[email protected] 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%