A retrospective cohort study of intensive gastric variceal ligation versus endoscopic gastric variceal obturation in the management of gastric variceal bleeding

Introduction

Gastroesophageal variceal bleeding is a significant complication of cirrhosis and has a mortality rate of approximately 10–20% (1). Gastric variceal bleeding is often more serious and can be fatal. Hepatitis C virus (HCV) etiology, hepatic encephalopathy, the model for end-stage liver disease (MELD) score and rebleeding were reported as prognostic factors for mortality (2). Treatments for gastric variceal bleeding include β-blockers, endoscopic variceal ligation, endoscopic variceal obturation, shunt surgery, transjugular intrahepatic portosystemic shunts (TIPS) and balloon-occluded retrograde transvenous obliteration (BRTO). Although shunt surgery results in the reduction of variceal bleeding, it is also associated with a significant increase in hepatic encephalopathy and mortality (3).

Currently, international consensus recommendations for the treatment of gastric variceal bleeding vary according to endoscopic classification (4-6), usually the Sarin classification (7), categorizes gastric varices as gastroesophageal varices (GOV1 and GOV2) or isolated gastric varices (IGV1 and IGV2). For GOV2/IGV1 gastric varices, recommended treatments include endoscopic injection of N-butyl-2-cyanoacrylate called as gastric variceal obturation (GVO), or BRTO/TIPS. Few studies have investigated ligation versus GVO for the treatment of gastric varices, and the current consensus is based on the results of 2 early prospective randomized controlled trials conducted by Lo et al. (8) and Tan et al. (9), respectively. Both studies concluded that ligation was associated with higher recurrence and rebleeding rates relative to GVO. However, these studies limited the number of bands for ligation of fundal varices. Therefore, a comprehensive and thorough ligation of fundal varices by intensive ligation without limiting band quantity, which is named as intensive gastric variceal ligation (IGVL), may reduce missed communicating branches of fundal varices. We conducted a retrospective cohort study to analyze the effectiveness and safety of IGVL and GVO for the treatment of fundal varices and to explore the predictors of rebleeding after initial endoscopic treatment as well as mortality. We present the following article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-22-138/rc).

Methods

Case description

In total, 374 patients with bleeding from esophageal and fundal varices were treated at the Second Hospital of Hebei Medical University between January 2016 and December 2020. Case data were retrieved from the inpatient medical record system of the hospital, while follow-up data were obtained by phone. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by research ethics committee of the Second Hospital of Hebei Medical University (No. 2017-R201). All patients provided informed consent. The case screening process is shown in Figure 1.

Figure 1 Flowchart of patient selection. GOV, gastroesophageal varices; EV, esophageal varices; IGV, isolated gastric varices; CYA, cyanoacrylate; IGVL, intensive gastroesophageal variceal ligation; EVO, esophageal variceal obturation; GVO, gastric variceal obturation.

The inclusion criteria

Patients with cirrhosis, aged 18 to 78 years; patients with a documented history of bleeding from ruptured gastroesophageal varices; patients with at least 1 endoscopic treatment and 1 follow-up endoscopy; patients with fundal varices, such as GOV2, GOV1 + GOV2, and IGV1; and patients who underwent endoscopic treatment, either IGVL or GVO.

The exclusion criteria

Patients with noncirrhotic portal hypertension such as hypertension due to portal vein spongelike changes; patients with endoscopic contraindications such as perforation of the digestive tract and allergy to sclerosing agents or tissue adhesives; patients with heart failure, renal failure, respiratory failure, or end-stage cancer; patients who underwent liver transplantation; patients who underwent endoscopic treatment in the past year; and patients who did not want to participate.

Materials and treatments

For IGVL, the endoscope (Olympus-260 endoscope, Olympus, Tokyo, Japan) was inverted at the fundus, and the varices were intensively ligated (6 Shooter Multi-Band Ligator, Cook Endoscopy, Inc., Winston-Salem, NC, USA) around the cardiac orifice (U-shaped ligation). The first row of ligation was performed adjacent to the cardiac orifice and usually consisted of 2 to 5 bands; the second row was parallel to the first row, with no gap. In other words, the vascular clusters were in close contact with those of the first row after ligation. Next, ligation continued towards the dome of the fundus until all visible fundal varices were fully and completely ligated. Figure 2 shows non-IGVL and IGVL treatment.

Figure 2 Intensive gastric variceal ligation vs. common gastric variceal ligation for gastric varices. (A) IGV1 gastric varices with active bleeding. (B) Band ligation for hemostasis, not intensive. (C) Endoscopic surveillance 6 months later. Gastric varices were not eliminated. (D) IGVL was carried out. (E) Gastric varices were eliminated 2 months later. IGV, isolated gastric varices; IGVL, intensive gastroesophageal variceal ligation.

