Elsevier

Journal of Hepatology

Volume 61, Issue 2, August 2014, Pages 252-259
Journal of Hepatology

Research Article
Effect of recombinant Factor VIIa on outcome of acute variceal bleeding: An individual patient based meta-analysis of two controlled trials

https://doi.org/10.1016/j.jhep.2014.03.035Get rights and content

Background & Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Introduction

The management of variceal bleeding in cirrhosis remains a clinical challenge although mortality has decreased from 42% [1] to 15–20% in the last 3 decades [2], [3]. Combined pharmacological and endoscopic therapy is currently the standard of care [4], [5], although early TIPS should be considered in high risk patients with active bleeding at endoscopy [6]. In patients with advanced cirrhosis, the synthesis of coagulation factors is decreased, notably factor VII, which can be corrected by infusion of rFVIIa (NovoNordisk A/S Denmark) [7].

In a randomized, controlled trial investigating the safety and efficacy of rFVIIa in patients with upper gastrointestinal bleeding and cirrhosis, there was no significant effect of rFVIIa treatment on the number of 5-day failures [8]. However, a posthoc analysis found that rFVIIa significantly reduced the number of 5-day failures and improved 24-h bleeding control in the subgroup of Child-Pugh B and C patients with endoscopic proven active variceal bleeding.

A second study was then performed to investigate the efficacy and safety of rFVIIa in patients with severe liver disease (Child-Pugh score >8 points) and spurting or oozing variceal bleeding at emergency endoscopy [9]. Patients were equally randomized to different doses of rFVIIa (600 μg/kg administered in four doses or 300 μg/kg administered in two doses) or placebo. It was decided beforehand that the 300 μg/kg would only be compared to placebo in case of a positive outcome of the high dose. No beneficial effect of 600 μg/kg of rFVII was found in 5-day failure. A major limitation of this second study was that the observed failure rate with placebo was actually much lower (23%) than predicted (40%) with loss of power. Moreover there was a marked heterogeneity in the treatment effect across participating centers. In fact, an exploratory analysis revealed a reduced treatment failure rate under rFVIIa administration at both low and high dose in centers with >10% failure rate, which would be in accordance with the results of the previous trial. The conclusion of this second study was that rFVIIa may not be used routinely for the treatment of variceal bleeding. However the aim of this study, which was to test the treatment effect in high risk patients, was not achieved because of some inadvertent patient selection bias and lack of power.

Therefore, the aim of the present study was to perform a meta-analysis of the two trials based on individual patient data with special focus on high risk patients with active bleeding at endoscopy.

Section snippets

Study design

This is an individual patient based meta-analysis of the two randomized placebo controlled, double blind trials [8], [9]. All the patients in the intention to treat (ITT) population from the two studies were included. Safety analysis included severe and total adverse events. A separate analysis has also been performed in two subgroups of patients at higher risk: (a) active variceal bleeding; (b) active variceal bleeding and Child Pugh score >8.

Patients

The two studies were identified as 1288 [8] and

Patient characteristics

In total 497 patients were eligible for the meta-analysis (Table 1) with 308 (62%) having active variceal bleeding at endoscopy and 283 of these (57%) having a Child-Pugh score >8. Baseline characteristics were similar between treatment groups (Table 2). Bleeding was found to be of variceal origin in 81% of placebo patients and in 86% in rFVIIa treated patients. Nearly all high risk patients with endoscopic verified active bleeding and a Child-Pugh score >8 received the mandatory vasoactive

Discussion

The present meta-analysis of the two studies showed beneficial effect on the composite endpoints for patients with endoscopical proven active variceal bleeding, which was further potentiated by inclusion of only patients with a Child-Pugh score above 8. No significant effect could be demonstrated on the control of bleeding, while rebleeding day 1–5 was lower in the active treated group. The significant effect on the composite endpoint was lost during day 5–42, mainly due to a high number of

Conflict of interest

Flemming Bendtsen received an unrestricted grant from NovoNordisk A/S to appoint a statistician for 3 months to do the statistical analyses of the study. Gennaro D’Amico, Eva Rusch, Roberto de Franchis, Per K. Andersen and Jaime Bosch have no conflicts of interest to declare.

Acknowledgements

We are grateful to NovoNordisk A/S for providing us with all the raw data from the two studies and for an unrestricted grant to perform independent statistical analyses.

References (21)

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