Recombinant factor VIIa for variceal bleeding in patients... : Hepatology (original) (raw)

Liver Failure/Cirrhosis/Portal Hypertension

Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial

Bosch, Jaime1*; Thabut, Dominique2; Albillos, Agustín3; Carbonell, Nicolas4; Spicak, Julius5; Massard, Julien2; D'Amico, Gennaro6; Lebrec, Didier7; de Franchis, Roberto8; Fabricius, Sφren9; Cai, Yan9; Bendtsen, Flemming10

1_Hepatic Hemodynamic Laboratory, Hospital Clinic and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Spain_

2_Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié Salpétrière, Paris, France_

3_Department of Gastroenterology, Hospital Universitario Ramón y Cajal and CIBEREHD, University of Alcalá, Madrid, Spain_

4_AP-HP, Hôpital Saint-Antoine, Paris, France_

5_Institute for Clinical and Experimental Medicine, Prague, Czech Republic_

6_Ospedale V. Cervello, Palermo, Italy_

7_Institut National de la Santé et de la Recherche Médicale, U773, Centre de Recherche Bichat-Beaujon CRB3, Paris and Service d'Hepatologie, Hôpital Beaujon, Clichy, France_

8_Ospedale Policlinico, Milan, Italy_

9_Novo Nordisk A/S, Bagsvaerd, Denmark_

10_Department of Medical Gastroenterology, Hvidovre Hospital and Faculty of Health Sciences, University of Copenhagen, Denmark_

*Address reprint requests to: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, CIBEREHD, University of Barcelona, Spain

Email:[email protected]

Received 13 July 2007; Accepted 20 December 2007

Published online in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Novo Nordisk A/S, 2880 Bagsvaerd, Denmark.

Potential conflict of interest: Drs. Bendtsen and D'Amico adivse Novo Nordisk. Dr. de Franchis is a consultant for Novo Nordisk.

fax (34) 93 227 9348.

Abstract

A beneficial effect of recombinant activated factor VII (rFVIIa) in Child-Pugh class B and C patients with cirrhosis who have variceal bleeding has been suggested. This randomized controlled trial assessed the efficacy and safety of rFVIIa in patients with advanced cirrhosis and active variceal bleeding. At 31 hospitals in an emergency setting, 256 patients (Child-Pugh > 8; Child-Pugh B = 26%, C = 74%) were randomized equally to: placebo; 600 μg/kg rFVIIa (200 + 4× 100 μg/kg); or 300 μg/kg rFVIIa (200 + 100 μg/kg). Dosing was intravenous at 0, 2, 8, 14, and 20 hours after endoscopy, in addition to standard vasoactive, prophylactic antibiotic, and endoscopic treatment. The primary composite endpoint consisted of failure to control 24-hour bleeding, or failure to prevent rebleeding or death at day 5. Secondary endpoints included adverse events and 42-day mortality. Baseline characteristics were comparable between groups. Administration of rFVIIa had no significant effect on the composite endpoint compared with placebo ( P = 0.37). There was no significant difference in 5-day mortality between groups; however, 42-day mortality was significantly lower with 600 μg/kg rFVIIa compared with placebo (odds ratio 0.31, 95% confidence interval = 0.13–0.74), and bleeding-related deaths were reduced from 12% (placebo) to 2% (600 μg/kg). A marked heterogeneity in the failure rate in all treatment groups was observed across participating centers. Adverse events, including overall thromboembolic events, were comparable between groups. Conclusion: Treatment with rFVIIa had no significant effect on the primary composite endpoint compared with placebo. Therefore, decision on the use of this hemostatic agent in acute variceal bleeding should be carefully considered, because results of this study do not support the routine use of rFVIIa in this setting. Adverse events were comparable across groups.

Abbreviations: RBC, red blood cell; rFVIIa, recombinant activated factor VII; TAB, trial advisory board; TIPS, transjugular intrahepatic portosystemic shunt; UGIB, upper gastrointestinal bleeding.