TIPS vs. NSBB Plus Endotherapy for the Prevention of Variceal Rebleeding in NSBB Non-responders of Primary Prophylaxis

Variceal bleeding (VB) is a life-threatening complication of cirrhosis with a 6-week mortality of approximately 15%-20%. The 1-year rate of recurrent VB is approximately 60% in patients without prophylaxis treatment. Therefore, all patients who survive VB must receive active treatments to prevent rebleeding. Usually, these patients are submitted to rebleeding prophylaxis with endoscopic band ligation (EBL) combined with non-selective beta-blockers (NSBB). Transjugular intrahepatic portosystemic shunts (TIPS) are reserved for those who failed endoscopic plus medical treatment.

A recent meta-analysis comparing combination therapy to monotherapy with EBL or drug therapy has demonstrated that combination therapy is only marginally more effective than NSBB alone. This suggests that NSBB is the cornerstone of combination therapy. The lowest rebleeding rates are observed in patients on secondary prophylaxis who are hepatic venous pressure gradient (HVPG) responders (defined as a reduction in HVPG below 12 mm Hg or > 20% from baseline). A recent study demonstrated that patients who have their first episode of variceal bleeding while on primary prophylaxis with NSBB have an increased risk of further bleeding and death, despite adding EBL. These patients possibly require alternative treatment approaches, such as TIPS.

The aim of the present study was to compare the effect of TIPS vs. EBL + NSBB for the prevention of rebleeding in NSBB non-responder for primary prophylaxis.

Study Overview

• Status: Unknown
• Conditions: Liver Cirrhosis; Variceal Hemorrhage; TIPS; NSBB
• Intervention / Treatment: Procedure: Transjugular intrahepatic portosystemic shunts; Other: Nonselective β-blocker (NSBB)+ endoscopic band ligation (EBL)

• Study Type: Interventional
• Enrollment (Anticipated): 114
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hui Chen, M.D.,Ph.D.; Phone Number: +862984771537; Email: qychenhui@163.com
• Study Contact Backup: Name: Jun Tie, Professor; Phone Number: +862984771537; Email: tiejun7776@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of liver cirrhosis
• Standard NSBB therapy was used for primary prophylaxis
• At least 5 days after index variceal bleeding
• Child-Pugh score <13, Model for end-stage liver disease score < 19

Exclusion Criteria:

• Gastric variceal bleeding (GOV2，IGV1，IGV2)
• History of shunt surgery
• Degree of portal vein thrombosis > 50%
• Refractory ascites
• Budd-Chiari syndrome
• Hepatocellular carcinoma or other malignant tumors
• Uncontrolled infection
• HIV
• Pregnant or breast-feeding woman
• Poor compliance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: TIPS; Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure that uses imaging guidance to connect the portal vein to the hepatic vein in the liver.	Procedure: Transjugular intrahepatic portosystemic shunts; Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure that uses imaging guidance to connect the portal vein to the hepatic vein in the liver. A small metal device called a stent is placed to keep the connection open and allow it to bring blood draining from the bowel back to the heart. TIPS may successfully reduce internal bleeding in the stomach and esophagus in patients with cirrhosis and may also reduce the accumulation of fluid in the abdomen (ascites).
ACTIVE_COMPARATOR: NSBB+EBL; Participants randomized to this group will receive the combination therapy of non-selective beta-blocker (NSBB) and endoscopic band ligation (EBL) . NSBB, including propranolol and carvidilol, will be started at day 5 after the index bleeding and elective EBL sessions started 2 weeks after the index bleeding.	Other: Nonselective β-blocker (NSBB)+ endoscopic band ligation (EBL); Combination therapy of nonselective β-blocker (NSBB) and endoscopic variceal ligation (EBL) will be used for participants in this group. NSBB, which will be titrated to the maximum tolerated dose aiming to decrease the heart rate by 25%, with a lower limit of 50 beats per minute, was started at day 5 after the index bleeding, unless a contraindication was present (severe arrhythmia, severe obstructive chronic obstructive pulmonary disease, or known intolerance). Endoscopic variceal ligation sessions started 2 weeks after the index bleeding and were performed every 2-4 weeks thereafter until eradication of varices, followed by endoscopic surveillance and retreatment, if indicated, every 6-12 months.; Other Names: Combination therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of clinically significant variceal rebleeding	Recurrent melena or hematemesis resulting in either hospital admission, blood transfusion, drop in hemoglobin of at least 3 g/L, or death within 6 weeks after rebleeding.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of variceal bleeding related mortality	Death due to variceal bleeding	12 months
Cumulative incidence of all cause mortality	Including liver related and non-liver related death	12 months
Cumulative incidence of hepatic encephalopathy (HE)	HE was evaluated and classified according to West-Haven criteria	12 months
Cumulative incidence of adverse events (AE)	All kinds of adverse events	12 months

Collaborators and Investigators

• Sponsor: Air Force Military Medical University, China

Publications and helpful links

General Publications

• de Souza AR, La Mura V, Reverter E, Seijo S, Berzigotti A, Ashkenazi E, Garcia-Pagan JC, Abraldes JG, Bosch J. Patients whose first episode of bleeding occurs while taking a beta-blocker have high long-term risks of rebleeding and death. Clin Gastroenterol Hepatol. 2012 Jun;10(6):670-6; quiz e58. doi: 10.1016/j.cgh.2012.02.011. Epub 2012 Feb 22. Erratum In: Clin Gastroenterol Hepatol. 2014 Jun;12(6):1056.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): June 1, 2020
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): December 31, 2022

Study Registration Dates

• First Submitted: November 27, 2019
• First Submitted That Met QC Criteria: December 19, 2019
• First Posted (ACTUAL): December 20, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 5, 2020
• Last Update Submitted That Met QC Criteria: February 2, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Hemorrhage; Liver Cirrhosis; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic beta-Antagonists
• Other Study ID Numbers: KY20192149-C-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No