Treatment for bleeding from enlarged veins in the oesophagus (food pipe) in people with advanced scarring of the liver

What is the aim of this Cochrane Review?
To find out the best available treatment for bleeding from oesophageal varices (enlarged veins in the oesophagus) in people with advanced scarring of the liver (liver cirrhosis, or late-stage scarring of the liver with complications). Bleeding from oesophageal varices in people with cirrhosis is a life-threatening event. Therefore, it is important to treat people when this happens, but the benefits and harms of different treatments available are currently unclear. The review authors collected and analysed all relevant randomised clinical trials (studies where participants are randomly assigned to one of two or more treatment groups) with the aim of finding out what the best treatment is. They found 52 randomised clinical trials. During analysis of data, the review authors used standard Cochrane methods, which allow the comparison of only two treatments at a time. The authors also used advanced techniques that allow comparison of multiple treatments at the same time (usually referred as 'network (or indirect) meta-analysis').

Date of literature search
17 December 2019

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 bleeding oesophageal varices. Participants were given different treatments for bleeding oesophageal varices. The authors excluded studies in people who had bleeding from the stomach, failed treatment by another method before study entry, those in whom bleeding was controlled by another method before taking part in the study, and those who previously had liver transplantation. The average age of participants, when reported, ranged from 39 to 62 years. The treatments used in the trials included endoscopic sclerotherapy (injecting a scar-forming liquid into the enlarged veins (the scarring blocks the veins thereby shrinking the veins) by looking through a tube inserted through the mouth), variceal band ligation (inserting bands around the dilated veins by seeing through a tube inserted through the mouth), somatostatin analogues (drugs that resemble gut hormones and narrow blood vessels), vasopressin analogues (drugs that resemble brain hormones and narrow blood vessels), and balloon tamponade (inserting a tube through the nose or mouth and inflating a balloon around the tube with the hope of pressing on the bleeding veins). The review authors wanted to gather and analyse data on death (percentage of participants who died within six weeks of receiving treatment), quality of life, serious adverse events and non-serious adverse events (i.e. serious and non-serious complications), recurrence of bleeding, and development of other complications of advanced liver disease.

What were the main results of the review?
The 52 trials included a small number of participants (4580 participants). Forty-eight trials with 4042 participants provided data for analyses. The follow-up of the trial participants ranged from less than one week to six weeks. The funding source for the research was unclear in 31 studies; commercial organisations funded 11 studies. There were no concerns regarding the source of funding for the remaining 10 studies. The review shows the following.

- None of the studies were conducted without flaws, and because of this, there is moderate to very high uncertainty in the findings.
- Approximately one in six people with cirrhosis and bleeding oesophageal varices who received the standard treatment of sclerotherapy died within six weeks.
- Somatostatin analogues alone and vasopressin analogues alone probably result in increased mortality, compared to sclerotherapy.
- Vasopressin analogues alone and band ligation alone probably result in fewer adverse events (complications), compared to sclerotherapy.
- Balloon tamponade plus sclerotherapy may result in large increase in serious adverse events compared to sclerotherapy.
- Sclerotherapy plus somatostatin analogues may result in large decrease in symptomatic rebleed compared to sclerotherapy.
- The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons.
- None of the trials reported health-related quality of life.
- Future well-designed randomised clinical trials are needed to find out the best treatment for people with cirrhosis and bleeding oesophageal varices.

Authors' conclusions: 

Based on moderate-certainty evidence, somatostatin analogues alone and vasopressin analogues alone (with supportive therapy) probably result in increased mortality, compared to endoscopic sclerotherapy. Based on moderate-certainty evidence, vasopressin analogues alone and band ligation alone probably result in fewer adverse events compared to endoscopic sclerotherapy. Based on low-certainty evidence, balloon tamponade plus sclerotherapy may result in large increases in serious adverse events compared to sclerotherapy. Based on low-certainty evidence, sclerotherapy plus somatostatin analogues may result in large decreases in symptomatic rebleed compared to sclerotherapy. In the remaining comparisons, the evidence indicates considerable uncertainty about the effects of the interventions, compared to sclerotherapy.

