Beta-blockers in cirrhosis: Therapeutic window or an aspirin for all?
Authors: Alberto Ferrarese, Emmanuel Tsochatzis, Andrew Kenneth Burroughs, Marco Senzolo
Journal: Journal of Hepatology (2014)

The changing role of beta-blocker therapy in patients with cirrhosisJournal of HepatologyVol. 60Issue 3PreviewCirrhosis is a leading cause of death in the United States and worldwide. Beta-blockers have been established in numerous studies as part of the cornerstone of the medical management of cirrhosis, particularly in the primary and secondary prevention of variceal hemorrhage. However, new evidence has cautioned the use of beta-blockers in patients with end-stage cirrhosis and refractory ascites. In this article, we review the beneficial effects of beta-blocker therapy, the potential harms of aggressive beta-blocker therapy, and provide suggestions regarding the appropriate use of this class of medications in patients with cirrhosis. Full-Text PDF Open AccessBeta-blockers in cirrhosis: Thank you for your attentionJournal of HepatologyVol. 61Issue 2PreviewWe graciously thank Drs. Ferrarese, Thalheimer, their colleagues, and the editorial board and worldwide readership of the Journal of Hepatology for their interest in our article [1]. We are humbled and honored by the international attention that our article has received, and are excited by the debate that it has ignited within the hepatology community. We have received numerous positive correspondences regarding our review [2]. In light of recent studies that have stirred controversy, and in anticipation of future studies that will continue to stir controversy, we believed a fresh objective look at the emerging evidence in the use of beta-blockers in cirrhosis was warranted. Full-Text PDF Open Access We have read with interest the review article by Ge and Runyon on the changing role of non-selective β-blockers (NSBBs) in cirrhosis [[1]Ge P.S. Runyon B.A. The changing role of beta-blocker therapy in patients with cirrhosis.J Hepatol. 2013; 60: 643-653Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar]. Their role in reduction of portal hypertension is accomplished by lowering portal inflow (β1 blockade) and inducing splanchnic vasoconstriction (β2 blockade). Risk of variceal bleeding correlates also with other factors, i.e., infections and severity of liver dysfunction, suggesting absence of a pure mechanical model. For this reason, patients with more severe disease (Child-Pugh Class C) should undergo primary prophylaxis even in the presence of small varices [[2]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: 762-768Abstract Full Text Full Text PDF PubMed Scopus (1183) Google Scholar]. In this paper, the authors suggested a “window hypothesis”, also supported by Krag and co-authors [[3]Krag A. Wiest R. Albillos A. Gluud L.L. The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease.Gut. 2012; 61: 967-969Crossref PubMed Scopus (154) Google Scholar], according to which NSBBs are beneficial only in decompensated patients with medium-large varices but not in patients with early or end-stage cirrhosis with refractory ascites. Their recommendation on patients with refractory ascites is mainly based on data from a study performed by Serstè and collaborators, which showed that mortality in patients with refractory ascites was increased in those taking NSBBs. The same group hypothesized that β-blockade could induce counter-regulatory over-activation of the Renin-Angiotensin-Aldosterone axis, increasing incidence of paracentesis-induced circulatory dysfunction, which could be associated with impaired renal function and reduced survival [4Serste T. Melot C. Francoz C. Durand F. Rautou P.E. Valla D. et al.Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (435) Google Scholar, 5Serste T. Francoz C. Durand F. Rautou P.E. Melot C. Valla D. et al.Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study.J Hepatol. 2011; 55: 794-799Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. These data were not confirmed by another study on patients with ascites taking propranolol [[6]Hernandez-Gea V. Aracil C. Colomo A. Garupera I. Poca M. Torras X. et al.Development of ascites in compensated cirrhosis with severe portal hypertension treated with beta-blockers.Am J Gastroenterol. 2012; 107: 418-427Crossref PubMed Scopus (106) Google Scholar]; moreover, by analyzing all published randomized controlled trials on prophylaxis for variceal hemorrhage, bleeding unrelated mortality was similar between patients on NSBBs and those treated with other therapies in primary (277/955 vs. 287/1175; OR 0.91 95% CI 0.73 to 1.15) and secondary prophylaxis (188/1143 vs. 225/1208; OR 0.87 95% CI 0.68 to 1.12) without heterogeneity amongst studies, while causes of death were not different between patients on and off NSBBs therapy. These results were confirmed in the subgroup analysis of studies with higher prevalence of ascites (>50%) [[7]Ferrarese A. Germani G. Rodriguez-Castro K.I. Nadal E. Zanetto A. Bortoluzzi I. et al.Bleeding-unrelated mortality is not increased in patients with cirrhosis and ascites on treatment with β-blockers: a meta-analysis.Dig Liver Dis. 2014; 46: e31https://doi.org/10.1016/j.dld.2014.01.072Abstract Full Text Full Text PDF Google Scholar]. Moreover the dose of propranolol should be further investigated as a potential factor associated with increased mortality; for instance, in the French study, high propranolol doses (mean 132 mg/day) could have contributed to altered haemodynamics [[8]Senzolo M. Nadal E. Cholongitas E. Burroughs A.K. Is hydrophobia necessary for the hepatologist prescribing nonselective beta-blockers in cirrhosis?.Hepatology. 2011; 53: 2149-2150Crossref PubMed Scopus (16) Google Scholar]. Furthermore, chronotropic and inotropic negative effect by NSBBs may reduce cardiac function in patients with more severe cirrhotic cardiomyopathy or new onset of sepsis. For instance, we admitted a patient with alcoholic cirrhosis on the waiting list for liver transplantation who developed spontaneous bacterial peritonitis and sepsis and required large volume paracentesis (LVP); systemic vascular resistances were severely reduced at baseline in respect of previous procedures, and at the end of LVP there was a further reduction of 31.2%; notwithstanding, a counterbalancing increase of cardiac output to 12.9 L/m (+30.9%) prevented development of hepatorenal syndrome after LVP. With regards to their role in early cirrhosis, we recently described the pleiotropic effect of NSBBs and the need for their evaluation as part of preventative strategies in patients with early cirrhosis [[9]Tsochatzis E.A. Bosch J. Burroughs A.K. Liver cirrhosis.Lancet. 2014; https://doi.org/10.1016/S0140-6736(14)60121-5Abstract Full Text Full Text PDF PubMed Scopus (1309) Google Scholar]; their potential effects include reduction in the incidence of ascites, reduction in bacterial translocation, and a potential anti-angiogenic effect [[10]Tsochatzis E.A. Bosch J. Burroughs A.K. New therapeutic paradigm for patients with cirrhosis.Hepatology. 2012; 56: 1983-1992Crossref PubMed Scopus (99) Google Scholar]. NSBBs may not be a risk factor per se for increased non-bleeding related mortality in patients with cirrhosis and ascites. Other acquired factors such as cirrhotic cardiomyopathy or sepsis could be detrimental in those patients with refractory ascites undergoing paracentesis. Therefore, temporary dose adjustment in the event of sepsis or large volume paracentesis might prove more beneficial than not prescribing NSBBs in the first place. Further dedicated studies should evaluate NSBBs dose and their hemodynamic consequences, to provide hepatologists with conclusive evidence between the possible increase in mortality and the use of NSBBs. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.