Treatment for ascites in adults with decompensated liver cirrhosis: a network meta‐analysis New

Abstract

Abstract Background

Approximately 20% of people with cirrhosis develop ascites. Several different treatments are available; including, among others, paracentesis plus fluid replacement, transjugular intrahepatic portosystemic shunts, aldosterone antagonists, and loop diuretics. However, there is uncertainty surrounding their relative efficacy.

Objectives

To compare the benefits and harms of different treatments for ascites in people with decompensated liver cirrhosis through a network meta‐analysis and to generate rankings of the different treatments for ascites according to their safety and efficacy.

Search methods

We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until May 2019 to identify randomised clinical trials in people with cirrhosis and ascites.

Selection criteria

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

Data collection and analysis

We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) 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 49 randomised clinical trials (3521 participants) in the review. Forty‐two trials (2870 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, without other features of decompensation, having mainly grade 3 (severe), recurrent, or refractory ascites. The follow‐up in the trials ranged from 0.1 to 84 months. All the trials were at high risk of bias, and the overall certainty of evidence was low or very low.

Approximately 36.8% of participants who received paracentesis plus fluid replacement (reference group, the current standard treatment) died within 11 months. There was no evidence of differences in mortality, adverse events, or liver transplantation in people receiving different interventions compared to paracentesis plus fluid replacement (very low‐certainty evidence). Resolution of ascites at maximal follow‐up was higher with transjugular intrahepatic portosystemic shunt (HR 9.44; 95% CrI 1.93 to 62.68) and adding aldosterone antagonists to paracentesis plus fluid replacement (HR 30.63; 95% CrI 5.06 to 692.98) compared to paracentesis plus fluid replacement (very low‐certainty evidence). Aldosterone antagonists plus loop diuretics had a higher rate of other decompensation events such as hepatic encephalopathy, hepatorenal syndrome, and variceal bleeding compared to paracentesis plus fluid replacement (rate ratio 2.04; 95% CrI 1.37 to 3.10) (very low‐certainty evidence).

None of the trials using paracentesis plus fluid replacement reported health‐related quality of life or symptomatic recovery from ascites.

Funding: the source of funding for four trials were industries which would benefit from the results of the study; 24 trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 21 trials was unclear.

Authors' conclusions

Based on very low‐certainty evidence, there is considerable uncertainty about whether interventions for ascites in people with decompensated liver cirrhosis decrease mortality, adverse events, or liver transplantation compared to paracentesis plus fluid replacement in people with decompensated liver cirrhosis and ascites. Based on very low‐certainty evidence, transjugular intrahepatic portosystemic shunt and adding aldosterone antagonists to paracentesis plus fluid replacement may increase the resolution of ascites compared to paracentesis plus fluid replacement. Based on very low‐certainty evidence, aldosterone antagonists plus loop diuretics may increase the decompensation rate compared to paracentesis plus fluid replacement.

Author(s)

Amine Benmassaoud, Suzanne C Freeman, Davide Roccarina, Maria Corina Plaz Torres, Alex J Sutton, Nicola J Cooper, Laura Iogna Prat, Maxine Cowlin, Elisabeth Jane Milne, Neil Hawkins, Brian R Davidson, Chavdar S Pavlov, Douglas Thorburn, Emmanuel Tsochatzis, Kurinchi Selvan Gurusamy

Abstract

Plain language summary

Treatments for ascites in people with advanced liver disease

What is the aim of this Cochrane review?
 To find out the best available treatment for ascites (abnormal build‐up of fluid in the tummy) in people with advanced liver disease (liver cirrhosis, or late‐stage scarring of the liver with complications). People with cirrhosis and ascites are at significant risk of death. Therefore, it is important to treat such people, but the benefits and harms of different treatments available are currently unclear. The authors of this review collected and analysed all relevant research studies with the aim of finding what the best treatment is. They found 49 randomised controlled trials (studies where participants are randomly assigned to one of two treatment groups). During analysis of data, authors used standard Cochrane methods, which allow comparison of only two treatments at a time. Authors also used advanced techniques that allow comparison of multiple treatments simultaneously (usually referred as 'network (or indirect) meta‐analysis').

Date of literature search
 May 2019

Key messages
 None of the studies were conducted without flaws, and because of this, there is very high uncertainty in the findings. Approximately one in three trial participants with cirrhosis and ascites who received the standard treatment of drainage of fluid (paracentesis) plus fluid replacement died within 11 months of treatment. The funding source for the research was unclear in 21 studies; commercial organisations funded four studies. There were no concerns regarding the source of funding for the remaining 24 trials.

