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Efficacy of endoscopic treatments for acute esophageal variceal bleeding in cirrhotic patients: systematic review and meta-analysis

Background and aim  Guidelines recommend use of ligation and vasoactive drugs as first-line therapy and as grade A evidence for acute variceal bleeding (AVB), although Western studies about this issue are lacking. Methods  We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy of endoscopic treatments for AVB in patients with cirrhosis. Trials that included patients with hepatocellular carcinoma, use of portocaval shunts or esophageal resection, balloon tamponade as first bleeding control measure, or that received placebo or elective treatment in one study arm were excluded. Results  A total of 8382 publications were searched, of which 36 RCTs with 3593 patients were included. Ligation was associated with a significant improvement in bleeding control (relative risk [RR] 1.08; 95 % confidence interval [CI] 1.02 – 1.15) when compared to sclerotherapy. Sclerotherapy combined with vasoactive drugs showed higher efficacy in active bleeding control compared to sclerotherapy alone (RR 1.17; 95 % CI 1.10 – 1.25). The combination of ligation and vasoactive drugs was not superior to ligation alone in terms of overall rebleeding (RR 2.21; 95 %CI 0.55 – 8.92) and in-hospital mortality (RR 1.97; 95 %CI 0.78 – 4.97). Other treatments did not generate meta-analysis. Conclusions  This study showed that ligation is superior to sclerotherapy, although with moderate heterogeneity. The combination of sclerotherapy and vasoactive drugs was more effective than sclerotherapy alone. Although current guidelines recommend combined use of ligation with vasoactive drugs in treatment of esophageal variceal bleeding, this study failed to demonstrate the superiority of this combined treatment.

A beneficial effect on survival has been observed in parallel with introduction of drugs that are capable of decreasing portal pressure, optimization of endoscopic therapy, and use of antibiotics and interventional radiologic procedures. During the same period, the 6-week mortality rate has decreased from approximately 40 % to 15 % [5,6].
Although overall survival has improved in recent years, mortality is still closely related to failure to control the initial bleeding or early rebleeding, which occurs in up to 30 % to 40 % of patients within the first 5 days after the index bleeding episode [5,6]. As a consequence, many patients with cirrhosis and AVB still suffer from failure to control bleeding and most of them die very early [2]. Therapeutic options include vasoactive drugs such as somatostatin, octreotide, and terlipressin; endoscopic treatments such as sclerotherapy and band ligation; and most recently, radiologic interventions, such as early-TIPS (transjugular intrahepatic portosystemic shunt) placement. Therefore, the goal of this study was to evaluate the efficacy and safety of the most-used endoscopic treatments for controlling AVB.

Methods
A meta-analysis and systematic review of published randomized controlled trials (RCTs) were carried out.

Criteria for inclusion and exclusion of studies
Only RCTs were included. To reduce the risk of bias, strict inclusion and exclusion criteria were defined prior to literature search. To be considered, a study had to include patients exclusively with cirrhosis, patients with acute variceal bleeding, have more than 10 patients in each arm, include only adults, and include treatments performed in the first 24 to 48 hours after bleeding. Studies were excluded if they included patients with hepatocellular carcinoma or other malignancies, use of porto-caval shunts or esophageal resection, recent use of balloon tamponade as first bleeding control measure, placebo or elective treatment in one study arm. When two publications existed covering the same study population, only the most recent was taken into account.

Endpoints
Endpoints were defined prior to the beginning of the meta-analysis. Main endpoints were treatment efficacy for bleeding control and in-hospital mortality. Secondary endpoints were rate of rebleeding from active bleeders at initial endoscopy, rate of overall rebleeding, rate of overall mortality, and rate of adverse events (AEs) related to each treatment.

Data extraction and assessment of quality
Two reviewers independently abstracted data from included articles (F.Q.O. and F.M.V.). Disagreements were resolved by consensus of all authors. Extracted information included patient population characteristics, intervention characteristics, comparator characteristics, outcomes assessed, and study quality. The latter used the framework suggested by the Cochrane Handbook for Systematic Reviews of Interventions (version 5·1·0), with evaluation of the following trial characteristics: random sequence generator method, concealment of treatment allocation, blinding of participants and personnel, blinding of outcome assessment, and for selective reporting [7]. Intention-to-treat analysis and the funding source of the studies were also assessed. The GRADE methodology [7] was used to define risk of bias for each of the outcomes that had available data.

Sources of support
This systematic review and meta-analysis was not supported by any grant.