For GVO of gastric varices, the needle (0910718212, MTW-Endoskopie Manufaktur, Wesel, Germany) was prefilled with lauromacrogol (Tianyu Pharmaceutical Co., Ltd., Xi’an, Shanxi Province, China). Once the needle was inserted into the vessel, 3 to 5 mL of lauromacrogol, 0.5 to 2.0 mL of tissue adhesive (α-cyano-n-butyl acrylate, Beijing Compont Medical Devices Co., Ltd., Beijing, China), and 2 to 3 mL of lauromacrogol were quickly injected, after which the needle was promptly withdrawn. The injection sites and the surrounding varices were explored with the needle sheath; if any soft varices were detected, additional injections were performed until all gastric varices were sclerosed.

The esophageal varices were ligated or sclerotherapy was performed after gastric variceal treatment in both groups. Any varicose vein with a diameter ≥5 mm was retreated during endoscopic follow-up.

Related definitions

Cirrhosis was diagnosed based on clinical manifestations of liver damage and portal hypertension.

Esophageal varices were considered “large” if the diameter was ≥5 mm or “small” if the diameter was <5 mm (10-12). Gastric varices were considered “large” if the diameter was >10 mm, “medium” if the diameter was 5–10 mm, and “small” if the diameter was <5 mm (9).

The acute bleeding period (6,13) was defined as bleeding that occurred during the first 120 hours after gastrointestinal bleeding and included vomiting blood and black stool. Any bleeding after 5 days was defined as initial rebleeding.

Outcome measures and follow-up

All patients were followed-up for more than 52 weeks. Gastrointestinal bleeding, time and severity of bleeding, propranolol application, out-of-hospital endoscopic review, complications, death, time of death and cause of death were recorded.

Outcome measures included the success rate of emergency hemostasis, 6-week mortality, 1-year mortality, rebleeding rate, rebleeding rate after initial treatment, and the incidence of adverse events. The predictors of rebleeding after initial treatment and mortality were analyzed.

Statistical analysis

SPSS v25 was used for the data analysis. Measurement data were expressed as the mean ± standard deviation and were analyzed using a t-test. Nonnormally distributed measurement data were analyzed using the Mann-Whitney U test. Count data were expressed as n (%) and analyzed using the χ² test or Fisher’s exact test. A Kaplan-Meier survival curve was used to describe survival and rebleeding, the logrank test was performed for univariate analysis to screen the potential predictors with a significance level of P<0.05, and a Cox proportional hazards regression model was used for multivariate analysis. All tests were 2-sided, and P<0.05 was considered statistically significant.

Results

Basic data

A total of 81 patients met the inclusion criteria for the study, including 42 in the IGVL group and 39 in the GVO group (2 patients in the GVO group were lost to follow-up). The mean follow-up time was 27.5±14.3 months (range, 3–59 months) in the IGVL group and 33.2±18.3 months (range, 2–63 months) in the GVO group. Baseline data were comparable between both groups. The basic data are shown in Table 1.

Endoscopic treatment

In the IGVL group, the number of bands for fundal varices averaged 14.21±7.4. The average amount of tissue adhesive used was 2.99±1.85 mL, with an average of 1.84±1.28 injection points in the GVO group. During the first year, the IGVL group received a total of 168 endoscopies and 133 endoscopic treatments, with an average of 3.17±3.178 endoscopies per patient. The GVO group received a total of 128 endoscopies and 82 endoscopic treatments, with an average of 2.22±1.456 endoscopies per patient. The mean number of treatments per patient was significantly higher in the IGVL group than in the GVO group (P<0.05). The success rate of endoscopic hemostasis was 100% (19/19) in the IGVL group and 84.2% (16/19) in the GVO group in the acute bleeding period, with no significant between-group difference.

Rebleeding

The overall rebleeding rate was 42.9% (18/42) in the IGVL group and 64.9% (24/37) in the GVO group (P=0.05). The rebleeding rate after initial treatment was 23.8% (10/42) in the IGVL group, which was significantly lower than that in the GVO group [48.6% (18/37), P=0.021]. After initial treatment, gastric varices were the most common bleeding site, with an incidence of 14.3% (6/42) in the IGVL group, which was lower than that in the GVO group [35.1% (13/37), P<0.05]. In the IGVL group, all bleeding was treatment-related, whereas in the GVO group, 8 of 13 incidences of bleeding were due to tissue adhesive displacement. Nine of 10 cases in the IGVL group and 11 of 18 cases in the GVO group required blood transfusions. The detailed results are shown in Table 2.

