Timing of Endoscopic Intervention for Acute Variceal Hemorrhage: an RCT

Summary

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Description

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 implemen...

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 acute variceal bleeding (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 April 2021 and December 2023. Original Glasgow-Blatchford Score is used to evaluate the condition of each patient instead of a 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 ? 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 pulse rate. 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 the 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 ?g/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 ?g/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 (?60 ys or <60 ys), SBP (?90 mmHg or <90 mmHg), pulse rate (?100 beats/min or <100 beats/min), etc. All the P values are two-tailed, and p < 0.05 is considered to be a significant difference.

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