Carvedilol Plus EVL or Not for the Primary Prevention of Esophageal Variceal Bleeding in Carvedilol Non-responders

Official title

Carvedilol Plus Endoscopic Ligation or Not for the Primary Prevention of Esophageal Variceal Bleeding in Carvedilol Non-responders: a Randomized Controlled Trial

Overview

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.

Detailed description

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.

Interventions

• Other Carvedilol plus endoscopic variceal ligation
  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.
• Drug Carvedilol alone
  Take carvedilol alone every day (start from 6.25 mg/d and then titrate to 12.5 mg/d if tolerable).

Primary outcome measures

• Esophageal variceal bleeding [Time frame: 3 years]

Secondary outcome measures (4)

• Other upper gastrointestinal bleeding [Time frame: 3 years]
• First/further nonbleeding liver decompensation [Time frame: 3 years]
• Overall survival [Time frame: 3 years]
• Adverse events [Time frame: 3 years]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Taiwan · 1 center

• Taipei Veterans General Hospital — Taipei

Publications

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• Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009 Mar;50(3):604-20. doi: 10.1016/j.jhep.2008.12.011. Epub 2008 Dec 31. PMID 19157625
• Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology. 2004 Mar;126(3):886-94. doi: 10.1053/j.gastro.2003.12.012. PMID 14988842
• Schubert K, Olde Damink SWM, von Bergen M, Schaap FG. Interactions between bile salts, gut microbiota, and hepatic innate immunity. Immunol Rev. 2017 Sep;279(1):23-35. doi: 10.1111/imr.12579. PMID 28856736
• Wahlstrom A, Sayin SI, Marschall HU, Backhed F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab. 2016 Jul 12;24(1):41-50. doi: 10.1016/j.cmet.2016.05.005. Epub 2016 Jun 16. PMID 27320064
• Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes. 2013 Sep-Oct;4(5):382-7. doi: 10.4161/gmic.25723. Epub 2013 Jul 12. PMID 23851335
• Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol. 2014 Jan;60(1):197-209. doi: 10.1016/j.jhep.2013.07.044. Epub 2013 Aug 28. No abstract available. PMID 23993913
• Baffy G. Potential mechanisms linking gut microbiota and portal hypertension. Liver Int. 2019 Apr;39(4):598-609. doi: 10.1111/liv.13986. Epub 2018 Nov 9. PMID 30312513

Identifiers

NCT: NCT06594783 · 2024-08-017A

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