Primary prevention of variceal bleeding in people with oesophageal varices due to liver cirrhosis: a network meta-analysis

Davide Roccarina, Lawrence M.J. Best, Suzanne C. Freeman, Danielle Roberts, Nicola J. Cooper, Alex J. Sutton, Amine Benmassaoud, Maria Corina Plaz Torres, Laura Iogna Prat, Mario Csenar, Sivapatham Arunan, Tanjia Begum, EJ Milne, Maxine Tapp, Chavdar S. Pavlov, Brian R. Davidson, Emmanuel Tsochatzis, Norman R. Williams, Kurinchi Selvan Gurusamy

    Research output: Contribution to journalArticlepeer-review

    13 Citations (Scopus)
    182 Downloads (Pure)

    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. 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. Objectives: 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. Search methods: 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. Selection criteria: 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. 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 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. Main results: 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. Authors' conclusions: 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.

    Original languageEnglish
    Article numberCD013121
    JournalCochrane Database of Systematic Reviews
    Volume2021
    Issue number4
    Early online date6 Apr 2021
    DOIs
    Publication statusPublished - 6 Apr 2021

    Funder

    Funding Information:
    Five trials were partly or fully funded by industrial organisations who would benefit from the results of the study (Pascal 1987; Conn 1991; PROVA study group 1991; D'Amico 2002; Shah 2014); 11 trials were funded by neutral organisations who had no vested interests in the results of the study (Lebrec 1988; Andreani 1990; VA Coop. Variceal Sclerotherapy Group 1991; Lay 1997; Svoboda 1999; Borroni 2002; Schepke 2004; Jutabha 2005; Wang 2006; Tripathi 2009; Drastich 2011); the source of funding for the remaining 50 trials was unclear (Conn 1969; Paquet 1982; Witzel 1985; Wordehoff 1987; Fleig 1988; Ideo 1988; Piai 1988; Santangelo 1988; Sauerbruch 1988; Snady 1988; Cales 1989a; Cales 1989b; Russo 1989; De Franchis 1991; Quer 1991; Rossi 1991; Angelico 1993; Fassio 1993; Kanazawa 1993; Duhamel 1994; Paquet 1994; Piscaglia 1998; De 1999; Lo 1999; Song 1999; Strauss 1999; Chen 2000; Merkel 2000; Agarwal 2001; Deplano 2001; Lui 2002; Lo 2004; Merkel 2004; Tomikawa 2004; Psilopoulos 2005; Thuluvath 2005; Lay 2006; Mishra 2007; Norbeto 2007; Lo 2010; Perez-Ayuso 2010; Feng 2012; Singh 2012; Sarin 2013; Bonilha 2015; Bhardwaj 2017; Khan 2017; Seo 2017; NCT00337740; NCT00921349). We acknowledge the help and support of the Cochrane Hepato-Biliary Group, Cochrane Central Editorial Unit, and copy editors. The authors would also like to thank the peer reviewers listed below who provided comments to improve the review. Peer reviewers of protocol: Emmanouil Giorgakis, USA; Fernanda S Tonin, Brazil Peer reviewers of review: Stella O'Brien, UK; Jamiu Aderonmu, Italy; Annalisa Berzigotti, Switzerland; Kerry Dwan, UK; Jaime Bosch, Switzerland; Roberto De Franchis, Italy Contact editor: Christian Gluud, Denmark Sign-off editor: Agostino Colli, Italy Abdomen and Endocrine Network Editor: Rachel Richardson, UK All authors approved the review for publication. Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of the Cochrane Hepato-Biliary Group through its investment in the Copenhagen Trial Unit, the Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Denmark. This project was funded by the National Institute for Health Research (NIHR) Systematic Reviews Programme (project number 16/114/17) and was supported by the Complex Reviews Support Unit, also funded by the National Institute for Health Research (project number 14/178/29). The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the 16/114/17 or 14/178/29 Programmes, the NIHR, the National Health Service, or the Department of Health. The views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or the Copenhagen Trial Unit.

    ASJC Scopus subject areas

    • Pharmacology (medical)

    Fingerprint

    Dive into the research topics of 'Primary prevention of variceal bleeding in people with oesophageal varices due to liver cirrhosis: a network meta-analysis'. Together they form a unique fingerprint.

    Cite this