Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis

Arun J Sanyal, MD
Section Editor
Bruce A Runyon, MD
Deputy Editor
Kristen M Robson, MD, MBA, FACG


Approximately half of patients with cirrhosis have esophageal varices, and one-third of all patients with varices will develop variceal hemorrhage, a major cause of morbidity and mortality in patients with cirrhosis [1,2]. The risk of hemorrhage has been related to the size and appearance of the varices, as well as the degree of hepatic dysfunction. (See "Prediction of variceal hemorrhage in patients with cirrhosis".)

Primary prophylaxis aims to prevent variceal hemorrhage in patients with esophageal varices who do not have a history of hemorrhage. Pre-primary prophylaxis refers to measures aimed at preventing the development of varices. Measures aimed at preventing hemorrhage in patients with a history of variceal hemorrhage are referred to as secondary prophylaxis.

An ideal treatment of portal hypertension would be one that is universally effective, safe, easy to administer, and cost-effective. While such a treatment does not currently exist, there are several medical and surgical modalities available for primary prophylaxis of variceal hemorrhage. These therapies are aimed at achieving one of the following results:

Decreasing portal hypertension (eg, beta blockers, surgical portal decompression, or transjugular intrahepatic shunts)

Treating the varices directly (eg, variceal ligation)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Dec 2017. | This topic last updated: Jan 04, 2018.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2018 UpToDate, Inc.
  1. North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988; 319:983.
  2. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 2017; 65:310.
  3. de Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63:743.
  4. Hwang JH, Shergill AK, Acosta RD, et al. The role of endoscopy in the management of variceal hemorrhage. Gastrointest Endosc 2014; 80:221.
  5. Tripathi D, Stanley AJ, Hayes PC, et al. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut 2015; 64:1680.
  6. Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology 1998; 28:926.
  7. Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985; 1:325.
  8. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005; 353:2254.
  9. Vlachogiannakos J, Goulis J, Patch D, Burroughs AK. Review article: primary prophylaxis for portal hypertensive bleeding in cirrhosis. Aliment Pharmacol Ther 2000; 14:851.
  10. Smith JL, Graham DY. Variceal hemorrhage: a critical evaluation of survival analysis. Gastroenterology 1982; 82:968.
  11. D'Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006; 131:1611.
  12. Chalasani N, Kahi C, Francois F, et al. Improved patient survival after acute variceal bleeding: a multicenter, cohort study. Am J Gastroenterol 2003; 98:653.
  13. 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; 95:3566.
  14. Beppu K, Inokuchi K, Koyanagi N, et al. Prediction of variceal hemorrhage by esophageal endoscopy. Gastrointest Endosc 1981; 27:213.
  15. Gana JC, Turner D, Mieli-Vergani G, et al. A clinical prediction rule and platelet count predict esophageal varices in children. Gastroenterology 2011; 141:2009.
  16. Abd Elrazek MA, Mahfouz H, Afifi M, et al. Detection of risky esophageal varices by two-dimensional ultrasound: when to perform endoscopy. Am J Med Sci 2014; 347:28.
  17. Berzigotti A, Seijo S, Arena U, et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 2013; 144:102.
  18. Li L, Yu C, Li Y. Endoscopic band ligation versus pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis. Can J Gastroenterol 2011; 25:147.
  19. Triantos CK, Burroughs AK. Prevention of the development of varices and first portal hypertensive bleeding episode. Best Pract Res Clin Gastroenterol 2007; 21:31.
  20. Hernández-Gea V, Aracil C, Colomo A, et al. Development of ascites in compensated cirrhosis with severe portal hypertension treated with β-blockers. Am J Gastroenterol 2012; 107:418.
  21. Senzolo M, Cholongitas E, Burra P, et al. beta-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009; 29:1189.
  22. de Franchis R, Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010; 53:762.
  23. Sanyal AJ, Shiffman ML. The pharmacologic treatment of portal hypertension. Annu Rev Gastrointest Pharmacol 1996; :242.
  24. de-Madaria E, Palazón JM, Hernández FT, et al. Acute and chronic hemodynamic changes after propranolol in patients with cirrhosis under primary and secondary prophylaxis of variceal bleeding: a pilot study. Eur J Gastroenterol Hepatol 2010; 22:507.
  25. Villanueva C, Aracil C, Colomo A, et al. Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding. Gastroenterology 2009; 137:119.
  26. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990; 99:1401.
  27. Sacerdoti D, Merkel C, Gatta A. Importance of the 1-month-effect of nadolol on portal pressure in predicting failure of prevention of rebleeding in cirrhosis. J Hepatol 1991; 12:124.
  28. Ferayorni L, Polio J, Groszmann RJ. Drug therapy for portal hypertension: A five year review. In: Portal Hypertension II: Proceedings of the second Baveno International workshop on definitions, methodology and therapeutic strategies, de Franchis R (Ed), Blackwell Science, Oxford 1996. p.68.
