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

Summary

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.

Timeline

Start

2025-01-06

Primary completion

2030-10

Completion

2030-10

Publications

• Background Chung CS, Chang PF, Liao CH, Lee TH, Chen Y, Lee YC, Wu MS, Wang HP, Ni YH. Differences of microbiota in small bowel and faeces between irritable bowel syndrome patients and healthy subjects. Scand J Gastroenterol. 2016;51(4):410-9. doi: 10.3109/00365521.2015.1116107. Epub 2015 Nov 23.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background Arab JP, Martin-Mateos RM, Shah VH. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg. Hepatol Int. 2018 Feb;12(Suppl 1):24-33. doi: 10.1007/s12072-017-9798-x. Epub 2017 May 26.
• Background Pande A, Kumar Sarin S, Jindal A, et al. Efficacy of carvedilol, endoscopic variceal ligation (EVL) or a combination for the prevention of first variceal bleed in child B and C cirrhosis with high risk varices: a randomized controlled trial. Hepatology 2019;v70:96A
• Background Giuffre M, Dupont J, Visintin A, Masutti F, Monica F, You K, Shung DL, Croce LS; NSBB-Elasto-Response-Prediction Group. Predicting response to non-selective beta-blockers with liver-spleen stiffness and heart rate in patients with liver cirrhosis and high-risk varices. Hepatol Int. 2025 Apr;19(2):460-471. doi: 10.1007/s12072-024-10649-7. Epub 2024 Apr 25.
• Background Bhardwaj A, Kedarisetty CK, Vashishtha C, Bhadoria AS, Jindal A, Kumar G, Choudhary A, Shasthry SM, Maiwall R, Kumar M, Bhatia V, Sarin SK. Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial. Gut. 2017 Oct;66(10):1838-1843. doi: 10.1136/gutjnl-2016-311735. Epub 2016 Jun 13.
• Background Wani ZA, Mohapatra S, Khan AA, Mohapatra A, Yatoo GN. Addition of simvastatin to carvedilol non responders: A new pharmacological therapy for treatment of portal hypertension. World J Hepatol. 2017 Feb 18;9(5):270-277. doi: 10.4254/wjh.v9.i5.270.
• Background Merkel C, Bolognesi M, Sacerdoti D, Bombonato G, Bellini B, Bighin R, Gatta A. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology. 2000 Nov;32(5):930-4. doi: 10.1053/jhep.2000.19322.
• Background Jachs M, Hartl L, Simbrunner B, Bauer D, Paternostro R, Balcar L, Hofer B, Pfisterer N, Schwarz M, Scheiner B, Stattermayer AF, Pinter M, Trauner M, Mandorfer M, Reiberger T. Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis. Clin Gastroenterol Hepatol. 2023 Aug;21(9):2318-2326.e7. doi: 10.1016/j.cgh.2022.06.007. Epub 2022 Jul 14.
• Background Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, Heinisch BB, Trauner M, Kramer L, Peck-Radosavljevic M; Vienna Hepatic Hemodynamic Lab. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut. 2013 Nov;62(11):1634-41. doi: 10.1136/gutjnl-2012-304038. Epub 2012 Dec 18.
• Background Kaplan DE, Ripoll C, Thiele M, Fortune BE, Simonetto DA, Garcia-Tsao G, Bosch J. AASLD Practice Guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology. 2024 May 1;79(5):1180-1211. doi: 10.1097/HEP.0000000000000647. Epub 2023 Oct 23. No abstract available.
• Background Banares R, Moitinho E, Matilla A, Garcia-Pagan JC, Lampreave JL, Piera C, Abraldes JG, De Diego A, Albillos A, Bosch J. Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology. 2002 Dec;36(6):1367-73. doi: 10.1053/jhep.2002.36947.
• Background de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974. doi: 10.1016/j.jhep.2021.12.022. Epub 2021 Dec 30.
• Background Sharma M, Singh S, Desai V, Shah VH, Kamath PS, Murad MH, Simonetto DA. Comparison of Therapies for Primary Prevention of Esophageal Variceal Bleeding: A Systematic Review and Network Meta-analysis. Hepatology. 2019 Apr;69(4):1657-1675. doi: 10.1002/hep.30220. Epub 2019 Feb 20.
• Background Villanueva C, Albillos A, Genesca J, Garcia-Pagan JC, Calleja JL, Aracil C, Banares R, Morillas RM, Poca M, Penas B, Augustin S, Abraldes JG, Alvarado E, Torres F, Bosch J. beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2019 Apr 20;393(10181):1597-1608. doi: 10.1016/S0140-6736(18)31875-0. Epub 2019 Mar 22.
• Background Gluud LL, Krag A. Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev. 2012 Aug 15;2012(8):CD004544. doi: 10.1002/14651858.CD004544.pub2.
• Background Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. N Engl J Med. 1999 Apr 1;340(13):988-93. doi: 10.1056/NEJM199904013401302.
• Background Garcia-Tsao G, Lim JK; Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol. 2009 Jul;104(7):1802-29. doi: 10.1038/ajg.2009.191. Epub 2009 May 19.
• Background El-Serag HB, Everhart JE. Improved survival after variceal hemorrhage over an 11-year period in the Department of Veterans Affairs. Am J Gastroenterol. 2000 Dec;95(12):3566-73. doi: 10.1111/j.1572-0241.2000.03376.x.
• Background Sanyal AJ, Bosch J, Blei A, Arroyo V. Portal hypertension and its complications. Gastroenterology. 2008 May;134(6):1715-28. doi: 10.1053/j.gastro.2008.03.007. No abstract available.

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