Statistical analysis
We performed direct random effects model meta-analyses of head-to-head comparisons for pooling effect sizes of reported comparisons and outcomes whenever enough data were provided in published studies. No data imputation was done, and studies not reporting information that allowed treatmenteffect calculation were not included in the meta-analyses. Summary effect for binary outcomes was calculated from risk ratios. Heterogeneity was evaluated with the inconsistency test proposed by Higgins (I 2 ), where values below 25 % were considered as low heterogeneity, and above 75 %, high heterogeneity [8,9]. Publication bias was assessed with funnel plots of comparisons with seven or more studies. Meta-analyses were carried out in Review Manager 5·3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2011). Prediction intervals were calculated with the Paule-Mandel estimator for tau squared and the Hartung-Knapp adjustment for random effects model. Prediction interval calculations were done with the software "R" (v 3.5.0) and package "Meta" (v 4.9 -4) [10].

Studies selection
A total of 8382 citations were screened, of them 6691 were evaluated after duplicates were removed (▶ Fig. 1). Of these, 69 were selected for full-text evaluation. Among them, only 36 randomized trials [11 -46] were identified that fulfilled the inclusion criteria (▶ Table 1): seven studies compared sclerotherapy with vasoactive drugs (two studies with somatostatin, three studies with octreotide, one with terlipressin and one with vasopressin plus nitroglycerin); two studies compared ligation with vasoactive drugs (one with octreotide and one with somatostatin); one study compared ligation with cyanoacrylate injection; 10 studies compared sclerotherapy with ligation; seven studies compared sclerotherapy with the combination of sclerotherapy and vasoactive drugs (six with octreotide and one with somatostatin); five studies compared ligation with sclerotherapy and ligation; two studies compared ligation with ligation and vasoactive drugs (one with somatostatin and with octreotide); one study compared sclerotherapy and octreotide with octreotide alone; and one study compared ligation and octreotide with octreotide alone. ▶ Table 1 Demographic data from included studies.

Studies characteristics
Only 32 RCTs had been published as full papers. Four trials were published as abstracts [32,40,44,45]. In six studies [11,23,24,31,32,35], patients were included only if they had ongoing bleeding at time of initial endoscopy. Alcoholic cirrhosis was the predominant cause of portal hypertension in 18 studies. In contrast, cirrhosis due to viral hepatitis infection was the leading cause in 13 studies (patients from Asia, Brazil, and the Middle East). Otherwise, baseline characteristics of the study populations, such as gender ratio, Child-Pugh class or mean age, were comparable (▶ Table 1). Only 11 of the 36 trials described separately the rebleeding rate of the different treatment modalities in active bleeders at the time of endoscopy, i. e., 25 studies analyzed together active and non-active bleeders (Supplementary Table 1 -Supporting Information).

Risk of bias within trials
The included trials had risk of bias evaluated according to the Cochrane recommendations for meta-analyses and systematic reviews (▶ Fig. 2). None of the included trials were placebocontrolled. The randomization-method of the majority of the trials was computer-generated random sequences, with only four trials (abstracts) having no information about randomization. Eighteen trials had low risk for concealment of treatment allocation. Blinding of outcome assessment was not stated in any of the peer-reviewed articles. Prediction intervals for random effects meta-analyses are presented in ▶ Table 2.

Risk of bias across trials
With respect to risk of publication bias, funnel plots were generally symmetrical, which indicates a low probability of publication bias in the present systematic review.

Comparison of sclerotherapy with vasoactive medications
Sclerotherapy was compared to somatostatin, octreotide, and vasopressin plus nitroglycerin in seven trials. The rate of complications was significantly higher with sclerotherapy (6 trials; relative risk [RR] 2.10; 95 % confidence interval [CI] 1.52 -2.90; P < 0.00001; I 2 = 0 %) when compared to vasoactive drug alone. There was no significant difference in the other analyzed outcomes. The studies by Planas and Escorsell had no specific description of in-hospital mortality, so they were not included in this analysis.
In patients with active bleeding at endoscopy, sclerotherapy was needed in 17 patients to achieve active bleeding control in one of them when compared to vasoactive drug alone (number needed to treat [NNT] 17, I 2 = 0 %, P < 0.05).

Comparison of ligation with vasoactive medications
Only two trials [38,44] compared ligation with vasoactive medications (somatostatin and octreotide). However, the study by Ximing was published as an abstract and did not have enough information to be included in the analysis.

