montalescot et al. JACC 2007

RELOAD – Collet et al. Circulation 2008

DIPSERSE 2 – Storey et al. JACC 2007PRINCIPLE TIMI-44 – Wiviot et al. Circulation 2007

Clopidogrel Clopidogrel Ticagrelor Ticagrelor Prasugrel Prasugrel

TRIT

ON

CU

RR

ENT

CU

RE

180mg180mg

PLA

TO

Study Design, Flow and Compliance25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)

Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

PCI 17,232 (70%)

Angio 24,769 (99%)

No PCI 7,855 (30%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

Randomized to receive (2 X 2 factorial):CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)

ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Clop in 1st 7d (median) 7d 7 d 2 d 7d

Complete Followup

99.8%

Compliance:

PLATO study design

Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;

randomised within 24 hours of index event (N=18,624)

PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

RAngiograpyTRITONPrasugrel LD 60mg + MD 10mg

PCI

Clopidogrel LD 300mg + MD 75mg

R

Ticagrelor 180mg + MD 90mgx2

PCIPLATO

Clopidogrel LD 600mg (16%)

RCURRENT

Angiograpy

PCIAngiograpy

99%

Clopidogrel LD 300mg + MD 75mg

Clopidogrel LD 300mg + MD 75mg

Clopidogrel LD 600mg + MD 150mg

81% 64.3%

70%

99%n= 13,608

n= 18,624

n= 25,087

100%

Baseline and index event characteristicsCharacteristic

CURE(n=12,562)

TRITON(n=13,608)

PLATO(n=18,624)

CURRENT(n=25,087)

Median age, years 64.2 61.0 62.0 -Women, % 38.5 26 28.4 24.5CV risk factors, % Habitual smoker Hypertension Dyslipidaemia Diabetes mellitus BMI

60.859na

22.6na

3864562328

35.865.446.625.027

37--

22.2-

History, % Myocardial Infarction Percutaneous coronary intervention Coronary-artery bypass grafting

32.217.7*

*

1813.17.5

20.513.36.0

---

Clinical Presentation % Unstable angina or NSTEMI STEMI TIMI Risk Score >3 TIMI Risk Score >5

74.925.133.333.3

7426--

62.337.744.620.6

70.829.2

--

ECG at entry, % Persistent ST-segment elevation ST-segment depression

na42.2

--

37.651.0

--

Troponin-I positive (all population) % Troponin-I positive (UA or NSTEMI) %

25.3na

?-

85.781.0

40-

Study medicationCURE

(n=12,562)TRITON

(n=13,608)PLATO

(n=18,624) CURRENT(n=25,087)

Start of randomised treatment

Time after start of chest pain, h, median - - 11.3 -Compliance, %

Premature discontinuation of study drug

Premature discontinuation of control

-

-

-

- 23.4

21.5

-

-Concomitent antithrombotic, %

Clopidogrel in hospital before randomisation

Loading dose of clopidogrel ≥ 600mg

Study-drug administration before PCI

GP IIbIIIa Inhibitor

-

0

-

-

-

0

25.5

54.5

46.1

16.6

? *

26.6

-

0

?

28.6Invasive procedures at index hospitalisation, %

Planned invasive treatment

Coronary angiography

PCI during index hospitalisation

Cardiac surgery

-

-

-

-

100

100

99

2.5

72.0

81.5

61.0

4.5

-

99

70

10

Relative Risk Reduction

PCI No PCI

CURECURE: Clopidogrel 300/75 mg v Placebo (CVD/MI): Clopidogrel 300/75 mg v Placebo (CVD/MI) 30%30%11 19%19%22

STEMI: STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI)Clopidogrel 300/75 mg v Placebo (CVD/MI) 46%46%33 9%9%44

TRITONTRITON: : Prasugrel v Clopidogrel 300/75mg (CVD/MI/Stroke)Prasugrel v Clopidogrel 300/75mg (CVD/MI/Stroke) 19%19%55 Not Not evaluatedevaluated

PLATO PLATO : Ticagrelor v Clopidogrel 300/75mg (CVD/MI/Stroke): Ticagrelor v Clopidogrel 300/75mg (CVD/MI/Stroke) 16%16%66 15%15%**NSNS

