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Prevention of Variceal Bleeding and Rebleeding by Nonselective Beta-Blockers

A Tailored Approach
  • Mathias Jachs
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • Thomas Reiberger
    Correspondence
    Corresponding author. Division of Gastroenterology and Hepatology, Department of Medicine III, Waehringer Guertel 18-20, Vienna A-1090, Austria.
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
Open AccessPublished:March 09, 2021DOI:https://doi.org/10.1016/j.cld.2021.01.004

      Keywords

      Key points

      • Nonselective beta-blockers are the cornerstone of medical therapy for the prevention of variceal bleeding and rebleeding.
      • Recent studies have shown that nonselective beta-blockers not only decrease bleeding rates, but also prolong decompensation-free survival in compensated cirrhosis.
      • Hepatic venous pressure gradient-guided therapy is the gold standard for the prophylaxis of variceal bleeding. Endoscopy represents a widely available alternative for prestratification and prognostication of patients.
      • A tailored, individualized approach to nonselective beta-blocker therapy in the prevention of first variceal bleeding and rebleeding based on hepatic venous pressure gradient availability or varix status is proposed.

      Background

      Two major pathophysiologic factors contribute to elevated levels of portal pressure in patients with cirrhosis: increased intrahepatic (sinusoidal) vascular resistance and increased portal blood inflow. Over the natural course of advanced chronic liver disease (ACLD), portal pressure rises, eventually surpassing the threshold of 10 mmHg or greater that defines clinically significant portal hypertension (CSPH).
      • Iwakiri Y.
      Pathophysiology of portal hypertension.
      In the setting of CSPH, progressive peripheral and splanchnic vasodilation ultimately lead to increases in both heart rate and cardiac output, defining the hyperdynamic circulatory portal-hypertensive syndrome.
      • Bolognesi M.
      • Di Pascoli M.
      • Verardo A.
      • et al.
      Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis.
      Endoscopic screening for gastroesophageal varices (GEV) is traditionally most commonly used in clinical practice to assess the presence of CSPH; however, the presence of other portosystemic collaterals on cross-sectional imaging
      • Simón-Talero M.
      • Roccarina D.
      • Martínez J.
      • et al.
      Association between portosystemic shunts and increased complications and mortality in patients with cirrhosis.
      and measurement of hepatic venous pressure gradient (HVPG)
      • Reiberger T.
      • Schwabl P.
      • Trauner M.
      • et al.
      Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
      allow an early diagnosis of CSPH when GEVs may not yet be present. Importantly, portal pressure, that is, the HVPG, is the main determinant for the risk of GEVs to rupture and to cause acute variceal bleeding, which is still associated with considerable mortality of up to 20%.
      • Reverter E.
      • Tandon P.
      • Augustin S.
      • et al.
      A MELD-based model to determine risk of mortality among patients with acute variceal bleeding.
      Hemodynamic changes in patients with portal hypertension are predominantly mediated through activation of the sympathetic nervous system, and in turn, beta-adrenergic blockade through nonselective beta-blockers (NSBBs) decreases the portal pressure, thereby decreasing the risk of variceal bleeding. Thus, NSBBs represent the medical treatment of choice both for primary
      • Poynard T.
      • Calès P.
      • Pasta 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.
      • Groszmann R.J.
      • Bosch J.
      • Grace N.D.
      • et al.
      Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage.
      • Schepke M.
      • Kleber G.
      • Nürnberg D.
      • et al.
      Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis.
      and secondary
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • et al.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
      ,
      • Gonzalez R.
      • Zamora J.
      • Gomez-Camarero J.
      • et al.
      Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis.
      prophylaxis of acute variceal bleeding. The therapeutic effect of carvedilol as an NSBB with additional anti-α1-adrenergic activity that has a stronger effect on portal pressure as well as on systemic vasodilation has been established in the setting of primary prophylaxis,
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      • Tripathi D.
      • Ferguson J.W.
      • Kochar N.
      • et al.
      Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.
      • Schwarzer R.
      • Kivaranovic D.
      • Paternostro R.
      • et al.
      Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study.
      but the evidence for its role in secondary prophylaxis
      • Tripathi D.
      • Ferguson J.W.
      • Kochar N.
      • et al.
      Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.
      ,
      • Pfisterer N.
      • Dexheimer C.
      • Fuchs E.-M.
      • et al.
      Betablockers do not increase efficacy of band ligation in primary prophylaxis but they improve survival in secondary prophylaxis of variceal bleeding.
      and in the setting of advanced disease with ascites
      • Sersté T.
      • Melot C.
      • Francoz C.
      • et al.
      Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.
      • Chirapongsathorn S.
      • Valentin N.
      • Alahdab F.
      • et al.
      Nonselective β-blockers and survival in patients with cirrhosis and ascites: a systematic review and meta-analysis.
      • Turco L.
      • Villanueva C.
      • La Mura V.
      • et al.
      Lowering portal pressure improves outcomes of patients with cirrhosis, with or without ascites: a meta-analysis.
      is still limited. Despite the strong body of evidence for the efficacy of NSBBs in the prevention of bleeding and potential other complications of CSPH, clinicians sometimes face difficult decisions regarding NSBB therapy in individual patients owing to side effects and tolerability issues, as well as concerns about safety in certain patient cohorts. Therefore, this article aims to provide a comprehensive review of NSBB therapy in different stages of portal hypertension, arguing for a tailored and individualized approach for the use of NSBBs for the prevention of first variceal bleeding and rebleeding.

