Predictors of endoscopic prophylaxis for rebleeding in esophageal varices combined type 2 gastroesophageal varices

Background: Patients with decompensated cirrhosis and esophageal varices (EVs) combined with type 2 gastroesophageal varices (GOV2) are at risk of rebleeding after endoscopic prophylaxis. This study was performed to evaluate the preventive ecacy of endoscopic treatment in patients with EVs combined with GOV2, and to identify the risk factor of rebleeding. Methods: We performed a single-center, observational, retrospective study of hospitalized patients with EVs combined with GOV2. The biochemical examination results, demographics, endoscopic performance measures and treatment methods of patients undergoing endoscopic treatment were collected. All patients were observed for 1-year, or were loss to follow-up. The predictors of rebleeding were analyzed by logistic regression analysis. Results: A total of 124 patients underwent endoscopic treatment, including 2 (1.6%) patients in whom bleeding failed to cease and 19 (15.3%) patients who were lost to follow-up. A total of 103 patients were observed until 1 year, including 11 (10.7%) patients who experienced rebleeding. The results indicated that EVs+GOV2 with GOV1, age, prothrombin time (PT), bilirubin level, platelet count, Child-Pugh grade, and model for end-stage liver disease (MELD) score were associated with rebleeding at 1 year in patients with EVs combined with GOV2. Multivariate logistic analysis revealed that age, EVs+GOV2 with GOV1, bilirubin level, and PT were independent risk factors for rebleeding. Conclusion: Endoscopic treatment is effective as a preventive treatment in patients with EVs combined with GOV2. EVs combined with GOV1, older age, coagulation failure, and increased bilirubin levels should be given close attention due to their associations with rebleeding after endoscopic prophylaxis. GOV1 may have a negative effect in patients with EVs +GOV2.

An-jiang wang First A liated Hospital of Nanchang University endoscopic band ligation (EBL), endoscopic variceal obturation (EVO), and combined therapy (9), is optimal for preventing the rebleeding of GOVs. GOV2 is a type that more prone to bleeding, but studies about the treatment effect and prognosis of rebleeding in GOV2 patients after endoscopic secondary prophylaxis treatment is uncertain. Due to the high mortality rate in GOV1 patients (3), it is necessary to explore whether GOV2 patients with GOV1 have a high risk of rebleeding. Therefore, we performed this study with the purpose of identifying the risk factors for rebleeding in GOV2 patients after endoscopic secondary prophylaxis treatment to guide clinical practice.

Study design
This was a single-center retrospective observational cohort conducted at a large tertiary level public hospital in South China between January 2009 and December 2018. The study protocol was approved by the Institutional Ethics Committee of the First A liated Hospital of Nanchang University. Informed written consent was obtained from all the study participants.

Study population and setting
The study cohort included all hospitalized patients aged ≥ 18 years with EVs combined with GOV2 based on gastroscopic diagnosis with endoscopic secondary prophylaxis treatment. Exclusion criteria were as follows: no bleeding history; malignant tumors of extrahepatic origin; varices caused by noncirrhotic causes such as cavernous transformation of the portal vein; patients with a transjugular intrahepatic portosystemic shunt (TIPS); patients who underwent balloon-occluded retrograde transvenous obliteration (BRTO); surgical pericardial devascularization; other patients with a shunt and devascularization; and incomplete clinical data. All patients were treated following accepted recommendations and guidelines after admission to the hospital, and they were followed up until death or 1 year.

Study protocol
Patients with EVs combined with GOV2 based on gastroscopic diagnosis with endoscopic secondary prophylaxis treatment were enrolled in the current study. During hospitalization, data regarding the demographic pro le, history, clinical features, presence of other comorbidities, etiology of cirrhosis, type of decompensation and number of complications, endoscopic performance, and blood laboratory parameters at admission were collected and compiled. Patients were followed up for 1 year to determine survival. Patients with incomplete follow-up at 1 year were not included in the nal analysis.

Statistical analysis
Statistical analyses were performed using SPSS software version 23.0 (SPSS Inc., Chicago, IL).
Continuous variables were tested by the Kolmogorov-Smirnova method for normality testing. Continuous data with normal distribution are described by the mean ± standard deviation, and compared by using Student's t-test. Continuous data without normal distribution are described by the median (interquartile range [IQR]), and compared by using Mann-Whitney U-test. Categorical variables are described as frequency (percentage [%]), and were compared by using Chi-squared analysis or Fisher's exact test.
Logistic regression analysis was employed to demonstrate the predictors for the rebleeding rate of patients with EVs combined with GOV2. All variables that were found to be associated with rebleeding (P<0.10) were included as candidate variables in forward conditional stepwise logistic regression analysis to identify independent predictors for rebleeding in patients with EVs combined with GOV2. All statistical tests were two-sided, and a value of P < 0.05 was considered statistically signi cant.

