Impact of Nonselective Beta-blocker on Acute Kidney Injury in Cirrhotic Patients With Esophageal Varices (AKI)

We will include patients with EV and EVB. They will be randomized to EVL vs. NSBB for primary prevention And EVL+long-term NSBB vs. EVL+short-term NSBB for secondary prevention. 150 patients will be included in a 3-year period. Primary end-points are formation/progression of ascites, acute kidney injury and survival. The other outcomes such as bleeding, rebleeding, infection and other risk factors will be also analyzed.

Study Overview

• Status: Unknown
• Conditions: Cirrhosis; Acute Kidney Injury; Esophageal Varices
• Intervention / Treatment: Drug: propranolol; Procedure: Esophageal varice ligation; Other: DC propranolol

Detailed Description

Despite advance in the prevention and treatment of esophageal variceal bleeding (EVB), it is still a majorcomplication of portal hypertension with the characteristic of a high mortality around 15~20% after anepisode of hemorrhage. Following development of EV and EVB, ascites and renal dysfunction occurs in a large portion of patients with time. The international consensus suggested use of non-selective beta-blocker(NSBB) to prevent EVB. Long-term use of NSBB was also found to decrease occurrence of encephalopathy and spontaneous bacterial peritonitis (SBP) and extend survival. Until 2010, Dr. Lebrec et al. found use of NSBB might decrease survival in cirrhotic patients with refractory ascites, therefore they suggested discontinued use of NSBB in these patients. The findings lead to a vigorous dispute between hepatologists. In 2011, the reputable team again found use of NSBB might cause post-paracentesis circulatory dysfunction (PPCD) in cirrhotic patients undergoing a large volume paracentesis. Occurrence of PPCD was known to cause acute kidney injury (AKI) and increase mortality. In 2014, Austria investigators found use of NSBB was associated with increased AKI and shortened survival in patients with SBP. Despite the findings of these studies implicated the harmful aspects of NSBB use, a major debate remained because lack of randomized controlled trial some unequal distribution of patients.Taipei Veterans General Hospital is renowned by its high profile research in portal hypertension and its related complications. The current proposal is aimed to clarify the strategy of NSBB use. We will include patients with EV and EVB. They will be randomized to EVL vs. NSBB for primary prevention And EVL+long-term NSBB vs. EVL+short-term NSBB for secondary prevention. 150 patients will be included in a 3-year period. Primary end-points are formation/progression of ascites, acute kidney injury and survival. The other outcomes such as bleeding, rebleeding, infection and other risk factors will be also analyzed.

• Study Type: Interventional
• Enrollment (Anticipated): 170
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ming-Chih Hou, MD; Phone Number: 7500 886-2-28712121; Email: mchou@vghtpe.gov.tw

Study Locations

• Taiwan
  • Taipei, Taiwan, 11217
    • Recruiting
    • Taipei Veterans General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Criteria

Inclusion Criteria:

Age of 20 to 85 years

Cirrhotic patients with esophageal varices regardless of bleeding event or not will be enrolled in this study.

Exclusion Criteria:

Terminal stage HCC/ other malignancy/ Stroke or active sepsis/ Chronic kidney disease stage 4 under renal replacement therapy/ Contraindications to non-selective beta-blockers/ A history of non-selective beta-blockers use, sclerotherapy, banding ligation, transjugular intrahepatic porto-systemic shunt, or shunt surgery/ Serum total bilirubin >10 mg/dL/ Refractory ascites/ Hepato-renal syndrome/ Pregnancy/ Severe heart failure (NYHA Fc III/IV)/ Bronchial asthma or chronic obstructive pulmonary disease/ Second or third degree atrioventricular block/ Severe hypotension/ Refusal to participate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Propranolol alone; TPropranolol 10mg BID initially and titrate dosage every week to achieve 25% drop of heart rate (keep heart rate>55 or systemic blood pressure>90mmHg)	Drug: propranolol; Propranolol 10mg BID initially and titrate dosage every week to achieve 25% drop of heart rate (keep heart rate>55 or systemic blood pressure>90mmHg)
Active Comparator: Esophageal variceal ligation alone; Esophageal variceal ligation every 3-4 weeks to achieve variceal eradication under endoscopy. After eradication, follow-up endoscopy every 3 months and variceal ligation again if recurrence.	Procedure: Esophageal varice ligation; Esophageal variceal ligation every 3-4 weeks to achieve variceal eradication under endoscopy
Experimental: Esophageal variceal ligation(DC inderal after EV eradication); Patients randomized to banding ligation group discontinue propranolol after eradication of esophageal varices.	Other: DC propranolol; Patients randomized to banding ligation group discontinue propranolol after eradication of esophageal varices.
No Intervention: Propranolol(Keep BB after EV eradication); Patients randomized to propranolol group continue propranolol after eradication of esophageal varices.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
overall survival	3 years
Acute kidney injury	3 years
Heparenal syndrome	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
EV bleeding/rebleeding	3 years
Infection rate	3 years

Collaborators and Investigators

• Sponsor: Taipei Veterans General Hospital, Taiwan

Study record dates

Study Major Dates

• Study Start: April 13, 2015
• Primary Completion (Actual): November 5, 2015
• Study Completion (Anticipated): July 30, 2020

Study Registration Dates

• First Submitted: August 29, 2019
• First Submitted That Met QC Criteria: August 29, 2019
• First Posted (Actual): August 30, 2019

Study Record Updates

• Last Update Posted (Actual): September 20, 2019
• Last Update Submitted That Met QC Criteria: September 18, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: portal hypertension, esophageal varices, non-selective beta-blocker, acute kidney injury.
• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Kidney Diseases; Urologic Diseases; Gastrointestinal Diseases; Liver Diseases; Renal Insufficiency; Esophageal Diseases; Hypertension, Portal; Wounds and Injuries; Esophageal and Gastric Varices; Acute Kidney Injury; Varicose Veins; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Propranolol
• Other Study ID Numbers: 2015-04-014A

Drug and device information, study documents

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