Nouveaux antithrombotiques dans les SCA

Quel traitement pour quel malade ? Quel

rapport efficacité/risque hémorragique ?

Philippe Gabriel Steg Département de Cardiologie

Hôpital Bichat – Claude Bernard, AP-HP

Université Paris Diderot

INSERM U-698

Paris, France

2

Ph. Gabriel Steg - Disclosures

• Research grant: Servier

• Speaking or consulting: Amgen, Astellas,

AstraZeneca,Bayer, Boehringer Ingelheim, BMS,

Daiichi-Sankyo-Lilly, Eisai, GSK, Merck, Pfizer, Roche,

sanofi-aventis, Servier, The Medicines Company

• Stockholding: Aterovax

Antithrombotiques dans les SCA

• C’est compliqué

Treatment of ACS is a jungle !

Antiplatelet RxASAClopidogrelPrasugrel? TicagrelorGpIIb/IIIa IV blockers? Cangrelor? TRA

Anticoagulant RxUFHEnoxaparinBivalirudinFondaparinuxWarfarin? Anti X? Anti II

RevascularizationPCIStents (BMS/DES)CABG

Bleeding riskComorbidities

Risk of thrombotic event

Patient

Timing

Antithrombotiques dans les SCA

• C’est compliqué

• Les essais cliniques nous donnent quelques

informations

TRITON-TIMI38 Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

Median duration of therapy - 12 months

N= 13,600

Planned PCI for :Mod-High Risk UA/NSTEMI (TRS > 3)STEMI: < 14 days (ischemia or Rx strategy)STEMI: Primary PCI

KnownAnatomy

Clopidogrel (N=6795)

%

Prasugrel (N=6813)%

PCI / CABG 99 / 1 99 / 1

Any Stent 95 94

BMS 47 48

DES 47 47

Multivessel PCI 14 14

UFH / LMWH / Bival 65 / 8 / 3 66 / 9 / 3

GP IIb/IIIa 55 54

LD of Study RxPre PCIDuring PCIPost PCI

25741

26731

Index Procedure

Components of Endpoint

Clopidogrel HRPrasugrel

12.1 0.819.9

2.4 0.892.1

9.5 0.767.3

1.0 1.021.0Nonfatal Stroke

Nonfatal MI

CV Death

CV Death, MI, Stroke

0.5 1 2Prasugrel Better Clopidogrel Better

All Cause Mortality 3.2 0.953.0

HR

Se méfier des analyses en sous-groupe

• La valeur du « p » dans un sous groupe importe

peu

– Faux positifs dans une analyse: 5%

– SI 5 analyses de sous groupe: 23%

– Si 10 analyses: 40%... (PLATO: 31 sous-groupes !)

ISIS 2Subgroup analysis by Astrological Birth Signs Vascular Deaths

(Isis 2, Lancet, 1988, 2,349-360)

Variations

across study

centers in

BHAT

Hazard ratios and 95% CIs for all-cause mortality a ccording to randomization center in the BHAT trial.

O’Shea JC, DeMets DL.Am Heart J 142:21-8

Quand prêter attention à un sous-groupe ?

• Analyse pré-spécifiée

• Plausibilité biologique

• Puissance statistique

• Interaction statistiquement significative entre effet du traitement et sous groupe (rare…)

• Sinon: l’effet du traitement dans chaque sous groupe est au mieux estimé par l’effet global

Antithrombotiques dans les SCA

• C’est compliqué

• Les essais cliniques nous donnent quelques

informations

• Les traitements ont un bénéfice et un risque

Risk versus benefit

Thrombosis

Bleeding

Mor

talit

y (%

)

Days from Randomization

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

30

10

25

20

1 yearEstimate

Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)

3.4%No MI or Major Bleed (N=12,557)MI only (without Major Bleed) (N=611) 8.6%

Impact of MI and Major Bleeding (non-CABG) in the F irst 30 Days on Risk of Death Over 1 Year in the ACUITY tri al

Stone GW. ACC 2007

HR [95% CI] P-valueAttributable

DeathsRisk Factor

Time-updated covariate adjusted Cox model relating 30-day events to outcomes in HORIZONS -AMI

