Endoscopic injection of cyanoacrylate glue versus other endoscopic procedures for acute bleeding gastric varices in people with portal hypertension

Background

Acute bleeding from ruptured gastric varices (enlarged veins), the most severe consequence of portal hypertension (that is increased pressure in the veins leading to the liver), is associated with high death rates. The most promising treatment for this condition is considered to be endoscopic sclerotherapy (passing a flexible tube with a camera at the end down the oesophagus (swallowing tube) allowing direct visualisation and treatment of bleeding varices) with N-butyl-2-cyanoacrylate (cyanoacrylate), which is a glue that causes blood clots to form and stops the bleeding. However, incidence of re-bleeding and complications have opened a debate on when this glue should be used compared with other endoscopic procedures.

Characteristic of included studies

This review includes six trials (following search of scientific databases through to September 2014) of three different comparisons regarding the use of cyanoacrylate: comparison of different dosages of cyanoacrylate (one trial, 91 participants), cyanoacrylate compared with alcohol-based compounds (one trial, 37 participants), and cyanoacrylate compared with endoscopic band ligation (where enlarged veins are tied off using elastic bands; four trials, 366 participants). Risk of bias (that is overestimation of benefits and underestimation of harms) was high in all trials. Outcomes assessed included death, bleeding-related death, treatment failure, re-bleeding, side effects, and bleeding control. Follow-up of people varied from six to 26 months. All people included in these trials had chronic liver disease of different severities and were predominantly men. Most of the trials came from Eastern countries, although it must be noted that prevalence of chronic liver disease is fairly similar worldwide, with differences in causes that may have no effect on variceal bleeding.

Results

One trial showed that death was similar between the group of people who received the lower dose (0.5 mL) of cyanoacrylate and people who received a higher dose (1.0 mL), but fewer people who were given the lower dose had fewer complications. However, because the trial was small, we cannot be certain that the doses have the same effect. One trial implied that cyanoacrylate may be better than endoscopic sclerotherapy using alcohol-based compounds in terms of bleeding control, control of bleeding in fundal varices (enlarged veins at the base of the oesophagus), and complications, but the trial was too small to be certain about this effect. Results from four trials suggested that cyanoacrylate may be better than endoscopic band ligation regarding re-bleeding, and that it seems as effective as endoscopic band ligation regarding bleeding control, treatment failure, and prevention of death.

Quality of evidence

The quality of evidence ranged from very low to low. The main reasons for downgrading the quality of evidence included high likelihood of bias (due to small numbers of participants), imprecision of results, and differences in populations studied in the trials.

Authors' conclusions: 

This review suggests that endoscopic sclerotherapy using cyanoacrylate may be more effective than endoscopic band ligation in terms of preventing re-bleeding from gastric varices. However, due to the very low quality of the evidence, we are very uncertain about our estimates on all-cause and bleeding-related mortality, failure of intervention, adverse events, and control of bleeding. The trials were at high risk of bias; the number of the included randomised clinical trials and number of participants included in each trial was small; and there was evidence of internal heterogeneity across trials, indirectness of evidence in terms of population, and possible publication bias.

The effectiveness of different doses of cyanoacrylate and the comparison of cyanoacrylate versus alcohol compounds to treat variceal bleeding in people with portal hypertension is uncertain due to the very low quality of the evidence.

The shortcomings mentioned call for more evidence from larger trials that need to be conducted according to the SPIRIT statement and reported according to CONSORT guidelines.

Read the full abstract...
Background: 

In people with portal hypertension, gastric varices are less prevalent than oesophageal varices. The risk of bleeding from gastric varices seems to be lower than from oesophageal varices; however, when gastric varices bleed, it is often severe and associated with higher mortality. Endoscopic sclerotherapy of bleeding gastric varices with N-butyl-2-cyanoacrylate glue (cyanoacrylate) is considered the best haemostasis with a lower risk of re-bleeding compared with other endoscopic methods. However, there are some inconsistencies between trials regarding mortality, incidence of re-bleeding, and adverse effects.

