A Retrospective Analysis of the Efficacy of Endoscopic Variceal Ligation versus Endoscopic Tissue Adhesive Injection in the Treatment of Esophagogastric Variceal Bleeding

Background: The aim of the study was to investigate the effectiveness and safety of endoscopic variceal ligation (EVL) and endoscopic tissue adhesive injection (TAI) in the treatment of esophagogastric variceal bleeding (EVB). Methods: A total of 245 patients with EVB who attended the First Affiliated Hospital of Bengbu Medical College from December 2017 to June 2021 were retrospectively collected. The participants were divided into the esophageal EVL (E-EVL) + gastric EVL (G-EVL) group (n = 103) and E-EVL + gastric TAI (G-TAI) group (n = 142), according to the procedure, comparing and assessing the clinical characteristics, laboratory results, operation time, rebleeding rate, efficacy, and complications. Results: The E-EVL + G-EVL group had significantly less varicose vein diameter and operative time than the E-EVL + G-TAI group (p < 0.05). No statistical difference in the length of hospital stay between the two groups was noted (p > 0.05). The total rebleeding rate in the E-EVL + G-EVL group was 9.7%, whereas that of the E-EVL + G-TAI group was 11.9%; no statistical difference between the two groups was noted (p > 0.05). The overall effective rate of the E-EVL + G-EVL group was 90.21%, whereas that of the E-EVL + G-TAI group was 92.81%; no statistical difference between the two groups was observed (p > 0.05). The postoperative ulcer in the E-EVL + G-EVL group was smaller and more superficial than that in the E-EVL + G-TAI group, and the wound surface was smoother. Conclusion: Both EVL and TAI have good therapeutic effects on EVB. Furthermore, owing to its effectiveness in preventing rebleeding, no reduction in efficacy and no increase in complications, shortened operative time, smaller and superficial ulcer, and smoother wounds, gastric EVL is worthy of further clinical promotion.


Introduction
Gastroesophageal varices (GOV) are a common complication of liver cirrhosis and a major cause of death in patients with cirrhosis, which are most often due to portal hypertension. As portal hypertension worsens, approximately one-third of patients with GOV will experience EVB [1,2]. Without prompt and effective treatment, the likelihood of death from EVB within 1 year can be as high as 70%. Despite advances in treatment, the 6-week mortality rate can be as high as 25% [3]; therefore, the accuracy of diagnosis and the timeliness of treatment are critical to patient survival and prognosis. Prevention of the development and progression of varices is key to the treatment of EVB [4]. In the last 20 years, with the development of medical technology, endoscopy has become the first line of investigation and treatment due to its versatility and effectiveness, and multiple endoscopic treatments can provide at least 5-10 years of survival for patients with cirrhotic decompensation. The main endoscopic treatments for EVB include endoscopic variceal ligation (EVL), tissue adhesive injection (TAI), and endoscopic injection sclerotherapy [5]. Current national and international guidelines [6,7] recommend EVL and EIS for esophageal varices (EV). In gastric varices (GV), previous studies have shown that TAI is effective in controlling bleeding in the acute phase of GV and that repeated treatment can rapidly eliminate varicose veins; however, the risk of complications associated with ectopic embolism, bleeding from draining ulcer, and sepsis is also higher [8,9]. However, some studies have also reported that EVL can relatively reduce the incidence of adverse effects without increasing side effects or decreasing overall efficiency [10]. GV bleeding is less common than EV bleeding; however, bleeding from GV is more serious, more difficult to treat, and has higher rebleeding rate and mortality; thus, particular attention should be given [11]. In clinical practice, to completely determine more personalised endoscopic treatment methods for different types of patients, we should combine the patient's actual condition, the hospital's objective conditions, and the doctor's technical experience. Few clinically controlled studies have been reported at this stage regarding the relationship between EVL and TAI. This study aimed to collect information on 245 patients with endoscopy-treated EVB in our hospital and further analyse and study the prognostic efficacy between the two groups.

Materials
Data of patients who attended the First Affiliated Hospital of Bengbu Medical College from December 2017 to June 2021 with a diagnosis of cirrhotic decompensation were retrospectively collected. The following were the inclusion criteria: (1) diagnosis of cirrhotic decompensation with EVB based on past medical history, clinical presentation, and ancillary investigations; (2) clear Sarin staging [12] as GOV1 or GOV2 by endoscopy; and (3) receiving either esophageal EVL and gastric EVL (E-EVL + G-EVL group) or esophageal EVL and gastric TAI (E-EVL + G-TAI group) on treatment. The following were the exclusion criteria: (1) combination of malignant tumours of the liver and (2) other treatments, including surgery and transjugular intrahepatic portosystemic shunt, have been performed.

