Timing of Endoscopic Intervention for Acute Variceal Hemorrhage: an RCT
Timing of Endoscopic Intervention for Acute Variceal Hemorrhage: an RCT
Acute variceal upper gastrointestinal bleeding remains a hot potato in cirrhotic patients.
 The purpose of this study is to figure out whether urgent endoscopy (within 6h after
 gastroenterological consultation) is superior to non-urgent endoscopy (between 6h and 24h
 after gastroenterological consultation) in reducing re-bleeding for these patients. This is a
 single-centered, prospective, randomized, and controlled trial. 400 eligible cirrhotic
 patients with acute variceal upper gastrointestinal hemorrhage will be randomized in a 1:1
 ratio to receive endoscopic intervention either within 6h or 6-24h. Randomization is
 conducted by permuted block randomization stratified by age, systolic blood pressure (SBP)
 and heart rate (HR). The primary efficacy endpoint is re-bleeding within 42 days after
 control of acute variceal bleeding. This trial will provide valuable insights into the
 efficacy between the urgent endoscopy group and the non-urgent endoscopy group.
Study design

 In this trial, we plan to conduct a single-centered, prospective, parallel-group randomized
 clinical trial. The study protocol observes the Standard Protocol Items rules:
 Recommendations for Interventional Trials (SPIRIT) 2013. The leader of the sponsoring
 organization strictly implements oversight of the protocol. We intend to compare the
 effectiveness of improving re-bleeding rates of cirrhotic patients with AVB between the
 urgent endoscopy and non-urgent endoscopy groups. Department of gastroenterology, affiliated
 Jinling Hospital, Medical School of Nanjing University will take full charge of this trial,
 including recruitment of patients, endoscopic intervention, admission education, in-hospital
 nursing, subsequent follow-up work, etc. Informed consent forms from every patient will be
 signed before enrollment, and approval from the Ethical Committees of Jinling Hospital has
 been obtained (authorized ethic No. DZQH-KYLL-21-01).

 Data processing

 Two investigators in our department are responsible for the data collection and storage. One
 investigator will inspect the data collected by another one. After finishing the inspection,
 the data will be input in the off-line database constructed by the investigators. Instantly
 they complete all of the data storage, the two investigators will conduct a double
 inspection. The eventual data will be used for data analysis. Theoretically, there will be no
 missing data because the investigators will inspect and record every patient's data timely.
 Patients with missing data will be excluded from the trial. We will perform source data
 verification by comparing them with authentic medical records to assess the accuracy,
 completeness, or representativeness of registry data.

 Patients enrollment

 An estimated 400 patients will be consecutively included in the study between March 2021 and
 December 2023. Original Glasgow-Blatchford Score is used to evaluate the condition of each
 patient instead of modified version. The indicators (measured within 2 hours after admission)
 are blood urea, hemoglobin, systolic blood pressure, pulse, melena, syncope, hepatic disease,
 and cardiac failure.

 Sample size

 According to research from Ardevol A et al, in the 646 cirrhotic patients with AVB performing
 endoscopy within 6h after admission, the 45-day re-bleeding rate was 26%, the results of
 which was similar to that in another research by Ping-Hsien Chen (the overall 6-week
 re-bleeding rate for cirrhotic patients with AVB was 25.7%). Then, we hypothesized a
 difference of 14% would be clinically significant in re-bleeding rate. Next, we calculated at
 least 189 patients in each group would embody the discrepancy (26% vs. 40%), with the
 statistical power of 80% and a two-sided α level of 5%. Assuming that a certain number of
 patients in each group will be lost to follow-up, a minimum of about 200 patients would be
 necessary for each group.

 Randomization and time set

 Eligible patients are randomly assigned in a 1:1 ratio to receive endoscopic intervention
 either within 6h or 6-24h. Randomization is conducted by permuted block randomization
 stratified by age, systolic blood pressure (SBP), and heart rate (HR). The block size is
 pre-specified, but physicians and investigators are not notified of this during the study.
 Allocation concealment is implemented by the mobile client randomization tool "Randomization
 Allocation Tool (RAT)". There are two primary sources of patients. The majority of these
 patients are from the emergency department, and the others are patients with cirrhosis who
 developed AVB during hospitalization. For patients from the emergency department, the
 interval between admission and receiving gastroenterological consultation will be controlled
 within 10 minutes by applying the emergency green channel. However, for patients during
 hospitalization, the time should be calculated as receiving an evaluation by the emergency
 endoscopic team (gastroenterological consultation). In order to make it easier to record, the
 time will be uniformly calculated as receiving gastroenterological consultation, whatever the
 sources of patients are. The patients will be randomly allocated to undergo urgent endoscopy
 within 6h or non-urgent endoscopy between 6h and 24h after gastroenterological consultation.
 The following time data will be recorded: (I) time from presenting with symptoms of acute
 variceal bleeding to admission (patients from the emergency department); (II) time from
 admission to gastroenterological consultation (patients from the emergency department); (III)
 time from admission to endoscopy (patients from the emergency department); (IV) time from
 presentation to gastroenterological consultation (patients develop AVB during
 hospitalization); (V) time from gastroenterological consultation to endoscopy (all of the
 patients).

