Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta‐analysis

LMJ Best, S Freeman, A Sutton, N Cooper, EL Tng, M Csenar, N Hawkins, C Pavlov, BR Davidson, D Thorburn, M Cowlin, EJ Milne, Emmanuel Tsochatzis, Kurinchi S. Gurusamy

Research output: Contribution to journalReview article

2 Citations (Scopus)

Abstract

Background

Hepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, the other potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogues or noradrenaline), renal vasodilator drugs (such as dopamine), transjugular intrahepatic portosystemic shunt (TIPS), and liver support with molecular adsorbent recirculating system (MARS). There is uncertainty over the best treatment regimen for hepatorenal syndrome.
Objectives

To compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis.
Search methods

We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers until December 2018 to identify randomised clinical trials on hepatorenal syndrome in people with cirrhosis.
Selection criteria

We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and hepatorenal syndrome. We excluded randomised clinical trials in which participants had previously undergone liver transplantation.
Data collection and analysis

Two authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of hepatorenal syndrome, liver transplantation, and other decompensation events. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, hazard ratio (HR), and mean difference (MD) with 95% credible intervals (CrI) based on an available‐case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.
Main results

We included a total of 25 trials (1263 participants; 12 interventions) in the review. Twenty‐three trials (1185 participants) were included in one or more outcomes. All the trials were at high risk of bias, and all the evidence was of low or very low certainty. The trials included participants with liver cirrhosis of varied aetiologies as well as a mixture of type I hepatorenal syndrome only, type II hepatorenal syndrome only, or people with both type I and type II hepatorenal syndrome. Participant age ranged from 42 to 60 years, and the proportion of females ranged from 5.8% to 61.5% in the trials that reported this information. The follow‐up in the trials ranged from one week to six months. Overall, 59% of participants died during this period and about 35% of participants recovered from hepatorenal syndrome. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone.

There was no evidence of a difference in mortality (22 trials; 1153 participants) at maximal follow‐up between the different interventions. None of the trials reported health‐related quality of life. There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants), number of participants with serious adverse events per participant (two trials; 166 participants), proportion of participants with any adverse events (four trials; 402 participants), the proportion of people who underwent liver transplantation at maximal follow‐up (four trials; 342 participants), or other features of decompensation at maximal follow‐up (one trial; 466 participants). Five trials (293 participants) reported number of any adverse events, and five trials (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51, 95% CrI 0.28 to 0.87). Eighteen trials (1047 participants) reported recovery from hepatorenal syndrome (as per definition of hepatorenal syndrome). In terms of recovery from hepatorenal syndrome, in the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery from hepatorenal syndrome than albumin plus terlipressin (HR 0.04; 95% CrI 0.00 to 0.25 and HR 0.26, 95% CrI 0.07 to 0.80 respectively). There was no evidence of differences between the groups in any of the other direct comparisons. In the network meta‐analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.

Funding: two trials were funded by pharmaceutical companies; five trials were funded by parties who had no vested interest in the results of the trial; and 18 trials did not report the source of funding.
Authors' conclusions

Based on very low‐certainty evidence, there is no evidence of benefit or harm of any of the interventions for hepatorenal syndrome with regards to the following outcomes: all‐cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low‐certainty evidence suggests that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low‐ or very low‐certainty evidence also found that albumin plus midodrine plus octreotide and albumin alone had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.

Future randomised clinical trials should be adequately powered; employ blinding, avoid post‐randomisation dropouts or planned cross‐overs (or perform an intention‐to‐treat analysis); and report clinically important outcomes such as mortality, health‐related quality of life, adverse events, and recovery from hepatorenal syndrome. Albumin plus noradrenaline and albumin plus terlipressin appear to be the interventions that should be compared in future trials.
Original languageEnglish
Article numberCD013103
Number of pages113
JournalCochrane Database of Systematic Reviews
Volume2019
Issue number9
DOIs
Publication statusPublished - 12 Sep 2019

Fingerprint

Hepatorenal Syndrome
Liver Cirrhosis
Albumins
Midodrine
Octreotide
Therapeutics
Norepinephrine
Liver Transplantation
Randomized Controlled Trials
Fibrosis
Mortality
Quality of Life
Transjugular Intrahepatic Portasystemic Shunt

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis : a network meta‐analysis. / Best, LMJ; Freeman, S; Sutton, A; Cooper, N; Tng, EL; Csenar, M; Hawkins, N; Pavlov, C; Davidson, BR; Thorburn, D; Cowlin, M; Milne, EJ; Tsochatzis, Emmanuel ; Gurusamy, Kurinchi S.

