Carvedilol as an Adjunct to Endoscopic Cyanoacrylate Injection for Secondary Prophylaxis of Gastric Variceal Bleeding

Carvedilol Plus Endoscopic Cyanoacrylate Injection Versus Endoscopic Cyanoacrylate Injection for Secondary Prophylaxis of Gastric Variceal Bleeding

Gastric variceal obturation is the current endoscopic therapy of choice for gastric variceal bleeding but is associated with a high rebleeding rate. Carvedilol is a potent non-selective β-blocker. The role of carvedilol in the prevention of recurrent gastric variceal bleeding is not studied. This study aimed at evaluating the efficacy of carvedilol as an adjunct to gastric variceal obturation in the secondary prophylaxis of gastric variceal bleeding.

Study Overview

• Status: Completed
• Conditions: Esophageal and Gastric Varices
• Intervention / Treatment: Drug: carvedilol; Drug: cyanoacrylate

Detailed Description

Gastric variceal bleeding is a lethal complication of portal hypertension. The rebleeding rate ranged between 30% to 50% in patients after initial hemostasis. Endoscopic cyanoacrylate injection is currently the choice of endoscopic therapy of acute gastric variceal bleeding and prevention of recurrent bleeding. However, the rebleeding rate is still high in the patients undergoing repeated endoscopic cyanoacrylate injection.

Non-selective β-blockers are frequently used for the secondary prophylaxis of variceal bleeding. In the case of esophageal varices, combination of non-selective β-blockers and endoscopic therapy significantly lowers the rebleeding rate compared with endoscopic therapy alone. However, propranolol failed to decrease the rebleeding rate as an adjunct to endoscopic cyanoacrylate injection and was associated with a higher incidence of adverse effects in gastric variceal bleeding patients. A more potent non-selective β-blocker than propranolol might further decrease portal pressure and decrease the rebleeding rate.

Carvedilol is a potent non-selective β-blocker with both beta and alpha-1 blocker effect. It significantly lowers portal pressure even in propranolol non-responders. However, it is unclear weather carvedilol will play a role in the prevention of recurrent gastric variceal bleeding. The investigators conducted a randomized controlled trial to compare the efficacy of carvedilol combined with endoscopic cyanoacrylate injection with endoscopic cyanoacrylate injection alone in secondary prophylaxis of gastric variceal bleeding.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Kaohsiung, Taiwan, 813
    • Kaohsiung Veterans General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age of 20 to 80 years
• Cirrhotic patients with acute gastric variceal bleeding proven by an endoscopy within 24 h of bleeding
• Stable hemodynamic condition for at least 3 days after cyanoacrylate injection

Exclusion Criteria:

• Previous treatment of gastric varices, including endoscopic therapy, transjugular intrahepatic porto-systemic shunt, or surgery
• Contraindications to non-selective beta-blockers or cyanoacrylate injection
• Serum total bilirubin >10 mg/dL
• Grade III/IV hepatic encephalopathy
• Hepato-renal syndrome
• Severe heart failure (NYHA Fc III/IV)
• Chronic kidney disease under renal replacement therapy
• Refractory ascites
• Malignancy other than hepatocellular carcinoma
• Pregnancy
• Pacemaker use
• Refusal to participate

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cyanoacrylate injection plus carvedilol; The patients undergo repeated endoscopic cyanoacrylate injection every 3-4 weeks until obturation of gastric varices. Oral carvedilol is administrated during the whole study period, starting at 6.25 mg daily and increased until the maximum tolerated dose.	Drug: carvedilol; Oral carvedilol is started after randomization at an initial dose of 6.25 mg daily. Doses are increased every 3 days during the admission or every 7 days in the out-patient clinics until the maximum tolerated dose was achieved or up to 25 mg daily, aiming at reducing resting pulse rate by 25 percent but not below 55 beats per minute with systolic blood pressure >90 mm Hg.; Drug: cyanoacrylate; The patients undergo repeated endoscopic cyanoacrylate injection every 3-4 weeks until obturation of gastric varices.
Active Comparator: Cyanoacrylate injection; The patients undergo repeated endoscopic cyanoacrylate injection every 3-4 weeks until obturation of gastric varices.	Drug: cyanoacrylate; The patients undergo repeated endoscopic cyanoacrylate injection every 3-4 weeks until obturation of gastric varices.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rebleeding From Gastric Varices	Rebleeding from gastric varices during the follow-up period	Within 6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All Upper Gastrointestinal Bleeding	All upper gastrointestinal bleeding during the follow-up period	Within 6 years
All Cause Mortality or Liver Transplantation	All cause mortality or liver transplantation during the study period	Within 6 years
All Adverse Effects	All adverse effects during the study period	Within 6 years

Collaborators and Investigators

• Sponsor: Kaohsiung Veterans General Hospital.
• Investigators: Principal Investigator: Wen-Chi Chen, MD, Kaohsiung Veterans General Hospital.

Publications and helpful links

General Publications

• Chen WC, Hsin IF, Chen PH, Hsu PI, Wang YP, Cheng JS, Lin HS, Hou MC, Lee FY. Addition of Carvedilol to Gastric Variceal Obturation Does Not Decrease Recurrence of Gastric Variceal Bleeding in Patients With Cirrhosis. Clin Gastroenterol Hepatol. 2019 Oct;17(11):2356-2363.e2. doi: 10.1016/j.cgh.2019.02.021. Epub 2019 Feb 14.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2011
• Primary Completion (Actual): February 1, 2017
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: July 18, 2015
• First Submitted That Met QC Criteria: July 20, 2015
• First Posted (Estimate): July 22, 2015

Study Record Updates

• Last Update Posted (Actual): August 21, 2017
• Last Update Submitted That Met QC Criteria: July 27, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: carvedilol; cyanoacrylate; Gastric varices
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Liver Diseases; Esophageal Diseases; Hypertension, Portal; Esophageal and Gastric Varices; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; 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; Carvedilol
• Other Study ID Numbers: VGHKS11-CT10-11

Drug and device information, study documents

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