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

http://www.action-coeur.org

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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Thank you !

Slides available at www.action-coeur.org