Methods of Operation
Routine blood, coagulation, biochemistry, electrocardiogram and CT portal venography on admission were completed. The patient's general condition was assessed; drugs were administered to dilate, suppress gastric acid, and lower portal pressure; and painless endoscopic treatment was performed once vital signs had stabilised. The procedures were all performed by our team of doctors with experience in EVB treatment. The patients were examined using electronic gastroscopy to determine the position, shape, size, number, and risk factors for EV and GV; subsequently, the next treatment plan was determined. We used the endoscope measuring ruler invented by Li et al. [13], which is simple and accurate and can directly measure the diameter of the GOV. Patients in the E-EVL + G-EVL group had GV ligated with a ligature from the cardia to the fundus of the stomach, gradually retreating the scope, followed by EV ligated intensively from the cardia spiral upward. In the E-EVL + G-TAI group, GV was performed using a "modified sandwich method" (lauromacrogol-tissue adhesive-lauromacrogol), followed by intensive ligation of the EV from the cardia spiral upward. Postoperative fasting was performed for 24-48 h, and proton pump inhibitors (PPIs) were routinely administered to promote ulcer healing. Patients in both groups were regularly followed up at 1, 3, and 6 months and 1 year postoperatively. Depending on the patient's outcome, the choice was made whether to repeat endoscopic treatment until the varicose veins no longer required treatment.

Effectiveness Evaluation
The following are the postoperative observation indicators: 1. Rebleeding: reappearance of signs of upper gastrointestinal bleeding, including vomiting blood, black stools, decreasing haemoglobin level, and shock that recurred after the first bleeding has been controlled, with early rebleeding showing active bleeding within 72 h to 6 weeks after the bleeding has been controlled and late rebleeding showing active bleeding 6 weeks after the bleeding has been controlled. 2. •ineffective: no improvement in varicose veins; •effective: varicose veins improve although shrink by less than 50%; and •markedly effective: massed or nodular veins change to cords, shrink by more than 50%, or completely disappear. 3. Complications: fever, retrosternal pain, ulcer formation, ectopic embolism, perforation, and death.
Statistics SPSS 26.0 was used for statistical analysis in this study. Normally distributed measures were expressed as means ± standard deviations (x ± s), and t test was used to compare differences between groups. Non-normally distributed measures and rank DOI: 10.1159/000528519 data were compared using the Mann-Whitney U test; count data were compared using χ 2 test and Fisher's test. p < 0.05 was considered statistically significant.

Comparison of Baseline Data between the Two Groups
According to the inclusion and exclusion criteria, a total of 245 patients were included in this study. Of the 245 patients, 103 (64 males, 39 females) were included in the E-EVL + G-EVL group, with a mean age of 51.8 ± 12.0 years. Additionally, regarding liver function, 45, 53, and 5 patients had Child-Pugh classes A, B, and C, respectively; 70 and 33 patients had GOV1 and GOV2 types, respectively. The E-EVL + G-TAI group consisted of 142 patients (103 males and 39 females), with a mean age of 50.6 ± 8.9 years. Moreover, regarding liver function, 66, 62, and 14 patients had Child-Pugh classes A, B, and C, respectively; 86 and 56 patients had GOV1 and GOV2 types, respectively. No statistically significant difference in the baseline levels of the two groups in terms of basic information, Child-Pugh classification of liver function, and classification was noted (p > 0.05) ( Table 1).

Varicose Vein Diameter, Operation Time, and Length of Hospital Stay
The varicose vein diameter in the E-EVL + G-EVL group was (1.1 ± 0.5) cm, the operative time was (18.5 ± 2.1) min, and the length of hospital stay was (16.0 ± 8.7) days. The varicose vein diameter in the E-EVL + G-TAI group was (1.6 ± 0.8) cm, the operative time was (35.2 ± 2.4) min, and the length of hospital stay was (16.9 ± 6.9) days. The E-EVL + G-EVL group had significantly less varicose vein diameter and operative time than the E-EVL + G-TAI group (p < 0.05), whereas no statistical difference between the two groups in terms of length of hospital stay was noted (p > 0.05) ( Table 2).