In: Cochrane Database of Systematic Reviews, Vol. 2019, No. 9, CD013103, 12.09.2019.

Research output: Contribution to journalReview article

Best, LMJ, Freeman, S, Sutton, A, Cooper, N, Tng, EL, Csenar, M, Hawkins, N, Pavlov, C, Davidson, BR, Thorburn, D, Cowlin, M, Milne, EJ, Tsochatzis, E & Gurusamy, KS 2019, 'Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta‐analysis' Cochrane Database of Systematic Reviews, vol. 2019, no. 9, CD013103. https://doi.org/10.1002/14651858.CD013103.pub2
Best, LMJ ; Freeman, S ; Sutton, A ; Cooper, N ; Tng, EL ; Csenar, M ; Hawkins, N ; Pavlov, C ; Davidson, BR ; Thorburn, D ; Cowlin, M ; Milne, EJ ; Tsochatzis, Emmanuel ; Gurusamy, Kurinchi S. / Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis : a network meta‐analysis. In: Cochrane Database of Systematic Reviews. 2019 ; Vol. 2019, No. 9.
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title = "Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta‐analysis",
abstract = "BackgroundHepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, the other potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogues or noradrenaline), renal vasodilator drugs (such as dopamine), transjugular intrahepatic portosystemic shunt (TIPS), and liver support with molecular adsorbent recirculating system (MARS). There is uncertainty over the best treatment regimen for hepatorenal syndrome.ObjectivesTo compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis.Search methodsWe searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers until December 2018 to identify randomised clinical trials on hepatorenal syndrome in people with cirrhosis.Selection criteriaWe included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and hepatorenal syndrome. We excluded randomised clinical trials in which participants had previously undergone liver transplantation.Data collection and analysisTwo authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of hepatorenal syndrome, liver transplantation, and other decompensation events. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, hazard ratio (HR), and mean difference (MD) with 95{\%} credible intervals (CrI) based on an available‐case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.Main resultsWe included a total of 25 trials (1263 participants; 12 interventions) in the review. Twenty‐three trials (1185 participants) were included in one or more outcomes. All the trials were at high risk of bias, and all the evidence was of low or very low certainty. The trials included participants with liver cirrhosis of varied aetiologies as well as a mixture of type I hepatorenal syndrome only, type II hepatorenal syndrome only, or people with both type I and type II hepatorenal syndrome. Participant age ranged from 42 to 60 years, and the proportion of females ranged from 5.8{\%} to 61.5{\%} in the trials that reported this information. The follow‐up in the trials ranged from one week to six months. Overall, 59{\%} of participants died during this period and about 35{\%} of participants recovered from hepatorenal syndrome. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone.There was no evidence of a difference in mortality (22 trials; 1153 participants) at maximal follow‐up between the different interventions. None of the trials reported health‐related quality of life. There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants), number of participants with serious adverse events per participant (two trials; 166 participants), proportion of participants with any adverse events (four trials; 402 participants), the proportion of people who underwent liver transplantation at maximal follow‐up (four trials; 342 participants), or other features of decompensation at maximal follow‐up (one trial; 466 participants). Five trials (293 participants) reported number of any adverse events, and five trials (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51, 95{\%} CrI 0.28 to 0.87). Eighteen trials (1047 participants) reported recovery from hepatorenal syndrome (as per definition of hepatorenal syndrome). In terms of recovery from hepatorenal syndrome, in the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery from hepatorenal syndrome than albumin plus terlipressin (HR 0.04; 95{\%} CrI 0.00 to 0.25 and HR 0.26, 95{\%} CrI 0.07 to 0.80 respectively). There was no evidence of differences between the groups in any of the other direct comparisons. In the network meta‐analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.Funding: two trials were funded by pharmaceutical companies; five trials were funded by parties who had no vested interest in the results of the trial; and 18 trials did not report the source of funding.Authors' conclusionsBased on very low‐certainty evidence, there is no evidence of benefit or harm of any of the interventions for hepatorenal syndrome with regards to the following outcomes: all‐cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low‐certainty evidence suggests that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low‐ or very low‐certainty evidence also found that albumin plus midodrine plus octreotide and albumin alone had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.Future randomised clinical trials should be adequately powered; employ blinding, avoid post‐randomisation dropouts or planned cross‐overs (or perform an intention‐to‐treat analysis); and report clinically important outcomes such as mortality, health‐related quality of life, adverse events, and recovery from hepatorenal syndrome. Albumin plus noradrenaline and albumin plus terlipressin appear to be the interventions that should be compared in future trials.",
author = "LMJ Best and S Freeman and A Sutton and N Cooper and EL Tng and M Csenar and N Hawkins and C Pavlov and BR Davidson and D Thorburn and M Cowlin and EJ Milne and Emmanuel Tsochatzis and Gurusamy, {Kurinchi S.}",
year = "2019",
month = "9",
day = "12",
doi = "10.1002/14651858.CD013103.pub2",
language = "English",
volume = "2019",
journal = "The Cochrane Library",
issn = "1361-6137",
publisher = "Wiley",
number = "9",