- Complete model with MACE components and major bleeding -

Hazard Ratio [95% CI]0.01 0.1 1 10 100

C-statistic = 0.87 Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

*9.7% of 93 total deaths**21.9% of 93 total deaths

Major bleeding(Non CABG)Incidence 238 (6.8%)26 deaths with event

4.66[2.84, 7.63] <0.001 20.4**

[16.8, 22.6]

ReinfarctionIncidence 69 (2.2%)10 deaths with event

9.75[2.72,34.91] <0.001 9.0*

[6.3, 9.7]

Net Clinical Benefit of Prasugrel in the TRITON trial Bleeding 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 analysis

Antithrombotiques dans les SCA

• C’est compliqué

• Les essais cliniques nous donnent quelques

informations

• Les traitements ont un bénéfice et un risque

• L’efficacité antithrombotique n’est pas

parfaitement corrélée au bénéfice clinique

“Standard Therapy” clopidogrel 75mg +placebo/day

“Standard Therapy” clopidogrel 75mg +placebo/day

“Tailored Therapy”clopidogrel 150-mg/day

Successful PCI with DES without major complication or GPIIb/IIIa use

Post-PCI VerifyNow P2Y12 Assay (PRU) 12-24 hours po st-PCI

PRU ≥ 230?

Non-Responder

Clinical Follow-up And VerifyNow Assessment at 30 d ays, 6 months

Primary Endpt: 6 month CV Death, Non-Fatal MI, ARC Def/Prob Stent Thrombosis

Yes No

N ~ 6600

N = 1100 N = 583

Responder

A B C

Random Selection

N = 1100

G R A V T A S

GRAVITAS Pharmacodynamics: Effect of SD vs HD Clopi dogrel

500

400

300

200

100

0

PRU value

Post-PCI

High-Dose

30 d 6 mo Post-PCI 30 d 6 mo

Standard-Dose

N=1013 N=940N=1105 N=1012 N=944N=1109

P = 0.98P < 0.001

ITT population

Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001

Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001

Price et al. JAMA 2011;305:1097-1105

GRAVITAS : CV Death, MI, Stent Thrombosis

Antithrombotiques dans les SCA

• C’est compliqué

• Les essais cliniques nous donnent quelques

informations

• Les traitements ont un bénéfice et un risque

• L’efficacité antithrombotique n’est pas parfaitement

corrélée au bénéfice clinique

• L’objectif du traitement est un bénéfice clinique

« Ne pas perdre de vue la balle »

Objectifs du traitement

1. Efficacité anti-thrombotique

2. Prévention des thromboses

3. Réduction des hémorragies

4. Réduction de la morbi-mortalité

« Ne pas perdre de vue la balle »

Objectifs du traitement

1. Efficacité anti-thrombotique

2. Prévention des thromboses

3. Réduction des hémorragies

4. Réduction de la morbi-mortalité

5. Réduction de la morbi-mortalité au meilleur coût

possible en termes de risque hémorragique

Antithrombotiques dans les SCA

• C’est compliqué

• Les essais cliniques nous donnent quelques

informations

• Les traitements ont un bénéfice et un risque

• L’efficacité antithrombotique n’est pas parfaitement

corrélée au bénéfice clinique

• L’objectif du traitement est un bénéfice clinique

• Les principes du traitement: 2 AAP et un anticoagulant

Mechanisms of interindividual variability in

clopidogrel responsiveness

Angiolillo. JACC 2007;49:1505

Clopidogrel for Coronary Stenting

Response Variability, “Drug Resistance”

Gurbel et al. Circulation 2003;107:2908

% N

onre

spon

ders

(D

Agg

r <1

0%)

Elective StentingClopidogrel: LD 300/ MD 75

Light Transmittance Plat AggrN=92

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

End

poin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138events

35events

Balance of Efficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

B

OVERALL

No GPIGPI

DESBMS

DMNo DM

>7565-74

<65

FemaleMale

STEMIUA/NSTEMI

0.5 1 2Prasugrel Better Clopidogrel BetterHR

Age

Reduction in risk (%)18

2112

25146

1430

2018

2116

19

21

Pinter = NS

CV Death, MI, StrokeMajor Subgroups

CrCl > 60CrCl < 60 14

20

PLATO: ticagrelor vs clopidogrel in all types of AC SPrimary endpoint time to CV death, MI or stroke