Survival

In the IGVL group and the GVO group, the overall mortality, 6-week mortality, and 1-year mortality were 14.3% (6/42) versus 32.4% (12/37), 0.0% (0/42) versus 2.7% (1/37), and 11.9% (5/42) versus 13.5% (5/37), respectively, with no significant between-group differences (all P>0.05). The >1-year mortality was significantly higher in the GVO group than in the IGVL group [23.3% (7/30) vs. 2.7% (1/37), P<0.05]. Bleeding-related mortality was also significantly higher in the GVO group than in the IGVL group [27.0% (10/37) vs. 9.5% (4/42), P<0.05]. The detailed results are shown in Table 3. The survival curves of both groups are shown in Figure 3.

Figure 3 Survival analysis of the patients in the IGVL and GVO groups. IGVL, intensive gastroesophageal variceal ligation; GVO, gastric variceal obturation.

Adverse events

The incidence of adverse events was 57.1% (24/42) in the IGVL group and 48.6% (18/37) in the GVO group, with no significant difference between the groups (P<0.05). The adverse events included transient fever, infection, chest pain or upper abdominal pain, nausea, and heartburn, but there were no serious life-threatening adverse events. Transient fever, mostly low-grade fever, was the most common and was resolved after 1 to 2 days. The incidence of transient fever was 42.9% (n=18) in the IGVL group and 27% (n=10) in the GVO group, with no significant between-group difference (P>0.05).

Analysis of risk factors

In the analyses of rebleeding after initial treatment, 29 variables, including sex and endoscopic treatment method, were included in the Kaplan-Meier survival curve for the univariate analysis. The results indicated 5 significant clinical risk factors, including endoscopic treatment method, total bilirubin, liver cancer, diabetes, and Child-Pugh score. These 5 variables were incorporated into the Cox proportional hazards regression model for multivariate analysis. The results showed that endoscopic treatment method (GVO), increased total bilirubin, liver cancer, and diabetes were independent risk factors.

In all, 32 variables were included in the Kaplan-Meier survival curve for the univariate analysis. The results showed that sex, total bilirubin, albumin, liver cancer, ascites, Child-Pugh score, rebleeding after initial treatment, and overall rebleeding rate were significant variables. Given that total bilirubin and albumin were related to the Child-Pugh score as well as to the sample size, 5 variables including sex, liver cancer, ascites, Child-Pugh score, and rebleeding after initial treatment were incorporated into the Cox proportional hazards regression model for multivariate analysis. The results showed that male sex, liver cancer, ascites, and rebleeding after initial treatment were the 4 independent risk factors for mortality.

Discussion

In 1988, Van Stiegmann et al. (14) reported that endoscopic ligation was safe and effective for the treatment of esophageal varices. However, conventional ligation may be associated with reoccurrence due to missed small or invisible varices. In 1995, Umehara et al. (15) proposed the concept of “intensive ligation”. In 1998, Nagamine et al. (16) treated esophageal varices with intensive ligation with better-than-expected outcomes, and the median nonrecurrence period reached 18 months. It remains to be seen whether this approach can be used for endoscopic treatment of gastric varices. The gastric cavity differs from the esophagus in its anatomical structure and acidic environment. Two main causes of rebleeding after ligation for gastric varices have been defined: post-ligation ulcer, which may be why several known related studies restricted the number of bands (8,9,17), and incomplete ligation of gastric varices with missed communicating branches. With the development of acid-suppressing drugs, the perioperative use of proton pump inhibitors effectively reduces the gastric acid level, which helps reduce the risk of postoperative ulcers and bleeding. Intensive ligation of fundal varices involves ligation of all visible fundal varices during a single procedure, with no communicating branches missed. Moreover, multiple bands are applied on the same varicose vein, which reduces the chance of bleeding in the event of detachment of any band. Thus, the use of intensive ligation for fundal varices is worthy of further investigation. In addition, for gastric varices, GVO has certain limitations, such as high risk of ectopic embolism for patients with a gastrorenal shunt (18,19). Intensive ligation may become a new treatment option for these patients. To the best of our knowledge, no studies have been conducted investigating intensive ligation versus GVO for fundal varices.

