An apology for beta blockers
Authors: Ulrich Thalheimer, Jaime Bosch, Andrew K. Burroughs
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 read with interest the recent review on beta-blockers in cirrhosis by Ge and Runyon [[1]Ge P.S. Runyon B.A. The changing role of beta-blocker therapy in patients with cirrhosis.J Hepatol. 2014; 60: 643-653Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. This topic is of great importance, as non-selective beta blockers are a pharmacological mainstay in the management of patients with cirrhosis; the amount of evidence has been increasing substantially since the first published trial of their use in the prevention of variceal bleeding [[2]Lebrec D. Nouel O. Corbic M. Benhamou J.P. Propranolol – a medical treatment for portal hypertension?.Lancet. 1980; 2: 180-182Abstract PubMed Scopus (256) Google Scholar], particularly in recent years. In their review, the authors dedicate a sub-heading to "Benefits of beta-blocker therapy". This consists of only two paragraphs, in which some trials of beta blockade for primary prevention of variceal bleeding are discussed. In the last line, the use of beta blockers in secondary prophylaxis of variceal bleeding is just about mentioned, and reference to a table (Table 1) is made. Table 1, titled "Key studies supporting beta-blocker usage", only lists trials of beta blockers for the primary prevention of variceal bleeding. For reasons best known to them (but not to us), the authors chose to completely ignore mountains of evidence for a wide range of non-selective beta blockers in patients with cirrhosis, including such trivialities as effects on mortality, risk of decompensation, development of ascites, renal failure, encephalopathy, and bacterial infections. This includes true landmark studies [[3]Abraldes J.G. Tarantino I. Turnes J. Garcia-Pagan J.C. Rodes J. Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.Hepatology. 2003; 37: 902-908Crossref PubMed Scopus (411) Google Scholar], the results of which have both been replicated [[4]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 (100) Google Scholar] and extensively discussed in the literature [[5]Thalheimer U. Bosch J. Burroughs A.K. How to prevent varices from bleeding: shades of grey – the case for nonselective beta blockers.Gastroenterology. 2007; 133: 2029-2036Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Similarly, the vast majority of the wide-ranging pharmacological effects of beta-blockers, particularly non-haemodynamic effects [5Thalheimer U. Bosch J. Burroughs A.K. How to prevent varices from bleeding: shades of grey – the case for nonselective beta blockers.Gastroenterology. 2007; 133: 2029-2036Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 6Thalheimer U. Triantos C.K. Samonakis D.N. Patch D. Burroughs A.K. Infection, coagulation, and variceal bleeding in cirrhosis.Gut. 2005; 54: 556-563Crossref PubMed Scopus (252) Google Scholar], are largely ignored, exception made for a single mentioning of bacterial translocation in Fig. 1. The authors then embark on a lengthy discussion of "adverse effects of beta-blocker therapy". The sub-heading itself spans 5 paragraphs (more than twice the length of the benefits!), but the successive elaboration on the inherent evil of beta blockers (variously termed "The differential effect of beta-blockers in cirrhosis", "Blood pressure and survival", "Beta-blockers in refractory ascites", and "Additional challenges of beta-blocker therapy") cover several pages. In this section, the authors discuss at length the possible adverse effects of beta blockers, quoting studies in patients without liver disease published mainly between 1969 and 1990. It is also rather puzzling that the use of beta blockers in arterial hypertension, cardiac failure, and acute coronary syndromes is discussed, as this debate has little importance to their use in liver disease. Interestingly, had the authors applied a bit more dedication to their "holistic" approach to beta-blockers, they might have stumbled across other rather informative (and much more recent) studies outlining the safety (and significant benefit) of beta blockers in COPD [7Farland M.Z. Peters C.J. Williams J.D. Bielak K.M. Heidel R.E. Ray S.M. Beta-Blocker use and incidence of chronic obstructive pulmonary disease exacerbations.Ann Pharmacother. 2013; 47: 651-656Crossref PubMed Scopus (38) Google Scholar, 8Short P.M. Lipworth S.I. Elder D.H. Schembri S. Lipworth B.J. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study.BMJ. 2011; 342: d2549Crossref PubMed Scopus (230) Google Scholar], peripheral vascular disease [[9]Paravastu S.C. Mendonca D.A. Da S.A. Beta blockers for peripheral arterial disease.Cochrane Database Syst Rev. 2013; 9: CD005508PubMed Google Scholar], and diabetes [[10]Ryden L. Standl E. Bartnik M. Van den Berghe G. Betteridge J. de Boer M.J. et al.Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD).Eur Heart J. 2007; 28: 88-136Crossref PubMed Scopus (19) Google Scholar]. Table 2, titled "Key studies suggesting potential harm from beta-blocker usage" clearly is meant to mirror Table 1 in size and importance. It strikes us that of the "key" studies mentioned in this table, the first only shows an increased likelihood of adverse events with beta blockers as compared to placebo (a finding which is hardly surprising), while the second study quite amusingly only investigates the prognostic importance of the cardiac index in cirrhosis without making use of beta blockers. The other two quoted studies are a heavily debated observational study and a cross-over study looking at paracentesis-induced circulatory dysfunction in 10 patients. By contrast, even the completely unrepresentative choice of key studies in Table 1 entirely consists of controlled trials. At this point it is of little further consequence to mention other surprising findings, such as the space given to the discussion of midodrine and ACE inhibitors in a review on beta blockers, and the fact that studies on midodrine are quoted as evidence "confirming the importance of maintaining cardiac output in patients with advanced cirrhosis" – indeed, midodrine is a vasoconstricting agent and does not increase cardiac output, but has actually been found to decrease it [[11]Singh V. Singh A. Singh B. Vijayvergiya R. Sharma N. Ghai A. et al.Midodrine and clonidine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study.Am J Gastroenterol. 2013; 108: 560-567Crossref PubMed Scopus (31) Google Scholar]. Finally, in their fervour against beta-blockers, the authors go as far as providing "recommendations" for the use of beta blockers in cirrhosis, the evidence for which is as feeble as the discussion leading up to it. Needless to say, these are to our mind very hazardous statements, which might well lead to a reduction in the use of this class of highly effective and very cheap agents, which have rightly been termed "the Hepatologist's Aspirin" [[12]Triantos C. Samonakis D. Thalheimer U. Patch D. Burroughs A. The relationship between liver function and portal pressure: what comes first, the chicken or the egg?.J Hepatol. 2005; 42: 146-147Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. Sadly, we feel that a great opportunity to discuss this crucial topic in Hepatology has been missed, as this review is ill-conceived and poorly researched, leading to conclusions which might be far more harmful than any effect beta blockers might have in patients with cirrhosis. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.