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

6,743

5,096

5,161

4,047

4,147

0 60 120 180 240 300 360

121110

9876543210

13

Cum

ulat

ive

inci

denc

e (%

)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin et al NEJM 2009

PLATO: Hierarchical testing major efficacy endpointsPLATO: Hierarchical testing major efficacy endpointsPLATO: Hierarchical testing major efficacy endpointsPLATO: Hierarchical testing major efficacy endpoints

All patients*All patients*All patients*All patients*TicagrelorTicagrelorTicagrelorTicagrelor

(n=9,333•(n=9,333•(n=9,333•(n=9,333•

ClopidogrelClopidogrelClopidogrelClopidogrel

(n=9,291•(n=9,291•(n=9,291•(n=9,291•HR for HR for HR for HR for

(95% CI•(95% CI•(95% CI•(95% CI• p valuep valuep valuep value

Primary objective, n (%•

CV death + MI + stroke 864 (9.8• 1,014 (11.7• 0.84 (0.77 0.92• <0.001

Secondary objectives, n (%•

Total death + MI + stroke

CV death + MI + stroke +

ischaemia + TIA + arterial

thrombotic events

Myocardial infarction

CV death

Stroke

901 (10.2•

1,290 (14.6•

504 (5.8•

353 (4.0•

125 (1.5•

1,065 (12.3•

1,456 (16.7•

593 (6.9•

442 (5.1•

106 (1.3•

0.84 (0.77 0.92•

0.88 (0.81 0.95•

0.84 (0.75 0.95•

0.79 (0.69 0.91•

1.17 (0.91 1.52•

<0.001

<0.001

0.005

0.001

0.22

Total death 399 (4.5• 506 (5.9• 0.78 (0.69 0.89• <0.001

The percentages are K-M estimates of the rate of the endpoint at 12 months.

Wallentin et al NEJM 2009

0 60 120 180 240 300 360

6

4

3

2

1

0

Clopidogrel

Ticagrelor

4.0

5.1

HR 0.79 (95% CI 0.69–0.91), p=0.001

7

5

9,291

9,333

8,865

8,294

8,780

8,822

8,589

Days after randomisation

7079

7119

5,441

5,482

4,364

4,4198,626

Cum

ulat

ive

inci

denc

e (%

)

PLATO: Cardiovascular death over time

PLATO : consistency of effect on primary endpoint

Wallentin et al NEJM 2009

Abciximab Placebo Placebo

Follow up through 90 days and 1 year

Primary PCI with Abciximab Infusion (12 h)

FINESSE: Study DesignAcute ST Elevation MI (or New LBBB) within 6h pain onset

Presenting at Hub or Spoke with estimated time to Cath between 1 and 4 hours

PlaceboPlacebo

Reteplase (5U+5U)*Abciximab

PlaceboAbciximab

Randomize 1:1:1N=3000 *Only 5U if ≥≥≥≥75 yr

Transfer To Cath LabASA, unfractionated heparin 40U/kg (max 3000U)

or enoxaparin (0.5 mg/kg IV + 0.3 mg/kg SC) – substu dy only

Double BlindDouble Dummy

Primary Endpoint

p=0.55

Adjunctive antithrombotic Rx for STEMI PCI:

what do the ESC revascularization guidelines say ?

Wijns & Kohl, Eur Heart J 2010

f: primarily if more efficient agents are contraindicatedd: depending on approval and availability

UFH for PCI: no placebo-controlled

randomized trial !

ATOLL Trial design

STEMI ���� Primary PCI

30-day results

Randomization as early as possible (MICU +++)Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before RxSimilar antiplatelet therapy in both groups

ENOXAPARIN IV0.5 mg/kg

with or without GPIIbIIIa

UFH IV50-70 IU with GP IIbIIIa

70-100IU without GP IIbIIIa(Dose ACT-adjusted)

IVRS

Primary PCI ENOXAPARIN SC UFH IV or SC

ATOLL: Enox vs UFH for primary PCI

Primary Endpoint: Death, Complication of MI, Procedure Failure or Maj or Bleeding

