Liver Cirrhosis, Portal Hypertension, Gastroesophageal Varices Bleeding, Esophageal Varices, Hepatic Encephalopathy
Conditions
Keywords
Cirrhosis, Portal hypertension, Esophageal variceal bleeding, Secondary prophylaxis, Transjugular intrahepatic portosystemic shunt, Underdilation, Endoscopic variceal ligation, Hepatic encephalopathy
Brief summary
Variceal bleeding is a major complication of portal hypertension in patients with cirrhosis and is associated with substantial risks of rebleeding and death. Current guidelines recommend endoscopic variceal ligation combined with nonselective beta-blockers as standard secondary prophylaxis for esophageal variceal bleeding and type 1 gastroesophageal variceal bleeding. Transjugular intrahepatic portosystemic shunt can markedly reduce portal pressure and prevent recurrent variceal bleeding, but its broader use in secondary prophylaxis is limited by the risk of post-TIPS hepatic encephalopathy and liver function deterioration. The VIATORR Controlled Expansion stent is designed to allow controlled expansion between 8 and 10 mm. However, even 8-mm TIPS may still be associated with a substantial risk of overt hepatic encephalopathy. This trial evaluates an underdilated VCX-TIPS strategy, in which a commercially available 8-10 mm VIATORR Controlled Expansion stent is initially dilated only with a 6-mm balloon, aiming to achieve sufficient portal decompression while reducing the risk of excessive shunting. This is a prospective, multicenter, open-label, parallel-group, randomized superiority trial. Eligible patients with cirrhosis who have recovered from acute esophageal variceal bleeding or type 1 gastroesophageal variceal bleeding and have entered the secondary prophylaxis phase will be randomly assigned in a 1:1 ratio to receive either underdilated VCX-TIPS or endoscopic variceal ligation plus nonselective beta-blockers. The primary outcome is the composite of all-cause death or clinically significant upper gastrointestinal rebleeding within 1 year after randomization.
Detailed description
This multicenter randomized controlled trial is designed to compare an underdilated VCX-TIPS strategy with standard secondary prophylaxis using endoscopic variceal ligation plus nonselective beta-blockers in patients with cirrhosis who have experienced esophageal variceal bleeding or type 1 gastroesophageal variceal bleeding. Patients with cirrhosis aged 18 to 75 years who have achieved successful control of acute variceal bleeding and are clinically stable will be screened. Eligible participants will be randomized after written informed consent has been obtained, generally between 5 and 21 days after successful hemostasis. Patients with ongoing bleeding, hemodynamic instability, a need for immediate rescue TIPS, or a strong indication for early or pre-emptive TIPS that makes randomization to EVL plus NSBB inappropriate will be excluded. Participants assigned to the experimental group will undergo TIPS using a commercially available 8-10 mm VIATORR Controlled Expansion stent. After stent deployment, the stent will be initially dilated only with a 6-mm balloon to achieve an initial effective shunt diameter of approximately 6 mm. Further dilation to 8 mm will not be performed solely because the portal pressure gradient remains above 12 mmHg. Additional dilation will be allowed only under predefined rescue conditions, such as persistent active bleeding, inadequate reduction of portal pressure gradient with persistent high-risk collateral perfusion despite embolization, or clinically significant rebleeding during follow-up. Selective embolization of responsible variceal inflow vessels may be performed according to standardized local procedures. Participants assigned to the control group will receive standard secondary prophylaxis with serial endoscopic variceal ligation and nonselective beta-blockers. Endoscopic variceal ligation will be repeated approximately every 4 weeks until variceal eradication or conversion to a low-risk status. Carvedilol will be the preferred nonselective beta-blocker, starting at 6.25 mg once daily and increasing to 12.5 mg once daily after 1 week if tolerated. Propranolol may be used if carvedilol is not tolerated or is clinically inappropriate. The primary endpoint is the time from randomization to the first occurrence of all-cause death or clinically significant upper gastrointestinal rebleeding within 365 days. Key secondary outcomes include transplant-free survival, overall survival, liver-related mortality, clinically significant rebleeding, variceal-related rebleeding, overt hepatic encephalopathy, severe overt hepatic encephalopathy, acute-on-chronic liver failure, liver function deterioration, TIPS dysfunction, actual stent diameter at 3 months, unplanned rehospitalization, length of hospital stay, transfusion requirement, direct medical costs, and adverse events. Participants will be followed for 12 months for the primary analysis and up to 24 months for extended secondary outcome analyses.
Interventions
PROCEDUREUnderdilated VCX-TIPS
Transjugular intrahepatic portosystemic shunt will be created using a VIATORR Controlled Expansion 8-10 mm stent. The stent will initially be dilated only with a 6-mm balloon. Portal pressure gradient will be measured before and after shunt creation. Additional embolization of responsible variceal inflow vessels may be performed if clinically indicated. Further dilation to 8 mm will be reserved for predefined rescue situations.
PROCEDUREEndoscopic Variceal Ligation
Serial endoscopic variceal ligation will be performed according to standardized endoscopic procedures. EVL will be repeated approximately every 4 weeks until variceal eradication or conversion to a low-risk status. For type 1 gastroesophageal varices with substantial gastric extension or high-risk bleeding stigmata, endoscopic tissue adhesive injection may be performed according to local standardized procedures.
DRUGNonselective Beta-Blockers
Carvedilol will be the preferred nonselective beta-blocker, starting at 6.25 mg once daily and increasing to 12.5 mg once daily after 1 week if tolerated. Dose adjustment, temporary discontinuation, or switching to propranolol will be allowed according to heart rate, blood pressure, renal function, infection status, and overall tolerability.