The rebleeding rate after initial treatment was significantly lower in the IGVL group than in the GVO group (23.8% vs. 48.6%, P<0.05), which differs from previous results. These differences may be due to several factors. (I) Intensive ligation has the advantage of allowing multiple bands on the same varicose vein, which in theory reduces the risk of rebleeding. (II) Few previous studies have been conducted in GOV2 patients. Lo et al. (8) included a total of 13 GOV2 patients, Tan et al. (9) included a total of 25, and Robles-Medranda et al. (17) included a total of 60 patients without detailed classification of gastroesophageal varices. In this study, the inclusion of 70 GOV2 patients was more than the total number of GOV2 cases in the above 3 studies. (III) The previous 3 studies showed that the rebleeding rate was higher for ligation than for GVO. However, subgroup analysis of the different types of gastroesophageal varices in these studies showed that for GOV2 patients, the rebleeding rate was comparable in the ligation and GVO groups. Thus, IGV1 and GOV1 patients were mainly responsible for the higher overall rebleeding rate in the ligation group. Qiao et al. (20) conducted a meta-analysis and reached the same conclusion. (IV) Subgroup analysis of a single gastric varix versus multiple gastric varices revealed that for patients with multiple gastric varices, the rebleeding rate after initial treatment was significantly lower in the IGVL group than in the GVO group [5/19 (26.3%) vs. 9/15 (60%), P<0.05]. This suggests that IGVL may be more advantageous than GVO for the treatment of multiple gastric varices, which was not mentioned in previous studies.

The >1-year mortality was significantly lower in the IGVL group than in the GVO group (1/37, 2.7% vs. 7/30, 23.3%), whereas in most cases, the cause of death was related to rebleeding (IGVL: 4/6, GVO: 10/12). This may be related to the difference in the number of 1-year endoscopic treatments between both groups. In the IGVL group, the average number of 1-year endoscopic treatments was 3.17±3.178 per patient, which was significantly higher than that in the GVO group (2.22±1.456 per patient; P<0.05). With more endoscopic treatments, it is easier to achieve good control and elimination of gastroesophageal varices. Due to the limitations of a retrospective analysis, we were unable to identify the elimination status of varices in some patients.

Multivariate analysis using the Cox proportional hazards regression model showed that male sex, ascites, liver cancer, and rebleeding after initial treatment were independent risk factors for mortality. Therefore, patients with these risk factors should receive more active interventions, such as TIPS, BRTO, and surgery (21,22).

In this study, it should be noted that the incidence of transient fever was 42.9% in the IGVL group, which may have been due to long operating time, pharyngeal injury due to repeated endoscopic maneuvers, or aspiration. All complications were resolved after conservative medical treatment or monitoring. No serious adverse events, such as ectopic embolism, were observed; however, several studies (18,23) showed that the incidence of ectopic embolism was approximately 3.1% after GVO for gastric varices, which was primarily related to the amount of tissue adhesive used and the presence of a gastrorenal shunt. Therefore, intensive ligation may be beneficial to patients with a gastrorenal shunt.

Due to the limitations of retrospective cohort analysis, some patients were excluded based on the exclusion criteria. The patients finally included in this study were comparable between the groups, but sample bias cannot be excluded. In this study, the rebleeding rate was 100% (3/3) in the IGVL group and 50% (3/6) in the GVO group for IGV1 patients. Further studies are needed to investigate whether IGVL is applicable to IGV1 patients. It should be noted that even when endoscopic findings showed elimination of varices after intensive ligation, 1 patient died of rebleeding within 6 months. The gastric mucosa is thick and becomes thicker in the presence of inflammatory edema, which makes it difficult to determine whether varices have been eliminated. This in turn may lead to a false-negative result. This is a possible reason for rebleeding after elimination of varices. Well-designed multicenter prospective studies are needed to further evaluate the recurrence of gastric varices after IGVL.

In summary, this study showed that for patients with variceal bleeding from fundal varices, intensive ligation and GVO of gastric varices were both effective in controlling acute bleeding, whereas the rebleeding rate after initial treatment was lower for intensive ligation, especially for patients with multiple fundal varices. The independent risk factors for rebleeding after initial treatment were liver cancer, diabetes, total bilirubin >17.1 μmol/L, and GVO. No significant between-group difference was observed in the 6-week mortality or 1-year mortality. For mortality, the independent predictors were male sex, ascites, liver cancer, and rebleeding after initial treatment.

Acknowledgments

Funding: This work was supported by the Hebei Provincial Department of Science and Technology (project No. 182777117D) and the Chinese Foundation for Hepatitis Prevention and Control-TianQing Liver Disease Research Fund Subject, China (No. TQGB20200050).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-22-138/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-22-138/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-138/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by research ethics committee of the Second Hospital of Hebei Medical University (No. 2017-R201). All patients provided informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: A. Muijlwijk)