      Diagnosis of clinically significant portal hypertension and assessing hemodynamic response to nonselective beta-blocker therapy by measurement of the hepatic venous pressure gradient

      The measurement of the HVPG represents the current gold standard for the diagnosis and monitoring of portal hypertension.
      • Reiberger T.
      • Schwabl P.
      • Trauner M.
      • et al.
      Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
      ,
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      The clinical use of HVPG measurements in chronic liver disease.
      Although the procedure is invasive and requires considerable expertise and specialized infrastructure, in trained hands the measurement of the HVPG is a safe and reproducible way to evaluate portal pressure and has indisputable advantages.
      • Reiberger T.
      • Schwabl P.
      • Trauner M.
      • et al.
      Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
      Importantly, compensated patients might have already developed CSPH, which is associated with an important prognostic implication,
      • Ripoll C.
      • Groszmann R.
      • Garcia–Tsao G.
      • et al.
      Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
      whereas the clinical signs of CSPH such as varices, portosystemic collaterals, and ascites occur only subsequently after CSPH has devleoped.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      Not all patients with ACLD will show a decrease in portal pressure with NSBB treatment
      • Thalheimer U.
      Monitoring target reduction in hepatic venous pressure gradient during pharmacological therapy of portal hypertension: a close look at the evidence.
      and the efficacy of NSBB is mostly evident after CSPH has developed, that is, when HVPG is 10 mmHg or greater and splanchnic vasodilation is present, as elegantly shown by Villanueva and colleagues
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • et al.
      Development of hyperdynamic circulation and response to β-blockers in compensated cirrhosis with portal hypertension.
      in a mechanistical study: In their study, the authors compared the effects of NSBBs in patients with subclinical portal hypertension, that is, an HVPG of 6 to 9 mmHg, versus patients with CSPH (HVPG ≥10 mmHg). It was found that mean relative decreases were significantly higher (−16%) in patients with CSPH, as compared with patients with subclinical portal hypertension (−8%). This result explains why NSBBs were shown to be generally ineffective in the setting of preprimary prophylaxis, that is, in patients subclinical portal hypertension who have not yet developed varices.
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      Sequential HVPG measurements before and after NSBB treatment initiation represent the only validated means to monitor the chronic hemodynamic effects of NSBBs, that is, to assess the hemodynamic HVPG response. The HVPG response is defined as a decrease to absolute values of 12 mmHg or less or a relative decrease of 10% or more (primary prophylaxis)
      • Schwarzer R.
      • Kivaranovic D.
      • Paternostro R.
      • et al.
      Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study.
      or of 20% or more (secondary prophylaxis).
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      The achievement of an HVPG response is an excellent predictor of a negligible risk of variceal bleeding and a low risk for mortality in the setting of secondary prophylaxis.
      • Mandorfer M.
      • Hernández-Gea V.
      • Reiberger T.
      • et al.
      Hepatic venous pressure gradient response in non-selective beta-blocker treatment—is it worth measuring?.
      However, the evaluation of chronic HVPG response by sequential HVPG measurements is resource intensive and, thus, is mostly performed only in specialized centers and/or within an academic or trial setting. Additionally, the predictive value of sequential HVPG measurements is limited by the potential loss of the HVPG response during follow-up that can be related to modifications of the NSBB dose, alcohol intake,
      • Villanueva C.
      • López-Balaguer J.M.
      • Aracil C.
      • et al.
      Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis.
      and worsening of liver function as by natural history of the underlying etiology of ACLD.
      • Merkel C.
      • Bolognesi M.
      • Berzigotti A.
      • et al.
      Clinical significance of worsening portal hypertension during long-term medical treatment in patients with cirrhosis who had been classified as early good-responders on haemodynamic criteria.
      However, as of this writing, no other biomarker has shown comparable predictive quality in comparison with the invasive assessment of HVPG response. Although the achievement of an acute hemodynamic response to intravenous propranolol yielded prognostic value, it may not essentially correlate with a chronic HVPG response,
      • Villanueva C.
      • Aracil C.
      • Colomo A.
      • et al.
      Acute hemodynamic response to β-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.
      especially when oral carvedilol is used later,
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      however, only a single procedure of liver vein catheterization is required.
      • Mandorfer M.
      • Hernández-Gea V.
      • Reiberger T.
      • et al.
      Hepatic venous pressure gradient response in non-selective beta-blocker treatment—is it worth measuring?.
      ,
      • Villanueva C.
      • Aracil C.
      • Colomo A.
      • et al.
      Acute hemodynamic response to β-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.

      Noninvasive diagnosis of clinically significant portal hypertension and dynamic surrogates of hemodynamic response to nonselective beta-blockers

      Among potential noninvasive markers for CSPH, the measurement of liver
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • et al.
      Noninvasive screening for liver fibrosis and portal hypertension by transient elastography—a large single center experience.
      and spleen stiffness
      • Colecchia A.
      • Montrone L.
      • Scaioli E.
      • et al.
      Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis.
      by different ultrasound-based elastography methods, spleen diameter,
      • Abraldes J.G.
      • Bureau C.
      • Stefanescu H.
      • et al.
      Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study.
      ,
      • Berzigotti A.
      • Seijo S.
      • Arena U.
      • et al.
      Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.
      platelet count and von Willebrand factor
      • Ferlitsch M.
      • Reiberger T.
      • Hoke M.
      • et al.
      Von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.
      have been widely assessed and have been integrated into composite scores for prediction of CSPH or ruling out varices needing treatment.
      • Abraldes J.G.
      • Bureau C.
      • Stefanescu H.
      • et al.
      Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study.
      ,
      • Augustin S.
      • Millán L.
      • González A.
      • et al.
      Detection of early portal hypertension with routine data and liver stiffness in patients with asymptomatic liver disease: a prospective study.
      Numerous other noninvasive and largely imaging-based methods have been assessed as dynamic surrogates for an HVPG response; changes in liver stiffness correlated well with changes in HVPG in a small cohort (n = 23) of patients, but have not yet been validated in a larger prospective study.
      • Choi S.-Y.
      • Jeong W.K.
      • Kim Y.
      • et al.
      Shear-wave elastography: a noninvasive tool for monitoring changing hepatic venous pressure gradients in patients with cirrhosis.
      In contrast, changes in spleen stiffness—which at least in theory better reflects the portal venous inflow component—as estimated by transient elastography
      • Colecchia A.
      • Montrone L.
      • Scaioli E.
      • et al.
      Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis.
      and shear wave elastography
      • Kim H.Y.
      • So Y.H.
      • Kim W.
      • et al.
      Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices.
      showed promising results. Last, it was shown that MRI-based estimated liver perfusion showed a strong positive correlation with HVPG; however, it remains to be explored in future prospective trials whether MRI perfusion studies are able to predict clinical outcomes.
      • Palaniyappan N.
      • Cox E.
      • Bradley C.
      • et al.
      Non-invasive assessment of portal hypertension using quantitative magnetic resonance imaging.
      Further studies on non–imaging-based HVPG response surrogates have demonstrated that Ras homolog family member A (RhoA) and RhoA-kinase 2 transcription in the antrum mucosa
      • Trebicka J.
      • von Heydebrand M.
      • Lehmann J.
      • et al.
      Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients.
      as well as serum levels of a phosphatidylcholine and a free fatty acid
      • Reverter E.
      • Lozano J.J.
      • Alonso C.
      • et al.
      Metabolomics discloses potential biomarkers to predict the acute HVPG response to propranolol in patients with cirrhosis.
      correlated well with acute HVPG-response to intravenous propranolol and, thus, these surrogates warrant further investigation. Importantly, potential predictors that might support clinicians in the evaluation of benefits of NSBB therapy do not solely comprise hemodynamic markers, because beneficial nonhemodynamic effects of NSBB treatment have been reported in previous studies. These include a decrease in markers of bacterial translocation mediated by an amelioration of intestinal permeability.
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • et al.
      Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
      Additionally, NSBB-related effects on markers of systemic inflammation were demonstrated in patients with acute-on-chronic liver failure.
      • Mookerjee R.P.
      • Pavesi M.
      • Thomsen K.L.
      • et al.
      Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure.
      Therefore, it should be investigated whether these novel biomarkers are able to reflect changes in HVPG and/or dynamic NSBB-related benefits in patients with CSPH. Ultimately, noninvasive biomarkers of CSPH should be tested for their prognostic value in patients with ACLD and if they are suited to be included in comprehensive risk scores for refined prognostication in personalized medicine.