Sponsors
West China Hospital
West China Xiamen Hospital
West China Tianfu Hospital
Southwest Hospital, China
The Second Affiliated Hospital of Chongqing Medical University
The Second Affiliated Hospital of Kunming Medical University
Chongqing Qianjiang Central Hospital
Chengdu Shangjin Nanfu Hospital
Study design
Allocation
NA
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 75 years, regardless of sex. * Diagnosis of liver cirrhosis based on previous histology, imaging, laboratory tests, and/or clinical manifestations. * Hospitalization for acute upper gastrointestinal bleeding, with endoscopic confirmation that the bleeding is related to esophageal varices or type 1 gastroesophageal varices. * Successful control of acute bleeding after standard acute-phase treatment, with stable vital signs and entry into the secondary prophylaxis phase. * Child-Pugh score of 5 to 13. * The investigator judges that both underdilated VCX-TIPS and EVL plus NSBB are clinically feasible and that randomization is appropriate. * The participant or legally authorized representative understands the study procedures and voluntarily signs written informed consent.
Exclusion criteria
* Hemodynamic instability, persistent active bleeding, or need for immediate rescue TIPS, surgical hemostasis, or interventional radiologic hemostasis. * A strong current indication for early or pre-emptive TIPS that makes randomization to EVL plus NSBB clinically inappropriate. * Child-Pugh score greater than 13. * Previous TIPS, surgical portosystemic shunt, BRTO, CARTO, PARTO, or other procedures that substantially alter portosystemic blood flow. * Isolated gastric varices, type 2 gastroesophageal varices, ectopic varices, or a bleeding source other than esophageal varices or type 1 gastroesophageal varices. * Non-cirrhotic portal hypertension. * Cavernous transformation of the portal vein or portal venous thrombosis that makes standardized TIPS technically infeasible. * Previous recurrent or refractory overt hepatic encephalopathy, or a history of West Haven grade II to IV overt hepatic encephalopathy unrelated to gastrointestinal bleeding. * Severe heart failure, severe pulmonary hypertension, severe tricuspid regurgitation, right heart failure, or other contraindications to TIPS. * Uncontrolled severe infection, sepsis, or multiple organ failure. * Hepatocellular carcinoma beyond the Milan criteria or other advanced malignancy. * Severe renal insufficiency requiring long-term renal replacement therapy. * Pregnancy or breastfeeding. * Absolute contraindication to EVL, NSBB, or TIPS. * Any condition that, in the investigator's judgment, makes the participant unsuitable for the study or unable to complete follow-up.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of All-Cause Death or Clinically Significant Upper Gastrointestinal Rebleeding | From randomization to 1 year | Time from randomization to the first occurrence of all-cause death or clinically significant upper gastrointestinal rebleeding. Clinically significant upper gastrointestinal rebleeding is defined as hematemesis, melena, fresh blood from a nasogastric tube, or endoscopically documented bleeding resulting in hospitalization, blood transfusion, a decrease in hemoglobin of at least 30 g/L, hemodynamic instability, urgent endoscopic, interventional radiologic, or surgical hemostatic therapy, or bleeding-related death. The rebleeding event does not have to be confirmed as variceal in origin for the primary endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transplant-Free Survival | From randomization to 12 and 24 months | Time from randomization to death from any cause or liver transplantation, whichever occurs first. |
| Liver-Related Mortality | From randomization to 12 and 24 months | Death attributed to liver-related causes, including variceal bleeding, liver failure, acute-on-chronic liver failure, infection related to cirrhosis decompensation, hepatorenal syndrome, or other cirrhosis-related complications. |
| Clinically Significant Upper Gastrointestinal Rebleeding | From randomization to 42 days, 90 days, 180 days, 365 days, and 24 months | Occurrence of clinically significant upper gastrointestinal rebleeding, regardless of whether the bleeding source is confirmed as variceal. |
| Variceal-Related Rebleeding | From randomization to 42 days, 90 days, 180 days, 365 days, and 24 months | Upper gastrointestinal rebleeding adjudicated as related to esophageal varices, type 1 gastroesophageal varices, post-EVL ulceration, portal hypertension-related lesions, or TIPS dysfunction. |
| Overt Hepatic Encephalopathy | From randomization to 12 and 24 months | Occurrence of overt hepatic encephalopathy, defined as West Haven grade II to IV hepatic encephalopathy. |
| Acute-on-Chronic Liver Failure | From randomization to 12 and 24 months | Occurrence of acute-on-chronic liver failure, defined according to the EASL-CLIF criteria. |
| TIPS Dysfunction | From TIPS placement to 3 months, 12 months, and 24 months | For participants in the TIPS group, TIPS dysfunction is defined as TIPS occlusion, significant stenosis, abnormal TIPS flow velocity associated with clinical recurrence, or the need for balloon dilation, stent revision, TIPS reduction, TIPS occlusion, or parallel TIPS placement. |
| Actual Stent Diameter at 3 Months | 3 months after TIPS placement | For participants in the TIPS group, actual stent diameter will be assessed by contrast-enhanced CT at 3 months. The imaging core laboratory will measure the minimum and mean diameters of the controlled expansion segment using centerline reconstruction and cross-sectional measurements perpendicular to the stent axis. |
| Adverse Events | From randomization to 24 months | Incidence, severity, relationship to study intervention, management, and outcome of adverse events and serious adverse events. |
Countries
China
Contacts
CONTACTXiaoze Wang, MD
Outcome results
None listed