}

TY - JOUR

T1 - Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis

T2 - a network meta‐analysis

AU - Best, LMJ

AU - Freeman, S

AU - Sutton, A

AU - Cooper, N

AU - Tng, EL

AU - Csenar, M

AU - Hawkins, N

AU - Pavlov, C

AU - Davidson, BR

AU - Thorburn, D

AU - Cowlin, M

AU - Milne, EJ

AU - Tsochatzis, Emmanuel

AU - Gurusamy, Kurinchi S.

PY - 2019/9/12

Y1 - 2019/9/12

N2 - BackgroundHepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, the other potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogues or noradrenaline), renal vasodilator drugs (such as dopamine), transjugular intrahepatic portosystemic shunt (TIPS), and liver support with molecular adsorbent recirculating system (MARS). There is uncertainty over the best treatment regimen for hepatorenal syndrome.ObjectivesTo compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis.Search methodsWe searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers until December 2018 to identify randomised clinical trials on hepatorenal syndrome in people with cirrhosis.Selection criteriaWe included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and hepatorenal syndrome. We excluded randomised clinical trials in which participants had previously undergone liver transplantation.Data collection and analysisTwo authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of hepatorenal syndrome, liver transplantation, and other decompensation events. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, hazard ratio (HR), and mean difference (MD) with 95% credible intervals (CrI) based on an available‐case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.Main resultsWe included a total of 25 trials (1263 participants; 12 interventions) in the review. Twenty‐three trials (1185 participants) were included in one or more outcomes. All the trials were at high risk of bias, and all the evidence was of low or very low certainty. The trials included participants with liver cirrhosis of varied aetiologies as well as a mixture of type I hepatorenal syndrome only, type II hepatorenal syndrome only, or people with both type I and type II hepatorenal syndrome. Participant age ranged from 42 to 60 years, and the proportion of females ranged from 5.8% to 61.5% in the trials that reported this information. The follow‐up in the trials ranged from one week to six months. Overall, 59% of participants died during this period and about 35% of participants recovered from hepatorenal syndrome. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone.There was no evidence of a difference in mortality (22 trials; 1153 participants) at maximal follow‐up between the different interventions. None of the trials reported health‐related quality of life. There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants), number of participants with serious adverse events per participant (two trials; 166 participants), proportion of participants with any adverse events (four trials; 402 participants), the proportion of people who underwent liver transplantation at maximal follow‐up (four trials; 342 participants), or other features of decompensation at maximal follow‐up (one trial; 466 participants). Five trials (293 participants) reported number of any adverse events, and five trials (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51, 95% CrI 0.28 to 0.87). Eighteen trials (1047 participants) reported recovery from hepatorenal syndrome (as per definition of hepatorenal syndrome). In terms of recovery from hepatorenal syndrome, in the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery from hepatorenal syndrome than albumin plus terlipressin (HR 0.04; 95% CrI 0.00 to 0.25 and HR 0.26, 95% CrI 0.07 to 0.80 respectively). There was no evidence of differences between the groups in any of the other direct comparisons. In the network meta‐analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.Funding: two trials were funded by pharmaceutical companies; five trials were funded by parties who had no vested interest in the results of the trial; and 18 trials did not report the source of funding.Authors' conclusionsBased on very low‐certainty evidence, there is no evidence of benefit or harm of any of the interventions for hepatorenal syndrome with regards to the following outcomes: all‐cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low‐certainty evidence suggests that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low‐ or very low‐certainty evidence also found that albumin plus midodrine plus octreotide and albumin alone had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.Future randomised clinical trials should be adequately powered; employ blinding, avoid post‐randomisation dropouts or planned cross‐overs (or perform an intention‐to‐treat analysis); and report clinically important outcomes such as mortality, health‐related quality of life, adverse events, and recovery from hepatorenal syndrome. Albumin plus noradrenaline and albumin plus terlipressin appear to be the interventions that should be compared in future trials.