Comparison of sclerotherapy with ligation
Ligation was associated with significant improvement in bleeding control (10 trials; RR 1.08; CI 1.02 -1.15; P = 0.01; I 2 = 49 %) compared to sclerotherapy (▶ Fig. 3). The heterogeneity was potentially explained by the differences in two identified subgroups: one formed by Lo [19], Hou [21], Lo [24], Squafat [27] and de la Peña [29] (mostly Asian studies) in which ligation was clearly superior to sclerotherapy and another group of five trials (mostly Western trials) in which both techniques had similar results.
Risk of overall rebleeding was statistically significantly higher (10 trials; RR 1.41 95 % CI 1.03 -1.94; P = 0.03; I 2 = 62 %) with sclerotherapy than with ligation. The high heterogeneity was explained by the same reasons as mentioned above.
Rebleeding rate from active bleeders (only 1 trial) could not generate meta-analysis. In-hospital mortality analysis (only 3 trials) had not shown statistical difference.
In-hospital mortality and overall mortality did not show difference in effect.
Combining sclerotherapy with vasoactive drug in seven patients resulted in control of active bleeding and reduced risk of rebleeding in one patient when compared to sclerotherapy alone (NNT 7, I 2 = 0 %, P < 0.05) . In addition, the combination of sclerotherapy with vasoactive drug was needed in six patients to reduce rebleeding from active bleeders in one of them when compared to sclerotherapy alone (NNT -6, I 2 = 0 %, P < 0.05). ▶

Comparison of ligation with the combination of ligation and sclerotherapy
Five trials [22,26,28,30,46] had evaluated ligation versus the combination of ligation and sclerotherapy. Risk of complications was significantly lower with ligation (5 trials, RR 0.58; 95 %CI 0.39 -0.88; P = 0.01; I 2 0 %) when compared to the combination of ligation and sclerotherapy. However, there were no statistically significant differences among the other analyzed outcomes.

Comparison of ligation with cyanoacrylate injection
Only one trial [42] evaluated ligation with cyanoacrylate injection and, therefore, could not generate meta-analysis. This trial showed no difference in efficacy of bleeding control, rebleed-ing rate, or mortality rate with cyanoacrylate injection compared with endoscopic ligation.

Comparison of ligation with ligation and vasoactive drugs
Only two trials evaluated this treatment combination, one with somatostatin and other with octreotide [20,39]. Among the outcomes analyzed, only overall rebleeding (▶ Fig. 8) and inhospital mortality (▶ Fig. 9) generated meta-analysis, but with no significant statistical difference.  Fig. 5 Forest plot of risk ratio for efficacy of bleeding control with sclerotherapy and vasoactive drug versus sclerotherapy alone.