Incidence of Rebleeding
Rebleeding occurred in 10 of the 103 patients in the E-EVL + G-EVL group, with an overall rebleeding rate of 9.7%, including 4 cases of early rebleeding, with an early rebleeding rate of 3.9%, and 6 cases of delayed rebleeding, with a delayed rebleeding rate of 5.8%. A total of 17 of the 142 patients in the E-EVL + G-TAI group had rebleeding, with a total rebleeding rate of 12.0%, including 7 cases of early rebleeding, with an early rebleeding rate of 4.9%, and 10 cases of late rebleeding, with a late rebleeding rate of 7.0%. No statistical difference in the total, early, and delayed rebleeding rates between the two groups was noted (p > 0.05) ( Table 3).

Comparison of Endoscopic Treatment Results
Patients in both groups were regularly followed up with endoscopy after treatment, and the choice was made whether to treat the varicose veins endoscopically again depending on the treatment of the varicose veins. After endoscopic follow-up and re-treatment or multiple, the GV of the 103 patients in the E-EVL + G-EVL group met the criteria of marked effectiveness in 44 cases, with a markedly effective rate of 42.7%; 49 cases met the criteria of effectiveness, with an effective rate of 47.6%; and 10 cases met the criteria of ineffectiveness, with an ineffectiveness rate of 9.7%. The GV of the 142 patients in the E-EVL + G-TAI group met the criteria of marked effectiveness in 67 cases, with a markedly effective rate of 47.2%; 65 cases met the criteria of effectiveness, with an effective rate of 45.8%; and 10 cases met the criteria of ineffectiveness, with an ineffectiveness rate of 7.0%. No statistical difference in GV treatment outcome between the two groups was observed (p > 0.05) ( Table 4).

Complications
Most patients had varying degrees of postoperative discomfort and pain behind the sternum, which disappeared with symptomatic management. In the E-EVL + G-EVL group, two (1.9%) and five (4.9%) cases had fever and postoperative bleeding, respectively; in the E-EVL + G-TAI group, six (4.2%) and three (2.1%) cases had fever and postoperative bleeding, respectively, which were symptomatically treated; subsequently, the temperature returned to normal, and the bleeding stopped after emergency haemostasis. Postoperative ulcer in the E-EVL + G-EVL group (Fig. 1a-f) was small and superficial with smoother wounds at endoscopic follow-up, and multiple forms of postoperative adhesive discharge ulcer were observed in the E-EVL + G-TAI group (Fig. 2a-f) at endoscopic follow-up. No serious complications, including ectopic embolism or perforation, occurred in either group.

