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High-dose antithrombin III in the traitment of severe sepsis in patients with a high risk of death: Efficacy and safety
Christian J. Wiedermann M.D. Johannes N.Crit. Care Med. 2006 vol. 34, N°2, 285-292
Gabriel DAMIANDESC Réanimation Médicale
Jeudi 07 Juin 2007
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Introduction
• Analyse en sous-groupe (pré définis) de l’étude « KyberSept »
( Warren B.L., Eid A., High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286: 1869-1878)
• Sepsis ± choc activation coagulation• Antithrombine III:
– glycoprotéine synthèse hépatique (58 KD)– anti-coagulante + anti-inflammatoire– Héparine inhibe l’action anti-inflammatoire…(Wiedermann C.J., Kaneider N.C., Comparison of mechanisms after post-hoc
analyses to the AT III and APC trials in severe sepsis. Ann Med 2004; 36: 194-203
AT III dans sepsis = pronostique (Mesters R.W., Mannucci P.W., Factor VII and antithrombin III activity during
sepsis and septic choc in neutropenic patients. Blood; 1996, 88: 881-886)
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KyberSept
• Étude de phase 3, randomisée, double aveugle, vs placebo
• 2314 patients en choc septique, 211 centres dans 19 pays
• 30000 UI AT III vs Albumine 1%• Objectif 1°: mortalité à J28 ( 15%)• Objectifs 2°: mortalité à J56 et J90, durée
d’hospitalisation en réa, apparition de défaillance organique, saignements
• Sous-population pré définies:– Sévérité du sepsis (SAPS II)– Utilisation concomitante d’héparine
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KyberSept
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KyberSept
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KyberSept
P= 0,94 P= 0,08
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KyberSept
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CCM 2006
• Analyse uni et multifactorielle du sous-groupe « haut risque de décès »:– Mortalité prédite 30~60% (SAPS II)
• 1008 patients (43,6%)
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P= 0,O7
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• Risque relatif de décès en SOUS-SOUS-GROUPE
AT III + efficace si:– AT III initiale > 60%– Patients médicaux– Sans TTT concomitant
par héparine
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Risque hémorragique
•Événement indésirable grave:•Hémorragie intra-cranienne•Hémorragie nécessitant transfusion > 3 CGR
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Conclusion de l’article
• AT III la mortalité jusqu’à J90 malgré saignement.
• Ce gain en mortalité est plus marqué sans héparinothérapie concomitante– Héparine inhibe l’action anti-inflammatoire
de AT III (syndecan récepteur)– Majoration du risque hémorragique
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Mortalité
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Discussion et (ma) conclusion
• Analyse en sous-(sous)groupe…2314 1008 302
• Le design de l’étude était orienté sur la mortalité de la globalité des sujets
• Faut-il se servir d’un score de gravité pour décider d’un traitement ? NON
• Il s’agit d’un traitement coûteux qui entraîne une surmortalité chez les patients peu grave ou très grave (SAPS II)
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KyberSept
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Discussion et (ma) conclusion
• Analyse en sous-(sous)-groupe…2314 1008 302
• Le design de l’étude était orienté sur la mortalité de la globalité des sujets
• Faut-il se servir d’un score de gravité pour décider d’un traitement ? NON
• Il s’agit d’un traitement coûteux qui entraîne une sur mortalité chez les patients peu grave ou très grave (SAPS II)
• Doit-on faire un choix: Héparine ou AT III ?