  29. Merkel C, Bolognesi M, Sacerdoti D, et al. 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; 32:930.
  30. Grace ND, Groszmann RJ, Garcia-Tsao G, et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998; 28:868.
  31. Bureau C, Péron JM, Alric L, et al. "A La Carte" treatment of portal hypertension: Adapting medical therapy to hemodynamic response for the prevention of bleeding. Hepatology 2002; 36:1361.
  32. Albillos A, Bañares R, González M, et al. Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a meta-analysis. Am J Gastroenterol 2007; 102:1116.
  33. Sanyal AJ. Hepatic venous pressure gradient: to measure or not to measure, that is the question. Hepatology 2000; 32:1175.
  34. Lebrec D, Hillon P, Muńoz C, et al. The effect of propranolol on portal hypertension in patients with cirrhosis: a hemodynamic study. Hepatology 1982; 2:523.
  35. Bosch J, Masti R, Kravetz D, et al. Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis. Hepatology 1984; 4:1200.
  36. Garcia-Tsao G, Grace ND, Groszmann RJ, et al. Short-term effects of propranolol on portal venous pressure. Hepatology 1986; 6:101.
  37. Bendtsen F, Henriksen JH, Sørensen TI. Long-term effects of oral propranolol on splanchnic and systemic haemodynamics in patients with cirrhosis and oesophageal varices. Scand J Gastroenterol 1991; 26:933.
  38. Bandi JC, García-Pagán JC, Escorsell A, et al. Effects of propranolol on the hepatic hemodynamic response to physical exercise in patients with cirrhosis. Hepatology 1998; 28:677.
  39. Pascal JP, Cales P. Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1987; 317:856.
  40. Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients. Final report of a multicenter randomized trial. The Italian Multicenter Project for Propranolol in Prevention of Bleeding. J Hepatol 1989; 9:75.
  41. Prophylaxis of first hemorrhage from esophageal varices by sclerotherapy, propranolol or both in cirrhotic patients: a randomized multicenter trial. The PROVA Study Group. Hepatology 1991; 14:1016.
  42. Andreani T, Poupon RE, Balkau BJ, et al. Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: results of a controlled trial comparing propranolol, endoscopic sclerotherapy and placebo. Hepatology 1990; 12:1413.
  43. Idéo G, Bellati G, Fesce E, Grimoldi D. Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: a prospective, randomized study. Hepatology 1988; 8:6.
  44. Lebrec D, Poynard T, Capron JP, et al. Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis. A randomized trial. J Hepatol 1988; 7:118.
  45. Merkel C, Marin R, Angeli P, et al. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004; 127:476.
  46. Hayes PC, Davis JM, Lewis JA, Bouchier IA. Meta-analysis of value of propranolol in prevention of variceal haemorrhage. Lancet 1990; 336:153.
  47. Calès P. Factors associated with failure of propranolol for the prevention of first bleeding in cirrhotic patients. The Study Group of Primary Prophylaxis. Gastroenterol Clin Biol 1992; 16:504.
  48. Bosch J. Carvedilol for portal hypertension in patients with cirrhosis. Hepatology 2010; 51:2214.
  49. Bañares R, Moitinho E, Piqueras B, et al. Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology 1999; 30:79.
  50. Bañares R, Moitinho E, Matilla A, et al. Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology 2002; 36:1367.
  51. Tripathi D, Ferguson JW, Kochar N, et al. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology 2009; 50:825.
  52. Reiberger T, Ulbrich G, Ferlitsch A, et al. Carvedilol for prophylaxis of variceal bleeding in cirrhotic patients with hemodynamic nonresponse to propranolol. Hepatology 2010; 52:329A.
  53. Hemstreet BA. Evaluation of carvedilol for the treatment of portal hypertension. Pharmacotherapy 2004; 24:94.
  54. Tripathi D, Therapondos G, Lui HF, et al. Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther 2002; 16:373.
  55. Lin HC, Yang YY, Hou MC, et al. Acute administration of carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of portal pressure in patients with viral cirrhosis. Am J Gastroenterol 2004; 99:1953.
  56. De BK, Das D, Sen S, et al. Acute and 7-day portal pressure response to carvedilol and propranolol in cirrhotics. J Gastroenterol Hepatol 2002; 17:183.
  57. Bruha R, Vitek L, Petrtyl J, et al. Effect of carvedilol on portal hypertension depends on the degree of endothelial activation and inflammatory changes. Scand J Gastroenterol 2006; 41:1454.
  58. Reiberger T, Ulbrich G, Ferlitsch A, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013; 62:1634.
  59. Bhardwaj A, Kedarisetty CK, Vashishtha C, et al. Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial. Gut 2017; 66:1838.
  60. Shah HA, Azam Z, Rauf J, et al. Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial. J Hepatol 2014; 60:757.
  61. Ge PS, Runyon BA. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol 2014; 60:643.
  62. Koshy A, Girod C, Lee SS, et al. Discrepancy between portal pressure and systemic hemodynamic changes after incremental doses of propranolol in awake portal hypertensive rats. Hepatology 1989; 9:269.
