Quels traitements antithrombosants dans les SCA ? G de Gevigney G de Gevigney Hôpital Cardiologique Hôpital Cardiologique Lyon, France Lyon, France Journées

Quels traitements Quels traitements antithrombosants antithrombosants

dans les SCA ?dans les SCA ?

G de GevigneyG de Gevigney Hôpital CardiologiqueHôpital Cardiologique

Lyon, FranceLyon, France

Journées de l’AFL Journées de l’AFL BeyrouthBeyrouth

11-12 mai 200711-12 mai 2007

IntroductionIntroduction

Aspirine Aspirine

Héparine Héparine

Clopidogrel Clopidogrel

HBPMHBPM

ThrombolytiquesThrombolytiques

Anti GP2B3AAnti GP2B3A

FondaparinuxFondaparinux

BivalirudineBivalirudine

Best-of 2004 des Best-of 2004 des valvulopathiesvalvulopathies

Les acquis Les acquis dans les SCA dans les SCA

ST+ et ST-ST+ et ST-

6/046/04

00 1.01.0 2.02.0 Favors PlaceboFavors Aspirin

Cairns

Lewis

Theroux

Wallentin

Pooled

Cairns

Lewis

Theroux

Wallentin

Pooled

Relative Risk — Death or MIRelative Risk — Death or MI

Acute Coronary Syndromes Without ST Acute Coronary Syndromes Without ST Evidence for Evidence for AspirinAspirin

6/046/04Oler A, JAMA 1996Oler A, JAMA 1996Oler A, JAMA 1996Oler A, JAMA 1996

Acute Coronary Syndromes without ST Acute Coronary Syndromes without ST Evidence for Evidence for HeparinHeparin Use (UFH + ASA versus ASA) Use (UFH + ASA versus ASA)

Relative Risk of Death or MIRelative Risk of Death or MIRelative Risk of Death or MIRelative Risk of Death or MI

Theroux (n = 243)

RISC (n = 399)

Cohen (n = 69)

Cohen (n = 214)

Holdright (n = 185)

Gurfinkel (n = 143)

Overall (n = 1353)

Theroux (n = 243)

RISC (n = 399)

Cohen (n = 69)

Cohen (n = 214)

Holdright (n = 185)

Gurfinkel (n = 143)

Overall (n = 1353)

0.50.5 11 1.51.5 22ASA + UFH BetterASA + UFH Better ASA BetterASA Better

00

2.662.66

6.876.87

P = 0.06P = 0.06

Clopidogrel Critère de jugement principal tous patients

20% RRR20% RRRpp=0.00009=0.00009n=12 562n=12 562

20% RRR20% RRRpp=0.00009=0.00009n=12 562n=12 562

Le bénéfice apparait dès les premières Le bénéfice apparait dès les premières heures et continue de croître à 12 moisheures et continue de croître à 12 mois

00 11 22 33 44 55 66 77 88 99 1010 1111 1212Suivi en moisSuivi en mois

% de patients présentant un événement ischémique% de patients présentant un événement ischémique( décès vasculaire, IDM, AVC)( décès vasculaire, IDM, AVC)

00

1010

1414

1212

44

88

66

22

Traitement standardTraitement standardClopidogrel + traitement standardClopidogrel + traitement standard

The CURE Investigators. The CURE Investigators. N Eng J Med N Eng J Med August 2001August 2001

Résultats à long terme de la randomisation à la fin du suivi

0.150.15

0.100.10

0.050.05

0.00.0

10100 4040 100100 200200 300300 400400

Cumulative hazard ratesCumulative hazard rates

31% RRR31% RRRpp=0.002=0.002n=2658n=2658

31% RRR31% RRRpp=0.002=0.002n=2658n=2658

Jours de suiviJours de suiviaa bb

a = délais médian randomisation /ACP (10 jours)a = délais médian randomisation /ACP (10 jours)b = 30 jours aprés ACPb = 30 jours aprés ACP

Tt conventionnelTt conventionnelClopidogrel + tt conventionnelClopidogrel + tt conventionnel

12.6%12.6%

8.8%8.8%

CritéreCritére: IDM + décès vasculaire: IDM + décès vasculaire

PCI-PCI-

Les acquis dans les SCALes acquis dans les SCA

ThrombolytiquesThrombolytiques

SCA ST +SCA ST +

échec dans SCA ST -échec dans SCA ST -

AntiGP-IIB-IIIAAntiGP-IIB-IIIA

SCA ST -SCA ST -

Best-of 2004 des Best-of 2004 des valvulopathiesvalvulopathiesHBPMHBPM

IDM ST+EXTRACT TIMI 25

HBPMHBPM

Antmann EM NEJM 2006 354

IDM ST+

20056 pts

fibrinolyse

HNFdurant 48H

ENOXAPARINE Bolus IV puis 1mg/kg SC 2 fois par jour si

< 75ans pas bolus et 0.75mg/kg si >75ansdurant toute l’hospitalisation

randomisée, double aveugle

30 joursCritères 1aires: décès et IDM

Critères IIaires : hémorragies majeures

Exclusion : chocExclusion : choccréatcréat>220>220

0

3

6

9

12

15

0 5 10 15 20 25 30

Pri

ma

ry E

nd

Po

int

(%)

