Beta-blockers in cirrhosis: Evidence-based indications and limitations

Lebrec, 1980, Propranolol–a medical treatment for portal hypertension?, Lancet, 2, 180, 10.1016/S0140-6736(80)90063-X Garcia-Tsao, 2010, Management of varices and variceal hemorrhage in cirrhosis, N Engl J Med, 362, 823, 10.1056/NEJMra0901512 Lebrec, 1981, Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study, N Engl J Med, 305, 1371, 10.1056/NEJM198112033052302 Pascal, 1987, Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices, N Engl J Med, 317, 856, 10.1056/NEJM198710013171403 Tsochatzis, 2014, Liver cirrhosis, Lancet, 383, 1749, 10.1016/S0140-6736(14)60121-5 Perez-Ayuso, 1991, Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis, Lancet, 337, 1431, 10.1016/0140-6736(91)93125-S Lo, 2008, Improved survival in patients receiving medical therapy as compared with banding ligation for the prevention of esophageal variceal rebleeding, Hepatology, 48, 580, 10.1002/hep.22358 Senzolo, 2009, beta-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis, Liver Int, 29, 1189, 10.1111/j.1478-3231.2009.02038.x Thiele, 2012, Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices, Aliment Pharmacol Ther, 35, 1155, 10.1111/j.1365-2036.2012.05074.x Wilkinson, 1980, Propranolol and portal hypertension in cirrhosis, Lancet, 2, 429, 10.1016/S0140-6736(80)90480-8 Serste, 2010, Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites, Hepatology, 52, 1017, 10.1002/hep.23775 Krag, 2012, The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease, Gut, 61, 967, 10.1136/gutjnl-2011-301348 Villanueva, 2019, beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial, Lancet, 393, 1597, 10.1016/S0140-6736(18)31875-0 Fernandez, 2004, Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice, Gastroenterology, 126, 886, 10.1053/j.gastro.2003.12.012 Sinagra, 2014, Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis, Aliment Pharmacol Ther, 39, 557, 10.1111/apt.12634 Villanueva, 2009, Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding, Gastroenterology, 137, 119, 10.1053/j.gastro.2009.03.048 Abraldes, 2003, Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis, Hepatology, 37, 902, 10.1053/jhep.2003.50133 D'Amico, 2006, Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review, Gastroenterology, 131, 1611, 10.1053/j.gastro.2006.09.013 Reiberger, 2013, Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol, Gut, 62, 1634, 10.1136/gutjnl-2012-304038 Turnes, 2006, Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis, Am J Gastroenterol, 101, 506, 10.1111/j.1572-0241.2006.00453.x Albillos, 2007, Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a meta-analysis, Am J Gastroenterol, 102, 1116, 10.1111/j.1572-0241.2007.01191.x de Franchis, 2015, Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension, J Hepatol, 63, 743, 10.1016/j.jhep.2015.05.022 European Association for the Study of the Liver. Electronic address: [email protected], European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69(2):406–460. Garcia-Tsao, 2017, Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases, Hepatology, 65, 310, 10.1002/hep.28906 1988, Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study, N Engl J Med, 319, 983, 10.1056/NEJM198810133191505 Poynard, 1991, N Engl J Med, 324, 1532, 10.1056/NEJM199105303242202 D'Amico, 1999, Pharmacological treatment of portal hypertension: an evidence-based approach, Semin Liver Dis, 19, 475, 10.1055/s-2007-1007133 Bosch, 2009, Pharmacological versus endoscopic therapy in the prevention of variceal hemorrhage: and the winner is, Hepatology, 50, 674, 10.1002/hep.23164 Gluud, 2012, Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults, Cochrane Database Syst Rev, 8, CD004544 Tripathi, 2009, Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed, Hepatology, 50, 825, 10.1002/hep.23045 Shah, 2014, Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial, J Hepatol, 60, 757, 10.1016/j.jhep.2013.11.019 Abd ElRahim, 2018, Efficacy of carvedilol versus propranolol versus variceal band ligation for primary prevention of variceal bleeding, Hepatol Int, 12, 75, 10.1007/s12072-017-9835-9 Tripathi, 2019, Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (CALIBRE trial), BMJ open Gastroenterol, 6, e000290, 10.1136/bmjgast-2019-000290 Sharma, 2019, Comparison of therapies for primary prevention of esophageal variceal bleeding: a systematic review and network meta-analysis, Hepatology, 69, 1657, 10.1002/hep.30220 Sarin, 2005, Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary prophylaxis of variceal bleeding, Am J Gastroenterol, 100, 797, 10.1111/j.1572-0241.2005.40468.x Seo, 2017, Multicenter prospective randomized controlled trial comparing propranolol, endoscopic band ligation, and combination therapy for the primary prophylaxis variceal bleeding in patients with liver cirrhosis, J Hepatol Suppl, 66, S35, 