Objectives: 

To assess the benefits and harms of sclerotherapy using cyanoacrylate compared with other endoscopic sclerotherapy procedures or with variceal band ligation for treating acute gastric variceal bleeding with or without vasoactive drugs in people with portal hypertension and to assess the best dosage of cyanoacrylate.

Search strategy: 

We searched the Cochrane Hepato-Biliary Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded from inception to September 2014 and reference lists of articles. We included trials irrespective of trial setting, language, publication status, or date of publication.

Selection criteria: 

Randomised clinical trials comparing sclerotherapy using cyanoacrylate versus other endoscopic methods (sclerotherapy using alcohol-based compounds or endoscopy band ligation) for acute gastric variceal bleeding in people with portal hypertension.

Data collection and analysis: 

We performed the review following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and the Cochrane Hepato-Biliary Module.

We presented results as risk ratios (RR) with 95% confidence intervals (CI), with I2 statistic values as a measure of intertrial heterogeneity. We analysed data with both fixed-effect and random-effects models, and reported the results with random-effects models. We performed subgroup, sensitivity, and trial sequential analyses to evaluate the robustness of the overall results, risk of bias, sources of intertrial heterogeneity, and risk of random errors.

Main results: 

We included six randomised clinical trials with three different comparisons: one trial compared two different doses of cyanoacrylate in 91 adults, bleeding actively from all types of gastric varices; one trial compared cyanoacrylate versus alcohol-based compounds in 37 adults with active or acute bleeding from isolated gastric varices only; and four trials compared cyanoacrylate versus endoscopic band ligation in 365 adults, with active or acute bleeding from all types of gastric varices. Main outcomes in the included trials were bleeding-related mortality, failure of intervention, re-bleeding, adverse events, and control of bleeding. Follow-up varied from six to 26 months. The participants included in these trials had chronic liver disease of different severities, were predominantly men, and most were from Eastern countries. We judged all trials at high risk of bias. Application of quality criteria for all outcomes yielded very low quality grade of the evidence in the three analyses, except for the low quality evidence rated for the re-bleeding outcome in the cyanoacrylate versus endoscopic band ligation comparison.

Two different doses of cyanoacrylate: we found very low quality evidence from one trial for the effect of 0.5 mL compared with 1.0 mL of cyanoacrylate on all-cause mortality (20/44 (45.5%) with 0.5 mL versus 21/47 (45%) with 1.0 mL; RR 1.02; 95% CI 0.65 to 1.60), 30-day mortality (RR 1.07; 95% CI 0.41 to 2.80), failure of intervention (RR 1.07; 95% CI 0.56 to 2.05), prevention of re-bleeding (RR 1.30; 95% CI 0.73 to 2.31), adverse events reported as fever (RR 0.56; 95% CI 0.32 to 0.98), and control of bleeding (RR 1.04; 95% CI 0.78 to 1.38).

Cyanoacrylate versus alcohol-based compounds: we found very low quality evidence from one trial for the effect of cyanoacrylate versus alcohol-based compounds on 30-day mortality (2/20 (10%) with cyanoacrylate versus 4/17 (23.5%) with alcohol-based compound; RR 0.43; 95% CI 0.09 to 2.04), failure of intervention (RR 0.36; 95% CI 0.09 to 1.35), prevention of re-bleeding (RR 0.85; 95% CI 0.30 to 2.45), adverse events reported as fever (RR 0.43; 95% CI 0.22 to 0.80), and control of bleeding (RR 1.79; 95% CI 1.13 to 2.84).

Cyanoacrylate versus endoscopic band ligation: we found very low quality evidence for the effect of cyanoacrylate versus endoscopic band ligation on bleeding-related mortality (44/185 (23.7%) with cyanoacrylate versus 50/181 (27.6%) with endoscopic band ligation; RR 0.83; 95% CI 0.52 to 1.31), failure of intervention (RR 1.13; 95% CI 0.23 to 5.69), complications (RR 2.81; 95% CI 0.69 to 11.49), and control of bleeding (RR 1.07; 95% CI 0.90 to 1.27). There was low quality evidence for the prevention of re-bleeding (RR 0.60; 95% CI 0.41 to 0.88). Trial sequential analysis showed that the analyses were underpowered (diversity-adjusted required information size was 5290 participants for bleeding-related mortality).

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