Pri

ma

ry E

nd

Po

int

(%)

ENOX

UFH

Days Days

9.9%(1017)

12.0%(1223)

4.7%

5.2%

RRRR0.90 0.90

(0.80 to 1.01)(0.80 to 1.01)

P=0.08P=0.08

48 h48 h

UFH ENOX

206 events

Relative RiskRelative Risk0.83 (0.77 to 0.90)0.83 (0.77 to 0.90)

P<0.0001P<0.0001

ST + : Primary End Point ST + : Primary End Point Death or Nonfatal MIDeath or Nonfatal MI

Bleeding Endpoints (TIMI) Bleeding Endpoints (TIMI) 30 Days30 Days

1,4 0,9 0,7

2,11,3 0,8

0

2

4

6

8

10 UFHUFHENOXENOX

%

% E

ven

tsE

ven

ts

Major BleedMajor Bleed(fatal + nonfatal)(fatal + nonfatal)

ICH ICH

ARD 0.7%ARD 0.7%RR 1.53RR 1.53

P<0.0001P<0.0001

ARD 0.1%ARD 0.1%RR 1.27RR 1.27

P = 0.14P = 0.14

NonfatalNonfatalMajor BleedMajor Bleed

ARD 0.4%ARD 0.4%RR 1.39RR 1.39

P = 0.014P = 0.014

Méta analyse HBPM vs HNF: ST+ thrombolysé

Eikelboom JW et Al Circulation 2005

Méta analyse HBPM vs HNF ST+ thrombolysé

Eikelboom JW et Al Circulation 2005

Outcomes during hospitalization/at 7 days with

LMWH vs UFH End point LMW

HUFH Odd

s ratio

95% CI

Reinfarction (%) 3.0 5.2 0.57 0.45-0.73

Death (%) 4.8 5.3 0.92 0.74-1.13

Major bleeding (%)

3.3 2.5 1.30 0.98-1.72

Minor bleeding (%)

22.8 19.4 1.26 1.12-1.43

SCA ST- décès ou infarctus à 30 jours

saignements majeurs : pas de différence significative

HBPMHBPM

Elkelboom Lancet 2000; 355: 1936

SCA ST- SYNERGY9978 patients SCA ST- randomisés HNF vs enoxaparine avec 92% patients

coronarographiés

HBPMHBPM

Ferguson J JAMA 2004 252 :45-54

Décès et IDM à30 jours

0 5 10 15 20 25 300.8

0.85

0.9

0.95

1.0

% p

atie

nts

sans

déc

ès n

i ID

M

Jours après randomisation

UFHUFHEnoxaparinEnoxaparin

30-Day Death/MI30-Day Death/MI

0.80.8 11 1.21.2

Hazard Ratio (95% CI)

Enoxaparin

Better

UFH

Better

15,913,3

0

5

10

15

20

Death or MI at 30 Days

UFH

ENOXAPARIN

Efficacy and Safety Outcomes With Consistent Therapy (Including

Crossovers)

18%18% RRRRRR

Pat

ien

ts (

%)

Pat

ien

ts (

%)

HR [95%]HR [95%]0.82 [0.73-0.95]0.82 [0.73-0.95]

®

SYNERGY Trial Investigators. JAMA. 2004;292:45-54.

HR=hazard ratio.

UFH ENOX

SCA ST- SYNERGYComplications hémorragiques

HBPMHBPM

Ferguson J JAMA 2004 252 :45-54

Enoxaparin UFH(n = 4993) (n = 4985) P-

value

GUSTO severe 2.9 2.40.106

TIMI major - clinical: 9.1 7.60.008 CABG-related 6.8 5.90.081 Non-CABG-related 2.4 1.80.025 H/H drop - algorithm 15.2 12.50.001

Any RBC transfusion 17.0 16.00.155

ICH < 0.1 < 0.1 NS

Chez patients avec SCA ST- HBPM au moins aussi efficace qu’HNF; avantages :

. administration SC

. pas surveillance coagulation

. meilleure prédictibilité et stabilité traitement

Chez Patients avec IDM ST+ avant 75 ans utilisation possible

HBPMHBPM

Best-of 2004 des Best-of 2004 des valvulopathiesvalvulopathiesAntiGP IIB III AAntiGP IIB III A

Best-of 2004 des Best-of 2004 des valvulopathiesvalvulopathiesFondaparinuxFondaparinux

Rappels

AnticoagulantsAnticoagulants

XIIa

XIa

IXa

Voie intrinsèque

Xa

Voie extrinsèque(facteur tissulaire)

VIIa

Thrombine (IIa)

Héparine / HBPMAT-III dépendant)

Hirudine/Hirulogbivalirudine

Antithrombine exclusifs polysaccharidesfondaparinux

Agents anti Xa exclusifs

Thrombine-Fibrine

Fondaparinux

pentasaccharide synthétique

élimination rénale

demi-vie d’élimination 17-21H

contre-indication : insuffisance rénale sévère

pas de cas de thrombopénie induite décrite pas de

surveillance numération plaquettaire

Anti-XaAnti-Xa

Patients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment Δ, cardiac markers

Patients with NSTE ACS, Chest discomfort < 24 hoursPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment 2 of 3: Age>60, ST Segment ΔΔ, , cardiac markerscardiac markers

Fondaparinux2.5 mg sc once daily

FondaparinuxFondaparinux2.5 mg sc once daily2.5 mg sc once daily

Study Design: Randomized, Double Blind

ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per

local practice

ASA, Clop, GP ASA, Clop, GP IIb/IIIaIIb/IIIa, , planned planned CathCath/PCI as per /PCI as per

local practicelocal practice

RandomizeRandomize

Enoxaparin1 mg/kg sc twice daily

EnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice daily

Primary: Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 daysRisk benefit: Death, MI, refractory ischemia, major bleeds 9 days

Secondary: Above & each component separately at day 30 & 6 monthsHypothesis: First test non-inferiority, then test superiority

Primary:Primary: EfficacyEfficacy:: Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days SafetySafety:: Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit:: Death, MI, refractory ischemia, major bleeds 9 daysDeath, MI, refractory ischemia, major bleeds 9 days

SecondarySecondary:: Above & each component Above & each component separatelyseparately at day 30 & 6 monthsat day 30 & 6 monthsHypothesisHypothesis:: First test nonFirst test non--inferiority, then test superiorityinferiority, then test superiority

Outcomes

PCI< 6 hPCI< 6 h,, No additional UFHNo additional UFHPCI >6 hPCI >6 h,, IV UFHIV UFHWith With IIb/IIIaIIb/IIIa 65 U/kg65 U/kgWithout Without IIb/IIIaIIb/IIIa 100 U/kg100 U/kg

PCI <6 hPCI <6 h:: IV Fonda 2.5 mgIV Fonda 2.5 mgwithout without IIb/IIIaIIb/IIIa, 0 with , 0 with IIb/IIIaIIb/IIIaPCI> 6 hPCI> 6 h:: IV Fonda 2.5 mg withIV Fonda 2.5 mg withand 5.0 mg without and 5.0 mg without IIb/IIIaIIb/IIIa

ExcludeAge < 21Any contra-ind to EnoxHem stroke< 12 mo.Creat> 3 mg/dL/265 umol/L

N=20,000

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

Cu

mu

lati

ve H

azar

d

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

Death or MI: 6 Months

Days

Cu

mu

lati

ve H

aza

rd

0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 20 40 60 80 100 120 140 160 180

HR 0.91HR 0.9195% CI 0.8495% CI 0.84--0.990.99

P=0.036P=0.036

Enoxaparin

Fondaparinux


CONCLUSION OASIS 5

• efficacité similaire fondaparinux/enoxaparine

• réduction hémorragies avec fondaparinux entrainant diminution mortalité

• limites : seulement 60% patients coronarographiés, 33% population a eu une ATL

groupe enoxaparine a reçu HNF pour angioplastie 65% patients sous clopidogrel lors angioplastie cas thrombus dans cathéter

YUSUF S NEJM 2006 1464-76

12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads

Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.

12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads

Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.

UFH UFH notnot indicated indicatedUFH UFH notnot indicated indicated

OASIS 6: Randomized, Double Blind, Double Dummy

Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)

StratificationStratificationStratificationStratification

UFH indicatedUFH indicatedUFH indicatedUFH indicated

Randomization Randomization

Fondaparinux2.5 mg Placebo

Fondaparinux2.5 mg UFH

Primary Efficacy OutcomeDeath/MI at 30 Days

Days

Cum

ulat

ive

Haz

ard

0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 3 6 9 12 15 18 21 24 27 30

UFH/Placebo

Fondaparinux

HR 0.86 95% CI 0.77-0.96

P = 0.008

Death at Study End (3 or 6 months)

Days

Cum

ulat

ive

Haz

ard

0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 18 36 54 72 90 108 126 144 162 180

UFH/Placebo

Fondaparinux

HR 0.88 95% CI 0.79-0.99

P = 0.029

Severe hemorrhage at 30 days


YUSUF S JAMA 2006 1519-30

OASIS 6

randomisation complexe

fondaparinux pas supérieure à l’HNF

plus complications lors angioplastie groupe fondaparinux

intérêt fondaparinux si pas de revascularisation par angioplastie envisagée

Best-of 2004 des Best-of 2004 des valvulopathiesvalvulopathiesBivalirudineBivalirudine

Rappels

AnticoagulantsAnticoagulants

XIIa

XIa

IXa

Voie intrinsèque

Xa

Voie extrinsèque(facteur tissulaire)

VIIa

Thrombine (IIa)

Héparine / HBPMAT-III dépendant)

Hirudine/Hirulogbivalirudine

Antithrombine exclusifs polysaccharidesfondaparinux

Agents anti Xa exclusifs

Thrombine-Fibrine

Moderateand highrisk ACS

(n=13,819)

Study Design – First RandomizationStudy Design – First Randomization

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice



UFH/Enox+ GP IIb/IIIa(n=4,603)

Bivalirudin+ GP IIb/IIIa(n=4,604)

BivalirudinAlone

(n=4,612)

R*

*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)


Medicalmanagement

PCI

CABG

56%

11%

33%

Study Design – Second RandomizationStudy Design – Second Randomization

UFH/Enox+ GP IIb/IIIa(N=4,603)

Bivalirudin+ GP IIb/IIIa(N=4,604)

BivalirudinAlone

(N=4,612)

R*

GPI upstream (N=2294)

GPI CCL for PCI (N=2309)

GPI upstream (N=2311)

GPI CCL for PCI (N=2293)





*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderateand highrisk ACS(n=13,819



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

5

15

25

Isch

emic

Co

mp

osi

te (

%)

Days from Randomization

10

20 UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

30 day

7.4%0.367.8%0.347.9%

—

EstimateP

(log rank)

16.3%0.3816.5%0.3116.4%

1 year

—

p=0.55

Bivalirudin alone vs. Hep+GPIHR [95% CI] = 1.05 (0.95-1.17)

Bivalirudin+GPI vs. Hep+GPIHR [95% CI] = 1.05 (0.94-1.16)

Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)

Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)

UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

Myocardial InfarctionMyocardial Infarction

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

5

10

15


UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

30 day

4.4%0.694.6%0.364.8%

—

EstimateP

(log rank)

6.2%0.636.4%0.107.1%

1 year

—

p=0.24

MI

(%)

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

4

5

Mo

rtal

ity

(%)


2

1

Mortality: 524 total deaths at 1-yearMortality: 524 total deaths at 1-yearUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

1.4%0.531.6%0.391.6%

—

EstimateP

(log rank)

4.4%0.934.2%0.663.8%

1 year

—

p=0.90

Bivalirudin+GPI vs. Hep+GPIHR [95% CI] = 0.99 (0.80-1.22)

30 day

3

Bivalirudin alone vs. Hep+GPIHR [95% CI] = 0.95 (0.77-1.18)

Mo

rtal

ity

(%)


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 First 30 Days on Risk of Death Over 1 Year

28.9%

12.5%

8.6%

3.4%

ConclusionsConclusions• In patients with moderate and high risk ACS

undergoing an early invasive strategy with the use of GP IIb/IIIa inhibitors

• Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin

• Compared to either UFH/enoxaparin with GP IIb/IIIa inhibitors or bivalirudin with GP IIb/IIIa inhibitors

• A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1-year

• The results of this study further establish the important relationship between iatrogenic bleeding complications and subsequent mortality in patients with ACS

Recommandations actuellesRecommandations actuelles

Maladie

coronarienneIDM ST+ACC ESC

SCA ST-ACC ESC

HNF 1C 1B 1A 1B

HBPM 2B - 1A 1A

HBPM préférée à

HNF - - 2A 2A

si enoxaparine

ConclusionsConclusions

• pas de recommendations par rapport fondaparinux et bivalirudine

• important de prendre en compte le risque hémorragique

Best-of 2004 des Best-of 2004 des valvulopathiesvalvulopathiesCONCLUSIONSCONCLUSIONS

Prise en charge des SCA sans élévation du segment ST

Documents

Quels traitements antithrombosants dans les SCA ? G de Gevigney G de Gevigney Hôpital Cardiologique Hôpital Cardiologique Lyon, France Lyon, France Journées