The goal of this clinical trial is to evaluate whether carvedilol plus endoscopic variceal ligation (EVL) is more effective for the primary prevention of esophageal variceal bleeding than carvedilol alone in carvedilol non-responders. It will also learn about the safety of carvedilol combined with EVL in patients with cirrhosis.

The main questions it aims to answer are:

Whether carvedilol plus EVL is more effective than carvedilol alone in preventing the first esophageal variceal bleeding in cirrhotic patients unresponsive to carvedilol.

What medical problems do participants have when taking carvedilol or taking carvedilol combined with undergoing EVL? Researchers will compare the efficacy and safety of carvedilol with or without EVL in preventing the first esophageal variceal bleeding in cirrhotic patients unresponsive to carvedilol.

Participants will:

Take carvedilol every day (start from 6.25 mg/d and then titrate to 12.5 mg/d if tolerable) and undergo EVL every 3-4 weeks until variceal eradication followed by regular endoscopic follow-up according to the protocol, or Take carvedilol alone every day (start from 6.25 mg/d and then titrate to 12.5 mg/d if tolerable).

Visit the clinic once every 2-3 months for checkups and tests. Keep a diary of their vital signs (SBP, DBP, and HR) as well as symptoms.

Gastro-esophageal variceal bleeding is a major complication of portal hypertension and carries a high rate of rebleeding and mortality. How to prevent the first esophageal variceal bleeding (EVB) in patients with cirrhosis and portal hypertension has always been a very important issue. According to the latest Baveno VII consensus on the treatment of portal hypertension published in December 2021, nonselective beta-blockers (NSBB) should be used first to prevent decompensation in patients with clinically significant portal hypertension. Endoscopic variceal ligation (EVL) is recommended for compensated patients with high-risk esophageal varices (EVs) who have contraindications or an intolerance to NSBBs.

Carvedilol is a kind of NSBB and has extra intrinsic anti-α1 adrenergic activity. Carvedilol can reduce hepatic venous pressure gradient (HVPG) better than propranolol, and is currently the drug of choice for the primary prevention of EVB in patients with cirrhosis and CSPH. Although the HVPG-lowering effect of carvedilol is stronger than that of propranolol, up to 38-46% patients with CSPH are still carvedilol non-responders. Follow-up upper gastrointestinal endoscopy of these patients may show EVs become larger, more numerous, or have new red color signs, which indicate the increasing risk of EVB. However, studies discussing treatment options for patients with cirrhosis and EVs who do not respond to carvedilol therapy are scarce.

In this project, the investigators will initiate an open-label randomized controlled trial aiming at comparing the efficacy of carvedilol plus EVL or not for the primary prevention of EVB in cirrhotic patients who are carvedilol non-responders. The investigators will also explore if there is any difference between the two groups in terms of other upper gastrointestinal bleeding, non-bleeding liver decompensation (such as new onset/worsening ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome), overall survival, adverse events, tolerability and safety. The investigators will also analyze whether there is a difference of the two groups in preventing the first EVB in patients with varying degrees of cirrhosis who are carvedilol non-responders.

Inclusion Criteria:

- Cirrhotic patients with esophageal varices who, after carvedilol treatment, continue to experience variceal enlargement or develop new red color signs.

Exclusion Criteria:

• Age under 18 or over 90 years.
• History of esophageal variceal bleeding.
• Previous treatment for esophageal varices, including endoscopic variceal ligation, endoscopic sclerotherapy, transjugular intrahepatic portosystemic shunt, or surgery.
• Contraindications to non-selective beta-blockers, including severe atrioventricular block, chronic obstructive pulmonary disease (COPD), asthma, uncontrolled diabetes mellitus, or severe peripheral artery disease.
• Presence of end-stage organ diseases, including hepatocellular carcinoma or other terminal cancers, heart failure, or renal failure.
• Pregnant women.
• Refusal to participate in the study.