Impact of Propranolol on the Prognosis of Patients With Decompensated Cirrhosis and MELD Score > 9

Official title

Impact of Propranolol on the Prognosis of Patients With Decompensated Cirrhosis and MELD Score > 9: a Non-inferiority Randomized Controlled Trial

Overview

Non selective beta blockers (NSBBs), such as propranolol and nadolol, are mainstay therapies for portal hypertension in cirrhosis, but their efficacy and safety vary depending on the stage of the disease. Emerging evidence suggests that NSBBs may worsen the prognosis of advanced cirrhosis, especially in patients with a model for end-stage liver disease (MELD) score of \>9. The purpose of this randomized controlled trial is to evaluate the effects of the use of propranolol as recommended by the guideline on the prognosis in cirrhotic patients with a MELD score of \>9.

Detailed description

This is a non-inferiority, randomized controlled trial. A total of 466 decompensated cirrhotic patients with a MELD score of \>9 will be enrolled. Participants will be stratified based on the presence or absence of acute decompensation at enrollment, and then randomly assigned at a 1:1 ratio to conventional treatment combined with or without propranolol groups. All patients will receive standard medical therapy in both groups, and then regularly followed. The primary outcome is further decompensation. The secondary outcomes include recompensation and death.

Interventions

• Other conventional therapy
  Conventional treatment of decompensated cirrhosis mainly includes anti-hepatic fibrosis drugs, albumin infusion, diuretics, peritoneal drainage, esophageal variceal ligation, endoscopic tissue adhesive injection, blood purification, and liver transplantation.
• Drug propranolol
  Propranolol will be started with 10-20 mg/day for the propranolol group, which will be gradually increased to the maximum tolerance dosage or achieve a heart rate of 55-60 beats per minute and a systolic blood pressure of 90mmHg.

Primary outcome measures

• The time from randomization to the occurrence of further decompensation [Time frame: Time to first further decompensation event, assessed from randomization up to the end of the study (maximum of approximately 96 weeks)]

Secondary outcome measures (5)

• The time from randomization to the occurrence of recompensation [Time frame: Time to first recompensation event, assessed from randomization up to the end of the study (maximum of approximately 96 weeks)]
• The time from randomization to the occurrence of death [Time frame: assessed from randomization up to the end of the study (maximum of approximately 96 weeks)]
• The composite endpoint of further decompensation and death [Time frame: assessed from randomization up to the end of the study (maximum of approximately 96 weeks)]
• The hierarchical composite endpoint of death and further decompensation [Time frame: assessed from randomization up to the end of the study (maximum of approximately 96 weeks)]
• The time from randomization to the occurrence of individual decompensation events [Time frame: assessed from randomization up to the end of the study (maximum of approximately 96 weeks]

Eligibility criteria

Inclusion criteria

• patients' age ≥18 years;
• patients with a definitive diagnosis of liver cirrhosis;
• patients with a MELD score of >9;
• patients with a history of decompensation or those who are experiencing their first decompensation, such as ascites, variceal bleeding, or hepatic encephalopathy (HE);
• patients' informed consents.

Exclusion criteria

• patients without a definite indication for NSBBs;
• patients with an absolute contraindication of NSBBs (severe bronchospasm, asthma, severe psychosis, high-degree atrioventricular block, etc.);
• patients with hypersensitivity to NSBBs;
• patients who had been treated with NSBBs before 2 weeks of enrollment;
• patients with occlusive portal vein thrombosis;
• patients who had undergone liver transplantation;
• patients who had undergone transjugular intrahepatic portosystemic shunt (TIPS);
• patients with a definitive diagnosis of hepatocellular carcinoma;
• patients with an estimated life time of <12 months due to the presence of any comorbidities;
• patients who are currently pregnant or breast-feeding.

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

China · 1 center

• Department of Gastroenterology, General Hospital of Northern Theater Command (formerly cal — Shenyang

Publications

• Alvarado-Tapias E, Ardevol A, Garcia-Guix M, Montanes R, Pavel O, Cuyas B, Graupera I, Brujats A, Vilades D, Colomo A, Poca M, Torras X, Guarner C, Concepcion M, Aracil C, Torres F, Villanueva C. Short-term hemodynamic effects of beta-blockers influence survival of patients with decompensated cirrhosis. J Hepatol. 2020 Oct;73(4):829-841. doi: 10.1016/j.jhep.2020.03.048. Epub 2020 Apr 13. PMID 32298768
• Serste T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, Moreau R, Lebrec D. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology. 2010 Sep;52(3):1017-22. doi: 10.1002/hep.23775. PMID 20583214
• Wang T, Wang X, Jia S, Zhao H, Wang L, Zhang X, Fang X, He Y, Li H, Tacke F, Qi X. Impact of non-selective beta blockers on further decompensation and death in decompensated cirrhosis: Benefit and risk stratification by MELD score. Aliment Pharmacol Ther. 2024 Nov;60(10):1409-1420. doi: 10.1111/apt.18261. Epub 2024 Sep 19. PMID 39300691
• Cales P, Bertrais S, Boursier J, Fouchard I, Oberti F; SNIFF 16 group. Non-selective beta-blockers increase overall and liver mortality in alcoholic cirrhosis with MELD >/= 12 over 5 years of follow-up. Liver Int. 2021 Jan;41(1):168-179. doi: 10.1111/liv.14674. PMID 32979020
• Tittanegro T, China L, Forrest E, Kallis Y, Ryder SD, Wright G, Freemantle N, O'Brien A. Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: Data from the ATTIRE trial. EClinicalMedicine. 2022 Nov 14;55:101716. doi: 10.1016/j.eclinm.2022.101716. eCollection 2023 Jan. PMID 36407574

Identifiers

NCT: NCT07652203 · XHNKKY-NSBBs-2.2

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