What is the aim of this Cochrane review?
To find out the best treatment for decreased kidney function (hepatorenal syndrome) in people with liver cirrhosis (a form of advanced liver disease with scarring of the liver) with complications. The authors collected and analysed all relevant studies to answer this question and found 25 randomised controlled trials (participants receive the treatment based on method similar to coin toss or lottery; this is to ensure that the people who receive the different treatments are similar in all aspects except the treatment, so that any differences in the results between the treatments can be attributed to the treatment rather than differences in the type of people who received the treatment). During analysis of data, authors used standard Cochrane techniques, which allows comparison of two treatments at a time. Authors also used advanced techniques, that allow comparison of many treatments at the same time (usually referred as 'network meta-analysis' or 'multiple treatment comparisons'). The aim is to gather reliable evidence on the relative benefits and harms of the different treatments.
Date of literature search
Only two studies were conducted well. The remaining studies had one or more flaws. Therefore, there is high uncertainty in the results of the analysis. The authors could not recommend one treatment over another on the basis of risk of death, serious complications, percentage of people who developed any complication, percentage of participants who underwent liver transplantation (replacement of a diseased liver with a healthy one), or the number of other liver failure events. Health-related quality of life was not reported in any of the trials. The number of complications of any severity was lower with albumin plus noradrenaline than albumin plus terlipressin. Recovery from hepatorenal syndrome may be lower with albumin plus midodrine plus octreotide and albumin alone than albumin plus terlipressin and albumin plus noradrenaline.
Funding source was unclear in 18 studies. Industrial organisations funded two studies and the remaining five studies did not receive any funding from industrial organisations.
What was studied in the review?
This review studied people of any sex, age, and origin, having advanced liver disease due to various causes, and who had developed hepatorenal syndrome. People were administered different treatments. The review authors excluded studies with liver-transplanted participants. Participants age, when reported, ranged from 42 to 60 years. The number of females ranged from 6 to 62 out of 100 in the studies that reported this information. The main treatments compared were albumin alone, albumin plus terlipressin, and albumin plus noradrenaline. The authors gathered and analysed data on death, quality of life, serious and non-serious complications, time to liver transplantation, recovery from hepatorenal syndrome, and disappearance of symptoms.
What were the main results of the review?
The 25 studies included a small number of participants (1263 participants). Study data were sparse. Twenty-three studies with 1185 participants provided data for analyses. The follow-up in the trials ranged from one week to six months. The review shows that:
- About 60 out of every 100 people died within three months, and 35 out of every 100 people recovered from hepatorenal syndrome.
- The provided treatment may make no difference to the percentage of people who died or developed serious complications, number of serious complications per person, percentage of people who developed complications of any severity, or the percentage of people undergoing liver transplantation.
- None of the trials reported health-related quality of life.
- The number of complications of any severity was lower with albumin plus noradrenaline than albumin plus terlipressin.
- Recovery from hepatorenal syndrome may be lower with albumin plus midodrine plus octreotide and albumin alone than albumin plus terlipressin and albumin plus noradrenaline.
- We have very low confidence in the overall results.
- Future trials with proper design and quality are needed to clarify the best treatment for people with advanced liver disease having hepatorenal syndrome.
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.
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.
To compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis.
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.
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.
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.
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 but two 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.