      State of the art in primary prophylaxis of variceal bleeding

      Since the first reports on their beneficial effects in the 1980s, NSBBs have been the cornerstone of medical treatment in portal hypertension owing to their mitigating effects on portal pressure that are paralleled by lower risks of variceal bleeding and rebleeding. Thus, the European Association for the Study of the Liver (EASL), the American Association for the Study of the Liver (AASLD), and the Baveno VI guidelines have recommended the use of NSBBs for primary and secondary (in combination with endoscopic band ligation [EBL]) prophylaxis of variceal bleeding in cirrhotic patients with GEVs.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      Still, concerns about the safety profile of NSBBs and potential deleterious effects in advanced cirrhosis have been raised in recent years, and the evidence for the benefits of NSBB treatment is weaker in certain patient cohorts, for example, in patients with refractory ascites.
      • Sersté T.
      • Melot C.
      • Francoz C.
      • et al.
      Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.
      As outlined elsewhere in this article, HVPG-guided NSBB therapy is preferably used in all patients with CSPH to precisely predict and monitor the benefits of NSBB treatment and optimize the patient’s clinical outcome.
      • Villanueva C.
      • Graupera I.
      • Aracil C.
      • et al.
      A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.
      However, we also acknowledge the limited availability of HVPG measurement, as well as its cost and invasive nature. Therefore, endoscopic screening for the presence of GEVs and, thus, evaluation for the risk of variceal bleeding, is currently used most widely. The subsequent overview on the evidence for best clinical practice for primary and secondary prophylaxis of variceal bleeding is, therefore, based on the prestratification of patients by the presence or absence of GEVs. This strategy provides a clinically relevant and widely feasible approach for a tailored NSBB treatment for the primary and secondary prophylaxis of variceal hemorrhage, which is complemented by data on the choice of NSBB type and doses in distinct clinical scenarios.

      Primary Prophylaxis: Patients with No or Small Varices

      The benefit of NSBB treatment in patients without varices was thoroughly investigated in a study by Groszmann and colleagues,
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      in which patients with cirrhosis and portal hypertension as defined by an HVPG of 6 mmHg or greater were randomly assigned to timolol or placebo. Patients were followed for a median of almost 5 years, and about 40% in both treatment groups reached the primary end point that comprised development of varices or variceal bleeding. Importantly, decreases in HVPG of 10% or greater were more frequent in the timolol group, as compared with placebo (53% vs 38%); however, the authors also reported a significantly higher rate of serious adverse events in the timolol group (18% vs 6%). Thus, there is no evidence for NSBB treatment for (pre-)primary prophylaxis in patients without CSPH and without varices as of today.
      Recently, the PREDESCI study that was conducted by Villanueva and colleagues
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • et al.
      β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      demonstrated that patients with compensated cirrhosis with CSPH without high-risk varices show lower rates of first decompensation under ongoing NSBB therapy. In a cohort of 201 patients (propranolol: n = 67; carvedilol: n = 33; inactive treatment: n = 101), the primary end point that was defined as ascites development, bleeding, or hepatic encephalopathy occurred in 16 patients (16%) in the active treatment cohort, as compared with 27 patients (27%) in the placebo cohort (hazard ratio, 0.51 [95% confidence interval, 0.26–0.97], P = .041). Serious adverse events were comparable between the 2 cohorts. This study demonstrated that NSBBs not only decrease the risk for variceal bleeding, but also modify the risk of first decompensation in compensated cirrhosis in general. The ultimate conclusion of this study is, thus, to consider initiation of NSBB therapy upon diagnosis of CSPH because NSBB seem to increase decompensation-free survival, regardless of varix status. Of note, this recommendation has not yet been implemented into international guidelines.
      However, there are controversial results on preprimary prophylaxis of variceal bleeding and on prevention of varix size progression from randomized controlled trials (RCTs) and a subsequent meta-analysis available.
      • Merkel C.
      • Marin R.
      • Angeli P.
      • et al.
      A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis 1.
      • Sarin S.K.
      • Mishra S.R.
      • Sharma P.
      • et al.
      Early primary prophylaxis with beta-blockers does not prevent the growth of small esophageal varices in cirrhosis: a randomized controlled trial.
      • Qi X.-S.
      Nonselective beta-blockers in cirrhotic patients with no or small varices: a meta-analysis.
      These conflicting results were likely obtained owing to the fact that different proportions of patients without varices and, importantly, also without CSPH were enrolled. Consequently, our research group repeated the meta-analysis, including only studies on patients with small varices (CSPH) at baseline,
      • Mandorfer M.
      • Peck-Radosavljevic M.
      • Reiberger T.
      Prevention of progression from small to large varices: are we there yet? An updated meta-analysis.
      also considering the results of the RCT by Bhardwaj and colleagues
      • Bhardwaj A.
      • Kedarisetty C.K.
      • Vashishtha C.
      • et al.
      Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial.
      observing a lower risk for progression from small to large varices with carvedilol therapy. Our updated meta-analysis revealed a trend toward a lower risk of large varix development under NSBB therapy in the fixed effect model. Of note, NSBB treatment is not recommended by recent guidelines for preprimary prophylaxis or for the prevention of varix progression. However, we argue for further research on the beneficial effects of NSBB as soon as the diagnosis of CSPH has been established, regardless of the presence or absence of varices.

