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

Study Overview
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Brief Summary
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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.

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

Conditions
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Variceal Hemorrhage, TIPS, NSBB, Liver Cirrhosis

Intervention / Treatment
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* Procedure: Transjugular intrahepatic portosystemic shunts
* Other: Nonselective β-blocker (NSBB)+ endoscopic band ligation (EBL)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TIPS<br>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<br>* 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).<br>|
| Active Comparator: NSBB+EBL<br>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)<br>* 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.<br>* Other names: Combination therapy;|

What is the study measuring?
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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 |