Prevention of rebleeding from enlarged veins in the food pipe (oesophagus) resulting from advanced liver disease

What is the aim of this Cochrane Review?
To find out the best available preventive treatment for repeated bleeding from oesophageal varices (enlarged veins in the food pipe) in people with advanced liver disease (liver cirrhosis, or late-stage scarring of the liver with complications). People with cirrhosis who had previously bled from oesophageal varices are at significant risk of death from another episode of bleeding. Therefore, it is important to provide preventive treatment to prevent rebleeding in such people, but the benefits and harms of different treatments available are currently unclear. The authors of this review collected and analysed all relevant randomised clinical trials with the aim of finding out the best treatment. They found 48 randomised clinical 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 at the same time (usually referred as 'network (or indirect) meta-analysis').

Date of literature search
December 2019

Key messages
None of the studies were conducted without flaws, and because of this, there is moderate to very high uncertainty in the findings of this review. Approximately one in five trial participants with cirrhosis who received preventive treatment after control of initial bleeding from oesophageal varices died within five years of treatment with sclerotherapy.

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 previous bleeding from oesophageal varices. Participants were given different treatments for preventing further bleeding oesophageal varices. The authors excluded studies in people who had bleeding from the stomach, who had no previous bleeding from the oesophageal varices, those who failed to respond to another treatment before study entry, and those who had liver transplantation previously. The average age of participants, when reported, ranged from 40 to 63 years. The treatments used in the trials included endoscopic sclerotherapy (injecting into the enlarged 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), beta-blockers (drugs that slow the heart and decrease the force of heart pumping resulting in decrease pressure in the blood vessels), and TIPS (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), portocaval shunt (performing surgery to create the artificial channel described for TIPS) among others. The review authors wanted to gather and analyse data on death, quality of life, serious and non-serious adverse events, recurrence of bleeding, and development of other complications of advanced liver disease.

What were the main results of the review?
The 48 studies included a small number of participants (3526 participants). Study data were sparse. Forty-six studies with 3442 participants provided data for analyses. The follow-up of the trial participants ranged from two months to five years.

The funding source for the research was unclear in 36 studies; commercial organisations funded five studies. There were no concerns regarding the source of funding for the remaining nine studies.

The review shows the following.
- The evidence indicates considerable uncertainty about the effect of the interventions on the risk of death
- Variceal band ligation might result in fewer serious adverse events than sclerotherapy
- The evidence indicates considerable uncertainty about the effect of the interventions on serious and non-serious adverse events
- Sclerotherapy probably results in decrease in further bleeding than no treatment
- Beta-blockers plus sclerotherapy and TIPS probably result in a decrease in further bleeding than sclerotherapy alone
- Portocaval shunt may result in a decrease in further bleeding than 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 trials are needed to find out the best treatment for people with cirrhosis and previous bleeding from oesophageal varices.

Authors' conclusions: 

The evidence indicates considerable uncertainty about the effect of the interventions on mortality. Variceal band ligation might result in fewer serious adverse events than sclerotherapy. TIPS might result in a large decrease in symptomatic rebleed than variceal band ligation. Sclerotherapy probably results in fewer 'any' variceal rebleeding than no active intervention. Beta-blockers plus sclerotherapy and TIPS probably result in fewer 'any' variceal rebleeding than sclerotherapy. Beta-blockers alone and TIPS might result in more other compensation events than sclerotherapy. The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Accordingly, high-quality randomised comparative clinical trials are needed.

Read the full abstract...
Background: 

Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years of diagnosis. Several different treatments are available, which include endoscopic sclerotherapy, variceal band ligation, beta-blockers, transjugular intrahepatic portosystemic shunt (TIPS), and surgical portocaval shunts, among others. However, there is uncertainty surrounding their individual and relative benefits and harms.

Objectives: 

To compare the benefits and harms of different initial treatments for secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis through a network meta‐analysis and to generate rankings of the different treatments for secondary prevention according to their safety and efficacy.

Search strategy: 

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

Selection criteria: 

We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and previous history of bleeding from oesophageal varices. We excluded randomised clinical trials in which participants had no previous history of bleeding from oesophageal varices, previous history of bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those who had acute bleeding at the time of treatment, and those who had previously undergone liver transplantation.

Data collection and analysis: 

We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), 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.

Main results: 

We included a total of 48 randomised clinical trials (3526 participants) in the review. Forty-six trials (3442 participants) were included in one or more comparisons. The trials that provided the information included people with cirrhosis due to varied aetiologies. The follow-up ranged from two months to 61 months. All the trials were at high risk of bias. A total of 12 interventions were compared in these trials (sclerotherapy, beta-blockers, variceal band ligation, beta-blockers plus sclerotherapy, no active intervention, TIPS (transjugular intrahepatic portosystemic shunt), beta-blockers plus nitrates, portocaval shunt, sclerotherapy plus variceal band ligation, beta-blockers plus nitrates plus variceal band ligation, beta-blockers plus variceal band ligation, sclerotherapy plus nitrates).

Overall, 22.5% of the trial participants who received the reference treatment (chosen because this was the commonest treatment compared in the trials) of sclerotherapy died during the follow-up period ranging from two months to 61 months. There was considerable uncertainty in the effects of interventions on mortality. Accordingly, none of the interventions showed superiority over another. None of the trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation may result in fewer serious adverse events (number of people) than sclerotherapy (OR 0.19; 95% CrI 0.06 to 0.54; 1 trial; 100 participants).

Based on low or very low-certainty evidence, the adverse events (number of participants) and adverse events (number of events) may be different across many comparisons; however, these differences are due to very small trials at high risk of bias showing large differences in some comparisons leading to many differences despite absence of direct evidence.

Based on low-certainty evidence, TIPS may result in large decrease in symptomatic rebleed than variceal band ligation (HR 0.12; 95% CrI 0.03 to 0.41; 1 trial; 58 participants). Based on moderate-certainty evidence, any variceal rebleed was probably lower in sclerotherapy than in no active intervention (HR 0.62; 95% CrI 0.35 to 0.99, direct comparison HR 0.66; 95% CrI 0.11 to 3.13; 3 trials; 296 participants), beta-blockers plus sclerotherapy than sclerotherapy alone (HR 0.60; 95% CrI 0.37 to 0.95; direct comparison HR 0.50; 95% CrI 0.07 to 2.96; 4 trials; 231 participants); TIPS than sclerotherapy (HR 0.18; 95% CrI 0.08 to 0.38; direct comparison HR 0.22; 95% CrI 0.01 to 7.51; 2 trials; 109 participants), and in portocaval shunt than sclerotherapy (HR 0.21; 95% CrI 0.05 to 0.77; no direct comparison) groups.

Based on low-certainty evidence, beta-blockers alone and TIPS might result in more, other compensation, events than sclerotherapy (rate ratio 2.37; 95% CrI 1.35 to 4.67; 1 trial; 65 participants and rate ratio 2.30; 95% CrI 1.20 to 4.65; 2 trials; 109 participants; low-certainty evidence).

The evidence indicates considerable uncertainty about the effect of the interventions including those related to beta-blockers plus variceal band ligation in the remaining comparisons.

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