Transplant Library

Abstract

PURPOSE:

Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are associated with significant mortality and morbidity. Extracorporeal liver support (ECLS) devices have been used as a bridge to liver transplant; however, the efficacy and safety of ECLS are unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the efficacy and safety of ECLS in liver failure.

METHODS:

We searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from inception through March 13, 2019. RCTs comparing ECLS to usual care in ALF or ACLF were included. We used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence.

RESULTS:

We identified 25 RCTs (1796 patients). ECLS use was associated with reduction in mortality (RR 0.84; 95% CI 0.74, 0.96, moderate certainty) and improvement in hepatic encephalopathy (HE) (RR 0.71; 95% CI 0.60, 0.84, low certainty) in patients with ALF or ACLF. The effect of ECLS on hypotension (RR 1.46; 95% CI 0.98, 2.2, low certainty), bleeding (RR 1.21; 95% CI 0.88, 1.66, moderate certainty), thrombocytopenia (RR 1.62; 95% CI 1.0, 2.64, very low certainty) and line infection (RR 1.92; 95% CI 0.11, 33.44, low certainty) was uncertain.

CONCLUSIONS:

ECLS may reduce mortality and improve HE in patients with ALF and ACLF. The effect on other outcomes is uncertain. However, the evidence is limited by risk of bias and imprecision, and larger trials are needed to better determine the effect of ECLS on patient-important outcomes.

CET Conclusion

Reviewer:	Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:	This is a systematic review and meta-anlaysis of 25 RCTs including a total of 1796 patients randomised to extra-corporeal liver support (ECLS) for acute liver failure or acute on chronic liver failure. Overall the review was conducted with several signs of good quality, by following the PRISMA statement and registering a protocol in advance. Multiple databases were searched and only RCTs were included. Report screening, data extraction and bias assessment were all completed in duplicate by 2 reviewers, another good indicator. Publication bias was assessed by funnel plot with Egger’s test. Among artificial systems, MARS (Teraklin AG, Germany, was the most commonly used (8 studies) followed by Biologic-DT (HemoCleanse, Inc., USA, 5 studies), FPSA (Prometheus, Fresenius Medical Care, Germany, 2 studies), plasma exchange with hemoperfusion, whole blood exchange, and charcoal hemoperfusion (1 study each). Bio-artifcial modalities included extracorporeal liver assist device (ELAD, Vital Terapies Inc., USA, 3 studies) and HepatAssist (Circe Biomedical Inc., USA, 1 study). Twenty four studies reported mortality and in meta-analysis extra-corporeal liver support was associated with improved mortality, albeit potentially a very small effect (RR=0.84, 95%CI= 0.74-0.96), with low-moderate heterogeneity. The use of ECLS was associated with improved hepatic encephalopathy compared to usual care (RR=0.71; 95% CI= 0.60- 0.84), with low heterogeneity between studies, however some evidence of publication bias was suspected following funnel plot and Egger’s test (P=0.041). There was no significant differences in the risk of bleeding, hypotension or thrombocytopenia. The authors include a number of sensitivity analyses as well to explore the effect of type of liver failure, type of ECLS and study risk of bias, not finding any significant interaction. This is a thorough study overall and if the level of certainty in the conclusions is low, it is not the fault of the authors here. The results suggest that ECLS may reduce mortality and hepatic encephalopathy in acute and acute on chronic liver failure but the degree of benefit for each of the different types of system is not clear. Each of the included studies was small and RCTs using new technology in specific groups of patients are required.

Reviewer:

Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford

Conclusion:

This is a systematic review and meta-anlaysis of 25 RCTs including a total of 1796 patients randomised to extra-corporeal liver support (ECLS) for acute liver failure or acute on chronic liver failure. Overall the review was conducted with several signs of good quality, by following the PRISMA statement and registering a protocol in advance. Multiple databases were searched and only RCTs were included. Report screening, data extraction and bias assessment were all completed in duplicate by 2 reviewers, another good indicator. Publication bias was assessed by funnel plot with Egger’s test. Among artificial systems, MARS (Teraklin AG, Germany, was the most commonly used (8 studies) followed by Biologic-DT (HemoCleanse, Inc., USA, 5 studies), FPSA (Prometheus, Fresenius Medical Care, Germany, 2 studies), plasma exchange with hemoperfusion, whole blood exchange, and charcoal hemoperfusion (1 study each). Bio-artifcial modalities included extracorporeal liver assist device (ELAD, Vital Terapies Inc., USA, 3 studies) and HepatAssist (Circe Biomedical Inc., USA, 1 study). Twenty four studies reported mortality and in meta-analysis extra-corporeal liver support was associated with improved mortality, albeit potentially a very small effect (RR=0.84, 95%CI= 0.74-0.96), with low-moderate heterogeneity. The use of ECLS was associated with improved hepatic encephalopathy compared to usual care (RR=0.71; 95% CI= 0.60- 0.84), with low heterogeneity between studies, however some evidence of publication bias was suspected following funnel plot and Egger’s test (P=0.041). There was no significant differences in the risk of bleeding, hypotension or thrombocytopenia. The authors include a number of sensitivity analyses as well to explore the effect of type of liver failure, type of ECLS and study risk of bias, not finding any significant interaction. This is a thorough study overall and if the level of certainty in the conclusions is low, it is not the fault of the authors here. The results suggest that ECLS may reduce mortality and hepatic encephalopathy in acute and acute on chronic liver failure but the degree of benefit for each of the different types of system is not clear. Each of the included studies was small and RCTs using new technology in specific groups of patients are required.

Study Details

Aims:	This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to examine the efficacy and safety of extracorporeal liver support (ECLS) in liver failure.
Interventions:	The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases were searched from inception through March 13, 2019. Randomized control trials (RCTs) comparing ECLS to usual care in acute liver failure (ALF) or acute chronic liver failure (ACLF) were included. Included studies met the following criteria: (1) the study design was a randomized controlled trial (RCT); (2) the population were adults with ALF or ACLF; (3) the interventions were any form of artificial or bio-artificial ECLS; (4) the control group received supportive care not including ECLS; (5) the outcomes were all-cause mortality or liver-related mortality, bridging to liver transplant, improvement of HE and adverse events such as hypotension, bleeding, thrombocytopenia, line infection, and citrate toxicity.
Participants:	A total of 25 randomized controlled trials, comprising 1796 patients were identified and used in this study.
Outcomes:	The main outcomes explored were mortality, hepatic encephalopathy and adverse effects.
Follow Up:	Up to 6 months

Metadata

Funding:	Industry funding and Non-industry funding
Publication type:	Meta-Analysis, Systematic Review
Review registration:	PROSPERO - CRD42018080201
Organ:	Liver
Language:	English
Author email:	alhazzaw@mcmaster.ca
MeSH terms:	Extracorporeal Circulation; Humans; Liver Failure; Randomized Controlled Trials as Topic; Liver Transplantation

Extracorporeal liver support in patients with liver failure: a systematic review and meta-analysis of randomized trials