Montalescot, ESC 2010

HORIZONS-AMI: ResultsHORIZONS-AMI: Results

1-Year All-Cause Mortality

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

1800 1705 1684 1669 15201802 1678 1663 1646 1486

Mor

talit

y (%

)

0

1

2

3

4

5

Time in Months

0 1 2 3 4 5 6 7 8 9 10 11 12

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802) 4.8%

3.4%

Diff [95%CI] =

-1.5% [-2.8,-0.1]

HR [95%CI] =

0.69 [0.50, 0.97]

P=0.029

3.1%

2.1%

∆ = 1.0%

P=0.049

∆ = 1.4%

Mehran, Lancet 2009

HORIZONS: 1-Year Stent Thrombosis

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

1611 1525 1504 1486 13561591 1495 1475 1457 1315

Ste

nt T

hrom

bosi

s (%

)

0

1

2

3

4

5

Time in Months

0 1 2 3 4 5 6 7 8 9 10 11 12

Bivalirudin alone (n=1611)

Heparin + GPIIb/IIIa (n=1591)

3.5%3.2%

HR [95%CI] =1.11 [0.76, 1.63]

P=0.59

2.7%

2.2%

∆ = 0.5%P=0.31

∆ = 0.3%

Two-Year All-Cause Mortality

1800 1690 1658 1627 13591802 1669 1637 1579 1324

p= 0.049

HR [95%CI]=0.75 [0.56, 1.00]

4.6%

6.1%A

ll-C

ause

Mor

talit

y (%

)

0

1

2

3

4

5

6

7

8

0 3 6 9 12 15 18 21 24

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802)

Months

3.1%

2.1% 1 monthP=0.049

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

3680 pts with STEMI with symptom onset > 20 min and

≤12 hours in ambulance or non-PCI hospital

Intent for PPCI

UFH ±±±± routine or bailout GPI (any of

the 3)

Bivalirudin monotherapy

with prolonged infusion

(Gp IIb/IIIa for bailout only)

Aspirin and thienopyridineR

1:1

Primary endpoint

30-day death, MI or non-CABG related major bleeding

Clinical FU at 30 days and 1 year

EUROMAX

Primary PCI ambulance trial

PrePre--Specified Subgroup AnalysesSpecified Subgroup Analyses

0.5 0.7 0.8 1.0 1.2 1.4 1.6 2.0

UFH/Plac better Hazard Ratio

Overall

None

Thrombolytic

Primary PCI

< 112

>=112

12092

2867

5436

3789

5958

6134

11.2%

15.1

13.6

4.9

4.3

18.0

9.7%

12.2

10.9

6.0

4.6

14.5

0.04

0.03

Initial Reperfusion Rx

GRACE Risk Score

N UFH/Placebo

Death or MI at 30 days

FondaInteraction

P value

Fonda better

Adjunctive antithrombotic Rx for STEMI PCI

Wijns & Kohl, Eur Heart J 2010

Mon algorithme

STEMI – Angioplastie primaire

• Aspirine

– Charge 500 mg

– Entretien 75 mg/j

• Prasugrel (sf si age, poids, AVC/AIT*)

– Charge 60 mg

– Entretien 10 mg

• Bivalirudine (prolongée 4 h post PCI)

• Abciximab si bailout

SCA sans sus décalage de ST

• Aspirine

– Charge 500 mg

– Entretien 75 mg/j

• Prasugrel (sf si age, poids, AVC/AIT*)

– Charge 60 mg

– Entretien 10 mg

• Fondaparinux

• Eptifibatide si PCI et troponine +

• Si CI au prasugrel: clopidogrel 600/75• Demain: remplacer Prasugrel par Ticagrelor

Antithrombotiques dans les SCA

• C’est compliqué

• Les essais cliniques nous donnent quelques

informations

• Les traitements ont un bénéfice et un risque

• L’efficacité antithrombotique n’est pas parfaitement

corrélée au bénéfice clinique

• L’objectif du traitement est un bénéfice clinique

• Les principes du traitement

• Nécessité d’un algorithme par consensus local

The spectrum of ACS care

A wide spectrum of clinical presentation

Chest pain

STEMI, NSTEMI, UA

Variations related to age, gender, prior medical history

A spectrum of care locations

Pre-hospital and ambulance

Emergency Room

CCU

Cath lab

Multiple stakeholders

Emergency physicians

CCU Cardiologists

Interventionalists

Cardiac Surgeons

Anesthesiologists, Intensive Care

Referring Cardiologists

Multiple therapeutic strategies

PCI

CABG

Medical therapy

Conclusions

• Le choix d’une stratégie antithrombotique doit intégrer risque

ischémique et risque hémorragique

• La combinaison aux nouveaux agents est intéressante:

