Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: A randomized, double-blind trial

Hospital Clinic, Liver Unit, Barcelona, Spain.
Gastroenterology (Impact Factor: 16.72). 11/2004; 127(4):1123-30. DOI: 10.1053/j.gastro.2004.07.015
Source: PubMed


Upper gastrointestinal bleeding (UGIB) is a severe and frequent complication of cirrhosis. Recombinant coagulation factor VIIa (rFVIIa) has been shown to correct the prolonged prothrombin time in patients with cirrhosis and UGIB. This trial aimed to determine efficacy and safety of rFVIIa in cirrhotic patients with variceal and nonvariceal UGIB.
A total of 245 cirrhotic patients (Child-Pugh < 13; Child-Pugh A = 20%, B = 52%, C = 28%) with UGIB (variceal = 66%, nonvariceal = 29%, bleeding source unknown = 5%) were randomized equally to receive 8 doses of 100 microg/kg rFVIIa or placebo in addition to pharmacologic and endoscopic treatment. The primary end point was a composite including: (1) failure to control UGIB within 24 hours after first dose, or (2) failure to prevent rebleeding between 24 hours and day 5, or (3) death within 5 days.
Baseline characteristics were similar between rFVIIa and placebo groups. rFVIIa showed no advantage over standard treatment in the whole trial population. Exploratory analyses, however, showed that rFVIIa significantly decreased the number of failures on the composite end point (P = 0.03) and the 24-hour bleeding control end point (P = 0.01) in the subgroup of Child-Pugh B and C variceal bleeders. There were no significant differences between rFVIIa and placebo groups in mortality (5- or 42-day) or incidence of adverse events including thromboembolic events.
Although no overall effect of rFVIIa was observed, exploratory analyses in Child-Pugh B and C cirrhotic patients indicated that administration of rFVIIa significantly decreased the proportion of patients who failed to control variceal bleeding. Dosing with rFVIIa appeared safe. Further studies are needed to verify these findings.

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    • "The two studies were identified as 1288 [8] and 1533 [9] NovoNordisk A/S studies, respectively, and will be identified simply by their identification number or by reference from now on throughout the text of this article. Inclusion criteria were; age P18 and <75 years [8] and <80 [9], cirrhosis with oesophageal or gastric varices or portal hypertensive gastropathy, with Child-Pugh score <12 in study 1288 and >8 in 1533; haematemesis or melaena within 24 h of inclusion, requiring hospital admission and volume replacement therapy in 1288 and endoscopy-proven, active oesophageal or gastro-oesophageal variceal bleeding in 1533. "
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    ABSTRACT: Two randomized controlled studies have evaluated the effect of recombinant Factor VIIa (rFVIIa) on variceal bleeding in cirrhosis without showing significant benefit. The aim of the present study was to perform a meta-analysis of the two trials on individual patient data with special focus on high risk patients. The primary outcome measure was the effect of rFVIIa on a composite five day endpoint: failure to control bleeding, 5-day rebleeding or death. Analysis was based on intention to treat. High risk was defined as active bleeding on endoscopy while under vasoactive drug infusion and Child-Pugh score>8. 497 patients were eligible for the meta-analysis; 308 (62%) had active variceal bleeding at endoscopy (oozing or spurting) and 283 of these had a Child-Pugh score>8. Analysis on the composite endpoint in all patients with bleeding from oesophageal varices did not show any beneficial treatment effect. However, failure rate for the primary composite end-point was significantly lower in treated patients with active bleeding at endoscopy (17%) compared to placebo (26%, p=0.049). This difference was highly significant in patients with Child-Pugh score>8 and active bleeding at endoscopy (rFVIIa 16%, placebo 27%; p=0.023). No significant treatment effect was found at 42 days. Five thromboembolic events occurred in rFVIIa treated patients compared to none in placebo treated patients. The current meta-analysis shows a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of rebleeding day 1-5 and 5-day mortality in patients with advanced cirrhosis and active bleeding from oesophageal varices at endoscopy. A major drawback of the treatment is a potential increased risk of arterial thrombo-embolic events. This treatment might be considered in patients with lack of control of bleeding after standard treatment.
    No preview · Article · Apr 2014 · Journal of Hepatology
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    • "Coagulopathy, if present, must be supported by appropriate blood product transfusion. The evidence for factor VII transfusions is equivocal [105, 106]. Either norfloxacin or ceftriaxone may be used for prophylaxis of SBP, with the latter being more effective in higher stage of liver disease [41, 107]. "
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    ABSTRACT: Mortality in cirrhosis is consequent of decompensation, only treatment being timely liver transplantation. Organ allocation is prioritized for the sickest patients based on Model for End Stage Liver Disease (MELD) score. In order to improve survival in patients with high MELD score it is imperative to preserve them in suitable condition till transplantation. Here we examine means to prolong life in high MELD score patients till a suitable liver is available. We specially emphasize protection of airways by avoidance of sedatives, avoidance of Bilevel Positive Airway Pressure, elective intubation in grade III or higher encephalopathy, maintaining a low threshold for intubation with lesser grades of encephalopathy when undergoing upper endoscopy or colonoscopy as pre transplant evaluation or transferring patient to a transplant center. Consider post-pyloric tube feeding in encephalopathy to maintain muscle mass and minimize risk of aspiration. In non intubated and well controlled encephalopathy, frequent physical mobility by active and passive exercises are recommended. When renal replacement therapy is needed, night-time Continuous Veno-Venous Hemodialysis may be useful in keeping the daytime free for mobility. Sparing and judicious use of steroids needs to be borne in mind in treatment of ARDS and acute hepatitis from alcohol or autoimmune process.
    Full-text · Article · Jul 2012
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    • "Outstandingly, the ability of recombinant activated FVII (rFVIIa) to affect hemostasis was investigating in patients with upper gastrointestinal bleeding and cirrhosis [9]. The results of a placebo-controlled multicenter trial in a high-risk population of patients with cirrhosis (n = 256; Child-Pugh score >8 points) and active variceal bleeding failed to show a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of re-bleeding, and reducing 5-day mortality. "
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    ABSTRACT: Variceal hemorrhage is a major cause of death in patients with cirrhosis. Much still could be performed in clinical practice to reduce the risk for bleeding in cirrhotic patients and accurate predictive rules should be provided for early recognition of high-risk patients. Liver cirrhosis patients present a complex hemostatic dysfunction with prolongation of bleeding time, chronic coagulation activation, and secondary hyperfibrinolysis. Therefore, liver failure determines an acquired coagulopathy that has been considered to be one potential underlying mechanism of bleeding. Endotoxemia may play a pivotal role in activating clotting system in portal and systemic circulation and it could represent a common mechanism accounting for portal vein thrombosis, systemic hyperfibrinolysis and eventually gastrointestinal bleeding. Nevertheless, clinical trials should also be planned to investigate the causal relationship between acquired coagulopathy and bleeding in patients with chronic liver disease.
    Full-text · Article · Apr 2010 · European Journal of Internal Medicine
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