      Primary Prophylaxis: Patients with Medium to Large or High-Risk Small Varices

      The current guidelines recommend the use of NSSBs to prevent variceal bleeding in patients with medium to large varices or high-risk small varices.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      NSBB treatment in primary prophylaxis is associated with an absolute risk reduction of −10% (25% vs 15%, as compared with inactive treatment) during 2-year follow-up, which translates into a number needed to treat (NNT) of 10 (10 patients need to be treated with NSBBs to prevent one episode of variceal hemorrhage within 2 years of follow-up).
      • D’Amico G.
      • Pagliaro L.
      • Bosch J.
      Pharmacological treatment of portal hypertension: an evidence-based approach.
      When only treating patients with medium to large varices, the absolute risk reduction is −16% (NNT = 6).
      • D’Amico G.
      • Pagliaro L.
      • Bosch J.
      Pharmacological treatment of portal hypertension: an evidence-based approach.
      Slightly different criteria for the definition of high-risk small varices have been proposed: Although the AASLD definition encompasses small varices in Child-Turcotte-Pugh score (Child) stage B/C or the presence of red wale marks,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      the EASL definition is restricted to small varices in Child C patients or the presence of red wale marks.
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      Concern about NSBB treatment owing to small varices without red wale marks in Child B/C was raised by Kalambokis and colleagues.
      • Kalambokis G.N.
      • Christodoulou D.
      • Baltayiannis G.
      • et al.
      Propranolol use beyond 6 months increases mortality in patients with Child-Pugh C cirrhosis and ascites: correspondence.
      ,
      • Kalambokis G.N.
      • Baltayiannis G.
      • Christou L.
      • et al.
      Red signs and not severity of cirrhosis should determine non-selective β-blocker treatment in Child-Pugh C cirrhosis with small varices: increased risk of hepatorenal syndrome and death beyond 6 months of propranolol use.
      In their cohort study, they demonstrated an increased risk of the hepatorenal syndrome and of overall mortality related to propranolol treatment in patients with Child B/C disease. Accordingly, it may be wise to base the decision of NSBB treatment initiation both on endoscopic findings of red wale marks and the severity of liver dysfunction, that is, Child stage. Still, no adequately powered prospective study specifically addressed the effects of NSBB treatment in patients with small varices and advanced liver dysfunction as of this writing, and we encourage future studies on this field of primary prophylaxis.
      In patients who have already developed medium to large varices, NSBB treatment or EBL are recommended for the primary prophylaxis of variceal bleeding.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      The choice between NSBB treatment or EBL should consider patient preference, availability of proficient endoscopy personnel and infrastructure, and patient intolerance or adverse events under treatment. A meta-analysis including 19 studies showed no difference in overall mortality or bleeding-related mortality between primary prophylaxis with NSBB versus EBL.
      • Gluud L.L.
      • Krag A.
      Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults.
      However, a more recent meta-analysis including 32 RCTs with a total of 3362 patients with large varices and no prior history of bleeding showed that NSBB monotherapy was associated with a better safety profile and an improvement in overall mortality, as compared with EBL.
      • Sharma M.
      • Singh S.
      • Desai V.
      • et al.
      Comparison of therapies for primary prevention of esophageal variceal bleeding: a systematic review and network meta-analysis.
      Importantly, although EBL is associated with a lower rate of adverse events overall, it may cause more severe and potentially life-threatening complications, such as EBL-associated ulcer bleeding. Moreover, in contrast with medical therapy with NSBBs, EBL does not impact the underlying levels of portal pressure and has no hemodynamic or disease-modifying effects. Last, EBL is associated with significantly lower time and cost efficiency as compared with NSBB treatment. However, EBL treatment is prone to achieve variceal obliteration that could lead to long anxiety-free intervals in high-risk patients and does not rely as much on treatment adherence, which is why EBL might be preferable in some scenarios.
      • Lo G.-H.
      Letter to the editor: beta-blockers are preferable to banding ligation for primary prophylaxis of variceal bleeding?.
      In contrast, it may be hypothesized that the results of the PREDESCI study—although excluding patients with high-risk varices—extend to all compensated patients under NSBB treatment for primary bleeding prophylaxis. Thus, patients might benefit more from NSBB treatment because it may lead to longer decompensation-free survival, as compared with endoscopic therapy.
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • et al.
      β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      Ultimately, both treatment options are validated for use in primary prophylaxis in patients with medium to large varices, and clinicians should always consider the individual patient’s opinion in the process of shared decision-making.