– Ex les nouveaux antiplaquettaires oraux peuvent éviter le besoin d’antiGpIIb/IIIa

et optimiser l’efficacité des anticoagulants

• La réduction de la mortalité doit rester le facteur de choix principale

d’une stratégie thérapeutique

• La mise en oeuvre peut être problématique

– Multiplicité des intervenants

– Contecte d’urgence

– Continuité des soins (pre-hospital/Urgences/USIC/Cath lab)

• Nécessité de consensus loco-régionaux

Thank you !

Backup slides

HORIZONS 2 year follow-up

• Cardiac mortality in ITT population

↓41%*

2.5%

4.2%

0

1

2

3

4

5

Months0 3 6 9 12 15 18 21 24

Car

diac

mor

talit

y (%

)

2.1%

3.7 %

↓43%*

1.8%

2.9%

↓38%*

All p≤0.03

Bivalirudin UFH+GPI

Stone et al TCT 2009

0

2

4

6

8

10

12

14

All Death MI UTVR StentThrombosis

CV Death/MI CV Death/MI/UTVR

CV Death/MI/Stroke

p=0.11

p=0.02

p=0.09p=0.02

p=0.007 p=0.03 p=0.02

Pro

port

ion

of p

opul

atio

n (%

)

Clopidogrel

Prasugrel

Montalescot et al. ESC 2008

CV = CardiovascularMI = Myocardial infarctionUTVR = Urgent target-vessel revascularisation

TRITON-STEMI - Efficacy endpoints at 15 months

ESC guidelines:

recommendations for

revascularization in

NSTE-ACS

• Recommendrevasculari

Wijns & Kohl, Eur Heart J 2010

Wijns & Kohl, Eur Heart J 2010

Benefit of early vs delayed intervention according to GRACE

risk score in ACS in the TIMACS trial

High-risk = GRACE risk score > 140

Interaction P = 0.01

Kaplan–Meier Cumulative Risk of the Primary Outcome (death/MI/Stroke)

Mehta et al NEJM 2009:360:2165-75

3031 pts randomized to undergo either routine early intervention (coronary angiography, < 24 hrs) or delayed intervention (coronary angiography >36 hrs)

