Carvedilol vs. Propranolol in Second Prophylaxis of Variceal Bleeding

Randomized Controlled Trial on the Effectiveness and Safety of Carvedilol vs. Propranolol Combined With Endoscopic Treatment in Second Prophylaxis of Variceal Bleeding in Cirrhosis

This randomized controlled trial was conducted to evaluate the efficacy and safety of carvedilol versus propranolol, combined with routine endoscopic treatment, in the secondary prophylaxis of variceal bleeding in patients with cirrhosis.

Study Overview

• Status: Not yet recruiting
• Conditions: Portal Hypertension; Cirrhosis, Liver; Varice Bleed
• Intervention / Treatment: Drug: Carvedilol; Drug: Propranolol

Detailed Description

Non-selective beta blockers combined with endoscopic variceal band ligation (EVL) is the most effective methods for the prevention of variceal bleeding. Carvedilol has emerged as the preferred NSBB for treating portal hypertension in compensated cirrhosis due to strong evidence demonstrating that it has a more pronounced effect than propranolol to reduce the hepatic vein pressure gradient (HVPG), together with good patient acceptability and safety profile. However, No data from prospectively designed trials are available on the efficacy of carvedilol in the secondary prophylaxis of variceal bleeding. The aim of this randomized controlled trial was to evaluate the effectiveness and safety of carvedilol compared to propranolol as secondary prophylaxis of variceal bleeding in patients with cirrhosis. All cirrhotic patients with at least one episode of variceal bleeding were included and randomized to the carvedilol or propranolol groups. EVL protocol was routinely performed in both groups. Variceal rebleeding, further decompensation, liver-related death, and overall survival was the outcomes of this trial.

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xuefeng Luo, M.D.; Phone Number: +8613880098212; Email: luo_xuefeng@wchscu.cn
• Study Contact Backup: Name: Xiaoze Wang, M.D.; Phone Number: +8615208207573; Email: wang_xiaoze@wchscu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Between 18 and 80 years old;
• With liver cirrhosis diagnosed by previous biopsy or by clinical criteria, and analytical image;
• At least 5 days after index variceal bleeding;
• Informed consent.

Exclusion Criteria:

• Refusal to participate in the study;
• Portal hypertension resulting from other causes than liver cirrhosis;
• More than 42 days after index variceal bleeding;
• Bleeding from cardiofundal gastric varices;
• Portal venous thrombosis >50% of the portal vein trunk;
• Contraindications to beta-blockers (asthma, chronic obstructive pulmonary disease, atrioventricular block, heart failure, bradycardia with HR ≤40 bpm, arteria hypotension with systolic blood pressure <90 mm Hg, peripheral arterial disease, uncontrolled diabetes);
• Prior NSBB+EVL combined treatment, TIPS implantation or surgical shunt as secondary prophylaxis of variceal bledding;
• Chronic kidney disease;
• Pregnancy or lactation;
• Neoplastic disease.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carvedilol; Carvedilol is started at a dose of 6.25mg/d, and titrated to a maximum dose of 12.5mg/d. Doses are increased 3 days later. Avoid systolic blood pressure <90 mmHg.	Drug: Carvedilol; Carvedilol is started at a dose of 6.25mg/d, and titrated to a maximum dose of 12.5mg/d. Doses are increased 3 days later. Avoid systolic blood pressure <90 mmHg.; Other Names: carvedilol as the nonselective beta-blockers
Active Comparator: Propranolol; Propranolol is started at a dose of 20 mg/d and the dose will be increased by 10 mg twice a day steps every 2-3 days until the target (heart rate: 55~60 bpm) or to a maximum dose of 160 mg/d. Systolic arterial pressure is not less than 90 mm Hg and heart rate is not less than 50 bpm.	Drug: Propranolol; Propranolol is started at a dose of 20 mg/d and the dose will be increased by 10 mg twice a day steps every 2-3 days until the target (heart rate: 55~60 bpm) or to a maximum dose of 160 mg/d. Systolic arterial pressure is not less than 90 mm Hg and heart rate is not less than 50 bpm.; Other Names: propranolol as the nonselective beta-blockers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variceal rebleeding rate	Acute variceal rebleeding rate at 1 year	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Further decompensation rate	This is a composite outcome that refers to rate of all further liver decompensation events at 1 year, including variceal rebleeding, recurrent or developement of ascites (grade≥2), overt hepatic encephalopathy, spontaneous bacterial peritonitis, acute kidney injury, acute-on-chronic liver failure, and liver-related death.	1 year
Adverse events	Hypotension (systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg), development of acute kidney injury/ hepatorenal syndrome, hyponatremia, weakness, shortness of breath, dizziness, gastrointestinal symptoms (nausea, constipation), or sexual and erectile dysfunction.	1 year
Transplant-free survival rate	The transplant-free survival rate at 1 year	1 year

Collaborators and Investigators

• Sponsor: West China Hospital
• Collaborators: Chengdu Shangjin Nanfu Hospital; West China Tianfu Hospital
• Investigators: Principal Investigator: Xuefeng Luo, M.D., West China Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: November 21, 2022
• First Submitted That Met QC Criteria: December 14, 2022
• First Posted (Estimate): December 15, 2022

Study Record Updates

• Last Update Posted (Estimate): December 15, 2022
• Last Update Submitted That Met QC Criteria: December 14, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; Hypertension, Portal; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Protective Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Propranolol; Carvedilol; Adrenergic beta-Antagonists
• Other Study ID Numbers: NSBB-RVB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No