      Carvedilol Versus Propranolol and Other Conventional Nonselective Beta-Blockers

      Carvedilol, in contrast with conventional NSBBs, has additional anti-α-1-adrenergic activity, which makes the compound more potent in decreasing portal pressure.
      • Bosch J.
      Carvedilol: the β-blocker of choice for portal hypertension?.
      It was shown in a meta-analysis that carvedilol leads to stronger decreases in portal pressure levels, as compared with propranolol (−22% vs −16%).
      • Sinagra E.
      • Perricone G.
      • D’Amico M.
      • et al.
      Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis.
      Importantly, carvedilol may lead to stronger decreases in mean arterial pressure owing to its anti-α-1-adrenergic activity in comparison with conventional NSBBs. In a meta-analysis by Sinagra and associates,
      • Sinagra E.
      • Perricone G.
      • D’Amico M.
      • et al.
      Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis.
      carvedilol showed a tendency toward a stronger decrease of mean arterial pressure levels, as compared with propranolol treatment (weighed mean difference, −10.40% vs 6.35%). Moreover, it seems that higher doses of carvedilol (>12.5 mg/d) do not lead to further reductions of HVPG, although they are associated with lower mean arterial pressure levels.
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      Therefore, carvedilol should not be used in doses higher than 12.5 mg/d, with the exception of patients who show increased levels of arterial blood pressure and would need higher doses of carvedilol for antihypertensive treatment anyway.
      In the setting of primary prophylaxis, an RCT comparing carvedilol versus EBL found lower rates of bleeding in the carvedilol cohort (10% vs EBL, 23%), although no differences regarding bleeding-related and overall mortality were found.
      • Tripathi D.
      • Ferguson J.W.
      • Kochar N.
      • et al.
      Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.
      A second RCT by Shah and colleagues
      • Shah H.A.
      • Azam Z.
      • Rauf J.
      • et al.
      Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial.
      also showed a trend toward lower bleeding rates with carvedilol (6.9% vs EBL, 8.5%). Of note, serious adverse events were more common in the EBL group.
      Although there is no head-to-head RCT that investigated the effects of carvedilol versus propranolol in primary prophylaxis, in a study that was conducted by our group, we found that carvedilol treatment led to HVPG response, that is, a 20% or greater decrease in the HVPG or a decrease to an absolute HVPG value of less than 12 mmHg, in a high proportion (58%) of patients who did not respond to propranolol treatment.
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      Hemodynamic nonresponders to carvedilol were treated with EBL. Lower rates of variceal bleeding (carvedilol, 5%; propranolol, 11%; EBL, 25%) and mortality (carvedilol, 11%; propranolol, 14%; EBL, 31%) were observed among hemodynamic responders to NSBB treatment, as compared with EBL treatment. In conclusion, we recommend carvedilol for the primary prophylaxis of variceal bleeding in patients with compensated cirrhosis owing to its higher potency to reduce portal pressure as compared with propranolol.
      Two RCTs compared carvedilol versus nadolol with or without isosorbidmononitrate in the setting of secondary prophylaxis.
      • Lo G.-H.
      • Chen W.-C.
      • Wang H.-M.
      • et al.
      Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding: prevention of variceal rebleeding.
      ,
      • Stanley A.J.
      • Dickson S.
      • Hayes P.C.
      • et al.
      Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding.
      In the study conducted by Lo and colleagues,
      • Lo G.-H.
      • Chen W.-C.
      • Wang H.-M.
      • et al.
      Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding: prevention of variceal rebleeding.
      comparable rebleeding rates (61% and 62%) were found, the survival was similar, and serious adverse events were more common in the nadolol with or without isosorbidmononitrate group. Stanley and colleagues,
      • Stanley A.J.
      • Dickson S.
      • Hayes P.C.
      • et al.
      Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding.
      who conducted the second RCT, found a rebleeding rate of 36%, irrespective of treatment. Notably, there was a trend toward an increased survival in the carvedilol group, whereas serious adverse event rates were similar between the 2 groups. Despite the promising results of these 2 RCTs, standalone carvedilol treatment has never been compared with the current state-of-the-art therapy for secondary prophylaxis, that is, combined NSBB and EBL treatment; thus, the Baveno VI faculty did not recommend its use for secondary prophylaxis.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      In summary, carvedilol is a potent compound for the reduction of portal pressure both in primary and secondary prophylaxis. However, we do not recommend the use of carvedilol in patients with severe ascites, because carvedilol seems to impair circulatory homeostasis and this setting.
      • Sersté T.
      • Melot C.
      • Francoz C.
      • et al.
      Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.

      State of the art in secondary prophylaxis of variceal bleeding

      The current guidelines recommend a combination of NSBB treatment and EBL for the secondary prophylaxis of recurrent variceal bleeding.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      These recommendations are based on 2 meta-analyses that confirmed the protective benefits of combined medical (NSBBs with or without isosorbidmononitrate) and endoscopic therapy, that is, EBL.
      • Thiele M.
      • Krag A.
      • Rohde U.
      • et al.
      Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices.
      ,
      • Puente A.
      • Hernández-Gea V.
      • Graupera I.
      • et al.
      Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review.
      Importantly, both meta-analyses showed a trend toward a lower risk of overall mortality in the combined treatment group, as compared with the EBL monotherapy group, whereas the addition of EBL to NSBB treatment was not associated with decreases in mortality. Thus, NSBBs are the cornerstone of treatment in the prophylaxis of recurrent bleeding. Interestingly, the impact of NSBB treatment on mortality seems to be restricted to secondary prophylaxis,
      • Pfisterer N.
      • Dexheimer C.
      • Fuchs E.-M.
      • et al.
      Betablockers do not increase efficacy of band ligation in primary prophylaxis but they improve survival in secondary prophylaxis of variceal bleeding.
      and it may be hypothesized that nonhemodynamic effects, such as a decrease in bacterial translocation,
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • et al.
      Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
      but possibly also anti-inflammatory effects related to NSBBs
      • Mookerjee R.P.
      • Pavesi M.
      • Thomsen K.L.
      • et al.
      Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure.
      might contribute to this finding.
      Patients for whom NSSBs are contraindicated or who do not tolerate medical therapy, should be evaluated for alternative treatment, for example, transjugular intrahepatic portosystemic shunt implantation.
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.