 Control of acute bleeding, persistent bleeding, and re-bleeding

 AVB under endoscopy refers to bleed gushing or seeping from esophageal or gastric varices.
 Control of AVB refers to persistent bleeding signs that do not occur within 24h after the
 initial endoscopic intervention. Persistent bleeding refers to bleeding that can not be
 controlled after initial endoscopic intervention within 24h. Persistent bleeding is defined
 as follows (at least one item appears): (I) vomiting of fresh blood or suction of more than
 100 ml fresh blood from the nasogastric tube; (II) occurring hemorrhagic shock; (III) review
 of hemoglobin level decreasing by 30 g/L in the absence of a blood transfusion. Re-bleeding
 refers to recurrent bleeding after control of acute bleeding. The re-bleeding is defined as
 follows (at least one item appears): (I) hematemesis/melena/hematochezia; (II) with systolic
 blood pressure dropping by more than 20mmHg from the original level or heart rate increases
 by 20 beats/min; (III) review of hemoglobin level decreasing by 30 g/L in the absence of a
 blood transfusion. Patients with persistent or re-bleeding will take secondary endoscopic
 intervention or be transferred to undergo other treatment (surgery or transjugular
 intrahepatic portosystemic stent-shunt [TIPSS]) instantaneously according to the patient's
 condition.

 Treatment

 (I) Before endoscopic intervention: all the patients take uninterrupted intravenous
 administration of high dose proton pump inhibitors (PPIs, 8 mg/h), somatostatin (250 μg/h),
 and preventive application of antibiotics; (II) Initial endoscopic intervention: patients who
 conform to non-variceal bleeding under endoscopy will not be included in this trial, but the
 emergency endoscopic team will still strictly follow the procedure to conduct standard
 treatment for them. For patients conforming to AVB, we use tissue
 adhesive/sclerotherapy/variceal ligation/covered stent as the treatment methods for varicose
 veins. The patient's position is chosen to expose the best field of vision under endoscopy,
 and the external cannula for endoscopy is used to prevent aspiration according to the
 patient's condition. Furthermore, initial endoscopic treatment aim at the varicose vein of
 the bleeding site solely. After the endoscopic treatment, the patients will be transferred to
 the gastroenterological care unit; (III) After the initial endoscopic intervention: all the
 patients are treated with continuous high dose PPIs (8 mg/h) and intravenous infusion of
 somatostatin (250 μg/h) for 72h, with the preventive application of antibiotics for no more
 than 120h; during the follow-up, oral propranolol and ultrasound-guided tissue glue injection
 therapy could be used as secondary prevention according to the patient's condition; (IV) The
 emergency endoscopic team consists of three experienced endoscopists, each with more than ten
 years of experience in endoscopy and over 500 cases of variceal hemostasis under endoscopy.
 Also, there are several seasoned endoscopic nurses included, who have experience in
 endoscopic work for more than five years, are proficient in applying endoscopic treatment
 instruments, and cooperate with endoscopists.

 Follow-up time

 After randomization, the follow-up work will begin. All the patients included will be
 followed up to no less than 42 days after control of AVB. When patients' conditions are
 stable, further treatment of varicose veins should be decided according to their wishes and
 statutory agents. Patients with good compliance will take standard endoscopic treatment every
 3-4 weeks after control of AVB or re-bleeding, and the follow-up time should be once a week;
 patients who decline to accept further treatment are followed up only once a week. The
 follow-up forms could be either by telephone or outpatient review. If the patients are lost
 to follow-up during the follow-up period, the eventual outpatient review or telephone dates
 will be treated as the follow-up endpoints.

 Statistical analysis

 The statistical analyses are performed using SAS software, version 9.4 (SAS Institute).
 Continuous variables are expressed in terms of mean ± standard deviation. Student's t-test
 and Wilcoxon rank-sum test are applied to compare normally and non-normally distributed data,
 respectively. Categorical variables are compared employing Fisher's exact test. The analyses
 for the primary efficacy endpoint of re-bleeding rate within 42 days between the urgent
 endoscopy and non-urgent endoscopy groups are performed in the intention-to-treat population.
 The rates difference and 95% CI of the two groups are calculated with and without the
 randomization stratification factors. Besides, the re-bleeding rates are also estimated using
 the Kaplan-Meier method. The log-rank test is used to compare the difference in mortality and
 re-bleeding rates between the two groups. Cox proportional hazards regression model is used
 to estimate the hazard ratio and 95% CI. A forest plot is employed to analyze risk factors
 affecting mortality and re-bleeding rates. Schoenfeld residual test is applied to verify
 whether the model meets the proportional risk (PH) hypothesis. The secondary efficacy
 endpoints are assessed in the per-protocol population. There is no prespecified plan to
 adjust for multiple comparisons of the secondary efficacy endpoints; the analyses for
 secondary efficacy endpoints should not be used to infer treatment effects. Prespecified
 subgroup analyses include age (≥40 ys or <40 ys), SBP (≥100 mmHg or <100 mmHg), HR (≥120
 beats/min or <120 beats/min), hemoglobin (≥80 g/L or <80 g/L), etc. All the P values are
 two-tailed, and p < 0.05 is considered to be a significant difference.
Inclusion Criteria:

 (I) patients who conform to variceal bleeding under endoscopy; (II) patients who have
 pathological or clinical and imaging evidence according with the diagnosis of cirrhosis;
 (III) clinical symptoms associated with AVB (hematemesis/melena/hematochezia) before
 admission or during hospitalization; (IV) hemodynamically stable before or after initial
 fluid resuscitation.

 Exclusion Criteria:

 (I) pregnancy; (II) lactation period; (III) less than 18 years.