Recherche Clinique en Cardiologie Interventionnelle
Institut de Cardiologie CHU Pitié-Salpêtrière
Pr. G. Montalescot
UMRS 1166
COI disponibles sur http://www.action-coeur.org
Organisation globale de RC
Organisation locale de RC
PEC médico-technique
Sévérité / Urgences
Maladies fréquentes
Nouvellestechniques
Centres experts
Difficultés de recrutement
A.R.O. / ACTION
Recherche Clinique en Cardiologie Interventionnelle
Core Lab for thrombus analyses
JACC 2011
A web-based registry with a genetic core lab JAMA 2011Hours (post LD2)
P2Y
12 R
eact
ion
Un
its
0
50
100
150
200
250
300
350Pre-treatment (30/30)No Pre-treatment (0/60)
Pre LD1(baseline)
Pre LD2 0.5 2 3 41 24
Approximatetime of PCI
*
*
30 mgLD1
PlaceboLD1
60 mgLD2
30 mgLD2
*P<0.05
Central Core Lab for Platelet Function NEJM 2013
Imaging Core LabFor New Devices
Eur Heart J 2014
ACTION: pour une recherche Hi-Tech
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ACTION: un réseau de centres efficaces!
ATOLL ARCTIC
Lancet 2011 NEJM 2012
ATOLL
ATOLL : primary PCI
STEMI Primary PCI
1° EP: Death, Complication of MI, Procedure Failure, Major Bleeding
Main 2° EP: Death, recurrent MI/ACS, Urgent Revascularization
30 days
Randomization as early as possible Real life population (shock, cardiac arrest included)
No anticoagulation before Rx
Similar antiplatelet therapy in both groups
ENOXAPARIN IV0.5 mg/kg
with or without GPIIbIIIa
UFH IV 50-70 IU with GP IIbIIIa
70-100IU without GP IIbIIIa(Dose ACT-adjusted)
Primary PCI ENOXAPARIN SC UFH IV or SC
Montalescot G, et al. Lancet. 2011;378:693-703
ATOLL: Primary end pointDeath, Complication of MI, Procedure Failure or Major Bleeding
33.7
28
0
5
10
15
20
25
30
35
40
UFHENOX
RRR = 17% P = 0.07
% o
f pat
ient
s
0.06
Intent-To-Treat
Montalescot G, et al. Lancet. 2011;378:693-703
Per-protocole
RRR = 23%P = 0.01
Collet JP et al. Am J Cardiol 2013;112:1367e1372
ATOLL: Main secondary end pointDeath, Recurrent ACS or Urgent Revascularization
0 5 10 15 20 25 30
0.0
00
.05
0.1
00
.15
Days
Mai
n se
cond
ary
EP
rate UFH
ENOX
Log-Rank Test
p=0.01 11.3%
6.7%
30d rate (%)
i 41%
Montalescot G, et al. Lancet. 2011;378:693-703
Intent-To-Treat Per-protocole
Collet JP et al. Am J Cardiol 2013;112:1367e1372
i73%p=0.006
UFHENOX
ATOLL: Major bleeding
RRR = 54%P = 0.04
Per-protocole
Collet JP et al. Am J Cardiol 2013;112:1367e1372
RRR = 8%P = NS
Intent-To-Treat
Montalescot G, et al. Lancet. 2011;378:693-703
% %
UFHENOX
Mortality in ATOLL
Per-protocole
RRR = 64%P = 0.003
RRR = 40%P = 0.08
Intent-To-Treat
Montalescot G, et al. Lancet. 2011;378:693-703 Collet JP et al. Am J Cardiol 2013;112:1367e1372
UFHENOX
Meta-analysis in PCI
J. Silvain et al. BMJ 2012
48%
34%
Standard of care
VerifyNow P2Y12 + ASA
Drug (ASA, clopidogrel, prasugrel, GP2b3a I.)
and Dose adjustments if high platelet reactivity
Coronary angiogram
Stent-PCI
Rd
Standard of care
Drug and Dose adjustments if high platelet reactivity at
Day 14
12-month FU
Stent-PCI
ARCTIC trial design
Primary endpoint at 12 months:• Death, MI, stroke, stent thrombosis,
urgent revascularization
Statistical considerations:• Assuming an annual risk of 9% and a
33% relative risk reduction (α risk at 5% and error β of 20%, bilateral test), 2,466 patients were necessary to demonstrate the superiority of the strategy of monitoring and adjustment
ARCTIC study protocol - Collet JP, et al. Am Heart J 2011;161:5-12
ARU>550 (Aspirin)
Reload with 500 mg IV aspirin
GPIIb/IIIai + clopidogrel (re)LD (>600 mg) or prasugrel LD 60 mg then,
MD clopidogrel 150 mg or prasugrel 10mg
VerifyNow before start of DES-PCI
%inh<15% and/or PRU>235(P2Y12)
%inh<15% and/or PRU>235
Doubling the aspirin dose ↗ Clopidogrel dose by at least 75 mg or switch to prasugrel 10mg
if clopidogrel 150mg ↘ 75mg if prasugrel clopidogrel 75mg
ARU>550 %inh>90%
VerifyNow @ day 14-30
Adjustment rules
Primary Endpoint to 1 yearDeath, MI, stroke, stent thrombosis, urgent revascularization
HR = 1.13 [0.98-1.29]p= 0. 096
ConventionalMonitoring
100 200 3000
34.6%
31.1%
ConventionalMonitoring
HR = 1.06 [0.74-1.52]p= 0. 77
100 200 3000
4.9%
4.6%
Main Secondary Endpoint to 1 yearStent thrombosis or urgent revascularization
Conventional Monitoring HR [95%CI] P
Major bleeding - % 3.3 2.3 0.70 [0.43; 1.14] 0.15
Minor bleeding - % 1.7 1.0 0.57 [0.28; 1.16] 0.12
Major or minor bleeding - % 4.5 3.1 0.69 [0.46; 1.05] 0.08
Key Safety Outcomes
STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006–17
2440 patients of the ARCTIC Study1136 pts without genetic data
10 pts with DNA w/o consent for genetic data
1394 pts in the ITT analysis for ARCTIC-GENE
238 in Conventional
Arm
221 inMonitoring
Arm
479 inMonitoring
Arm
456 inConventional
Arm
459 SLOW Metabolizers
12-month Follow-Up
Flow Chart
935 RAPID Metabolizers
Metabolizer Phenotype
HAP F *1i*17
HAP N *1inon *17
HAP S *2inon *17
F=fast metabolizer haplotypeN=normal metabolizer haplotypeS= slow metabolizer haplotype
*1 *17*1 *17
*1 *17*1 non *17
*1 non *17*1 non *17
*1 *17*2 non *17
*1 non*17*2 non *17
*2 non *17*2 non *17
F/F
F/N
N/N
F/P
N/S
S/S
Extensive
Normal
Poor
RAPID
SLOW
SLOW (n=221) RAPID (n=479)0
10
20
30
40
50
60
70
80
40.27
69.1
59.73
30.9
GOODPOOR
Kappa : 0.0919 ; 95% CI [0.0167-0.0172]
Concordance between predicted metabolizer profile and PD response
AUC for PRU : 0.497 [0.45 ; 0.54]p = 0.96
AUC: 0.523 [0.48 ; 0.57]P=0.92 for PRUP= 0.36 for metabolizer profile
Pharmacodynamic model Metabolizer and PD model
Diagnostic Accuracy(primary end-point)
1. Marker of Clopidogrel Response® Higher rate of clopidogrel poor response at
randomization AND at D-14 in slow metabolizer® Low concordance
2. Not associated with Tx adjustment in poor responders i Reflection of the study protocol
3. Does not predict clinical outcome
Predicted Clopidogrel Metabolizer Profile
6-18 more months of FU
SAPTDAPT
Rd #2
12-month FU
Standard of careVerifyNow and
drug adjustment
Coronary angiogram
Stent-PCI
Rd
Standard of care
Stent-PCI
VerifyNow and drug adjustment
1° EP: Death, MI, stroke, stent thrombosis, urg. revasc.
ARCTIC-INTERRUPTION design
Primary Endpoint up to 18 months
Death, MI, stroke, stent thrombosis, urgent revascularizationEven
t P
rob
ab
ilit
y
N at risks DAPT 635 633 613 593 513 440 SAPT 624 611 591 572 488 411
Follow-up (days)
HR = 1.17 [0.68-2.03]p= 0. 5750
DAPT SAPT -----
3.8%4.3%
DAPT SAPT HR [95%CI] P
Primary End Point* 3.8 4.3 1.17 [0.68; 2.03] 0.57
Stent thrombosis or Urgent Revasc 1.3 1.6 1.30 [0.51;3.30] 0.58
Death or myocardial Infarction - % 2.2 2.7 1.26 [0.62 ;2.55] 0.52
Any death - % 1.1 1.4 1.32 [0.49 ;3.55] 0.58
Myocardial infarction - % 1.4 1.4 1.04 [0.41 ;2.62] 0.94
Stent thrombosis - % 0 0.5
Stroke or TIA- % 0.9 0.6 0.69 [0.19;2.44] 0.56
Urgent revascularization - % 1.3 1.4 1.17 [0.45 ;3.04] 0.74
All ischemic Endpoints
*Any death, Myocardial infarction, stent thrombosis, stroke or transient ischemic attack, urgent revascularization
DAPT SAPT HR [95%CI] P
Major bleeding - % 1.1 0.2 0.15 [0.02; 1.20] 0.073
Minor bleeding - % 0.8 0.3 0.41 [0.08 ;2.13] 0.29
Major or minor bleeding - % 1.9 0.5 0.26 [0.07 ;0.91] 0.035
BARC III and V 1.1 0.2 0.15 [0.02 ;1.20] 0.073
Key Safety OutcomeWhole population
STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006–17
Conventional Arm :Prasugrel 5 mg
Groupe 1
No monitoring
Monitoring Arm :Prasugrel 5 mg
PRU≥208
Prasugrel 10 mg/day
1rst assessment : Verifynow P2Y12 : 2 weeks ± 2 d
Groupe 2
Clopidogrel 75 mg/dayPrasugrel 5 mg
Assessment of the primary end point (net clinical benefit )over 12 monthsBleeding type 2,3,5 of the BARC definition andMACE :CV death, MI, urgent revascularisation, stent thrombosis, stroke
PRU ≤30
2nd assessment and adjustment:Verifynow P2Y12 : 2 weeks ± 2 d
30<PRU<208
ACS/PCI-STENT ≥ 75 years
NEJM sept 2013The ACCOAST Trial
The ARCTIC Trial
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