      Dose titration and nonselective beta-blocker treatment in patients with ascites

      The limited availability of HVPG measurement forces many clinicians to rely on the aforementioned noninvasive signs and biomarkers for the diagnosis of portal hypertension and, thus, the initiation and monitoring of prophylactic NSBB therapy. The absence of HVPG measurement availability often necessitates empiric treatment and titration of NSBB doses, usually to a certain target heart rate at 60 bpm
      • Patch D.
      • Sabin C.A.
      • Goulis J.
      • et al.
      A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis.
      or even 50 to 55 bpm.
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      However, this concept is challenged by the fact that, in decompensated patients, worsening of liver function is paralleled by more pronounced sympathetic nervous system activation, leading to higher heart rates and a progressive hyperdynamic state, which implies that those patients would need higher NSBB doses to achieve those target heart rates. However, cardiac reserve is limited in end-stage cirrhotic patients, for example, in patients with refractory ascites, and Sersté and colleagues
      • Sersté T.
      • Melot C.
      • Francoz C.
      • et al.
      Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.
      were the first to report deleterious effects of NSBB treatment in patients with refractory ascites. Of note, one-half of the patients (46.7%) received high-dose propranolol treatment (160 mg/d) in their prospective cohort study. Recently, it has been demonstrated in an elegant quasi-experimental, prospective proof-of-concept study by Téllez and colleagues
      • Téllez L.
      • Ibáñez-Samaniego L.
      • Pérez del Villar C.
      • et al.
      Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.
      that, in patients with refractory ascites, high-dose treatment with propranolol might indeed be detrimental to patients’ circulatory homeostasis and kidney function, which could potentially worsen their prognosis. Importantly, a Danish nationwide study showed a differential impact of NSBB treatment in 81 patients with spontaneous bacterial peritonitis.
      • Madsen B.S.
      • Nielsen K.F.
      • Fialla A.D.
      • et al.
      Keep the sick from harm in spontaneous bacterial peritonitis: dose of beta blockers matters.
      Although high-dose propranolol treatment, that is, 160 mg/d, was associated with increased mortality after spontaneous bacterial peritonitis (hazard ratio, 2.27, unadjusted analysis), doses of 80 mg or less per day were associated with decreased mortality after spontaneous bacterial peritonitis (hazard ratio, 0.56).
      Although the potential harmful effects of (high-dose) NSBB treatment in patients with advanced disease warrant further investigation, there is evidence that carefully titrated and closely monitored NSBB treatment is not harmful to patients with ascites in general.
      • D’Amico G.
      • Malizia G.
      • Bosch J.
      Beta-blockers in 2016: still the safest and most useful drugs for portal hypertension? D’Amico et al.
      • Garcia-Tsao G.
      Beta blockers in cirrhosis: the window re-opens.
      • Bossen L.
      • Krag A.
      • Vilstrup H.
      • et al.
      Nonselective β-blockers do not affect mortality in cirrhosis patients with ascites: post hoc analysis of three randomized controlled trials with 1198 patients: liver Failure/Cirrhosis/Portal Hypertension.
      • Leithead J.A.
      • Rajoriya N.
      • Tehami N.
      • et al.
      Non-selective β-blockers are associated with improved survival in patients with ascites listed for liver transplantation.
      This finding was corroborated by the results of 2 meta-analyses. The first one concluded that NSBB treatment was not associated with an increased risk of mortality in patients with ascites or refractory ascites,
      • Chirapongsathorn S.
      • Valentin N.
      • Alahdab F.
      • et al.
      Nonselective β-blockers and survival in patients with cirrhosis and ascites: a systematic review and meta-analysis.
      and the second one found that the achievement of an HVPG response was associated with a significantly lower odds of decompensation, liver transplantation, and death, regardless of the presence of ascites.
      • Turco L.
      • Villanueva C.
      • La Mura V.
      • et al.
      Lowering portal pressure improves outcomes of patients with cirrhosis, with or without ascites: a meta-analysis.
      The results of these studies indicate that, in patients with advanced disease, NSBB treatment seems to be a valid option for the prophylaxis of variceal bleeding, although hemodynamic treatment targets and maximum doses may have to be reconsidered. However, no RCT has thoroughly investigated the titration schemes of NSBB treatment, and the need for international recommendations remains unmet. In the absence of evidence-based guidelines on NSBB dose regimens in advanced decompensated cirrhosis, clinicians should make decisions based on individual risk/benefit considerations.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      Signs of systemic circulatory dysfunction, severe hyponatremia,
      • Sersté T.
      • Gustot T.
      • Rautou P.-E.
      • et al.
      Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites.
      a low mean arterial pressure,
      • Llach J.
      • Ginès P.
      • Arroyo V.
      • et al.
      Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites.
      low cardiac output,
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • et al.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      and increasing levels of serum creatinine
      • Ruiz-del-Arbol L.
      Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
      allow for the identification of vulnerable patients, in which dose reduction or transient or permanent treatment discontinuation might be warranted.
      Therefore, the Baveno VI consensus proposed that, in patients with refractory ascites and (i) a systolic arterial blood pressure of less than 90 mmHg, or (ii) a serum creatinine of greater than 1.5 mg/dL, or (iii) hyponatremia of less than 130 mmol/L, dose reduction or treatment discontinuation should be considered.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.

