1. Recherche Clinique en Cardiologie Interventionnelle
Institut de Cardiologie
CHU Pitié-Salpêtrière
Pr. G. Montalescot
UMRS 1166
COI disponibles sur http://www.action-coeur.org

2. Organisation globale de RC
Organisation locale de RC
PEC médico-technique
Sévérité / Urgences
Maladies fréquentes
Nouvelles
techniques
Centres experts
Difficultés de
recrutement
A.R.O. / ACTION
Recherche Clinique
en Cardiologie Interventionnelle

3. Core Lab for thrombus analyses
JACC 2011
A web-based registry with a genetic core lab JAMA 2011
Hours (post LD2)
P2Y12
ReactionUnits
0
50
100
150
200
250
300
350
Pre-treatment (30/30)
No Pre-treatment (0/60)
Pre LD1
(baseline)
Pre LD2 0.5 2 3 41 24
Approximate
time of PCI
*
*
30 mg
LD1
Placebo
LD1
60 mg
LD2
30 mg
LD2
*P<0.05
Central Core Lab for Platelet Function
NEJM 2013
Imaging Core Lab
For New Devices
Eur Heart J 2014
ACTION: pour une recherche Hi-Tech
http://www.action-coeur.org

4. ACTION: un réseau de centres efficaces!
ATOLL ARCTIC
Lancet 2011 NEJM 2012

5. ATOLL

6. 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 IV
0.5 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

7. ATOLL: Primary end point
Death, Complication of MI, Procedure Failure or Major Bleeding
33.7
28
0
5
10
15
20
25
30
35
40
UFH
ENOX
RRR = 17%
P = 0.07
%ofpatients
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

8. ATOLL: Main secondary end point
Death, Recurrent ACS or Urgent Revascularization
0 5 10 15 20 25 30
0.000.050.100.15
Days
MainsecondaryEPrate
UFH
ENOX
Log-Rank Test
p=0.01
11.3%
6.7%
30d rate (%)
i41%
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
UFH
ENOX

9. 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
% %
UFH
ENOX

10. 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
UFH
ENOX

11. Meta-analysis in PCI
J. Silvain et al. BMJ 2012
 48%
 34%

12. Standard of care
VerifyNow
P2Y12 + ASA
Drug
(ASA, clopidogrel, pras
ugrel, 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

13. %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

14. Primary Endpoint to 1 year
Death, MI, stroke, stent thrombosis, urgent revascularization
HR = 1.13 [0.98-1.29]
p= 0. 096
Conventional
Monitoring
100 200 3000
34.6%
31.1%

15. Conventional
Monitoring
HR = 1.06 [0.74-1.52]
p= 0. 77
100 200 3000
4.9%
4.6%
Main Secondary Endpoint to 1 year
Stent thrombosis or urgent revascularization

16. 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

17. 2440 patients of the ARCTIC Study
1136 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 in
Monitoring
Arm
479 in
Monitoring
Arm
456 in
Conventional
Arm
459 SLOW Metabolizers
12-month Follow-Up
Flow Chart
935 RAPID Metabolizers

18. Metabolizer Phenotype
HAP F *1 *17
HAP N *1 non *17
HAP S *2 non *17
F=fast metabolizer haplotype
N=normal metabolizer haplotype
S= 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

19. 40.27
69.1
59.73
30.9
0
10
20
30
40
50
60
70
80
SLOW (n=221) RAPID (n=479)
GOOD
POOR
Kappa : 0.0919 ; 95% CI [0.0167-0.0172]
Concordance between predicted
metabolizer profile and PD response

20. AUC for PRU : 0.497 [0.45 ; 0.54]
p = 0.96
AUC: 0.523 [0.48 ; 0.57]
P=0.92 for PRU
P= 0.36 for metabolizer profile
Pharmacodynamic model Metabolizer and PD model
Diagnostic Accuracy
(primary end-point)

21. 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
Reflection of the study protocol
3. Does not predict clinical outcome
Predicted Clopidogrel
Metabolizer Profile

22. 6-18 more months of FU
SAPTDAPT
Rd #2
12-month FU
Standard of care
VerifyNow 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

23. Primary Endpoint up to 18 months
Death, MI, stroke, stent thrombosis, urgent revascularizationEventProbability
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%

24. 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

25. 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 Outcome
Whole population
STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006–17

26. Conventional Arm :Prasugrel 5 mg
Groupe 1
No monitoring
MonitoringArm :Prasugrel 5 mg
PRU≥208
Prasugrel 10 mg/day
1rst assessment : Verifynow P2Y12 : 2 weeks ± 2 d
Groupe 2
Clopidogrel 75mg/dayPrasugrel 5 mg
Assessmentofthe primary end point (net clinical benefit )over 12 months
Bleeding type 2,3,5 of the BARC definition and
MACE:CV death, MI, urgent revascularisation,stentthrombosis,stroke
PRU≤30
2nd assessment and adjustment:
Verifynow P2Y12 : 2 weeks ± 2 d
30<PRU<208
ACS/PCI-STENT ≥ 75 years

27. NEJM sept 2013The ACCOAST Trial
The ARCTIC Trial

28. Issues with Clinical trials where ACTION can perform
better with its network
http://www.action-coeur.org

29. www.action-coeur.org

30. Public information
Who is supposed to inform/educate the people?
-Newspapers/TV?: no interest
-Upper management of the company?: no expertise
-GP?: no time
-Internet?: quality issue

31. Twitter: @actioncoeur

32. Thank you !
Slides available at www.action-coeur.org