Recherche Clinique en Cardiologie Interventionnelle
Institut de Cardiologie
CHU Pitié-Salpêtrière
Pr. G. Montalescot
UMRS ...
Organisation globale de RC
Organisation locale de RC
PEC médico-technique
Sévérité / Urgences
Maladies fréquentes
Nouvelle...
Core Lab for thrombus analyses
JACC 2011
A web-based registry with a genetic core lab JAMA 2011
Hours (post LD2)
P2Y12
Rea...
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: Deat...
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
U...
ATOLL: Main secondary end point
Death, Recurrent ACS or Urgent Revascularization
0 5 10 15 20 25 30
0.000.050.100.15
Days
...
ATOLL: Major bleeding
RRR = 54%
P = 0.04
Per-protocole
Collet JP et al. Am J Cardiol 2013;112:1367e1372
RRR = 8%
P = NS
In...
Mortality in ATOLL
Per-protocole
RRR = 64%
P = 0.003
RRR = 40%
P = 0.08
Intent-To-Treat
Montalescot G, et al. Lancet. 2011...
Meta-analysis in PCI
J. Silvain et al. BMJ 2012
 48%
 34%
Standard of care
VerifyNow
P2Y12 + ASA
Drug
(ASA, clopidogrel, pras
ugrel, GP2b3a I.) and
Dose adjustments if
high platele...
%inh<15% and/or PRU>235
Doubling the aspirin dose ↗ Clopidogrel dose by at least 75
mg or switch to prasugrel 10mg
if clop...
Primary Endpoint to 1 year
Death, MI, stroke, stent thrombosis, urgent revascularization
HR = 1.13 [0.98-1.29]
p= 0. 096
C...
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 thro...
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....
2440 patients of the ARCTIC Study
1136 pts without genetic data
10 pts with DNA w/o consent for genetic data
1394 pts in t...
Metabolizer Phenotype
HAP F *1 *17
HAP N *1 non *17
HAP S *2 non *17
F=fast metabolizer haplotype
N=normal metabolizer hap...
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 [0.0167-0.017...
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
Pharmac...
1. Marker of Clopidogrel Response
Higher rate of clopidogrel poor response at
randomization AND at D-14 in slow metabolize...
6-18 more months of FU
SAPTDAPT
Rd #2
12-month FU
Standard of care
VerifyNow and
drug adjustment
Coronary angiogram
Stent-...
Primary Endpoint up to 18 months
Death, MI, stroke, stent thrombosis, urgent revascularizationEventProbability
N at risks
...
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...
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] 0.2...
Conventional Arm :Prasugrel 5 mg
Groupe 1
No monitoring
MonitoringArm :Prasugrel 5 mg
PRU≥208
Prasugrel 10 mg/day
1rst ass...
NEJM sept 2013The ACCOAST Trial
The ARCTIC Trial
Issues with Clinical trials where ACTION can perform
better with its network
http://www.action-coeur.org
www.action-coeur.org
Public information
Who is supposed to inform/educate the people?
-Newspapers/TV?: no interest
-Upper management of the com...
Twitter: @actioncoeur
Thank you !
Slides available at www.action-coeur.org
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Recherche clinique en cardiologie interventionnelle - Gilles MONTALESCOT - Rencontres de la Recherche Clinique

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Recherche clinique en cardiologie interventionnelle - Gilles MONTALESCOT - Rencontres de la Recherche Clinique

  1. 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. 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. 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. 4. ACTION: un réseau de centres efficaces! ATOLL ARCTIC Lancet 2011 NEJM 2012
  5. 5. ATOLL
  6. 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. 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. 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. 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. 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. 11. Meta-analysis in PCI J. Silvain et al. BMJ 2012  48%  34%
  12. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 27. NEJM sept 2013The ACCOAST Trial The ARCTIC Trial
  28. 28. Issues with Clinical trials where ACTION can perform better with its network http://www.action-coeur.org
  29. 29. www.action-coeur.org
  30. 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. 31. Twitter: @actioncoeur
  32. 32. Thank you ! Slides available at www.action-coeur.org

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