  63. Sersté T, Melot C, Francoz C, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010; 52:1017.
  64. Wong F, Salerno F. Beta-blockers in cirrhosis: friend and foe? Hepatology 2010; 52:811.
  65. Llach J, Ginès P, Arroyo V, et al. Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites. Gastroenterology 1988; 94:482.
  66. Ruiz-del-Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005; 42:439.
  67. Zipprich A, Garcia-Tsao G, Seufferlein T, et al. The presence of esophageal varices (EV), but not treatement with beta-blockers, is associated with a poorer survival in patients with cirrhosis and ascites. Hepatology 2011; 54:461A.
  68. Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 2014; 146:1680.
  69. Gluud LL, Langholz E, Krag A. Meta-analysis: isosorbide-mononitrate alone or with either beta-blockers or endoscopic therapy for the management of oesophageal varices. Aliment Pharmacol Ther 2010; 32:859.
  70. Stiegmann GV, Goff JS, Michaletz-Onody PA, et al. Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl J Med 1992; 326:1527.
  71. Lay CS, Tsai YT, Teg CY, et al. Endoscopic variceal ligation in prophylaxis of first variceal bleeding in cirrhotic patients with high-risk esophageal varices. Hepatology 1997; 25:1346.
  72. Sarin SK, Lamba GS, Kumar M, et al. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. N Engl J Med 1999; 340:988.
  73. Lo GH, Lai KH, Cheng JS, et al. Prophylactic banding ligation of high-risk esophageal varices in patients with cirrhosis: a prospective, randomized trial. J Hepatol 1999; 31:451.
  74. Lui HF, Stanley AJ, Forrest EH, et al. Primary prophylaxis of variceal hemorrhage: a randomized controlled trial comparing band ligation, propranolol, and isosorbide mononitrate. Gastroenterology 2002; 123:735.
  75. Lo GH, Chen WC, Chen MH, et al. Endoscopic ligation vs. nadolol in the prevention of first variceal bleeding in patients with cirrhosis. Gastrointest Endosc 2004; 59:333.
  76. Schepke M, Kleber G, Nürnberg D, et al. Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2004; 40:65.
  77. Drastich P, Lata J, Petrtyl J, et al. Endoscopic variceal band ligation compared with propranolol for prophylaxis of first variceal bleeding. Ann Hepatol 2011; 10:142.
  78. Pérez-Ayuso RM, Valderrama S, Espinoza M, et al. Endoscopic band ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhotic patients with high risk esophageal varices. Ann Hepatol 2010; 9:15.
  79. Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology 2001; 33:802.
  80. Khuroo MS, Khuroo NS, Farahat KL, et al. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding. Aliment Pharmacol Ther 2005; 21:347.
  81. Gluud LL, Klingenberg S, Nikolova D, Gluud C. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: systematic review of randomized trials. Am J Gastroenterol 2007; 102:2842.
  82. Gluud LL, Krag A. Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev 2012; :CD004544.
  83. Sarin SK, Wadhawan M, Agarwal SR, et al. Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary prophylaxis of variceal bleeding. Am J Gastroenterol 2005; 100:797.
  84. Lo GH, Chen WC, Wang HM, Lee CC. Controlled trial of ligation plus nadolol versus nadolol alone for the prevention of first variceal bleeding. Hepatology 2010; 52:230.
  85. Imperiale TF, Klein RW, Chalasani N. Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding. Hepatology 2007; 45:870.
  86. Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial. J Hepatol 2011; 54:1161.
  87. Tissue Adhesives: A Review. Techniques in Gastrointestinal Endoscopy 2006; 8:33.
  88. Pagliaro L, D'Amico G, Sörensen TI, et al. Prevention of first bleeding in cirrhosis. A meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med 1992; 117:59.
  89. Paquet KJ. Prophylactic endoscopic sclerosing treatment of the esophageal wall in varices -- a prospective controlled randomized trial. Endoscopy 1982; 14:4.
  90. Witzel L, Wolbergs E, Merki H. Prophylactic endoscopic sclerotherapy of oesophageal varices. A prospective controlled study. Lancet 1985; 1:773.
  91. Piai G, Cipolletta L, Claar M, et al. Prophylactic sclerotherapy of high-risk esophageal varices: results of a multicentric prospective controlled trial. Hepatology 1988; 8:1495.
  92. Veterans Affairs Cooperative Variceal Sclerotherapy Group. Prophylactic sclerotherapy for esophageal varices in men with alcoholic liver disease. A randomized, single-blind, multicenter clinical trial. N Engl J Med 1991; 324:1779.
  93. Avgerinos A, Armonis A, Manolakopoulos S, et al. Endoscopic sclerotherapy plus propranolol versus propranolol alone in the primary prevention of bleeding in high risk cirrhotic patients with esophageal varices: a prospective multicenter randomized trial. Gastrointest Endosc 2000; 51:652.
  94. Resnick RH, Chalmers TC, Ishihara AM, et al. A controlled study of the prophylactic portacaval shunt. A final report. Ann Intern Med 1969; 70:675.
  95. Conn HO, Lindenmuth WW, May CJ, Ramsby GR. Prophylactic portacaval anastomosis. Medicine (Baltimore) 1972; 51:27.
  96. Jackson FC, Perrin EB, Felix WR, Smith AG. A clinical investigation of the portacaval shunt. V. Survival analysis of the therapeutic operation. Ann Surg 1971; 174:672.