10.1016/S0168-8278(17)30330-6 Turco, 2019, Lowering portal pressure improves outcomes of patients with cirrhosis, with or without ascites: a meta-analysis, Clin Gastroenterol Hepatol Mandorfer, 2014, Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis, Gastroenterology, 146, 1680, 10.1053/j.gastro.2014.03.005 Aday, 2016, The beneficial effect of beta-blockers in patients with cirrhosis, portal hypertension and ascites, Am J Med Sci, 351, 169, 10.1016/j.amjms.2015.11.018 Bang, 2016, Effect of propranolol on survival in patients with decompensated cirrhosis: a nationwide study based Danish patient registers, Liver Int, 36, 1304, 10.1111/liv.13119 Bossen, 2016, Nonselective beta-blockers do not affect mortality in cirrhosis patients with ascites: post Hoc analysis of three randomized controlled trials with 1198 patients, Hepatology, 63, 1968, 10.1002/hep.28352 Leithead, 2015, Non-selective beta-blockers are associated with improved survival in patients with ascites listed for liver transplantation, Gut, 64, 1111, 10.1136/gutjnl-2013-306502 Mookerjee, 2016, Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure, J Hepatol, 64, 574, 10.1016/j.jhep.2015.10.018 Sinha, 2017, Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites, J Hepatol, 67, 40, 10.1016/j.jhep.2017.02.005 Cales, 1999, Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomized trial. French-Speaking Club for the Study of Portal Hypertension, Eur J Gastroenterol Hepatol, 11, 741, 10.1097/00042737-199907000-00011 Groszmann, 2005, Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis, N Engl J Med, 353, 2254, 10.1056/NEJMoa044456 Villanueva, 2016, Development of hyperdynamic circulation and response to beta-blockers in compensated cirrhosis with portal hypertension, Hepatology, 63, 197, 10.1002/hep.28264 Sarin, 2013, Early primary prophylaxis with beta-blockers does not prevent the growth of small esophageal varices in cirrhosis: a randomized controlled trial, Hepatol Int, 7, 248, 10.1007/s12072-012-9353-8 Merkel, 2004, A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis, Gastroenterology, 127, 476, 10.1053/j.gastro.2004.05.004 Bhardwaj, 2017, Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial, Gut, 66, 1838, 10.1136/gutjnl-2016-311735 Qi, 2015, Nonselective beta-blockers in cirrhotic patients with no or small varices: a meta-analysis, World J Gastroenterol, 21, 3100, 10.3748/wjg.v21.i10.3100 Ripoll, 2007, Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis, Gastroenterology, 133, 481, 10.1053/j.gastro.2007.05.024 Bernard, 1997, Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis, Hepatology, 25, 63, 10.1002/hep.510250112 Gluud, 2010, Meta-analysis: isosorbide-mononitrate alone or with either beta-blockers or endoscopic therapy for the management of oesophageal varices, Aliment Pharmacol Ther, 32, 859, 10.1111/j.1365-2036.2010.04418.x Puente, 2014, Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review, Liver Int, 34, 823, 10.1111/liv.12452 Albillos, 2017, Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis, Hepatology, 66, 1219, 10.1002/hep.29267 Lo, 2012, Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding, J Gastroenterol Hepatol, 27, 1681, 10.1111/j.1440-1746.2012.07244.x Stanley, 2014, Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding, J Hepatol, 61, 1014, 10.1016/j.jhep.2014.06.015 Yang, 2019, The efficacy comparison of carvedilol plus endoscopic variceal ligation and traditional, nonselective beta-blockers plus endoscopic variceal ligation in cirrhosis patients for the prevention of variceal rebleeding: a meta-analysis, Eur J Gastroenterol Hepatol, 31, 1518, 10.1097/MEG.0000000000001442 Korula, 1991, Demonstration of two distinct subsets of gastric varices. Observations during a seven-year study of endoscopic sclerotherapy, Dig Dis Sci, 36, 303, 10.1007/BF01318201 Sarin, 1992, Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients, Hepatology, 16, 1343, 10.1002/hep.1840160607 Mishra, 2011, Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial, J Hepatol, 54, 1161, 10.1016/j.jhep.2010.09.031 Hung, 2012, Efficacy of non-selective beta-blockers as adjunct to endoscopic prophylactic treatment for gastric variceal bleeding: a randomized controlled trial, J Hepatol, 56, 1025, 10.1016/j.jhep.2011.12.021 Lo, 2007, A prospective, randomized controlled trial of transjugular intrahepatic portosystemic shunt versus cyanoacrylate injection in the prevention of gastric variceal rebleeding, Endoscopy, 39, 679, 10.1055/s-2007-966591 Henry, 2014, Gastric and ectopic varices, Clin Liver Dis, 18, 371, 10.1016/j.cld.2014.01.002 Lebrec, 1985, Ectopic varices in portal hypertension, Clin Gastroenterol, 14, 105, 10.1016/S0300-5089(21)00639-8 Norton, 1998, Management of ectopic varices, Hepatology, 28, 1154, 10.1002/hep.510280434 Cubillas, 2010, Portal hypertensive gastropathy: a review, Liver Int, 