Baseline characteristics
As shown in Figure 1

Discussion
Variceal bleeding is still one of the most common serious complications in patients with liver cirrhosis. Even with developments in medicine and endoscopic therapy, acute variceal bleeding has a high rate of mortality (15%-20%) (15)(16)(17). According to the Sarin classi cation, although the frequency of GOV2 is lower than GOV1, the rebleeding risk of GOV2 is signi cantly higher than GOV1. Prognosis is an essential part of the assessment of rebleeding; it is the basis not only for the information that a physician provides to the patient, but also for any decision-making process. EVs combined with GOV1 has a high detection rate and are widely studied, but there is limited study on EVs combined with GOV2 (18,19). This study intended to analyze the endoscopic treatment effect and risk factors for rebleeding at 1-year to identify high-risk patients with rebleeding and take corresponding treatment measures to improve their prognosis. Considering that EVs+ GOV2 is often accompanied by GOV1 in the clinic, patients were divided into two groups based on their clinical and endoscopic features, EVs+GOV2 without GOV1 and EVs+GOV2 with GOV1, and compared because no studies have directly compared the clinical and endoscopic features between patients with EVs+GOV2 without GOV1 and those with EVs+GOV2 with GOV1.
In our study, the cause of both groups was mainly hepatitis virus related cirrhosis, which is consistent with the epidemiological characteristics of cirrhosis in China. A total of 124 patients underwent secondary prophylaxis, among whom 2 (1.6%) experienced hemostasis failure, 19 (15.3%) were lost to follow-up, 11 (10.7%) experienced rebleeding within 1-year. As expected, the rebleeding incidence in patients who underwent endoscopic prophylaxis was similar with other study (16,17). In Dong XJ's study on 29 patients with EVs+GOV2, 3 patients (10.3%) experienced hemostatic failure, and 7 patients (24.1%) experienced rebleeding within 6 weeks after undergoing EBL. The incidence of rebleeding in the patients in Dong XJ's study is higher than our study, which may be caused by the severity of liver disease in patients in Dong XJ's study (20). No signi cant differences were found in endoscopic characteristics or clinical features were found between EVs+GOV2 without GOV1 group and EVs+GOV2 with GOV1 groups.
Multivariate logistic regression analysis identi ed age, EVs+GOV2 with GOV1, bilirubin, and PT as risk factors for 1-years rebleeding in patients with EVs +GOV2. An increasing number of studies have been focused in predict esophageal and gastric variceal bleeding. Xu L's study showed that PTA>18s (OR=62.83, 95% CI:9.39-420.56) and moderate/severe ascites (OR=11.35,95% CI:1.93-66.7) were independent risk factors for early rebleeding after endoscopic treatment (21). Kim SJ's study indicated that Child-Pugh grade C was an independent risk factor for rebleeding in GV patients (22). Our study showed that the Child-Pugh score was associated with rebleeding in patients with EVs+GOV2, but the Child-Pugh score was not associated with rebleeding in the multivariate logistic regression. This inconsistent conclusion may be related to the small number of Child-Pugh C patients, the in uence of albumin infusion on the degree of ascites degree and level of albumin in some patients in our study during treatment. The blood provision of GOV1 and GOV2 is different, suggesting elevated portal vein pressure when present at the same time. Our study found that patients with EVs+ GOV2 with GOV1 had an increased risk of rebleeding at 1 year, and EVs+ GOV2 with GOV1 was identi ed as an independent risk factor (OR=31.063, 95% CI:  (26). We showed that the MELD score was associated with rebleeding in patients with EVs+ GOV2, but it was not an independent risk factor and may be related to the low MELD score of patients in this study. In this study, factors such as age, EV+GOV2 with GOV1, bilirubin, and PT were identi ed as independent risk factors for rebleeding in EVs combined with GOV2 after endoscopic prophylaxis, therefore it is necessary to identify the patients with high risk of rebleeding. Any patient with persistent bleeding or severe rebleeding should be considered for TIPS.
The platelet count could serve as a noninvasive index to predict the severity of varices, and a decrease in the platelets can indirectly re ect increased portal pressure (27,28). In this study, the platelet count in the rebleeding group was signi cantly lower than non-rebleeding group; however, no signi cant correlation was found in multivariate analyses. One patient in the rebleeding group had underwent splenectomy, which may have affected this result.
This study also has several limitations. First, as a single-center retrospective cohort study, the analysis may have a hereditary limitation and some patients were lost to follow-up, which may have resulted result in the selection bias. Second, the hepatic venous pressure gradient (HVPG) was not measured in all patients all patients due to limitations such as economic status and the acceptance of invasive examinations. Last, our study focused mainly on EBL treatment, and different endoscopic treatment methods were not considered.