Discussion
Thirty-six trials, including 3593 patients, evaluated treatments for AVB control.
Among them, 10 trials compared sclerotherapy with ligation, favoring ligation in terms of efficacy of bleeding control, rebleeding, overall mortality, and rate of complications in a statistically significant fashion. However, this comparison showed a moderate heterogeneity.
The heterogeneity was potentially explained by the differences in two identified subgroups as stated above (results chapter): one formed mostly by Asian studies [19,21,24,27,29] in which ligation was clearly superior to sclerotherapy and another formed mostly by Western trials [13 -15, 43, 45] in which both techniques had similar results. In the first subgroup of studies, the main cause of cirrhosis was viral and in three of five trials, the sclerosant used was tetradecyl sulfate with 50 % dextrose. In the second subgroup, the majority of patients had cirrhosis secondary to excessive alcohol intake and only one study used tetradecyl sulfate with 50 % dextrose as sclerosant. Moreover, the second subgroup had higher percentages of active bleeders at initial endoscopy in all ligation arms compared to the sclerotherapy arms, which was not noticed in the first subgroup of studies. Prevalence of Child-Pugh C patients was similar in both subgroups.
Although ligation currently is considered the gold standard endoscopic method compared to sclerotherapy, this meta-analysis could not demonstrate clearly the superiority of one technique over the other, because there was a moderate heterogeneity (I 2 = 49 %) among the studies included. We have no doubt that ligation is better than sclerotherapy, but the advantage of ligation may not be in the bleeding episode, but in the secondary prophylaxis with a faster and safer variceal eradication.
Sclerotherapy and vasoactive drugs combined were superior to sclerotherapy alone in regard to efficacy of bleeding control, overall rebleeding rate, and rebleeding rate from active bleeders in seven, six and four trials, respectively (▶ Fig. 5, ▶ Fig. 6,  ▶ Fig. 7). There is a compelling body of evidence that the combination of sclerotherapy and vasoactive drugs is more effective than sclerotherapy alone in hemorrhage control. This meta-analysis confirmed that with a highly significant statistical difference and a low heterogeneity among the studies ( was no difference in respect to mortality in the meta-analysis and in any individual RCT. It is interesting to note that none of these studies were performed in North America (2 European, 1 Brazilian and 4 Asian trials).
Many previous trials and meta-analyses have shown that vasoactive drugs are better than placebo, vasoactive drugs are similar to sclerotherapy, and the combination of vasoactive drugs and sclerotherapy is superior to sclerotherapy alone [25,47,48]. A recent meta-analysis [47] even compared therapeutic interventions for AVB with placebo, which has been unacceptable as a treatment option since the early 1990 s.
Another technique that generated a meta-analysis and is not performed anymore is the combination of ligation and sclerotherapy. This therapy was abandoned due to a high incidence of side effects, which was confirmed by our study; nonetheless in this meta-analysis, it was demonstrated to be as effective as ligation alone in bleeding control, rebleeding, and mortality.
In this study, when we analyzed separately active bleeders at the moment of initial endoscopy, use of sclerotherapy with vasoactive drugs was superior to sclerotherapy alone. In 439 patients from four studies, combined therapy reduced rebleeding by 22 % (95 %CI 1.13 -1.32) with no heterogeneity. We could not evaluate mortality in this subgroup of patients because the studies, when quoting mortality, did not state this outcome separately (they quoted mortality for both active and non-active bleeders).
Although most studies reported in the literature included patients with recent and ongoing hemorrhage, it should be em-phasized that therapies used after bleeding had spontaneously stopped will have their results overestimated. Active bleeding at endoscopy is a well-known risk factor for worse outcomes in patients with variceal as well as non-variceal bleeding [3]. Only six studies of the 36 analyzed included only patients with active variceal bleeding, four of them compared sclerotherapy with the combination of sclerotherapy and octreotide. The other 30 RCTs pooled together the results of the different treatments among active and non-active bleeders at time of endoscopy.
Notwithstanding we have done a meta-analysis with solely two studies comparing ligation plus vasoactive drug versus ligation alone, this is the only available meta-analysis grouping this treatment, which is recommended by AASLD, the American Society of Gastrointestinal Endoscopy (ASGE) and EASL guidelines as the gold standard in management of variceal bleeding (considered as level of evidence 1a, grade A recommendation) [49 -51]. ESGE has no current guideline about this issue. Although that recommendation is routinely used in clinical practice, just two Asian studies evaluated use of ligation plus vasoactive drugs in comparison to ligation alone [20,40] and another trial compared ligation plus octreotide versus octreotide alone [42].
In the study by Sung et al., ligation and somatostatin was highly superior to ligation alone in management of variceal bleeding. On the other hand, in the study by Sarin et al., published as an abstract, the combination of ligation and octreotide did not show an advantage over ligation alone. When performing a meta-analysis of both these studies, there was clearly  Fig. 9 Forest plot of risk ratio for in-hospital mortality with ligation alone versus ligation and vasoactive drug. no benefit of combination therapy in terms of rebleeding and mortality. It is important to note that no Western study evaluated the role of ligation plus vasoactive drug in treatment of AVB.
There was no study evaluating use of early TIPS in AVB included in this meta-analysis. The only study using early TIPS selected was excluded because all patients received ligation or sclerotherapy in the first 24 hours, before randomization [52].
As in every meta-analysis, comparison of studies may have been impaired by differing in-hospital follow-up, which in some studies is evaluated at 5 days and in others at 6 weeks. In this study, those data have been pooled together as overall mortality. Time until rebleeding occurred also varied among studies, ranging from 2 to 5 days and was considered as one sole group. Notably, we excluded patients with hepatocellular carcinoma, who comprise at least one-fifth of bleeders. However, this population of patients has a worse response to any treatment and should be evaluated separately.
Furthermore, we also excluded a few articles that were not published in English due to their unavailability, although their inclusion would not affect the final analysis. Other possible limitations of our study are the unclear risk for concealment of treatment allocation in 18 trials and high risk for blinding of participants/personnel in 10 trials. Meanwhile, the blinding of endoscopists and patients undergoing upper digestive endoscopy is impossible, as in studies involving surgical interventions. Moreover, only nine of 36 studies mentioned conflict of interest. In addition, prediction intervals indicated a significant amount of uncertainty on treatment effect sizes and direction for several of the meta-analytic comparisons performed, which means that many of the research questions addressed are still unanswered. Larger and well-designed trials are needed in this field.
On the other hand, studies using placebo as a treatment were not included because there are well-established treatments available for AVB.
During the last decade, mortality rates with acute variceal bleeds have decreased. Routine medical care varied with respect to use of diagnostic and/or therapeutic endoscopy, balloon tamponade, resuscitation policy, and antibiotic prophylaxis for spontaneous bacterial peritonitis.

Conclusion
In summary, the combination of sclerotherapy and vasoactive drugs is superior to sclerotherapy or vasoactive drugs alone in management of variceal bleeding. Ligation was better than sclerotherapy as a treatment option for variceal bleeding, although heterogeneity of the results may invalidate this assumption. Although society guidelines recommend the combination of endoscopic band ligation and vasoactive medications for treatment of AVB, this statement could not be evidenced in the literature.

Competing interests
Author J.P.L. is a proctor of Boston Scientific. The other authors declare no Conflict of Interests for this article.