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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. Aspirine Héparine Clopidogrel HBPM Thrombolytiques Anti GP2B3A Fondaparinux Bivalirudine. Les acquis

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Quels traitements antithrombosants dans les SCA ?

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  1. Quels traitements antithrombosants dans les SCA ? G de Gevigney Hôpital Cardiologique Lyon, France Journées de l’AFL Beyrouth 11-12 mai 2007

  2. Introduction • Aspirine • Héparine • Clopidogrel • HBPM • Thrombolytiques • Anti GP2B3A • Fondaparinux • Bivalirudine

  3. Les acquis dans les SCA ST+ et ST- Best-of 2004 des valvulopathies

  4. 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

  5. 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

  6. % 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

  7. 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

  8. Les acquis dans les SCA • Thrombolytiques • SCA ST + • échec dans SCA ST - • AntiGP-IIB-IIIA • SCA ST -

  9. HBPM Best-of 2004 des valvulopathies

  10. 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

  11. 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

  12. 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

  13. Méta analyse HBPM vs HNF: ST+ thrombolysé Eikelboom JW et Al Circulation 2005

  14. Méta analyse HBPM vs HNF ST+ thrombolysé Outcomes during hospitalization/at 7 days with LMWH vs UFH Eikelboom JW et Al Circulation 2005

  15. HBPM SCA ST- décès ou infarctus à 30 jours saignements majeurs : pas de différence significative Elkelboom Lancet 2000; 355: 1936

  16. 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

  17. 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.

  18. 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

  19. 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

  20. AntiGP IIB III A Best-of 2004 des valvulopathies

  21. Fondaparinux Best-of 2004 des valvulopathies

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. Severe hemorrhage at 30 days

  29. 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

  30. Bivalirudine Best-of 2004 des valvulopathies

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. Recommandations actuelles  si enoxaparine

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

  41. CONCLUSIONS Best-of 2004 des valvulopathies

  42. Prise en charge des SCA sans élévation du segment ST

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