Invasive vs Cons 7962

10 102 ∞ 11 101020.5 215%0% 10% 0.50.1 2 1012.5%0% 5%

Odds ratio and 95% CI NNT and 95% CI Odds ratio and 95% CIIncidence Incidence

Death or MISize Major bleeds

Exp+ Ctrl+ Exp+ Ctrl+ Exp+ Ctrl+

DTI vs UFH 24701

LMWH vs UFH 21946

GP IIb/IIIa vs Ctrl 31402

Heparin vs Ctrl 2858

Aspirin vs Ctrl 3096

15%

0.84

0.88

0.91

0.91

0.55

0.47

63

102

113

111

31

17

1.3

1.1

1.6

2.3

1.4

NSTE-ACS – Summary of Treatment Approaches

RISC ’90

Cohen ’94

Holdright ’94

Gurfinkel ’95

All

399

214

285

143

2859

Theroux ’88

Cohen ’90

243

69

10 102 ∞ 11 101020.25 20% 20% 0.50.1 2 1013%0% 6%

Odds ratio and 95% CI NNT and 95% CI Odds ratio and 95% CIIncidence

0.55 (0.39-0.77) 31 (23-62) 2.3 (0.97-5.4)4.7% vs 7.4%

Incidence

1.1% vs 0.5%

Death or MI at end study medicationSize Major bleeds

Heparin + Ctrl+ Heparin + Ctrl+ Heparin + Ctrl+

0.5 140%

FRISC ’96 1506

000

00

0

0

Randomized trials of UFH/LMWH (dark bars ) vs Control

ACUTE-II ’02

INTERACT ’03

A to Z ’04

SYNERGY ’04

All

525

746

3620

9974

21946

ESSENCE ’97

TIMI-11B ’99

3171

3910

10 102 ∞ 11 101020.5 2110%0% 20% 0.50.1 2 1015%0% 10%

Odds ratio and 95% CI NNT and 95% CI Odds ratio and 95% CIIncidence

0.91 (0.83-0.99) 113 (61-1438) 1.1 (0.96-1.3)10.1% vs 11.0%

Incidence

3.9% vs 3.7%

Death or MI at 30 daysSize Major bleeds

LMWH+ UFH+ LMWH+ UFH+ LMWH+ UFH+

Randomized trials Enoxaparin (dark bars) vs UFH (open bars)

Death/MI/RI: Day 9

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0.04

0.05

0.06

0 1 2 3 4 5 6 7 8 9

Enoxaparin

Fondaparinux

HR 1.01 95% CI 0.90-1.13

Major Bleeding: 9 Days

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR 0.53 95% CI 0.45-0.62

P<<0.00001

Enoxaparin

Fondaparinux

Mortality: Day 30

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0 3 6 9 12 15 18 21 24 27 30

HR 0.83 HR 0.83 95% CI 0.7195% CI 0.71--0.970.97

P=0.022P=0.022

Enoxaparin

Fondaparinux

Mortality at 6 Months

Days

Cum

ulat

ive

Haz

ard

0.0

0.02

0.04

0.06

0 20 40 60 80 100 120 140 160 180

HR 0.89HR 0.8995% CI 0.7995% CI 0.79--0.99 0.99

P=0.037P=0.037

Enoxaparin

Fondaparinux

OASIS 5: bleeding reduction and mortality benefit f or Fondaparinux vs Enoxaparin

OASIS 5 Investigators. N Engl J Med 2006;354:1464-7 6

OASIS 5 (Randomized trial (n=20, 078) of Fondaparinux vs. Enoxaparin in ACS)

OASIS 5 Trial: Fondaparinux vs. Enoxaparin reduced major bleeding by 48% and mortality by 17% in NSTEACS

OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Major Bleeding at 9 days

-

48% relative

risk reduction

Days

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR: 0.52 95% CI: 0.44 -0.61 p<0.0001

Enoxaparin

Fondaparinux

4.1 %

2.2 %

Mortality at 30 days

Fondaparinux: 295 deathsEnoxaparin: 352 deaths

Days

0 3 6 9 12 15 18 21 24 27 30

0.0

0.01

0.02

0.03

HR: 0.83 95% CI: 0.71 -0.97p=0.02

Enoxaparin

Fondaparinux

0.043.5 %

2.9 %

-

17 % RRR

GUSTO-2B ’95

OASIS pilot ’97

OASIS ’99

Klootwijk ’99

All

12142

909

10141

300

32699

10 102 ∞ 11 101020.5 2110%0% 20% 0.50.1 2 1013%0% 6%

Odds ratio and 95% CI NNT and 95% CI Odds ratio and 95% CIIncidence

0.93 (0.85-1.0) 176 (89-∞) 1.0 (0.89-1.2)7.7% vs 8.3%

Incidence

2.3% vs 2.3%

Death or MI at 30 daysSize Major bleeds

DTI+ UFH+ DTI+ UFH+ DTI+ UFH+

ACUITY ’06 9207

Randomized trials Direct thrombin inhibitors (DTIs) (dark bars) vs UFH/LMWH

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and str oke in high risk patients

Antithrombotic Trialists' Collaboration

Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

Primary Outcome –

MI/Stroke/CV Death

Clopidogrel + ASA*

3 6 9

Placebo + ASA*

Months of Follow-Up

P = 0.00009N = 12,562

0 12

* In addition to other standard therapies.CURE Investigators. N Engl J Med. 2001;345:494

20%Relative RiskReduction

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.8595% CI 0.74-0.99

P=0.036

15% RRR

CV Death, MI or Stroke

Mehta et al. Lancet 2010

EARLY ACS no benefit of routine upstream eptifibatide in NSTE -ACS

Dea

th, M

I, R

IUR

or

TB

O (

%)