CURRENT : CURRENT : Clopidogrel 600/150 v 300/75mg (CVD/MI/Stroke)Clopidogrel 600/150 v 300/75mg (CVD/MI/Stroke) 15%15%77 ddeleterious ?eleterious ?+17%+17%**p=0.14p=0.14

Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCI

1. Mehta SR, et al. Lancet 2001; 358(9281):527-33.2. Fox KAA, et al. Circulation 2004;110:1202-83. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.4. Chen ZM Lancet 2005;366:1607-214. Boersma E et al. Lancet 2002; 359:1895. Wiviott S et al. N Engl J Med 20072007; 357: 2001–15.

6. Wallentin L et al. N Engl J Med 20097. Metha et al. presented at the ESC09

0 30 60 90 180 270 360 450 days

5

10

15

Endp

oint

(%)

0

9.8

11.7

Ticagrelor 90mg x2

HR 0.84 (0.77–0.92) p=0.0003*

12.1

9.9Prasugrel

10mg

Clopidogrel 75mg

HR 0.81 (0.73-0.90) p=0.0004*

TRITON and PLATOPrimary endpoint = CV Death / MI / Stroke 12-15 months

0 10 20 30 days

8

6

4

2

0

Cum

ulat

ive

inci

denc

e (%

)

EARLY CV Death / MI / Stroke (30days)

Ticagrelor 180mg + 90mg x2

4.8 % (Ticagrelor PLATO)

5.4 % (Clopidogrel 75 PLATO)

HR 0.88 (95% CI 0.77–0.95), p=0.045*Clopidogrel 75mg vs Ticagrelor 90mg x2 - 12%

7.1% (Clopidogrel 75 TRITON)

5.6% 5.6% (Prasugrel TRITON)

Prasugrel 60mg + 10mg4.7%

HR 0.77 (95% CI 0.67–0.88), p<0.001*Clopidogrel 75mg vs Prasugrel 10mg - 23%

Clopidogrel 300mg + 75mg

Clopidogrel 600mg + 150mg

4.2 % (Clopidogrel 150 CURRENT)4.4 % (Clopidogrel 75 CURRENT)

HR 0.96 (95% CI 0.85-1.08), p=0.47Clopidogrel 75mg vs Clopidogrel 150mg - 4%

TRITON, PLATO and CURRENT

31 90 150 210 330

8

6

4

2

0

Clopidogrel 75mg

Ticagrelor 90mg x25.3

6.6

Cum

ulat

ive

inci

denc

e (%

)

LATE CV Death / MI / Stroke (30- 360 days) TRITON and PLATO

270

5.6

390 450

6.9

Prasugrel 10mg

HR 0.80 (95% CI 0.70–0.91), p=0.003* (TRITON)HR 0.80 (95% CI 0.70–0.91), p<0.001 (PLATO)

p=0.62 p<0.0019K

-M e

stim

ated

rate

8

7

6

5

4

3

2

1

0

4.5

5.9

All cause Mortality (12-15 months)

3.23.0

p=NS

6.25.8

450 days

ASA

onl

y

360 days360 days

-9% - 5% -22%TicagrelorClopidogrel 150Clopidogrel 75

Prasugrel

2.1 2.2

30 days and CV deaths only !

CURRENT TRITON PLATOCURE

p=0.6

- 4%

Haz

ard

Rat

io

Stent Thrombosis (12-15 months)

2.4% vs 1.1% (142/68)

Significant reductions both with BMS, DESSignificant reductions both with BMS, DESSignificant reductions in early and late stent thrombosesSignificant reductions in early and late stent thromboses

2.3% vs 1.6%(199 vs 136) 2.8% vs 2.1

(158/118)

p=0.03* p=0.025*

9K

-M e

stim

ated

rate

8

7

6

5

4

3

2

1

0

2.82.2

Safety = TIMI Major Non-CABG Bleeds (12-15 months)

1.8

2.4

p=0.001*

2.7

3.7

450 days

ASA

onl

y

360 days360 days

+27% +25% +22%

TicagrelorClopidogrel 150Clopidogrel 75

Prasugrel

1.04 0.95

30 days !