What was studied in the review?
 This review looked at adults of any sex, age, and ethnic origin, with advanced liver disease due to various causes and ascites. Participants were given different treatments for ascites. The authors excluded studies in people who had previously had liver transplantation. The average age of participants, when reported, ranged from 43 to 64 years. The treatments used in the trials included paracentesis plus fluid replacement (currently considered the standard treatment), different classes of diuretics (drugs which increase the passing of urine), and transjugular intrahepatic portosystemic shunt (an artificial channel that connects the different blood vessels that carry oxygen‐depleted blood (venous system)) within the liver to reduce the pressure built‐up in the portal venous system, one of the two venous systems draining the liver. The review authors wanted to gather and analyse data on death (percentage dead at maximal follow‐up), quality of life, serious and non‐serious adverse events, time to liver transplantation, resolution of ascites, and development of other complications of advanced liver disease.
 
 What were the main results of the review?
 The 49 studies included a small number of participants (3521 participants). Study data were sparse. Forty‐two studies with 2870 participants provided data for analyses. The follow‐up of the trial participants ranged from less than a week to seven years. The review shows that there is low‐ or very low‐certainty evidence for the following:

‐ Approximately one in three people with cirrhosis and ascites who received the standard treatment of drainage of fluid (paracentesis) plus fluid replacement died within 11 months.
 ‐ None of the interventions decrease percentage of deaths, number of complications, and liver transplantation compared to paracentesis plus fluid replacement.
 ‐ Transjugular intrahepatic portosystemic shunt may be nine times more effective in resolution of ascites compared to paracentesis plus fluid replacement.
 ‐ Adding aldosterone antagonists (a class of diuretics) may be 30 times more effective in resolution of ascites compared to paracentesis plus fluid replacement.
 ‐ Using aldosterone antagonists plus loop diuretics (another class of diuretics) as a substitute for paracentesis plus fluid replacement may double the development of other liver complications of cirrhosis.
 ‐ None of the trials that compared other treatments to paracentesis plus fluid replacement reported health‐related quality of life or symptomatic recovery from ascites.
 ‐ Future well designed trials are needed to find out the best treatment for people with cirrhosis and ascites.

Author(s)

Amine Benmassaoud, Suzanne C Freeman, Davide Roccarina, Maria Corina Plaz Torres, Alex J Sutton, Nicola J Cooper, Laura Iogna Prat, Maxine Cowlin, Elisabeth Jane Milne, Neil Hawkins, Brian R Davidson, Chavdar S Pavlov, Douglas Thorburn, Emmanuel Tsochatzis, Kurinchi Selvan Gurusamy

Reviewer's Conclusions

Authors' conclusions

Implications for practice

Based on very low‐certainty evidence, there is considerable uncertainty about whether other interventions decrease mortality, adverse events, or liver transplantation compared to paracentesis plus fluid replacement in people with decompensated liver cirrhosis and ascites. Based on very low‐certainty evidence, transjugular intrahepatic portosystemic shunt and adding aldosterone antagonists to paracentesis plus fluid replacement may increase the resolution of ascites compared to paracentesis plus fluid replacement. Based on very low‐certainty evidence, aldosterone antagonists plus loop diuretics may increase the decompensation rate compared to paracentesis plus fluid replacement.

Implications for research

Further well‐designed randomised clinical trials are necessary. Some aspects of the design of the randomised clinical trials are as follows.

Study design: parallel, randomised clinical trial

Participants: people with liver cirrhosis and grade 3 or diuretic‐refractory ascites

Interventions/control: transjugular intrahepatic portosystemic shunt versus diuretics plus paracentesis plus fluid replacement versus paracentesis plus fluid replacement.

Outcomes:

Primary outcome: medium‐term mortality (one‐year all‐cause mortality)

Secondary outcomes: health‐related quality of life, decompensation events, adverse events, resolution of ascites, and resource utilisation measures including length of hospital stay, costs

Minimum length of follow‐up: one year

Sample size:

For a simple two‐arm parallel randomised clinical trial, the sample size required to detect or reject a relative risk reduction of 20% in the experimental group from the control group proportion of 36.8% mortality, with type I error of 5%, and type II error of 20%, 1282 participants are required.

Other aspects:

Trials need to be conducted and reported according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement (Chan 2013) and CONSORT statement (Schulz 2010).

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