0

5

10

15

Time Since Randomization (Hours)

10.0%

9.3%

P = 0.23(stratified for intended early

clopidogrel use)

Delayed provisional eptifibatide

Routine early eptifibatide

0 8 16 24 32 40 48 56 64 72 80 88 96

EARLY ACS:

Kaplan-Meier Curves for 30-day Death or MI

Dea

th o

r M

I (%

)

0

5

10

15

Time Since Randomization (Days)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

12.4%

11.2%

P = 0.079

(stratified for intended early clopidogrel use)

Delayed provisional eptifibatide

Routine early eptifibatide

Kastrati et al. JAMA 2006

ISAR REACT -2Death, Myocardial Infarction, or Urgent Target Vess el Revascularization

Kastrati, A. et al. JAMA 2006

ISAR REACT -2Benefit of GpIIb/IIIIa blockade according to Tropon in Levels (>0.03 µg/L)

Wallentin et al. Lancet 2010:376,

Benefit of Ticagrelor over Clopidogrel in PLATO consistent regardless of LOF genotype

0 60 120 180 240 300 360

Days since randomisation

0

2

4

6

8

10

12E

stim

atio

n K

-M (

%)

(K-M) estimate of the primary endpoint in relation to CYP2C 19 lof allele

Nbr of patients

Clopidogrel LOF*Clopidogrel non LOF**

Ticagrelor LOF*Ticagrelor non LOF**

1,3883,516

1,3843,554

1,2753,321

1,3053,352

1,2593,256

1,2743,301

1,2263,186

1,2503,222

1,0272,691

1,0532,718

8012,123

8342,127

6581,757

6831,761

Clopidogrel LOF

Clopidogrel non LOF

Ticagrelor LOF

Ticagrelor non LOF

11.2

10.08.88.6

Shuldiner, A. R. et al. JAMA 2009;302:849-857.

Association of CYP2C19*2 (rs4244285) Loss-of-Functi on Variant With Adenosine Diphosphate-Stimulated Platelet Aggregation Before and After Cl opidogrel

CYP2C19*2 accounts for 12% of the variability

Paraoxonase-1 is a major determinant of clopidogrel efficacyKaplan-Meier curves for individuals with coronary stent implantation and their

pharmacokinetic and pharmacodynamic responses to clopidogrel

Bouman et al. Nat Med 2011;17:110-16

Predictive value of platelet function tests followi ng stentingSurvival free from MI, stent thrombosis and stroke

Breet et al. JAMA 2010;303(8):754-62

Test IMPACT-R

Tau

x d’

évén

emen

ts (

%)

These tests had at best modest predictive value. No ne provided reliable information regarding bleeding ri sk

15

10

5

0Log-rank P=.17

Temps (jours)

15

10

5

0Log-rank P=.42

Test PFA-100 Collagen/ADP

0 100 200 300 400

Test IMPACT-R ADP

Log-rank P=.22

Log-rank P=.001

Test INNOVANCE

0 100 200 300 400

Temps (jours)

Test LTA 5 µmol/L ADP

Tau

x d’

évén

emen

ts (

%)

15

10

5

0Log-rank P<.001

Temps (jours)

15

10

5

0Log-rank P<.001

Test Plateletworks

0 100 200 300 400

Test LTA 20 µmol/L ADP

Log-rank P<.001

Log-rank P<.001

Test VerifyNowPRU

0 100 200 300 400

Temps (jours)

On treatment platelet reactivity

High PR

Normal PR

The problems of bespoke therapyThe problems of bespoke therapyThe problems of bespoke therapyThe problems of bespoke therapyWhen to measure response to clopidogrel ?How to select poor responders ?Which therapy for poor responders ? Where are the clinical proofs of benefit ?

GRAVITAS ?

Trigger-PCI ?

CLOVIS ?

ARCTIC ?

Collet, et al. J Am Coll Cardiol Intv 2011;4:392-402

CLOVIS-2: using high doses of clopidogrel to overc ome genetic resistancePharmacokinetic Response According to CYP2C19*2 and Clopidogrel LDs

The case for ready-to wear antiplatelet therapy

Ford Model T