CURRENT TRITON PLATOCURE

p=0.002*

9K

-M e

stim

ated

rate

8

7

6

5

4

3

2

1

0

Safety = (12-15 months)

0.10.4

TicagrelorClopidogrel 150Clopidogrel 75

Prasugrel

p=NS

450 days

+75% +0%

0.2 0.2

+0%

0.3 0.3?

0.2

p=0.66

Fatal Bleeds Intracranial Bleeds

0.3 0.3

p=0.74+0%

0.3

+33%p=0.06

TRITON PLATOCURE TRITON PLATOCURE

p=0.01*

p=0.7

9K

-M e

stim

ated

rate

8

7

6

5

4

3

2

1

0

5.8

Safety = Life-threatening Bleeds (12-15 months)

0.91.4

TicagrelorClopidogrel 150Clopidogrel 75

Prasugrel

p=0.13

450 days 360 days360 days

+55%

+0%

1.82.2

+19%

5.8

DEFINITION Rate of CABG!

TRITON PLATOCURE

Le futur proche

LLes es EEnjeux njeux PPratiques du ratiques du FFuturutur

Le switch

Le préhospitalier

La place des anti-IIb/IIIa?

Le NSTEMI

Les sujets fragiles

Les coûts

Max

imal

Pla

tele

t Agg

rega

tion

(%)

(20

µM A

DP)

Pre-LD Post-LD Visit 3 (day 15) Visit 4 (day 29)

Clopidogrel150 mg

Prasugrel10 mg

*

* p = 0.003 vs. clopidogrel 900 mg

(n = 32)

Prasugrel Clopidogrel n = 19Clopidogrel Prasugrel n = 18

0

10

20

30

40

50

60

70

80

90

Clopidogrel900 mg

Pre-LD Clopidogrel150 mg

Prasugrel10 mg

p = 0.016 p = 0.001

TThe he AACAPULCO CAPULCO SStudytudyAA Randomized, Double-Blind, Randomized, Double-Blind, CCrossover Study Comparing the Pharmacodynamic Response in Subjects with rossover Study Comparing the Pharmacodynamic Response in Subjects with AAcute cute

Coronary Syndrome Receiving 14 Days of 10-mg Maintenance Dose Coronary Syndrome Receiving 14 Days of 10-mg Maintenance Dose PPrasugrel versus 14 Days of 150-mg Maintenance rasugrel versus 14 Days of 150-mg Maintenance Dose Clopidogrel After Dose Clopidogrel After UUsing a 900-mg sing a 900-mg LLoading Dose of oading Dose of CClopidogrel to Reduce lopidogrel to Reduce OOngoing Platelet Activationngoing Platelet Activation

Net Clinical BenefitBleeding Risk Subgroups

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)+ 37

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysisPost-hoc analysis

TRITON-TIMI 38: Patients Age<75 and Weight ≥60 TRITON-TIMI 38: Patients Age<75 and Weight ≥60 and no history of TIA/strokeand no history of TIA/stroke

CI=confidence interval

Days From Randomization0 30 90 180 270 360 450

0

2

4

6

8

10

12

14

16

End

poin

t (%

)

Hazard Ratio, 1.240(95% CI, 0.911-1.687)P=0.170

Hazard Ratio, 0.745(95% CI, 0.657-0.84)P<0.001

Clopidogrel

Prasugrel

Clopidogrel

Prasugrel 1.95%1.50%

11%

8.4%

Aspirin aloneST: 0.5%Death, MI, stroke (ST not considered): 4%Major bleed: 0.5%

Dual OAT (aspirin and clopidogrel)ST: 0.35%Death, MI, stroke (ST not considered): 3%Major bleed: 0.6%

Dual OAT (apirin and prasugrel)ST: 0.20%Death, MI, stroke (ST not considered): 2.5%Major bleed: 0.8%

5%5%

NNet et CClinical linical BBenefit enefit afterafter 1 year 1 year

4%4%

3.5%3.5%