HVPG-guided Laparoscopic Versus Endoscopic Therapy for Variceal Rebleeding in Portal Hypertension: A Multicenter Randomized Controlled Trial (CHESS1803)

Study Overview
=================
Brief Summary
-----------------
The development of portal hypertension is a vital event in the natural progression of cirrhosis and is associated with severe complications including gastroesophageal varices bleeding. Cirrhotic patients with hemorrhagic shock and/or liver failure caused by variceal bleeding face a mortality of 5-20%. Hepatic venous pressure gradient (HVPG) is the recommended golden standard for portal pressure assessment globally with favorable consistency and repeatability. Reducing the HVPG to levels of 12mmHg or below is associated with protection of variceal hemorrhage. An HVPG> 16mmHg indicates a higher risk of death and HVPG ≥ 20mmHg predicts failure to control bleeding, early rebleeding, and death during acute variceal hemorrhage. The management of portal hypertension has showed a trend of diversification with the development of medication, endoscopy, radiological intervention and liver transplantation. Although medication and endoscopic therapy have achieved preferable effects and are recommended as standard of care for the prevention of variceal rebleeding, patients with HVPG≥ 16mmHg still have a high risk of treatment failure and a high rate of rebleeding. Recent years, early TIPS is recommended as the first-line therapy for the prevention of rebleeding in cirrhotic patients with HVPG≥ 20mmHg. However, for those with HVPG values between 16 to 20mmHg, there is still lack of strong evidence to demonstrate the best practice for the management. With the rapid advancement of laparoscopic device and technique, the utility of laparoscopic splenectomy and pericardial devascularization showed less surgical trauma, bleeding and complications while retaining dependable effects compared to traditional open surgery, especially for portal hypertension with hypersplenism. In the study, the investigators aim to conduct a multicenter randomized controlled trial to compare the safety and effectiveness of HVPG-guided (16 to 20mmHg) laparoscopic versus endoscopic therapy for variceal rebleeding in patients with portal hypertension.

Detailed Description
-----------------
The development of portal hypertension is a vital event in the natural progression of cirrhosis and is associated with severe complications including gastroesophageal varices bleeding. Cirrhotic patients with hemorrhagic shock and/or liver failure caused by variceal bleeding face a mortality of 5-20%. Hepatic venous pressure gradient (HVPG) is the recommended golden standard for portal pressure assessment globally with favorable consistency and repeatability. Reducing the HVPG to levels of 12mmHg or below is associated with protection of variceal hemorrhage. An HVPG> 16mmHg indicates a higher risk of death and HVPG ≥ 20mmHg predicts failure to control bleeding, early rebleeding, and death during acute variceal hemorrhage. The management of portal hypertension has showed a trend of diversification with the development of medication, endoscopy, radiological intervention and liver transplantation. Although medication and endoscopic therapy have achieved preferable effects and are recommended as standard of care for the prevention of variceal rebleeding, patients with HVPG≥ 16mmHg still have a high risk of treatment failure and a high rate of rebleeding. Recent years, early TIPS is recommended as the first-line therapy for the prevention of rebleeding in cirrhotic patients with HVPG≥ 20mmHg. However, for those with HVPG values between 16 to 20mmHg, there is still lack of strong evidence to demonstrate the best practice for the management. With the rapid advancement of laparoscopic device and technique, the utility of laparoscopic splenectomy and pericardial devascularization showed less surgical trauma, bleeding and complications while retaining dependable effects compared to traditional open surgery, especially for portal hypertension with hypersplenism. In the study, the investigators aim to conduct a multicenter (Shunde Hospital of Southern Medical University, Xingtai People's Hospital, The Fifth Medical Center of Chinese PLA General Hospital, The First Hospital of Lanzhou University) randomized controlled trial to compare the safety and effectiveness of HVPG-guided (16 to 20mmHg) laparoscopic versus endoscopic therapy for variceal rebleeding in patients with portal hypertension.

Official Title
-----------------
HVPG-guided Laparoscopic Versus Endoscopic Therapy for Variceal Rebleeding in Portal Hypertension: A Multicenter Randomized Controlled Trial (CHESS1803)

Conditions
-----------------
Portal Hypertension, Variceal Rebleeding

Intervention / Treatment
-----------------
* Drug: Propranolol
* Procedure: Laparoscopic splenectomy and pericardial devascularization
* Procedure: Endoscopic therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinically and/or pathologically diagnosed cirrhosis with portal hypertension History of varicial bleeding without receiving endoscopic treatment HVPG values between 16-20 mmHg ECOG score ≤ 2 or KPS score ≥ 60 during screening Voluntarily participated in the study and able to provide written informed consent, understand and willing to comply with the requirements of the study Child-Pugh class A or B Exclusion Criteria: Pregnant or breastfeeding women Prior known or suspected malignancy (hepatocellular carcinoma, cholangiocarcinoma etc.) Limited coagulation situation (Quick< 50%, PTT> 50 sec, thrombocyte count <50000 / μl or disturbed thrombocyte function) Massive ascites Child-Pugh class C Refuse or inadequate for HVPG measurement Other situations whose existence judged inadequate for participation by the investigators

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Procedure: Laparoscopic splenectomy and pericardial devascularization Drug: Propranolol | Drug: Propranolol<br>* Propranolol was administrated orally while keeping monitoring heart rate and blood pressure daily.<br>Procedure: Laparoscopic splenectomy and pericardial devascularization<br>* Including splenectomy and pericardial devascularizaion under laparoscopy<br>|
| Active Comparator: Control group<br>Procedure: Endoscopic therapy Drug: Propranolol | Drug: Propranolol<br>* Propranolol was administrated orally while keeping monitoring heart rate and blood pressure daily.<br>Procedure: Endoscopic therapy<br>* Either endoscopic variceal ligation (EVL) or cyanoacrylate injection was applied according to the condition of varices<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variceal rebleeding | The occurrence rate of gastroesophageal varices rebleeding within 1-year follow-up | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The number of participants still alive 1 year after the therapy | 1 year | 
| Hepatocellular carcinoma occurrence | The occurrence rate of hepatocellular carcinoma 1 year after the therapy | 1 year | 
| Venous thrombosis | The occurrence rate of venous thrombosis upon each follow-up | 1 year | 
| Quality of life score | The quality of life score measured using the 36-item Short Form Health Survey (SF-36) questionnaire upon each follow-up. | 1 year | 
| Karnofsky score | The Karnofsky score categorized into low (score 10-40), intermediate (50-70), and high (80-100) upon each follow-up. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Variceal Rebleeding, Hepatic venous pressure gradient, Laparoscopic Therapy, Endoscopic Therapy