      Summary: a tailored approach to nonselective beta-blocker treatment

      NSBB treatment markedly reduces the risk of variceal bleeding in primary (absolute risk reduction, 25%–15%; NNT = 10) and secondary prophylaxis (absolute risk reduction, 63%–42%; NNT = 5), as compared with inactive treatment.
      • D’Amico G.
      • Pagliaro L.
      • Bosch J.
      Pharmacological treatment of portal hypertension: an evidence-based approach.
      Accordingly, NSBBs are recommended both in primary and secondary prophylaxis by current guidelines. Although NSBBs are the first choice of medical therapy for the prevention of variceal bleeding, a considerable number of patients have to be treated to prevent a single episode of variceal hemorrhage. In addition, a large proportion of patients do not achieve the HVPG response that is associated with considerably lower bleeding rates and a lower risk of mortality.
      • Thalheimer U.
      Monitoring target reduction in hepatic venous pressure gradient during pharmacological therapy of portal hypertension: a close look at the evidence.
      ,
      • D’Amico G.
      • Pagliaro L.
      • Bosch J.
      Pharmacological treatment of portal hypertension: an evidence-based approach.
      Therefore, clinicians need to be endowed with reliable, feasible methods to accurately predict the benefit of NSBB treatment in their individual patients.
      A summary of our proposed treatment algorithm is given in Fig. 1. Sequential HVPG measurements before and under ongoing NSBB remain the most reliable but invasive tool to assess the individual patient’s response to treatment: Achieving a chronic HVPG response, that is, a reduction of 10% or more (primary prophylaxis) or 20% or more (secondary prophylaxis), or to an absolute value 12 mmHg or less is associated with a strong decrease in bleeding rates and increase in survival in secondary prophylaxis.
      • Groszmann R.J.
      • Bosch J.
      • Grace N.D.
      • et al.
      Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage.
      ,
      • Feu F.
      • García-Pagán J.C.
      • Bosch J.
      • et al.
      Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.
      The evaluation of an acute response to NSBB can predict decompensating events accurately, but still requires 1 invasive HVPG measurement.
      • Villanueva C.
      • Aracil C.
      • Colomo A.
      • et al.
      Acute hemodynamic response to β-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.
      ,
      • La Mura V.
      • Abraldes J.G.
      • Raffa S.
      • et al.
      Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension.
      Despite its obvious limitations in the daily clinical routine, we argue for HVPG-guided therapy in all stages of portal hypertension, because its implementation can improve clinical outcomes in patients with portal hypertension.
      • Villanueva C.
      • Graupera I.
      • Aracil C.
      • et al.
      A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.
      Nonetheless, the field of noninvasive surrogates for the monitoring of NSBB treatment effects remains highly relevant, and promising results were demonstrated for sequential ultrasound-based elastography assessment of the spleen.
      • Kim H.Y.
      • So Y.H.
      • Kim W.
      • et al.
      Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices.
      Figure thumbnail gr1
      Fig. 1A tailored approach to NSBB therapy for the prevention of first and recurrent variceal bleeding in patients with portal hypertension. The treatment algorithm for the use of NSBBs for the prevention of variceal bleeding in primary and secondary prophylaxis is shown. In primary prophylaxis, we recommend carvedilol/NSBB as the treatment of choice, whereas EBL is an alternative to NSBB therapy in case of safety or tolerability concerns or patient preference. The doses of carvedilol/NSBB should be slowly titrated and may not exceed 12.5 mg/d for carvedilol or 120 mg/d for propranolol. Close monitoring is warranted in patients with advanced liver disease considering Baveno VI recommendations for the use of NSBB therapy in patients with refractory ascites. EBL, endoscopic banding ligature; RA, refractory ascites; SAP, systolic arterial pressure; sCrea, serum creatinine.
      If endoscopic evaluation for GEVs is the only means of assessing portal hypertension, the initiation of NSBB treatment is recommended in all patients with medium to large varices or with high-risk varices.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      Although patients without varices should undergo regular follow-up endoscopy for early detection of varix development, we recommend NSBB therapy also for patients with small varices even without additional risk factors such as red spot signs or advanced liver dysfunction, that is, Child stages B or C. Recent data also suggest that NSBBs prolong decompensation-free survival in compensated patients with CSPH without high-risk varices, potentially owing to nonhemodynamic effects, and thus, we recommend NSBB treatment in all of these patients.
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • et al.
      β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      In primary prophylaxis, we prefer carvedilol over propranolol owing to its greater potency to decrease portal pressure that is accompanied by a similar safety profile, as compared with propranolol.
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      ,
      • Tripathi D.
      • Ferguson J.W.
      • Kochar N.
      • et al.
      Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.
      ,
      • Sinagra E.
      • Perricone G.
      • D’Amico M.
      • et al.
      Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis.
      ,
      • Shah H.A.
      • Azam Z.
      • Rauf J.
      • et al.
      Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial.
      In patients with low arterial pressure or slow heart rate, cautious dose titration under close monitoring of side effects is warranted.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      NSBBs combined with EBL for variceal obliteration remains the standard of care for secondary prophylaxis of variceal bleeding.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      In patients with end-stage liver disease, for example, patients with refractory ascites, we tend to avoid carvedilol given the current lack of prospective studies that specifically addressed its use in this setting. In patient with ascites, the NSBB dose should be carefully titrated, and changing to EBL treatment in patients with refractory ascites who show a systolic arterial pressure of less than 90 mmHg, hyponatremia of less than 130 mmol/L, or a serum creatinine of more than 1.5 mg/dL should be considered.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      We want to emphasize, however, that in contrast with EBL monotherapy, NSBB treatment does not only decrease the risk of bleeding and even mortality in secondary prophylaxis, but it is also associated with potential nonhemodynamic benefits as compared with EBL.
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • et al.
      Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
      ,
      • Mookerjee R.P.
      • Pavesi M.
      • Thomsen K.L.
      • et al.
      Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure.
      We propose a patient-centered, tailored approach for the prevention of bleeding in patients with portal hypertension that considers the distinct stage of CSPH and preferably the individual patient’s HVPG levels, or endoscopic varix stage for stratification.

      Outlook: The Viennese approach to hepatic venous pressure gradient-guided nonselective beta-blocker therapy in patients with compensated advanced chronic liver disease

      Considering recent evidence
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • et al.
      β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      ,
      • Mandorfer M.
      • Peck-Radosavljevic M.
      • Reiberger T.
      Prevention of progression from small to large varices: are we there yet? An updated meta-analysis.
      ,
      • Reiberger T.
      • Bucsics T.
      • Paternostro R.
      • et al.
      Small esophageal varices in patients with cirrhosis-should we treat them?.
      on top of international (Baveno VI,
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      AASLD,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      EASL
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ) and national recommendations (Billroth III consensus),
      • Reiberger T.
      • Püspök A.
      • Schoder M.
      • et al.
      Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III).
      we propose an individualized NSBB treatment algorithm for patients with compensated ACLD (Fig. 2). Our algorithm is based on 2 principles: (i) noninvasive risk stratification and (ii) HVPG-guided diagnosis and treatment of CSPH. In patients with suspected compensated ACLD as evident by significantly elevated liver stiffness (≥15 kPa) or thrombocytopenia (platelet count of <150 g/L) we conduct screening endoscopy for the early detection of varices, but always also recommend HVPG measurement for the early detection of CSPH. If CSPH is present and the patient shows an acute 10% or greater HVPG response to intravenously applied propranolol, carvedilol (titrated to 12.5 mg/d) therapy is initiated. In case of nonresponse to intravenous propranolol, we initiate carvedilol nonetheless and assess chronic hemodynamic response after 4 to 5 weeks. In patients who achieve a chronic HVPG response to carvedilol, we keep the patient on carvedilol. However, in patients who do not achieve a chronic HVPG response to carvedilol, EBL is recommended for primary prophylaxis in case of large varices and/or red spot signs.
      Figure thumbnail gr2
      Fig. 2The Viennese HVPG-based NSBB treatment algorithm in patients with cACLD. A summary of the Viennese algorithm on HVPG-guided NSBB therapy in patients with cACLD. ACLF, acute-on-chronic liver failure; AD, acute decompensation; cACLD, compensated advanced chronic liver disease; EBL, endoscopic banding ligature; MELD, Model for End-stage Liver Disease; PLT, platelet count; TE, transient elastography; VITRO, von Willebrand factor/PLT ratio; VWFAg, von Willebrand factor antigen activity.
      When patients progress from compensated to decompensated disease, we recommend reevaluating the type and dose of NSBB (eg, switch to propranolol or decrease the dose of NSBB in patients with refractory ascites and low arterial blood pressure). Importantly, NSBB treatment should not be discontinued in acute decompensation as long as the patient is hemodynamically stable, and therapy should be reinitiated as soon as possible in patients in whom transient treatment discontinuation cannot be avoided. In case of significant increases in Model for End-stage Liver Disease score or other noninvasive biomarkers for disease severity (such as von Willebrand factor antigen activity or the VITRO score), we aim for a reassessment of HVPG after stabilization of the patient. Last, if acute variceal bleeding occurs, we add EBL to NSBB-based therapy for secondary prophylaxis of variceal bleeding. A summary of our Viennese approach to HVPG-guided therapy in patients with compensated ACLD is given in Fig. 2.

