What was the aim of this Cochrane Review?
We aimed to find the best available treatment for prevention of first bleeding from oesophageal varices (enlarged veins in the food pipe (oesophagus)) in people with advanced liver scarring (liver cirrhosis, or late stage scarring of the liver with complications). People with cirrhosis and oesophageal varices are at significant risk of bleeding and death. Therefore, treatment is important, but the benefits and harms of different treatments available are currently unclear. The review authors collected and analysed 66 randomised clinical trials (clinical studies where people are randomly put into one of two or more treatment groups) with the aim of finding what the best treatment is. During analysis of data, we used standard Cochrane methods, which allow the comparison of only two treatments at a time. We also used advanced techniques that allow comparison of multiple treatments at the same time (referred to as 'network (or indirect) meta-analysis').
Date of literature search
December 2019
Key messages
We found that only one of the trials was conducted without flaws, and because of this, there is high to very high uncertainty in the findings. Approximately one in five trial participants with cirrhosis and oesophageal varices who never had bleeding previously and received the standard treatment of beta-blockers died within five years of treatment.
The funding source for the research was unclear in 50 trials; commercial organisations funded five trials. There were no concerns regarding the source of funding for the remaining 11 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 oesophageal varices, but never had bleeding from the oesophageal varices. Participants were given different treatments for prevention of first bleeding from oesophageal varices. The authors excluded studies in people who had previous bleeding from the oesophageal varices and those who had had a liver transplant or already received treatment for oesophageal varices previously. The average age of participants, when reported, ranged from 40 years to 63 years. The treatments included 'non-selective beta-blockers' or simply 'beta-blockers' (drugs that slow the heart and decrease the force of heart pumping resulting in decrease pressure in the blood vessels; they also increase the pressure in the gut blood vessels decreasing the amount of blood reaching the oesophageal veins), endoscopic sclerotherapy (injecting clotting agents into the enlarged veins by looking through a tube inserted through the mouth), variceal band ligation (inserting elastic bands around the widened veins by using a tube inserted through the mouth), and nitrates (medicines that decrease the pressure in the gut blood vessels by widening them). The review authors wanted to gather and analyse data on death (percentage dead at maximal follow-up), quality of life, serious and non-serious side effects, percentage of people who developed bleeding, and development of other complications of advanced liver disease.
What were the main results of the review?
The 66 studies included a relatively small number of participants (6653 people). Sixty studies with 6212 participants provided data for analyses. The follow-up of the trial ranged from six months to five years in studies that reported the outcomes that we were interested in. The review found the following:
– Approximately one in five people with cirrhosis and oesophageal varices (without previous bleeding) who receive the beta-blockers died within five years.
– Beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates all may result in fewer deaths than no treatment.
– Variceal band ligation may result in a higher number of serious side effects than beta-blockers.
– Sclerotherapy, beta-blockers plus nitrates, and beta-blockers plus variceal band ligation may result in more side effects (when serious and non-serious adverse events were put together) than beta-blockers.
– Beta-blockers plus variceal band ligation may result in fewer people who develop bleeding than beta-blockers alone based on a single small trial.
– Nitrates alone may result in more people who develop bleeding than beta-blockers alone.
– 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.
What are our conclusions?
Beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates may decrease the death rate compared to no treatment in people with high-risk oesophageal varices in people with cirrhosis and no history of bleeding. Variceal band ligation may result in a higher number of serious side effects than beta-blockers. The evidence indicates considerable uncertainty about the effect of beta-blockers versus variceal band ligation on variceal bleeding. The evidence also indicates considerable uncertainty about the effect of the interventions in most of the remaining comparisons. Future well designed trials are needed to find out the best treatment to prevent first bleeding from people with cirrhosis and oesophageal varices.
Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates may decrease mortality compared to no intervention in people with high-risk oesophageal varices in people with cirrhosis and no previous history of bleeding. Based on low-certainty evidence, variceal band ligation may result in a higher number of serious adverse events than beta-blockers. The evidence indicates considerable uncertainty about the effect of beta-blockers versus variceal band ligation on variceal bleeding. The evidence also indicates considerable uncertainty about the effect of the interventions in most of the remaining comparisons.
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. There are several different treatments to prevent bleeding, including: beta-blockers, endoscopic sclerotherapy, and variceal band ligation. However, there is uncertainty surrounding their individual and relative benefits and harms.
To compare the benefits and harms of different treatments for prevention of first variceal bleeding from oesophageal varices in adults with liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for prevention of first variceal bleeding from oesophageal varices according to their safety and efficacy.
We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to December 2019 to identify randomised clinical trials in people with cirrhosis and oesophageal varices with no history of bleeding.
We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and oesophageal varices with no history of bleeding. We excluded randomised clinical trials in which participants had previous bleeding from oesophageal varices and those who had previously undergone liver transplantation or previously received prophylactic treatment for oesophageal varices.
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 for Health and Care Excellence Decision Support Unit guidance. We performed the direct comparisons from randomised clinical trials using the same codes and the same technical details.
We included 66 randomised clinical trials (6653 participants) in the review. Sixty trials (6212 participants) provided data for one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those at high risk of bleeding from oesophageal varices. The follow-up in the trials that reported outcomes ranged from 6 months to 60 months. All but one of the trials were at high risk of bias. The interventions compared included beta-blockers, no active intervention, variceal band ligation, sclerotherapy, beta-blockers plus variceal band ligation, beta-blockers plus nitrates, nitrates, beta-blockers plus sclerotherapy, and portocaval shunt.
Overall, 21.2% of participants who received non-selective beta-blockers ('beta-blockers') − the reference treatment (chosen because this was the most common treatment compared in the trials) − died during 8-month to 60-month follow-up.
Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates all had lower mortality versus no active intervention (beta-blockers: HR 0.49, 95% CrI 0.36 to 0.67; direct comparison HR: 0.59, 95% CrI 0.42 to 0.83; 10 trials, 1200 participants; variceal band ligation: HR 0.51, 95% CrI 0.35 to 0.74; direct comparison HR 0.49, 95% CrI 0.12 to 2.14; 3 trials, 355 participants; sclerotherapy: HR 0.66, 95% CrI 0.51 to 0.85; direct comparison HR 0.61, 95% CrI 0.41 to 0.90; 18 trials, 1666 participants; beta-blockers plus nitrates: HR 0.41, 95% CrI 0.20 to 0.85; no direct comparison). No trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation had a higher number of serious adverse events (number of events) than beta-blockers (rate ratio 10.49, 95% CrI 2.83 to 60.64; 1 trial, 168 participants).
Based on low-certainty evidence, beta-blockers plus nitrates had a higher number of 'any adverse events (number of participants)' than beta-blockers alone (OR 3.41, 95% CrI 1.11 to 11.28; 1 trial, 57 participants). Based on low-certainty evidence, adverse events (number of events) were higher in sclerotherapy than in beta-blockers (rate ratio 2.49, 95% CrI 1.53 to 4.22; direct comparison rate ratio 2.47, 95% CrI 1.27 to 5.06; 2 trials, 90 participants), and in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison rate ratio 1.72, 95% CrI 1.08 to 2.76; 1 trial, 140 participants).
Based on low-certainty evidence, any variceal bleed was lower in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison HR 0.21, 95% CrI 0.04 to 0.71; 1 trial, 173 participants). Based on low-certainty evidence, any variceal bleed was higher in nitrates than beta-blockers (direct comparison HR 6.40, 95% CrI 1.58 to 47.42; 1 trial, 52 participants).
The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons.