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The changing role of beta-blocker therapy in patients with cirrhosis

  • Phillip S. Ge
    Affiliations
    Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
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  • Bruce A. Runyon
    Correspondence
    Corresponding author. Address: Division of Digestive Diseases/Hepatology, Santa Monica-UCLA Medical Center, 1223 16th Street, Suite 3100, Santa Monica, CA 90404, United States. Tel.: +1 310 582 6240; fax: +1 424 259 7789.
    Affiliations
    Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
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Open AccessPublished:September 27, 2013DOI:https://doi.org/10.1016/j.jhep.2013.09.016

      Summary

      Cirrhosis 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.

      Keywords

      Linked Article

      • Beta-blockers in cirrhosis: Thank you for your attention
        Journal of HepatologyVol. 61Issue 2
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          We 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.
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      • An apology for beta blockers
        Journal of HepatologyVol. 61Issue 2
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          We read with interest the recent review on beta-blockers in cirrhosis by Ge and Runyon [1]. 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], particularly in recent years.
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      • Beta-blockers in cirrhosis: Therapeutic window or an aspirin for all?
        Journal of HepatologyVol. 61Issue 2
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          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]. 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].
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      Introduction

      Cirrhosis is a leading cause of mortality in the United States and worldwide [
      • Lim Y.S.
      • Kim W.R.
      The global impact of hepatic fibrosis and end-stage liver disease.
      ,
      • Asrani S.K.
      • Larson J.J.
      • Yawn B.
      • Therneau T.M.
      • Kim W.R.
      Underestimation of liver-related mortality in the United States.
      ]. Within the developed world, the leading causes of cirrhosis include alcoholic liver disease, hepatitis C, and more recently, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Ever since NASH was described as a cause for cryptogenic cirrhosis [
      • Powell E.E.
      • Cooksley W.G.
      • Hanson R.
      • Searle J.
      • Halliday J.W.
      • Powell L.W.
      The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.
      ], there has been increasing recognition that NASH may become the most common cause of advanced liver disease in the coming decades [
      • Vernon G.
      • Baranova A.
      • Younossi Z.M.
      Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.
      ]. It is projected that between 2015 and 2030, NASH cirrhosis will overtake hepatitis C cirrhosis as the most common indication for liver transplantation in the United States [
      • Charlton M.
      Nonalcoholic fatty liver disease: a review of current understanding and future impact.
      ]. Studies have also implicated NASH risk factors including metabolic disease as being co-morbid with chronic hepatitis C [
      • Monto A.
      • Alonzo J.
      • Watson J.J.
      • Grunfeld C.
      • Wright T.L.
      Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol.
      ] and alcoholic liver disease [
      • Raynard B.
      • Balian A.
      • Fallik D.
      • Capron F.
      • Bedossa P.
      • Chaput J.C.
      • et al.
      Risk factors of fibrosis in alcohol-induced liver disease.
      ]. Some patients have all three insults to their liver.
      Given the comorbidity of hypertension, metabolic syndrome, and NASH cirrhosis, increasing numbers of patients with chronic liver disease are now on antihypertensives for essential hypertension. In a study of outpatient antihypertensive prescribing behavior, ambulatory visits by adults having uncomplicated essential hypertension increased 33% from 29.8 million visits in 1993 to 39.6 million visits in 2004 [
      • Ma J.
      • Lee K.V.
      • Stafford R.S.
      Changes in antihypertensive prescribing during US outpatient visits for uncomplicated hypertension between 1993 and 2004.
      ]. Beta-adrenergic antagonists (“beta-blockers”) have been established as part of the cornerstone of the medical management of hypertension [
      • Chobanian A.V.
      • Bakris G.L.
      • Black H.R.
      • Cushman W.C.
      • Green L.A.
      • Izzo Jr., J.L.
      • et al.
      The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
      ], as well as acute coronary syndrome [
      • Smith Jr., S.C.
      • Benjamin E.J.
      • Bonow R.O.
      • Braun L.T.
      • Creager M.A.
      • Franklin B.A.
      • et al.
      AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
      ], and congestive heart failure [
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • Butler J.
      • Casey Jr., D.E.
      • Drazner M.H.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ].
      Beta-blockers have also been well established in the prevention of variceal hemorrhage in patients with cirrhosis [
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ,
      • Pascal J.P.
      • Cales P.
      Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
      ,
      • Poynard T.
      • Cales P.
      • Pasta L.
      • Ideo G.
      • Pascal J.P.
      • Pagliaro L.
      • et al.
      Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group.
      ,
      • Garcia-Tsao G.
      • Bosch J.
      Management of varices and variceal hemorrhage in cirrhosis.
      ]. The use of non-selective beta-blocker therapy in the secondary prevention of variceal hemorrhage was first introduced in 1981 [
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ]. Subsequent studies expanded the role of non-selective beta-blockers to include primary prevention of variceal hemorrhage in patients with known cirrhosis and large esophageal varices [
      • Pascal J.P.
      • Cales P.
      Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
      ]. Beta-blocker therapy has been demonstrated to be cost-effective [
      • Hayes P.C.
      • Davis J.M.
      • Lewis J.A.
      • Bouchier I.A.
      Meta-analysis of value of propranolol in prevention of variceal haemorrhage.
      ,
      • Imperiale T.F.
      • Klein R.W.
      • Chalasani N.
      Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding.
      ,
      • Spiegel B.M.
      • Targownik L.
      • Dulai G.S.
      • Karsan H.A.
      • Gralnek I.M.
      Endoscopic screening for esophageal varices in cirrhosis: is it ever cost effective?.
      ], and may be also beneficial in the prevention of other complications of cirrhosis and portal hypertension, including bleeding from portal hypertensive gastropathy [
      • 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.
      ,
      • Perez-Ayuso R.M.
      • Pique J.M.
      • Bosch J.
      • Panes J.
      • Gonzalez A.
      • Perez R.
      • et al.
      Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis.
      ], and the development of spontaneous bacterial peritonitis [
      • Senzolo M.
      • Cholongitas E.
      • Burra P.
      • Leandro G.
      • Thalheimer U.
      • Patch D.
      • et al.
      Beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis.
      ]. However, new studies have cautioned the use of beta-blockers in patients with decompensated cirrhosis [
      • Serste 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.
      ,
      • Serste 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.
      ]. Updated recommendations are therefore needed regarding the appropriate use of beta-blockers in patients with cirrhosis.

      Beta-blockers in cirrhosis

      In its early stages, liver disease is often asymptomatic. As cirrhosis advances, portal hypertension develops, resulting in ascites, hepatic encephalopathy, and variceal hemorrhage. Ascites is the most common major complication of cirrhosis, occurring in 50% of patients within ten years of diagnosis [
      • Runyon B.A.
      Care of patients with ascites.
      ]. The presence of ascites is an ominous landmark in the progression of cirrhosis, as 15% of patients with ascites will succumb within 1 year, and 44% within 5 years [
      • Planas R.
      • Montoliu S.
      • Balleste B.
      • Rivera M.
      • Miquel M.
      • Masnou H.
      • et al.
      Natural history of patients hospitalized for management of cirrhotic ascites.
      ]. Over one third of patients diagnosed with cirrhosis develop esophageal varices within three years of diagnosis [
      • 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.
      ].
      Circulatory disturbances also develop, including increased cardiac output and heart rate, decreased systemic vascular resistance, and decreased mean arterial blood pressure. The most widely accepted explanation of the hemodynamics in cirrhosis, the peripheral arterial vasodilatation hypothesis [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ], states that systemic vasodilatation from reduced systemic vascular resistance leads to arterial underfilling, which together with the sequestration of fluid into the peritoneal cavity, activates salt-retaining mechanisms and neurohormonal systems such as the sympathetic nervous system and the renin-angiotensin-aldosterone system to counteract low arterial blood pressures [
      • Moller S.
      • Bendtsen F.
      • Henriksen J.H.
      Effect of volume expansion on systemic hemodynamics and central and arterial blood volume in cirrhosis.
      ]. As a result, although plasma and blood volume is increased in cirrhosis, patients with decompensated cirrhosis and ascites have a decreased effective arterial blood volume [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ,
      • Moller S.
      • Bendtsen F.
      • Henriksen J.H.
      Effect of volume expansion on systemic hemodynamics and central and arterial blood volume in cirrhosis.
      ,
      • Henriksen J.H.
      • Bendtsen F.
      • Sorensen T.I.
      • Stadeager C.
      • Ring-Larsen H.
      Reduced central blood volume in cirrhosis.
      ,
      • Arroyo V.
      • Gines P.
      Mechanism of sodium retention and ascites formation in cirrhosis.
      ]. Paracentesis further induces arteriolar vasodilation and results in additional decrease in effective arterial blood volume [
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Jimenez W.
      • Garcia-Plaza A.
      • Arroyo V.
      • Rodes J.
      Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis.
      ].
      It is in this pathophysiological context that beta-adrenergic blockade has both theoretical benefits as well as adverse effects. Non-selective beta-blockers such as propranolol and nadolol achieve their effects through the dual mechanism of reducing cardiac output via beta-1 adrenergic blockade, and reducing portal blood flow through splanchnic vasoconstriction via beta-2 adrenergic blockade [
      • Garcia-Tsao G.
      • Lim J.K.
      Members of Veterans Affairs Hepatitis CRCP. 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.
      ]. Both mechanisms are clearly necessary for these medications to be safe and effective in cirrhosis; selective beta-1 antagonists such as metoprolol and atenolol have been shown to be less effective and are not recommended for the prophylaxis of variceal hemorrhage [
      • Hillon P.
      • Lebrec D.
      • Munoz C.
      • Jungers M.
      • Goldfarb G.
      • Benhamou J.P.
      Comparison of the effects of a cardioselective and a nonselective beta-blocker on portal hypertension in patients with cirrhosis.
      ,
      • Westaby D.
      • Melia W.M.
      • Macdougall B.R.
      • Hegarty J.E.
      • Gimson A.E.
      • Williams R.
      B1 selective adrenoreceptor blockade for the long term management of variceal bleeding. A prospective randomised trial to compare oral metoprolol with injection sclerotherapy in cirrhosis.
      ].

      Benefits of beta-blocker therapy

      The use of non-selective beta-blocker therapy was first introduced by Lebrec and colleagues in 1981 [
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ]. In their study, 74 patients presenting with a first episode of variceal bleeding were randomized to either placebo or oral propranolol targeted to a 25% reduction in heart rate. They found that 96% of patients in the propranolol group were free of recurrent gastrointestinal bleeding at one year, compared to 50% of patients in the placebo group [
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ]. The findings from this and additional studies established the role of non-selective beta-blockers in the secondary prevention of gastrointestinal hemorrhage [
      • Poynard T.
      • Lebrec D.
      • Hillon P.
      • Sayegh R.
      • Bernuau J.
      • Naveau S.
      • et al.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a prospective study of factors associated with rebleeding.
      ].
      Subsequent studies expanded the role of non-selective beta-blockers. Pascal and colleagues in 1987 studied the role of propranolol in the prevention of a first upper gastrointestinal bleeding event in patients with known cirrhosis [
      • Pascal J.P.
      • Cales P.
      Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
      ]. In their study, 230 patients with large esophageal varices without previous episodes of bleeding were randomized to either placebo or propranolol targeted to a 20–25% reduction in heart rate. They found that 74% of patients in the propranolol were free of variceal bleeding at one year, compared to 39% in the placebo group, suggesting that propranolol has a role in decreasing the incidence of the first episode of upper gastrointestinal bleeding in patients with cirrhosis [
      • Pascal J.P.
      • Cales P.
      Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
      ]. Similarly, two year survival was 72% in the propranolol group, compared to 51% in the placebo group, demonstrating a significant survival benefit in the use of propranolol in patients with cirrhosis and large esophageal varices [
      • Pascal J.P.
      • Cales P.
      Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
      ]. A meta-analysis from Poynard and colleagues in 1991 analyzed four randomized clinical trials [
      • Pascal J.P.
      • Cales P.
      Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
      ,
      • Lebrec D.
      • Poynard T.
      • Capron J.P.
      • Hillon P.
      • Geoffroy P.
      • Roulot D.
      • et al.
      Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis. randomized trial.
      ,
      • Ideo G.
      • Bellati G.
      • Fesce E.
      • Grimoldi D.
      Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: a prospective, randomized study.
      ,
      • Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients
      Final report of a multicenter randomized trial. Italian multicenter project for propranolol in prevention of bleeding.
      ], and determined that non-selective beta-blockers are effective in preventing first bleeding episode and reducing the mortality rate from gastrointestinal bleeding among patients with cirrhosis [
      • Poynard T.
      • Cales P.
      • Pasta L.
      • Ideo G.
      • Pascal J.P.
      • Pagliaro L.
      • et al.
      Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group.
      ]. Additional meta-analyses have since established the use of non-selective beta-blockers as first-line pharmacotherapy in both primary and secondary prevention of variceal hemorrhage (Table 1) [
      • Garcia-Tsao G.
      • Bosch J.
      Management of varices and variceal hemorrhage in cirrhosis.
      ,
      • Bernard B.
      • Lebrec D.
      • Mathurin P.
      • Opolon P.
      • Poynard T.
      Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis.
      ].
      Table 1Key studies supporting beta-blocker usage.
      n.s., not significant.

      Adverse effects of beta-blocker therapy

      Despite the proven clinical effectiveness of beta-blocker therapy, its success is limited by potential adverse effects and suboptimal treatment adherence. Studies in the cardiology literature have shown that patient adherence to beta-blocker therapy following myocardial infarction decline substantially over time [
      • Smith D.H.
      • Kramer J.M.
      • Perrin N.
      • Platt R.
      • Roblin D.W.
      • Lane K.
      • et al.
      A randomized trial of direct-to-patient communication to enhance adherence to beta-blocker therapy following myocardial infarction.
      ]. Similarly, studies in the hepatology literature have suggested that despite well established guidelines and recommendations, as few as 6–22% of patients with known medium or large varices received primary prophylaxis with beta-blockers [
      • Mellinger J.L.
      • Volk M.L.
      Multidisciplinary management of patients with cirrhosis: a need for care coordination.
      ]. Side effects led to treatment discontinuation in approximately 15% of patients in the various beta-blocker trials in patients with cirrhosis [
      • Garcia-Tsao G.
      • Lim J.K.
      Members of Veterans Affairs Hepatitis CRCP. 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.
      ].
      Beta-blocker therapy can result in both cardiac as well as non-cardiac adverse effects. The decrease in cardiac output from beta-1 antagonism may cause major cardiac side effects. Despite the central role of beta-blockers in the management of congestive heart failure, beta-blockers may also exacerbate heart failure, or even precipitate heart failure in patients with pre-existing cardiac dysfunction and borderline compensation who are reliant upon sympathetic drive [
      • Swedberg K.
      Beta-blockers in worsening heart failure: good or bad?.
      ]. Beta-blockers also significantly decrease chronotropy, depressing conduction through the atrioventricular node. This can result in symptomatic bradycardia, or even high grade heart block [
      • Ko D.T.
      • Hebert P.R.
      • Coffey C.S.
      • Curtis J.P.
      • Foody J.M.
      • Sedrakyan A.
      • et al.
      Adverse effects of beta-blocker therapy for patients with heart failure: a quantitative overview of randomized trials.
      ].
      The acute withdrawal of beta-blocker therapy can lead to serious morbidity and potential mortality [
      • Houston M.C.
      Abrupt cessation of treatment in hypertension: consideration of clinical features, mechanisms, prevention and management of the discontinuation syndrome.
      ]. Abrupt cessation of beta-blocker therapy can result in accelerated angina, myocardial infarction, and sudden death, even in patients who do not previously have coronary artery disease [
      • Psaty B.M.
      • Koepsell T.D.
      • Wagner E.H.
      • LoGerfo J.P.
      • Inui T.S.
      The relative risk of incident coronary heart disease associated with recently stopping the use of beta-blockers.
      ,
      • Miller R.R.
      • Olson H.G.
      • Amsterdam E.A.
      • Mason D.T.
      Propranolol-withdrawal rebound phenomenon. Exacerbation of coronary events after abrupt cessation of antianginal therapy.
      ]. These symptoms are presumably due to rebound sympathetic activity resulting in a hyperadrenergic state, which is more likely to occur with shorter-acting medications such as propranolol [
      • Krukemyer J.J.
      • Boudoulas H.
      • Binkley P.F.
      • Lima J.J.
      Comparison of hypersensitivity to adrenergic stimulation after abrupt withdrawal of propranolol and nadolol: influence of half-life differences.
      ].
      Most of the major non-cardiac adverse effects of beta-blockers result from the non-selective beta-adrenergic blockade. Non-selective beta-blockers can result in increased airways resistance in patients with bronchospasm, and therefore should be avoided in patients with known bronchospastic diseases [
      • Skinner C.
      • Gaddie J.
      • Palmer K.N.
      Comparison of effects of metoprolol and propranolol on asthmatic airway obstruction.
      ]. Nonselective beta-blockers can also cause exacerbations of peripheral artery disease due to the reduction of cardiac output and blockade of beta-2-adrenergic skeletal muscle vasodilation, resulting in local vascular insufficiency. Initial studies of patients with peripheral artery disease taking propranolol showed complications of claudication, cold extremities, absent pulses, cyanosis, and impending gangrene [
      • Frohlich E.D.
      • Tarazi R.C.
      • Dustan H.P.
      Peripheral arterial insufficiency. A complication of beta-adrenergic blocking therapy.
      ]. Additionally, in patients with diabetes mellitus, glucose recovery from insulin-induced hypoglycemia is dependent on epinephrine-mediated beta-adrenergic mechanisms, which can be dangerously impaired by the use of non-selective beta-blockers such as propranolol [
      • Popp D.A.
      • Tse T.F.
      • Shah S.D.
      • Clutter W.E.
      • Cryer P.E.
      Oral propranolol and metoprolol both impair glucose recovery from insulin-induced hypoglycemia in insulin-dependent diabetes mellitus.
      ]. Finally, commonly reported side effects from beta-blockers also include depression, fatigue, and sexual dysfunction [
      • Rosen R.C.
      • Kostis J.B.
      • Jekelis A.W.
      Beta-blocker effects on sexual function in normal males.
      ]. It has been previously hypothesized that these symptoms are associated with central nervous system effects of older generation lipophilic beta-blockers such as propranolol, however a meta-analysis of clinical trials showed no increased risk of depression and small increases in fatigue and sexual dysfunction, without significant differences by the degree of beta-blocker lipid solubility [
      • Ko D.T.
      • Hebert P.R.
      • Coffey C.S.
      • Sedrakyan A.
      • Curtis J.P.
      • Krumholz H.M.
      Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction.
      ].
      Studies of beta-blockers in the cardiology literature have almost uniformly suggested that side effects are decreased with selective beta-1 antagonists. However, selective beta-1 antagonists such as metoprolol and atenolol have been shown to be less effective in portal hypertension and are not recommended for the prophylaxis of variceal hemorrhage [
      • Hillon P.
      • Lebrec D.
      • Munoz C.
      • Jungers M.
      • Goldfarb G.
      • Benhamou J.P.
      Comparison of the effects of a cardioselective and a nonselective beta-blocker on portal hypertension in patients with cirrhosis.
      ,
      • Westaby D.
      • Melia W.M.
      • Macdougall B.R.
      • Hegarty J.E.
      • Gimson A.E.
      • Williams R.
      B1 selective adrenoreceptor blockade for the long term management of variceal bleeding. A prospective randomised trial to compare oral metoprolol with injection sclerotherapy in cirrhosis.
      ]. Additional studies focused on adverse effects of non-selective beta-blockers have been generally lacking. It should be noted that adverse effects of beta-blockers have mostly been reported in the cardiology literature, rather than the hepatology literature. In clinical trials and meta-analyses in the hepatology literature, beta-blockers have not shown decreased survival, and have almost consistently shown benefit. It is therefore not clear whether the lack of reported adverse effects are due to existing studies not having been specifically designed to uncover adverse effects, the inability to generalize results from the cardiology literature to patients with cirrhosis, or other immeasurable factors such as patient non-compliance or type II statistical error.

      The differential effect of beta-blockers in cirrhosis

      Recent studies suggest that beta-blockers may be effective only within a particular clinical window of advanced liver disease [
      • 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.
      ]. Outside of this window, beta-blockers may be ineffective in early cirrhosis with some increase in adverse events, and potentially harmful in advanced cirrhosis (Table 2 and Fig. 1).
      Table 2Key studies suggesting potential harm from beta-blocker usage.
      CI, cardiac index; MAP, mean arterial pressure.
      Figure thumbnail gr1
      Fig. 1The differential effect of beta-blockers in cirrhosis. Modified with permission from: Krag A, Wiest R, Albillos A, Gluud LL. 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;61:967–969. Copyright © 2012 BMJ Group.
      In patients with early cirrhosis, the ineffectiveness of beta-blocker therapy can be attributed to a milder splanchnic and systemic hyperdynamic circulatory state [
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ]. This was suggested in a large multicenter clinical trial from Groszmann and colleagues in 2005, which showed the non-selective beta-blocker timolol to be ineffective in preventing the development of varices in unselected patients with cirrhosis and portal hypertension [
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ]. In their study, 213 patients with cirrhosis and portal hypertension confirmed with hepatic venous pressure gradient (HVPG) measurements were randomized to receive either placebo or timolol targeted to a 25% reduction in heart rate or a goal heart rate of 55 beats per minute. At a median follow-up period of 54.9 months, the trial showed no significant difference in the development of gastrointestinal varices or variceal bleeding. However, the study demonstrated a statistically significant increase in the number of adverse events (48% in the timolol group vs. 32% in the placebo group), which included bradycardia, fatigue, shortness of breath, syncope, claudication, and impotence. It was noted that drug intolerance limited the ability to further up-titrate timolol dosing, as patients were reluctant to tolerate its side effects. The study concluded that the use of beta blockers cannot be widely recommended because of the increased incidence of serious side effects [
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ].
      In advanced cirrhosis, a number of circulatory changes occur, including the up-regulation of the sympathetic nervous system [
      • Murray J.F.
      • Dawson A.M.
      • Sherlock S.
      Circulatory changes in chronic liver disease.
      ,
      • Willett I.
      • Esler M.
      • Burke F.
      • Leonard P.
      • Dudley F.
      Total and renal sympathetic nervous system activity in alcoholic cirrhosis.
      ] and of the renin-angiotensin-aldosterone system [
      • Rosoff Jr., L.
      • Williams J.
      • Moult P.
      • Williams H.
      • Sherlock S.
      Renal hemodynamics and the renin–angiotensin system in cirrhosis: relationship to sodium retention.
      ,
      • Rosoff Jr., L.
      • Zia P.
      • Reynolds T.
      • Horton R.
      Studies of renin and aldosterone in cirrhotic patients with ascites.
      ]. These circulatory changes, along with the development of sodium and water retention and the formation of ascites, are aimed at maintaining adequate cardiac output and organ perfusion. They reflect an adaptive response to the peripheral vasodilation, effective hypovolemia, and arterial hypotension that accompanies advanced cirrhosis. However, as cirrhosis progresses, the cardiovascular system eventually loses its compensatory ability. It is at this stage that the maintenance of blood pressure and cardiac output is paramount in prolonging overall survival, and there is evidence that the hemodynamic effects of beta-blockers in reducing blood pressure and cardiac output may actually result in decreased survival in this subset of patients [
      • Serste 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.
      ,
      • 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.
      ,
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ].

      Blood pressure and survival

      The correlation between blood pressure and survival in patients with cirrhosis was suggested by Llach and colleagues in 1988 [
      • Llach J.
      • Gines P.
      • Arroyo V.
      • Rimola A.
      • Tito L.
      • Badalamenti S.
      • 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.
      ]. In their survival analysis of 139 patients with cirrhosis and ascites, mean arterial pressure was found to be an independent predictor of survival [
      • Llach J.
      • Gines P.
      • Arroyo V.
      • Rimola A.
      • Tito L.
      • Badalamenti S.
      • 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.
      ]. Mean arterial pressure of ⩽82 mmHg was the single variable most strongly correlated with shortened survival; the survival probability rate of patients with mean arterial pressure ⩽82 mmHg was approximately 20% at 24 months and 0% at 48 months, in contrast with approximately 70% at 24 months and 50% at 48 months among patients with mean arterial pressure >82 mmHg [
      • Llach J.
      • Gines P.
      • Arroyo V.
      • Rimola A.
      • Tito L.
      • Badalamenti S.
      • 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.
      ]. It was also observed that patients with ascitic fluid protein ⩽1 g/dl correlated with a significantly shorter survival, similar to previous observations that patients with low ascitic fluid protein levels are predisposed to developing spontaneous bacterial peritonitis [
      • Runyon B.A.
      Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.
      ]. The study concluded that the increased activity of the renin-angiotensin-aldosterone and sympathetic nervous systems in patients with cirrhosis with ascites is a homeostatic response to maintain arterial pressures near or within normal range, and that mean arterial pressure is possibly itself a reflection of the degree of alteration of the splanchnic and portal circulation [
      • Llach J.
      • Gines P.
      • Arroyo V.
      • Rimola A.
      • Tito L.
      • Badalamenti S.
      • 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.
      ].
      A hyperdynamic circulation with arterial underfilling from splanchnic vasodilation also results in the development of hepatorenal syndrome, a major cause of mortality in patients with cirrhosis [
      • Arroyo V.
      • Terra C.
      • Gines P.
      Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome.
      ]. Krag and colleagues demonstrated that a low cardiac output state predicts the development of hepatorenal syndrome and subsequent survival in patients with cirrhosis and ascites [
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ]. In their study of 24 patients with cirrhosis and ascites, patients with a cardiac index below 1.5 L/min/m2 had significantly decreased survival compared to those with a cardiac index above 1.5 L/min/m2 [
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ]. The study also showed that cumulative survival in patients with mean arterial pressure below 80 mmHg was 60% at 6 months and <40% at 12 months; in contrast, survival in patients with mean arterial pressure above 80 mmHg was >80% at 6 months and >70% at 12 months [
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ]. The study concluded with a suggestion that in patients with low cardiac indices and ascites, beta-blockers and/or other methods of decreasing systemic pressures may worsen hemodynamics, resulting in the development of hepatorenal syndrome and subsequent mortality [
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ].

      Midodrine

      Additional evidence confirming the importance of maintaining cardiac output in patients with advanced cirrhosis has been suggested among studies of midodrine, an alpha-1 adrenergic agonist [
      • Angeli P.
      • Volpin R.
      • Piovan D.
      • Bortoluzzi A.
      • Craighero R.
      • Bottaro S.
      • et al.
      Acute effects of the oral administration of midodrine, an alpha-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites.
      ,
      • Kalambokis G.
      • Fotopoulos A.
      • Economou M.
      • Pappas K.
      • Tsianos E.V.
      Effects of a 7-day treatment with midodrine in non-azotemic cirrhotic patients with and without ascites.
      ,
      • Wong F.
      • Pantea L.
      • Sniderman K.
      Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome.
      ,
      • McTavish D.
      • Goa K.L.
      Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders.
      ,
      • Singh V.
      • Dhungana S.P.
      • Singh B.
      • Vijayverghia R.
      • Nain C.K.
      • Sharma N.
      • et al.
      Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study.
      ]. Angeli and colleagues in 1998 demonstrated that midodrine has a preferential effect on the splanchnic circulation, and its acute administration overall improves systemic hemodynamics, renal function, and sodium excretion in non-azotemic patients with ascites [
      • Angeli P.
      • Volpin R.
      • Piovan D.
      • Bortoluzzi A.
      • Craighero R.
      • Bottaro S.
      • et al.
      Acute effects of the oral administration of midodrine, an alpha-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites.
      ]. Their findings were followed by subsequent studies, which introduced the combination of octreotide and midodrine as a treatment for type 1 hepatorenal syndrome [
      • Angeli P.
      • Volpin R.
      • Gerunda G.
      • Craighero R.
      • Roner P.
      • Merenda R.
      • et al.
      Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.
      ,
      • Esrailian E.
      • Pantangco E.R.
      • Kyulo N.L.
      • Hu K.Q.
      • Runyon B.A.
      Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome.
      ]. In a recent randomized controlled study from Singh and colleagues, midodrine therapy was shown to result in a significant increase in urinary volume, urinary sodium excretion, and mean arterial pressure; with decrease in plasma renin activity and in overall mortality [
      • Singh V.
      • Dhungana S.P.
      • Singh B.
      • Vijayverghia R.
      • Nain C.K.
      • Sharma N.
      • et al.
      Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study.
      ]. The study concluded that midodrine improved systemic hemodynamics without causing renal or hepatic dysfunction [
      • Singh V.
      • Dhungana S.P.
      • Singh B.
      • Vijayverghia R.
      • Nain C.K.
      • Sharma N.
      • et al.
      Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study.
      ].

      ACE inhibitors

      Studies investigating the effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with cirrhosis have likewise shown that reducing cardiac index and mean arterial pressures results in worsened outcomes in patients with advanced cirrhosis and ascites [
      • Wood L.J.
      • Goergen S.
      • Stockigt J.R.
      • Powell L.W.
      • Dudley F.J.
      Adverse effects of captopril in treatment of resistant ascites, a state of functional bilateral renal artery stenosis.
      ,
      • Schepke M.
      • Werner E.
      • Biecker E.
      • Schiedermaier P.
      • Heller J.
      • Neef M.
      • et al.
      Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension.
      ,
      • Gonzalez-Abraldes J.
      • Albillos A.
      • Banares R.
      • Del Arbol L.R.
      • Moitinho E.
      • Rodriguez C.
      • et al.
      Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis.
      ,
      • Tripathi D.
      • Therapondos G.
      • Lui H.F.
      • Johnston N.
      • Webb D.J.
      • Hayes P.C.
      Chronic administration of losartan, an angiotensin II receptor antagonist, is not effective in reducing portal pressure in patients with preascitic cirrhosis.
      ]. The latest clinical practice guidelines from both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver on the management of adult patients with ascites due to cirrhosis recommend against the use of ACE inhibitors and ARBs in patients with ascites due to concerns of hypotension and renal failure [
      • Runyon B.A.
      Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012.
      ,
      • Runyon B.A.
      AASLD PRACTICE GUIDELINE management of adult patients with ascites due to cirrhosis: update 2012.
      ,
      • European Association for the Study of the Liver
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      ].

      Carvedilol

      Similarly, studies of newer-generation beta-blockers such as carvedilol concluded that while carvedilol has a potent portal hypotensive effect that may be superior to propranolol, it has greater potential to cause systemic hypotension, especially in patients with cirrhosis and ascites [
      • Forrest E.H.
      • Bouchier I.A.
      • Hayes P.C.
      Acute haemodynamic changes after oral carvedilol, a vasodilating beta-blocker, in patients with cirrhosis.
      ,
      • Banares R.
      • Moitinho E.
      • Piqueras B.
      • Casado M.
      • Garcia-Pagan J.C.
      • de Diego A.
      • 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.
      ,
      • Banares R.
      • Moitinho E.
      • Matilla A.
      • Garcia-Pagan J.C.
      • Lampreave J.L.
      • Piera C.
      • et al.
      Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis.
      ,
      • Tripathi D.
      • Ferguson J.W.
      • Kochar N.
      • Leithead J.A.
      • Therapondos G.
      • McAvoy N.C.
      • et al.
      Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.
      ]. Thus far, evidence supporting the use of carvedilol for portal hypertension has been limited [
      • Bosch J.
      Carvedilol for portal hypertension in patients with cirrhosis.
      ]. In one study from Banares and colleagues, 35 patients were randomized to carvedilol, propranolol, or placebo [
      • Banares R.
      • Moitinho E.
      • Piqueras B.
      • Casado M.
      • Garcia-Pagan J.C.
      • de Diego A.
      • 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.
      ]. Carvedilol was found to markedly reduce HVPG greater than propranolol; patients receiving carvedilol achieved HVPG <12 mmHg or >20% decrease from baseline HVPG in a greater proportion than propranolol (64% vs. 14%, p <0.05). However, carvedilol also caused significant arterial hypotension with average decrease in mean arterial pressure of −17.2% in the carvedilol group vs. −3.4% in the propranolol group [
      • Banares R.
      • Moitinho E.
      • Piqueras B.
      • Casado M.
      • Garcia-Pagan J.C.
      • de Diego A.
      • 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.
      ]. In a follow-up study, 51 patients were randomized to long-term carvedilol or propranolol [
      • Banares R.
      • Moitinho E.
      • Matilla A.
      • Garcia-Pagan J.C.
      • Lampreave J.L.
      • Piera C.
      • et al.
      Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis.
      ]. Carvedilol was shown to cause a greater decrease in HVPG than propranolol, with a greater proportion of patients achieving an HVPG reduction of >20% or <12 mmHg. However, the study again showed a significant decrease in mean arterial pressure of −11% in the carvedilol group vs. −5% in the propranolol group. Patients receiving carvedilol also had significant increases in plasma volume, body weight, and worsening of pre-existing ascites [
      • Banares R.
      • Moitinho E.
      • Matilla A.
      • Garcia-Pagan J.C.
      • Lampreave J.L.
      • Piera C.
      • et al.
      Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis.
      ].
      More recently, Tripathi and colleagues compared carvedilol vs. variceal band ligation in a randomized controlled trial of 152 patients with medium or large esophageal varices [
      • Tripathi D.
      • Ferguson J.W.
      • Kochar N.
      • Leithead J.A.
      • Therapondos G.
      • McAvoy N.C.
      • et al.
      Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.
      ]. The carvedilol group was found to have lower rates of first variceal bleeding of 10% vs. 23% in the variceal band ligation group. There were no significant differences in overall mortality or bleeding-related mortality. The study concluded that carvedilol is effective for primary prophylaxis of variceal bleeding in patients with high-risk esophageal varices [
      • Tripathi D.
      • Ferguson J.W.
      • Kochar N.
      • Leithead J.A.
      • Therapondos G.
      • McAvoy N.C.
      • et al.
      Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.
      ]. Thus, while initial studies concluded that the clinical applicability of carvedilol is limited by its systemic hypotensive effects, more recent studies suggest a potential role for carvedilol in the primary and secondary prevention of variceal bleeding. However, the data at present is inconclusive at best and merits additional investigation.
      Despite the central role of beta-blockers in the treatment of hypertension, acute coronary syndrome, and congestive heart failure, recent concerns have been raised by the cardiology community regarding the use of beta-blockers. Several studies have suggested that no evidence existed that beta-blockers prevent first episodes of cardiovascular events in patients with hypertension, and in some trials, beta-blockers actually had worse outcomes compared to other classes of antihypertensives [
      • Che Q.
      • Schreiber Jr., M.J.
      • Rafey M.A.
      Beta-blockers for hypertension: are they going out of style?.
      ]. One meta-analysis concluded that beta-blockers were associated with a higher risk of death from cardiovascular causes when compared to renin-angiotensin blockade [
      • Balamuthusamy S.
      • Molnar J.
      • Adigopula S.
      • Arora R.
      Comparative analysis of beta-blockers with other antihypertensive agents on cardiovascular outcomes in hypertensive patients with diabetes mellitus: a systematic review and meta-analysis.
      ]. Newer guidelines no longer recommend the use of beta-blockers in the initial treatment of hypertension [
      • Mancia G.
      • De Backer G.
      • Dominiczak A.
      • Cifkova R.
      • Fagard R.
      • Germano G.
      • et al.
      2007 Guidelines for the management of arterial hypertension: he Task Force for the Management of ArteTrial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ,
      • Rosendorff C.
      • Black H.R.
      • Cannon C.P.
      • Gersh B.J.
      • Gore J.
      • Izzo Jr., J.L.
      • et al.
      Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention.
      ]. Furthermore, data from the POISE trial studying the effects of perioperative metoprolol in patients undergoing non-cardiac surgery found that although metoprolol decreased the risk of myocardial infarction, cardiac revascularization, and atrial fibrillation, it also resulted in an excess risk of death, stroke, and clinically significant hypotension and bradycardia [
      • Devereaux P.J.
      • Yang H.
      • Yusuf S.
      • Guyatt G.
      • Leslie K.
      • Villar J.C.
      • et al.
      Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial.
      ].

      Beta-blockers in refractory ascites

      The challenges and adverse effects of beta-blockers appear to be most pronounced in patients with advanced cirrhosis and refractory ascites. In 2010, almost 30 years following their landmark article on the use of propranolol for the prevention of recurrent variceal bleeding [
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ], Lebrec and colleagues (Serste et al.) showed in a prospective observational study that the use of beta-blockers in patients with refractory ascites may be associated with poor survival, suggesting that beta-blockers should be contraindicated in this subclass of patients [
      • Serste 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.
      ], Their study included 151 patients with cirrhosis and refractory ascites, who all regularly underwent large-volume paracentesis and intravenous albumin administration. The overall mean survival was 10 months, with a 41% probability of survival at 1 year. However, the median survival was dramatically lower in patients treated with propranolol (5 months, with 19% probability of survival at 1 year), as compared to the median survival in patients who were not treated with propranolol (20 months, with 64% probability of survival at 1 year) [
      • Serste 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.
      ]. This four-fold decrease in median survival with the administration of propranolol in patients with refractory ascites was highly statistically significant [
      • Serste 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.
      ]. In their editorial regarding this study, Wong and Salerno stated that although there were methodological concerns to the study, an important question was raised as to the safety of propranolol in patients with cirrhosis and refractory ascites [
      • Wong F.
      • Salerno F.
      Beta-blockers in cirrhosis: friend and foe?.
      ].
      A subsequent self-controlled cross-over study by Lebrec and colleagues (Serste et al.) showed that beta-blockers are associated with the development of paracentesis-induced circulatory dysfunction, further suggesting that beta-blockers are correlated with poor survival in this group of patients [
      • Serste 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.
      ]. In this study involving 10 patients in a cross-over design, patients given propranolol experienced a significant decrease in mean arterial pressure with no significant change in heart rate following paracentesis, with the development of paracentesis-induced circulatory dysfunction in eight of the ten patients [
      • Serste 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.
      ]. After discontinuation of beta-blockers, patients experienced a significant increase in heart rate with no significant change in mean arterial pressure following paracentesis, with the development of paracentesis-induced circulatory dysfunction in only one of the ten patients. The study concluded that among patients with cirrhosis and refractory ascites, beta-blockers may be associated with an increased risk of paracentesis-induced circulatory dysfunction, which although may be clinically silent in itself, is associated with shortened survival [
      • Gines A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • Vila C.
      • Domenech E.
      • Abecasis R.
      • et al.
      Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
      ].
      One important observation mentioned by Lebrec and colleagues in their recent study [
      • Serste 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.
      ] is that the effects of beta-blockers in the subset of patients with cirrhosis and refractory ascites had actually never been studied. Even the original studies, which demonstrated a clear and convincing survival advantage of beta-blockers in patients with cirrhosis and esophageal varices, excluded the subset of patients with refractory ascites. One of the specific inclusion criteria in the original study by Lebrec and colleagues in 1981 was that “ascites was absent or mild and transient” [
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ]. In the study by Pascal and colleagues in 1987, patients were included only if they had a Child-Pugh score of less than 14 [
      • Pascal J.P.
      • Cales P.
      Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
      ]. In the meta-analysis from Poynard and colleagues in 1991 of four trials of beta-blockers in the primary prevention of esophageal variceal bleeding, advanced cirrhosis and the presence of ascites were independently associated with death in both patients receiving propranolol and not receiving propranolol [
      • Poynard T.
      • Cales P.
      • Pasta L.
      • Ideo G.
      • Pascal J.P.
      • Pagliaro L.
      • et al.
      Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group.
      ]. However, patients with refractory ascites were again excluded from any of the trials used in the meta-analysis [
      • Poynard T.
      • Cales P.
      • Pasta L.
      • Ideo G.
      • Pascal J.P.
      • Pagliaro L.
      • et al.
      Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group.
      ]. Certainly additional research is needed to fully study the effects of beta-blockers in this population; however, based on the available evidence, it is likely that such studies will show a detrimental effect of beta-blockers in patients with advanced cirrhosis and refractory ascites.
      At present, due to the paucity of available studies, we have determined that although recent studies are suggesting harm in the use of beta-blockers in patients with advanced cirrhosis and refractory ascites, there exists insufficient evidence to draw definitive conclusions. The existing studies do not share enough homogeneity for pooled analysis or meta-analysis to be reliably and confidently performed. Additional studies to evaluate the role and safety of beta-blockers in patients with advanced cirrhosis and refractory ascites are critically needed; however developing a large randomized controlled trial to answer aspects of this question is certain to be difficult especially as beta-blockers are increasingly becoming generic.

      Additional challenges affecting beta-blocker therapy

      There are several additional challenges to beta-blocker therapy in cirrhosis. First, the appropriate dosing of beta-blockers in cirrhosis can be problematic and demands further investigation. The current propranolol dosing regimen was established by several of the early non-selective beta-blocker clinical trials (Table 3), without explanation to the origin or scientific validity of such a dosing regimen. Lebrec’s original study called for propranolol to be given at increasing doses until the heart rate was reduced by approximately 25%, with doses ranging from 20 to 180 mg given twice a day [
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ]. Subsequent clinical studies evaluating the hemodynamic effects of propranolol continued to utilize this dosing regimen [
      • Bataille C.
      • Bercoff E.
      • Pariente E.A.
      • Valla D.
      • Lebrec D.
      Effects of propranolol on renal blood flow and renal function in patients with cirrhosis.
      ,
      • Lebrec D.
      • Hillon P.
      • Munoz C.
      • Goldfarb G.
      • Nouel O.
      • Benhamou J.P.
      The effect of propranolol on portal hypertension in patients with cirrhosis: a hemodynamic study.
      ,
      • Vorobioff J.
      • Picabea E.
      • Villavicencio R.
      • Puccini V.
      • Rossi O.
      • Bordato J.
      • et al.
      Acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients.
      ]. Additional investigations regarding the dosing of beta-blockers have since escaped scientific study.
      Table 3Beta-blocker dosing-regimens.
      A number of the beta-blocker trials determined that a decrease in portal pressure during chronic treatment, as measured by a decrease in the hepatic venous pressure gradient (HVPG) to <12 mmHg or by >20% from baseline, was a strong predictor of clinical effectiveness [
      • 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.
      ,
      • Villanueva C.
      • Minana J.
      • Ortiz J.
      • Gallego A.
      • Soriano G.
      • Torras X.
      • et al.
      Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.
      ]. Studies have shown that assessment of hemodynamic response with the HVPG may be the best predictor of clinical efficacy in patients being treated with beta-blockers [
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ,
      • Merkel C.
      • Bolognesi M.
      • Sacerdoti D.
      • Bombonato G.
      • Bellini B.
      • Bighin R.
      • 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.
      ]. However, dosing to HVPG goals is problematic as this method is invasive, impractical, and not routinely performed in most institutions in the United States except in clinical research studies [
      • Albillos A.
      • Banares R.
      • Gonzalez M.
      • Ripoll C.
      • Gonzalez R.
      • Catalina M.V.
      • et al.
      Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a meta-analysis.
      ].
      Second, previous studies have implicated patients’ unwillingness to tolerate the side effects of beta-blockers as a factor in treatment failure [
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ]. Regardless of whether or not the side effects have been confirmed in rigorous meta-analyses, in our anecdotal experience patients routinely complain of side effects including fatigue, lightheadedness, and erectile dysfunction, and many unilaterally discontinue or dose-reduce the medication without reporting this to their physician [
      • Stoudemire A.
      • Thompson 2nd, T.L.
      Medication noncompliance: systematic approaches to evaluation and intervention.
      ]. It is therefore not surprising that an increasing amount of evidence suggests that many patients fail to receive evidence-proven treatments [
      • Mellinger J.L.
      • Volk M.L.
      Multidisciplinary management of patients with cirrhosis: a need for care coordination.
      ,
      • Kanwal F.
      • Kramer J.R.
      • Buchanan P.
      • Asch S.M.
      • Assioun Y.
      • Bacon B.R.
      • et al.
      The quality of care provided to patients with cirrhosis and ascites in the Department of Veterans Affairs.
      ].
      Third, the limited therapeutic window during which beta-blockers provide a survival benefit demands close follow-up to minimize the risk of causing harm to the patient, and to ensure that beta-blockers are discontinued when the patient’s disease progresses beyond this window. In our experience, we increasingly encounter patients with cirrhosis on multiple antihypertensives who invariably develop azotemia, hypotension, and end-organ damage as their cirrhosis progresses. Beta-blockers should not be recommended to patients who have poor follow-up or who have issues with non-compliance; the initiation and continuation of beta-blockers demands meticulous follow-up, ideally with home monitoring of blood pressure by patients and frequent clinic visits with the physician. The hemodynamic effects of these medications are significant and may become dangerous as these patients develop worsening cirrhosis.
      Fourth, discontinuity of care is an increasingly challenging issue in modern medicine. The widely popular hospitalist movement has separated the outpatient physician from the inpatient physician, creating discontinuity at a critical juncture in patient care. Patients may be started on beta-blockers during their initial hospitalization for a life-threatening variceal bleeding event, only to be left in an “autopilot” state upon discharge. They may either subsequently present to an emergency department months later with systemic hypotension and azotemia, potentially at a different hospital which has no records for the patient, or may develop symptoms or side effects and unilaterally discontinue their medication. This concern is supported by a recent study, which showed that the increasing involvement of hospitalists was associated with a significant decrease in continuity of care [
      • Sharma G.
      • Fletcher K.E.
      • Zhang D.
      • Kuo Y.F.
      • Freeman J.L.
      • Goodwin J.S.
      Continuity of outpatient and inpatient care by primary care physicians for hospitalized older adults.
      ]. Recent studies aimed at care coordination may help to decrease the discontinuity of care and improve outpatient follow-up and medication compliance [
      • Morando F.
      • Maresio G.
      • Piano S.
      • Fasolato S.
      • Cavallin M.
      • Romano A.
      • et al.
      How to improve care in outpatients with cirrhosis and ascites: a new model of care coordination by consultant hepatologists.
      ].

      Recommendations and conclusions

      One of the few benefits of advanced cirrhosis may be that cirrhosis effectively cures hypertension. The emerging prevalence of NAFLD and NASH cirrhosis, our society’s ongoing struggles with metabolic syndrome and its comorbid diabetes mellitus and essential hypertension, and the changing healthcare environment in the United States draws new implications regarding the use of beta-blocker therapy in patients with cirrhosis. Our overall recommendations for the use of beta-blockers are summarized in Table 4 and Fig. 2.
      Table 4Summary of recommendations for beta-adrenergic antagonists in patients with cirrhosis.
      Figure thumbnail gr2
      Fig. 2Algorithmic approach for beta-adrenergic antagonists in patients with cirrhosis. BP, blood pressure; EGD, esophagogastroduodenoscopy.
      Perhaps the most appropriate timing for beta-blocker therapy was outlined in a recent hypothesis from Krag and colleagues known as the “window hypothesis” (Fig. 1), which suggests that beta-blockers improve survival only in a narrow clinical window in the course of cirrhosis [
      • 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.
      ]. In early cirrhosis, beta-blockers have no effect on survival, increase adverse events and do not prevent the formation of varices [
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ]. In this early stage, the initiation of beta-blockers is not recommended for the purpose of preventing gastrointestinal bleeding, although they may be indicated for cardiac comorbidities such as coronary artery disease and congestive heart failure.
      As portal pressures increase and the sympathetic nervous system becomes increasingly activated, medium to large esophageal varices develop, and there is increased risk of variceal bleeding and bacterial translocation from the gut [
      • Runyon B.A.
      • Squier S.
      • Borzio M.
      Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis.
      ]. Ascites also begins to develop at this stage. From a cardiovascular perspective, systemic hemodynamics is still relatively preserved, cardiovascular reserve is intact, and blood pressure and cardiac output are maintained to deliver adequate end-organ perfusion. In this middle stage of cirrhosis, beta-blockers have been shown in numerous trials to have survival benefit [
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ,
      • Poynard T.
      • Cales P.
      • Pasta L.
      • Ideo G.
      • Pascal J.P.
      • Pagliaro L.
      • et al.
      Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group.
      ,
      • Garcia-Tsao G.
      • Bosch J.
      Management of varices and variceal hemorrhage in cirrhosis.
      ,
      • 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.
      ]. Beta-blockers are therefore indicated and recommended for the primary and secondary prevention of gastrointestinal bleeding, although they should be promptly discontinued in the setting of either sepsis or hepatorenal syndrome.
      However, as cirrhosis progresses and cardiovascular reserve becomes impaired, the sympathetic nervous system is maximally stimulated to maintain cardiac output and end-organ perfusion. Additional complications such as cirrhotic cardiomyopathy may also develop [
      • Ma Z.
      • Lee S.S.
      Cirrhotic cardiomyopathy: getting to the heart of the matter.
      ]. In this advanced stage of cirrhosis, generally reflected by refractory ascites, the evidence now suggests that beta-blockers reduce survival. The inability of the circulatory system to increase cardiac output via the beta-adrenergic system during situations of increased physiological stress results in decreased mean arterial pressures, decreased perfusion to vital organs, azotemia, and subsequent increased risk for hepatorenal syndrome and end-organ damage [
      • Serste 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.
      ,
      • Serste 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.
      ,
      • 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.
      ,
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ]. In this final stage of decompensated cirrhosis, beta-blockers should neither be recommended nor initiated. Additionally, beta-blockers should be tapered and discontinued in those patients who develop refractory ascites, worsening hypotension, or worsening azotemia [
      • Runyon B.A.
      Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012.
      ,
      • Runyon B.A.
      AASLD PRACTICE GUIDELINE management of adult patients with ascites due to cirrhosis: update 2012.
      ]. Endoscopic band ligation of varices can be considered as a substitute treatment to prevent variceal hemorrhage [
      • Pascal J.P.
      • Cales P.
      Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
      ,
      • Lo G.H.
      • Chen W.C.
      • Chen M.H.
      • Hsu P.I.
      • Lin C.K.
      • Tsai W.L.
      • et al.
      Banding ligation versus nadolol and isosorbide mononitrate for the prevention of esophageal variceal rebleeding.
      ]. Consideration should also be given to agents such as midodrine that increase cardiac output and blood pressure [
      • Angeli P.
      • Volpin R.
      • Piovan D.
      • Bortoluzzi A.
      • Craighero R.
      • Bottaro S.
      • et al.
      Acute effects of the oral administration of midodrine, an alpha-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites.
      ]. One potential option in patients with end-stage cirrhosis that merits additional investigation would be to consider simultaneously using non-selective beta-blockers for the prevention of variceal bleeding, and midodrine to improve systemic hemodynamics.
      Figure thumbnail fx5

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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