Read the full abstract...
Background: 

Approximately 40% to 95% of people with liver cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed within about one to three years after diagnosis. Several different treatments are available, including, among others, endoscopic sclerotherapy, variceal band ligation, somatostatin analogues, vasopressin analogues, and balloon tamponade. However, there is uncertainty surrounding the individual and relative benefits and harms of these treatments.

Objectives: 

To compare the benefits and harms of different initial treatments for variceal bleeding from oesophageal varices in adults with decompensated liver cirrhosis, through a network meta‐analysis; and to generate rankings of the different treatments for acute bleeding oesophageal varices, according to their benefits and harms.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until 17 December 2019, to identify randomised clinical trials (RCTs) in people with cirrhosis and acute bleeding from oesophageal varices.

Selection criteria: 

We included only RCTs (irrespective of language, blinding, or status) in adults with cirrhosis and acutely bleeding oesophageal varices. We excluded RCTs in which participants had bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those in whom initial haemostasis was achieved before inclusion into the trial, and those who had previously undergone liver transplantation.

Data collection and analysis: 

We performed a network meta-analysis with OpenBUGS software, using Bayesian methods, and calculated the differences in treatments using odds ratios (OR) and rate ratios 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 performed also the direct comparisons from RCTs using the same codes and the same technical details.

Main results: 

We included a total of 52 RCTs (4580 participants) in the review. Forty-eight trials (4042 participants) were included in one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those with and without a previous history of bleeding. We included outcomes assessed up to six weeks. All trials were at high risk of bias.

A total of 19 interventions were compared in the trials (sclerotherapy, somatostatin analogues, vasopressin analogues, sclerotherapy plus somatostatin analogues, variceal band ligation, balloon tamponade, somatostatin analogues plus variceal band ligation, nitrates plus vasopressin analogues, no active intervention, sclerotherapy plus variceal band ligation, balloon tamponade plus sclerotherapy, balloon tamponade plus somatostatin analogues, balloon tamponade plus vasopressin analogues, variceal band ligation plus vasopressin analogues, balloon tamponade plus nitrates plus vasopressin analogues, balloon tamponade plus variceal band ligation, portocaval shunt, sclerotherapy plus transjugular intrahepatic portosystemic shunt (TIPS), and sclerotherapy plus vasopressin analogues). We have reported the effect estimates for the primary and secondary outcomes when there was evidence of differences between the interventions against the reference treatment of sclerotherapy, but reported the other results of the primary and secondary outcomes versus the reference treatment of sclerotherapy without the effect estimates when there was no evidence of differences in order to provide a concise summary of the results.

Overall, 15.8% of the trial participants who received the reference treatment of sclerotherapy (chosen because this was the commonest treatment compared in the trials) died during the follow-up periods, which ranged from three days to six weeks. Based on moderate-certainty evidence, somatostatin analogues alone had higher mortality than sclerotherapy (OR 1.57, 95% CrI 1.04 to 2.41; network estimate; direct comparison: 4 trials; 353 participants) and vasopressin analogues alone had higher mortality than sclerotherapy (OR 1.70, 95% CrI 1.13 to 2.62; network estimate; direct comparison: 2 trials; 438 participants).

None of the trials reported health-related quality of life. Based on low-certainty evidence, a higher proportion of people receiving balloon tamponade plus sclerotherapy had more serious adverse events than those receiving only sclerotherapy (OR 4.23, 95% CrI 1.22 to 17.80; direct estimate; 1 RCT; 60 participants).

Based on moderate-certainty evidence, people receiving vasopressin analogues alone and those receiving variceal band ligation had fewer adverse events than those receiving only sclerotherapy (rate ratio 0.59, 95% CrI 0.35 to 0.96; network estimate; direct comparison: 1 RCT; 219 participants; and rate ratio 0.40, 95% CrI 0.21 to 0.74; network estimate; direct comparison: 1 RCT; 77 participants; respectively). Based on low-certainty evidence, the proportion of people who developed symptomatic rebleed was smaller in people who received sclerotherapy plus somatostatin analogues than those receiving only sclerotherapy (OR 0.21, 95% CrI 0.03 to 0.94; direct estimate; 1 RCT; 105 participants).

The evidence suggests considerable uncertainty about the effect of the interventions in the remaining comparisons where sclerotherapy was the control intervention.

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