      Clinics care points

      • The measurement of the hepatic venous pressure gradient (HVPG) is the gold standard for assessing the severity of portal hypertension and enables the detection of clinically significant portal hypertension (CSPH, i.e. HVPG ≥10 mmHg) before varices or other CSPH-related complications develop.
      • NSBB treatment should be initated in all patients with CSPH, and HVPG-guided therapy should be applied whenever available. In settings where the measurement of the HVPG is not available, screening endoscopy should be performed. NSBB therapy should be initiated upon detection of varices.
      • In patients with compensated liver cirrhosis, carvedilol is the treatment of choice for primary prophylaxis of variceal bleeding – dosed at 12.5 mg once daily.
      • In patients with advanced disease, i.e. refractory ascites, propranolol should be preferred over carvedilol treatment but high doses of propranolol (>120 mg daily) should be avoided due to potential deleterious effects on circulatory homestasis by blunting critical sympathetic compensatory mechanisms.
      • In case of intolerance or contraindications to NSBB treatment, endoscopic band ligation (EBL) should be considered for primary prophylaxis. Combined NSBB and EBL is the treatment of choice in secondary prophylaxis.

      Disclosure

      M. Jachs has nothing to declare. T. Reiberger received grant support from AbbVie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from AbbVie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche.

      References

        • Iwakiri Y.
        Pathophysiology of portal hypertension.
        Portal Hypertens. 2014; 18: 281-291
        • Bolognesi M.
        • Di Pascoli M.
        • Verardo A.
        • et al.
        Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis.
        World J Gastroenterol. 2014; 20: 2555-2563
        • Simón-Talero M.
        • Roccarina D.
        • Martínez J.
        • et al.
        Association between portosystemic shunts and increased complications and mortality in patients with cirrhosis.
        Gastroenterology. 2018; 154: 1694-1705.e4
        • Reiberger T.
        • Schwabl P.
        • Trauner M.
        • et al.
        Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
        J Vis Exp. 2020;
        • Reverter E.
        • Tandon P.
        • Augustin S.
        • et al.
        A MELD-based model to determine risk of mortality among patients with acute variceal bleeding.
        Gastroenterology. 2014; 146: 412-419.e3
        • Poynard T.
        • Calès P.
        • Pasta 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.
        N Engl J Med. 1991; 324: 1532-1538
        • Groszmann R.J.
        • Bosch J.
        • Grace N.D.
        • et al.
        Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage.
        Gastroenterology. 1990; 99: 1401-1407
        • Schepke M.
        • Kleber G.
        • Nürnberg D.
        • et al.
        Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis.
        Hepatology. 2004; 40: 65-72
        • Lebrec D.
        • Poynard T.
        • Hillon P.
        • et al.
        Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
        N Engl J Med. 1981; 305: 1371-1374
        • Gonzalez R.
        • Zamora J.
        • Gomez-Camarero J.
        • et al.
        Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis.
        Ann Intern Med. 2008; 149: 109
        • Reiberger T.
        • Ulbrich G.
        • Ferlitsch A.
        • et al.
        Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
        Gut. 2013; 62: 1634-1641
        • Tripathi D.
        • Ferguson J.W.
        • Kochar N.
        • et al.
        Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.
        Hepatology. 2009; 50: 825-833
        • Schwarzer R.
        • Kivaranovic D.
        • Paternostro R.
        • et al.
        Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study.
        Aliment Pharmacol Ther. 2018; 47: 1162-1169
        • Pfisterer N.
        • Dexheimer C.
        • Fuchs E.-M.
        • et al.
        Betablockers do not increase efficacy of band ligation in primary prophylaxis but they improve survival in secondary prophylaxis of variceal bleeding.
        Aliment Pharmacol Ther. 2018; 47: 966-979
        • Sersté T.
        • Melot C.
        • Francoz C.
        • et al.
        Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.
        Hepatology. 2010; 52: 1017-1022
        • Chirapongsathorn S.
        • Valentin N.
        • Alahdab F.
        • et al.
        Nonselective β-blockers and survival in patients with cirrhosis and ascites: a systematic review and meta-analysis.
        Clin Gastroenterol Hepatol. 2016; 14: 1096-1104.e9
        • Turco L.
        • Villanueva C.
        • La Mura V.
        • et al.
        Lowering portal pressure improves outcomes of patients with cirrhosis, with or without ascites: a meta-analysis.
        Clin Gastroenterol Hepatol. 2020; 18: 313-327.e6
        • Bosch J.
        • Abraldes J.G.
        • Berzigotti A.
        • et al.
        The clinical use of HVPG measurements in chronic liver disease.
        Nat Rev Gastroenterol Hepatol. 2009; 6: 573-582
        • Ripoll C.
        • Groszmann R.
        • Garcia–Tsao G.
        • et al.
        Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
        Gastroenterology. 2007; 133: 481-488
        • de Franchis R.
        • Baveno VI Faculty
        Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
        J Hepatol. 2015; 63: 743-752
        • Thalheimer U.
        Monitoring target reduction in hepatic venous pressure gradient during pharmacological therapy of portal hypertension: a close look at the evidence.
        Gut. 2004; 53: 143-148
        • Villanueva C.
        • Albillos A.
        • Genescà J.
        • et al.
        Development of hyperdynamic circulation and response to β-blockers in compensated cirrhosis with portal hypertension.
        Hepatology. 2016; 63: 197-206
        • Groszmann R.J.
        • Garcia-Tsao G.
        • