Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK.
Division of Surgery and Interventional Science, University College London, London, UK.
Cochrane Database Syst Rev. 2021 Apr 6;4(4):CD013121. doi: 10.1002/14651858.CD013121.pub2.
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.
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.
约 40% 至 95% 的肝硬化患者有食管静脉曲张。约 15%至 20% 的食管静脉曲张在大约 1 至 3 年内出血。有几种不同的治疗方法可以预防出血，包括β受体阻滞剂、内镜下套扎治疗和食管静脉曲张结扎术。然而，它们各自和相对的益处和危害存在不确定性。
通过网络荟萃分析比较不同治疗方法预防肝硬化患者首次食管静脉曲张出血的益处和危害，并根据安全性和疗效对预防首次食管静脉曲张出血的不同治疗方法进行排名。
我们检索了 CENTRAL、MEDLINE、Embase、Science Citation Index Expanded、世界卫生组织国际临床试验注册平台和试验注册库，以获取截至 2019 年 12 月关于无出血史的肝硬化和食管静脉曲张患者的随机临床试验。
我们仅纳入了有肝硬化和无出血史的食管静脉曲张患者的随机临床试验（无论语言、盲法或状态如何）。我们排除了先前有食管静脉曲张出血史的参与者以及先前接受过肝移植或预防性治疗食管静脉曲张的参与者。
我们使用 OpenBUGS 通过贝叶斯方法进行了网络荟萃分析，并根据可用病例分析，使用风险比（HR）、优势比（OR）和速率比以及 95%可信区间（CrI）计算了治疗方法的差异，根据国家卫生与保健卓越技术支持单位的指导进行。我们使用相同的代码和相同的技术细节从随机临床试验中进行了直接比较。
我们纳入了 66 项随机临床试验（6653 名参与者）。60 项试验（6212 名参与者）提供了审查中一项或多项比较的数据。提供信息的试验包括因不同病因导致的肝硬化患者和有高出血风险的食管静脉曲张患者。试验报告结果的随访时间从 6 个月到 60 个月不等。除了一项试验之外，所有试验都有较高的偏倚风险。比较的干预措施包括β受体阻滞剂、无活性干预、食管静脉曲张结扎术、硬化剂治疗、β受体阻滞剂加食管静脉曲张结扎术、β受体阻滞剂加硝酸盐、硝酸盐、β受体阻滞剂加硬化剂以及门体分流术。总的来说，接受非选择性β受体阻滞剂（“β受体阻滞剂”）治疗的参与者（选择β受体阻滞剂作为参考治疗，因为这是试验中最常见的比较治疗）在 8 个月至 60 个月的随访中，有 21.2%的人死亡。基于低质量证据，β受体阻滞剂、食管静脉曲张结扎术、硬化剂治疗和β受体阻滞剂加硝酸盐治疗与无活性干预相比，死亡率均较低（β受体阻滞剂：HR 0.49，95%CrI 0.36 至 0.67；直接比较 HR：0.59，95%CrI 0.42 至 0.83；10 项试验，1200 名参与者；食管静脉曲张结扎术：HR 0.51，95%CrI 0.35 至 0.74；直接比较 HR：0.49，95%CrI 0.12 至 2.14；3 项试验，355 名参与者；硬化剂治疗：HR 0.66，95%CrI 0.51 至 0.85；直接比较 HR：0.61，95%CrI 0.41 至 0.90；18 项试验，1666 名参与者；β受体阻滞剂加硝酸盐治疗：HR 0.41，95%CrI 0.20 至 0.85；无直接比较）。没有试验报告健康相关的生活质量。基于低质量证据，与β受体阻滞剂相比，食管静脉曲张结扎术有更高的严重不良事件（事件数量）发生率（比值比 10.49，95%CrI 2.83 至 60.64；1 项试验，168 名参与者）。基于低质量证据，β受体阻滞剂加硝酸盐治疗的不良事件（参与者数量）发生率高于β受体阻滞剂单药治疗（比值比 3.41，95%CrI 1.11 至 11.28；1 项试验，57 名参与者）。基于低质量证据，与β受体阻滞剂相比，硬化剂治疗的不良事件（事件数量）发生率更高（比值比 2.49，95%CrI 1.53 至 4.22；直接比较比值比 2.47，95%CrI 1.27 至 5.06；2 项试验，90 名参与者），与β受体阻滞剂加食管静脉曲张结扎术相比，不良事件（事件数量）发生率更高（直接比较比值比 1.72，95%CrI 1.08 至 2.76；1 项试验，140 名参与者）。基于低质量证据，与β受体阻滞剂相比，β受体阻滞剂加食管静脉曲张结扎术的任何静脉曲张出血发生率较低（直接比较 HR 0.21，95%CrI 0.04 至 0.71；1 项试验，173 名参与者）。基于低质量证据，与β受体阻滞剂相比，硝酸盐的任何静脉曲张出血发生率更高（直接比较 HR 6.40，95%CrI 1.58 至 47.42；1 项试验，52 名参与者）。证据表明，在其余的比较中，干预措施的效果存在相当大的不确定性。
基于低质量证据，与无干预相比，β受体阻滞剂、食管静脉曲张结扎术、硬化剂治疗和β受体阻滞剂加硝酸盐治疗可能降低高危食管静脉曲张的肝硬化患者的死亡率，这些患者无既往出血史。基于低质量证据，与β受体阻滞剂相比，食管静脉曲张结扎术可能导致更多的严重不良事件。证据表明，β受体阻滞剂与食管静脉曲张结扎术在静脉曲张出血方面的效果存在相当大的不确定性。证据还表明，在大多数其余的比较中，干预措施的效果存在相当大的不确定性。