Discussion
GV is located in the submucosa, which is deeper and has a larger average diameter than EV, and is exposed to an acidic environment and pepsin for a long period. Once GV ruptures, blood loss is more severe, and the prognosis is poor, which can be a serious threat to the patient's life [15]. The principle of EVL is that the ligature blocks the flow of blood through the varicose veins, causing thrombosis, tissue necrosis, and gradual fibrosis, which eventually lead to the gradual disappearance of the varicose veins to achieve the desired effect of stopping bleeding and reducing rebleeding. Given the good efficacy and prognosis of EVL, national and international guidelines [3,6] recommend it as a first-line treatment for EV. Shiha et al. [16] first proposed EVL for GV in 1999 as a safe and effective treatment for different types of GV, particularly isolated GV. However, clinical studies at home and abroad in recent years have shown that EVL for GV still has certain limitations due to the following reasons: (1) the gastric mucosa is thicker than the esophageal mucosa, which increases the difficulty of inhalation during snare; (2) the GV are relatively thick and difficult to completely enter the snare, which can easily cause cutting and bleeding; and (3) the snare only partially fibrosis the varices, which can easily cause postoperative rebleeding and variceal regeneration [17][18][19]. TAI injections of tissue adhesive into varicose veins cause rapid aggregation, solidification, and occlusion of the vessel to control varicose bleeding and thus achieve haemostasis. However, a higher dosage of tissue adhesive increases the risk of ectopic embolism and increases the likelihood of bleeding from draining ulcer and pulmonary embolism in patients with large gastric-renal shunts and hepatopulmonary syndrome [20][21][22].
In recent years, there has been increasing interest in the choice of GV treatment modality [23]. Although the use of EVL in EV treatment is well established, only a few studies have evaluated the utility and effectiveness of EVL in GV treatment. Most of the studies were small, singlecentre, and incomparable. A single-centre retrospective study [24] showed no statistical difference in the rates of acute bleeding control and early rebleeding between EVL and TAI for GV; however, the EVL group had a lower rate of delayed rebleeding than the TAI group. El Amin et al. [25], in a randomised controlled study including 150 patients, found no statistical difference between EVL and TAI in controlling acute bleeding from GV, and both were similar in terms of postoperative rebleeding rates; however, the complication rate after TAI treatment was higher, suggesting that EVL is likely to be an alternative treatment for GV. Moreover, national studies [9,26] have concluded that there is no statistical difference between EVL and TAI in terms of acute haemostasis of GV, variceal elimination, and risk of rebleeding; however, EVL has a lower complication rate. The results of prospective randomised trials by Lo et al. [27] and Tan et al. [28] enrolling 60 and 97 patients, respectively, indicate that TAI may be safer and more effective in the treatment of GV. One study [29] comparing the efficacy of EVL and TAI for GV showed that both treatment modalities were equally effective in controlling active bleeding, and no difference in the overall survival between the two groups was noted; however, the EVL group had a higher rebleeding rate than the TAI group.
This study retrospectively summarised 245 patients with cirrhosis in the decompensated phase with EVB, and the results showed that the varicose vein diameter and the operative time were significantly less in the E-EVL + G-EVL group than those in the E-EVL + G-TAI group (p < 0.05). Additionally, no statistical difference in the length of hospital stay between the two groups was observed (p > 0.05). The total rebleeding rate in the E-EVL + G-EVL DOI: 10.1159/000528519 group was 9.7%, of which the early and delayed rebleeding rates were 3.9% and 5.8%, respectively; the total rebleeding rate in the E-EVL + G-TAI group was 12.0%, of which the early and delayed rebleeding rates were 4.9% and 7.0%, respectively. No statistical difference in the total, early, and late rebleeding rates between the two groups was noted (p > 0.05). The overall effective rate of the E-EVL + G-EVL group was 90.3%, of which the markedly effective, effective, and ineffectiveness rates were 47.6%, 42.7%, and 9.7%, respectively; the overall effective rate of the E-EVL + G-TAI group was 93.0%, of which the markedly effective, effective, and ineffectiveness rates were 45.8%, 47.2%, and 7.0%, respectively, with no statistical difference between the two groups (p > 0.05). Neither the EVL nor EHI method can prevent gastric acid and pepsin from eroding the gastric mucosa [30]. Postoperative ulcer was small and superficial with smoother wounds in the E-EVL + G-EVL group at endoscopic follow-up, and multiple forms of postoperative adhesive discharge ulcer were observed in the E-EVL + G-TAI group at endoscopic follow-up. No serious complications, including ectopic embolism or perforation, occurred in either group. Compared with previous studies, the improvement in the rebleeding rate in this study may be related to the regular use of PPIs in all patients and regular follow-up followed by re-treatment or multiple treatments [31].
In conclusion, both EVL and TAI have good therapeutic effects on GV. EVL can effectively prevent rebleeding, without reducing curative effect and without increasing complications. The ulcer is small and superficial, and the wound surface is smoother. The present study confirms the feasibility, efficacy, and safety of EVL and TAI in the treatment of GV, which can provide some basis and reference value for clinical treatment. G-EVL is suitable for patients with EVB with subcardial fundic vessels, vessels up to 1.5 cm in diameter, small vessels with a trailing distribution, re-treatment, or multiple treatments due to its minimal invasion, simple operation, rapid action, flat treatment wound, and no significant adverse effects. So that the patient can more easily tolerate the anaesthetic and have a clearer view during gastroscopy, EVL is performed after the patient's vital signs have stabilised. Furthermore, the necessary postoperative fasting, antibiotics, and PPIs can further improve the outcome. This is a retrospective study without information from prospective, multicentre, large-sample controlled studies, and there may be issues of bias. Whether EVL is superior to TAI for the treatment of EVB requires to be further explored, as it needs to be supported by a large amount of clinical data.

Statement of Ethics
Study approval was obtained from the Ethics Committee of The First Affiliated Hospital of Bengbu Medical College (No. 2020026). All experiments were performed in accordance with relevant guidelines and regulations. Written informed consent was obtained from participants.