AB - BackgroundHepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, the other potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogues or noradrenaline), renal vasodilator drugs (such as dopamine), transjugular intrahepatic portosystemic shunt (TIPS), and liver support with molecular adsorbent recirculating system (MARS). There is uncertainty over the best treatment regimen for hepatorenal syndrome.ObjectivesTo compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis.Search methodsWe searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers until December 2018 to identify randomised clinical trials on hepatorenal syndrome in people with cirrhosis.Selection criteriaWe included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and hepatorenal syndrome. We excluded randomised clinical trials in which participants had previously undergone liver transplantation.Data collection and analysisTwo authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of hepatorenal syndrome, liver transplantation, and other decompensation events. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, hazard ratio (HR), and mean difference (MD) with 95% credible intervals (CrI) based on an available‐case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.Main resultsWe included a total of 25 trials (1263 participants; 12 interventions) in the review. Twenty‐three trials (1185 participants) were included in one or more outcomes. All the trials were at high risk of bias, and all the evidence was of low or very low certainty. The trials included participants with liver cirrhosis of varied aetiologies as well as a mixture of type I hepatorenal syndrome only, type II hepatorenal syndrome only, or people with both type I and type II hepatorenal syndrome. Participant age ranged from 42 to 60 years, and the proportion of females ranged from 5.8% to 61.5% in the trials that reported this information. The follow‐up in the trials ranged from one week to six months. Overall, 59% of participants died during this period and about 35% of participants recovered from hepatorenal syndrome. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone.There was no evidence of a difference in mortality (22 trials; 1153 participants) at maximal follow‐up between the different interventions. None of the trials reported health‐related quality of life. There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants), number of participants with serious adverse events per participant (two trials; 166 participants), proportion of participants with any adverse events (four trials; 402 participants), the proportion of people who underwent liver transplantation at maximal follow‐up (four trials; 342 participants), or other features of decompensation at maximal follow‐up (one trial; 466 participants). Five trials (293 participants) reported number of any adverse events, and five trials (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51, 95% CrI 0.28 to 0.87). Eighteen trials (1047 participants) reported recovery from hepatorenal syndrome (as per definition of hepatorenal syndrome). In terms of recovery from hepatorenal syndrome, in the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery from hepatorenal syndrome than albumin plus terlipressin (HR 0.04; 95% CrI 0.00 to 0.25 and HR 0.26, 95% CrI 0.07 to 0.80 respectively). There was no evidence of differences between the groups in any of the other direct comparisons. In the network meta‐analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.Funding: two trials were funded by pharmaceutical companies; five trials were funded by parties who had no vested interest in the results of the trial; and 18 trials did not report the source of funding.Authors' conclusionsBased on very low‐certainty evidence, there is no evidence of benefit or harm of any of the interventions for hepatorenal syndrome with regards to the following outcomes: all‐cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low‐certainty evidence suggests that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low‐ or very low‐certainty evidence also found that albumin plus midodrine plus octreotide and albumin alone had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.Future randomised clinical trials should be adequately powered; employ blinding, avoid post‐randomisation dropouts or planned cross‐overs (or perform an intention‐to‐treat analysis); and report clinically important outcomes such as mortality, health‐related quality of life, adverse events, and recovery from hepatorenal syndrome. Albumin plus noradrenaline and albumin plus terlipressin appear to be the interventions that should be compared in future trials.

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U2 - 10.1002/14651858.CD013103.pub2

DO - 10.1002/14651858.CD013103.pub2

M3 - Review article

VL - 2019

JO - The Cochrane Library

JF - The Cochrane Library

SN - 1361-6137

IS - 9

M1 - CD013103

ER -