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Quels traitements antithrombosants dans les SCA ?. G de Gevigney Hôpital Cardiologique Lyon, France. Journées de l’AFL Beyrouth 11-12 mai 2007. Introduction. Aspirine Héparine Clopidogrel HBPM Thrombolytiques Anti GP2B3A Fondaparinux Bivalirudine. Les acquis

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quels traitements antithrombosants dans les sca

Quels traitements antithrombosants dans les SCA ?

G de Gevigney

Hôpital Cardiologique

Lyon, France

Journées de l’AFL

Beyrouth

11-12 mai 2007

introduction
Introduction
  • Aspirine
  • Héparine
  • Clopidogrel
  • HBPM
  • Thrombolytiques
  • Anti GP2B3A
  • Fondaparinux
  • Bivalirudine
acute coronary syndromes without st evidence for aspirin

Cairns

Lewis

Theroux

Wallentin

Pooled

0

1.0

2.0

Favors Aspirin

Favors Placebo

Acute Coronary Syndromes Without ST Evidence for Aspirin

Relative Risk — Death or MI

acute coronary syndromes without st evidence for heparin use ufh asa versus asa

Relative 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)

2.66

6.87

P = 0.06

0

0.5

1

1.5

2

ASA Better

ASA + UFH Better

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

Oler A, JAMA 1996

clopidogrel crit re de jugement principal tous patients

% de patients présentant un événement ischémique

( décès vasculaire, IDM, AVC)

14

12

10

8

6

4

2

0

Clopidogrel Critère de jugement principal tous patients

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

20% RRR

p=0.00009

n=12 562

Traitement standard

Clopidogrel + traitement standard

0

1

2

3

4

5

6

7

8

9

10

11

12

Suivi en mois

The CURE Investigators. N Eng J Med August 2001

slide7

PCI-

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

Cumulative hazard rates

0.15

12.6%

31% RRR

p=0.002

n=2658

8.8%

0.10

Tt conventionnel

Clopidogrel + tt conventionnel

0.05

Critére: IDM + décès vasculaire

0.0

0

10

40

100

200

300

400

Jours de suivi

a

b

a = délais médian randomisation /ACP (10 jours)

b = 30 jours aprés ACP

les acquis dans les sca
Les acquis dans les SCA
  • Thrombolytiques
      • SCA ST +
      • échec dans SCA ST -
  • AntiGP-IIB-IIIA
      • SCA ST -
slide10

IDM ST+

20056 pts

fibrinolyse

randomisée, double aveugle

ENOXAPARINE

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

< 75ans pas bolus et 0.75mg/kg si >75ans

durant toute l’hospitalisation

HNF

durant 48H

30 jours

Critères 1aires: décès et IDMCritères IIaires : hémorragies majeures

HBPM

IDM ST+

EXTRACT TIMI 25

Exclusion : choc

créat>220

Antmann EM NEJM 2006 354

st primary end point death or nonfatal mi
ST + : Primary End Point Death or Nonfatal MI

48 h

UFH

12.0%(1223)

206 events

9.9%(1017)

ENOX

Primary End Point (%)

5.2%

Relative Risk0.83 (0.77 to 0.90)P<0.0001

4.7%

RR0.90 (0.80 to 1.01)P=0.08

UFH

ENOX

Days

bleeding endpoints timi 30 days
Bleeding Endpoints (TIMI) 30 Days

UFH

ENOX

ARD 0.7%RR 1.53P<0.0001

ARD 0.4%RR 1.39P = 0.014

ARD 0.1%RR 1.27P = 0.14

% Events

Major Bleed(fatal + nonfatal)

NonfatalMajor Bleed

ICH

m ta analyse hbpm vs hnf st thrombolys
Méta analyse HBPM vs HNF: ST+ thrombolysé

Eikelboom JW et Al Circulation 2005

m ta analyse hbpm vs hnf st thrombolys14
Méta analyse HBPM vs HNF ST+ thrombolysé

Outcomes during hospitalization/at 7 days with LMWH vs UFH

Eikelboom JW et Al Circulation 2005

slide15

HBPM

SCA ST-

décès ou infarctus à 30 jours

saignements majeurs : pas de différence significative

Elkelboom Lancet 2000; 355: 1936

d c s et idm 30 jours

1.0

0.95

0.9

% patients sans décès ni IDM

0.85

Enoxaparin

UFH

0.8

0

5

10

15

20

25

30

Jours après randomisation

HBPM

Décès et IDM à30 jours

SCA ST- SYNERGY

9978 patients SCA ST- randomisés HNF vs enoxaparine avec 92% patients coronarographiés

Ferguson J JAMA 2004 252 :45-54

efficacy and safety outcomes with consistent therapy including crossovers
Efficacy and Safety Outcomes With Consistent Therapy (Including Crossovers)

HR [95%]

0.82 [0.73-0.95]

®

18%

RRR

Patients (%)

UFH

ENOX

HR=hazard ratio.