30, 1094, 10.1111/j.1478-3231.2010.02286.x Lo, 2001, The effects of endoscopic variceal ligation and propranolol on portal hypertensive gastropathy: a prospective, controlled trial, Gastrointest Endosc, 53, 579, 10.1067/mge.2001.114062 Sarin, 2000, The natural history of portal hypertensive gastropathy: influence of variceal eradication, Am J Gastroenterol, 95, 2888, 10.1111/j.1572-0241.2000.03200.x Hosking, 1987, The role of propranolol in congestive gastropathy of portal hypertension, Hepatology, 7, 437, 10.1002/hep.1840070304 Primignani, 2000, Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC), Gastroenterology, 119, 181, 10.1053/gast.2000.8555 Longacre, 2008, A pilot project examining the predicted preferences of patients and physicians in the primary prophylaxis of variceal hemorrhage, Hepatology, 47, 169, 10.1002/hep.21945 Garcia-Tsao, 1986, Short-term effects of propranolol on portal venous pressure, Hepatology, 6, 101, 10.1002/hep.1840060119 Leithead, 2015, Non-selective β-blockers are associated with improved survival in patients with ascites listed for liver transplantation, Gut, 64, 1111, 10.1136/gutjnl-2013-306502 Bossen, 2016, Nonselective β-blockers do not affect mortality in cirrhosis patients with ascites: post hoc analysis of three randomized controlled trials with 1198 patients, Hepatology, 63, 1968, 10.1002/hep.28352 Bhutta, 2018, Beta-blockers in hospitalised patients with cirrhosis and ascites: mortality and factors determining discontinuation and reinitiation, Aliment Pharmacol Ther, 47, 78, 10.1111/apt.14366 Robins, 2014, Beta-blockers in cirrhosis patients with refractory ascites, Hepatology, 59, 2054, 10.1002/hep.26676 Onali, 2017, Non-selective beta-blockers are not associated with increased mortality in cirrhotic patients with ascites, Liver Int, 37, 1334, 10.1111/liv.13409 Tergast, 2019, Systemic arterial blood pressure determines the therapeutic window of non-selective beta blockers in decompensated cirrhosis, Aliment Pharmacol Ther, 50, 696, 10.1111/apt.15439 Serste, 2011, Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study, J Hepatol, 55, 794, 10.1016/j.jhep.2011.01.034 Giannelli, 2019, Impact of cardiac function, refractory ascites and beta blockers on the outcome of patients with cirrhosis listed for liver transplantation, J Hepatol Chirapongsathorn, 2016, Nonselective β-blockers and survival in patients with cirrhosis and ascites: a systematic review and meta-analysis, Clin Gastroenterol Hepatol, 14, 1096, 10.1016/j.cgh.2016.01.012 Facciorusso, 2018, Nonselective beta-blockers do not affect survival in cirrhotic patients with ascites, Dig Dis Sci, 63, 1737, 10.1007/s10620-018-5092-6 Wong, 2019, Assessing the safety of beta-blocker therapy in cirrhosis patients with ascites: a meta-analysis, Liver Int, 39, 1080, 10.1111/liv.14040 Moctezuma-Velazquez, 2017, Beta-blockers in patients with advanced liver disease: has the dust settled?, Liver Transpl, 23, 1058, 10.1002/lt.24794 Njei, 2016, Beta-blockers in patients with cirrhosis and ascites: type of beta-blocker matters, Gut, 65, 1393, 10.1136/gutjnl-2016-312129 de Souza, 2012, Patients whose first episode of bleeding occurs while taking a β-blocker have high long-term risks of rebleeding and death, Clin Gastroenterol Hepatol, 10, 670, 10.1016/j.cgh.2012.02.011 Tripathi, 2007, Variceal band ligation versus beta-blockers for primary prevention of variceal bleeding: a meta-analysis, Eur J Gastroenterol Hepatol, 19, 835, 10.1097/MEG.0b013e3282748f07 Bai, 2014, Combined therapies versus monotherapies for the first variceal bleeding in patients with high-risk varices: a meta-analysis of randomized controlled trials, J Gastroenterol Hepatol, 29, 442, 10.1111/jgh.12396 Zacharias, 2018, Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices, Cochrane database Syst Rev, 10, CD011510 Dwinata, 2019, Carvedilol vs endoscopic variceal ligation for primary and secondary prevention of variceal bleeding: systematic review and meta-analysis, World J Hepatol, 11, 464, 10.4254/wjh.v11.i5.464 Malandris, 2019, Carvedilol for prevention of variceal bleeding: a systematic review and meta-analysis, Ann Gastroenterol, 32, 287 Cheung, 2009, Systematic review: secondary prevention with band ligation, pharmacotherapy or combination therapy after bleeding from oesophageal varices, Aliment Pharmacol Ther, 30, 577, 10.1111/j.1365-2036.2009.04075.x Funakoshi, 2010, Benefit of combination beta-blocker and endoscopic treatment to prevent variceal rebleeding: a meta-analysis, World J Gastroenterol, 16, 5982 Kalambokis, 2016, Propranolol use beyond 6 months increases mortality in patients with Child-Pugh C cirrhosis and ascites, Hepatology, 64, 1806, 10.1002/hep.28575 Kim, 2017, Beneficial and harmful effects of nonselective beta blockade on acute kidney injury in liver transplant candidates, Liver Transpl, 23, 733, 10.1002/lt.24744