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

slide18

HBPM

SCA ST- SYNERGY

Complications hémorragiques

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

GUSTO severe 2.9 2.4 0.106

TIMI major - clinical: 9.1 7.6 0.008 CABG-related 6.8 5.9 0.081 Non-CABG-related 2.4 1.8 0.025

H/H drop - algorithm 15.2 12.5 0.001

Any RBC transfusion 17.0 16.0 0.155

ICH < 0.1 < 0.1 NS

Ferguson J JAMA 2004 252 :45-54

slide19

HBPM

  • 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
slide23

Anticoagulants

Voie extrinsèque

(facteur tissulaire)

Voie intrinsèque

Rappels

XIIa

VIIa

Héparine / HBPMAT-III dépendant)

XIa

IXa

Hirudine/Hirulog

bivalirudine

Antithrombine exclusifs

Xa

polysaccharides

fondaparinux

Agents anti Xa exclusifs

Thrombine (IIa)

Thrombine-Fibrine

slide24

Anti-Xa

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

slide29

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

oasis 6 randomized double blind double dummy
OASIS 6: Randomized, Double Blind, Double Dummy

12,000 Patients with STEMI < 12 h of symptom onset

Inclusion: ST   2 mm prec leads or  1 mm limb leads

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

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

Stratification

UFH not indicated

UFH indicated

Randomization

Randomization

Fondaparinux

2.5 mg

Placebo

Fondaparinux

2.5 mg

UFH

primary efficacy outcome death mi at 30 days
Primary Efficacy OutcomeDeath/MI at 30 Days

0.12

UFH/Placebo

0.10

Fondaparinux

0.08

0.06

Cumulative Hazard

HR 0.86

95% CI 0.77-0.96

P = 0.008

0.04

0.02

0.0

0

3

6

9

12

15

18

21

24

27

30

Days

death at study end 3 or 6 months
Death at Study End (3 or 6 months)

0.12

UFH/Placebo

0.10

Fondaparinux

0.08

0.06

Cumulative Hazard

HR 0.88

95% CI 0.79-0.99

P = 0.029

0.04

0.02

0.0

0

18

36

54

72

90

108

126

144

162

180

Days

slide34

Fondaparinux

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

YUSUF S JAMA 2006 1519-30

slide36

Anticoagulants

Voie extrinsèque

(facteur tissulaire)

Voie intrinsèque

Rappels

XIIa

VIIa

Héparine / HBPMAT-III dépendant)

XIa

IXa

Hirudine/Hirulog

bivalirudine

Antithrombine exclusifs

Xa

polysaccharides

fondaparinux

Agents anti Xa exclusifs

Thrombine (IIa)

Thrombine-Fibrine

study design first randomization
Study Design – First Randomization

Medical

management

UFH/Enox

+ GP IIb/IIIa

(n=4,603)

PCI

Bivalirudin

+ GP IIb/IIIa

(n=4,604)

Angiography within 72h

R*

Bivalirudin

Alone

(n=4,612)

CABG

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

33%

Moderate

and high

risk ACS

(n=13,819)

56%

Aspirin in all

Clopidogrel

dosing and timing

per local practice

11%

*Stratified by pre-angiography thienopyridine use or administration

study design second randomization
Study Design – Second Randomization

UFH/Enox

+ GP IIb/IIIa

(N=4,603)

GPI upstream (N=2294)

GPI CCL for PCI (N=2309)

Bivalirudin

+ GP IIb/IIIa

(N=4,604)

GPI upstream (N=2311)

R*

GPI CCL for PCI (N=2293)

Bivalirudin

Alone

(N=4,612)

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

Moderate

and high

risk ACS

(n=13,819

Aspirin in all

Clopidogrel

dosing and timing

per local practice

*Stratified by pre-angiography thienopyridine use or administration

ischemic composite endpoint death mi unplanned revascularization for ischemia
Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)

30 day

P

(log rank)

1 year

P

(log rank)

Estimate

Estimate

p=0.55

UFH/Enoxaparin + IIb/IIIa

7.4%

16.3%

0.36

0.38

Bivalirudin + IIb/IIIa

7.8%

16.5%

0.34

0.31

Bivalirudin alone

7.9%

16.4%

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

25

20

15

Ischemic Composite (%)

10

Bivalirudin+GPI vs. Hep+GPI

HR [95% CI] = 1.05 (0.94-1.16)

5

Bivalirudin alone vs. Hep+GPI

HR [95% CI] = 1.05 (0.95-1.17)

0

0

30

60

90

120

150

180

210

240

270

300

330

360

390

Days from Randomization

myocardial infarction
Myocardial Infarction

p=0.24

UFH/Enoxaparin + IIb/IIIa

Bivalirudin + IIb/IIIa

Bivalirudin alone

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

15

30 day

P

(log rank)

1 year

P

(log rank)

Estimate

Estimate

4.4%

6.2%

4.6%

0.69

6.4%

0.63

10

4.8%

0.36

7.1%

0.10

MI (%)

5

0

0

30

60

90

120

150

180

210

240

270

300

330

360

390

Days from Randomization

mortality 524 total deaths at 1 year
Mortality: 524 total deaths at 1-year

p=0.90

UFH/Enoxaparin + IIb/IIIa

Bivalirudin + IIb/IIIa

Bivalirudin alone

P

(log rank)

1 year

P

(log rank)

Estimate

Estimate

1.4%

4.4%

0.53

0.93

1.6%

4.2%

0.39

0.66

1.6%

3.8%

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

5

Bivalirudin+GPI vs. Hep+GPI

HR [95% CI] = 0.99 (0.80-1.22)

4

Bivalirudin alone vs. Hep+GPI

HR [95% CI] = 0.95 (0.77-1.18)

3

Mortality (%)

2

30 day

1

0

0

30

60

90

120

150

180

210

240

270

300

330

360

390

Days from Randomization

slide42

Major Bleed only (without MI) (N=551)

12.5%

MI only (without Major Bleed) (N=611)

8.6%

No MI or Major Bleed (N=12,557)

Both MI and Major Bleed (N=94)

28.9%

3.4%

Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year

1 yearEstimate

30

28.9%

25

20

Mortality (%)

15

12.5%

10

8.6%

5

3.4%

0

0

30

60

90

120

150

180

210

240

270

300

330

360

390

Days from Randomization

conclusions
Conclusions
  • 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
slide44

Recommandations actuelles

 si enoxaparine

slide45

Conclusions

  • pas de recommendations par rapport fondaparinux et bivalirudine
  • important de prendre en compte le risque hémorragique
ad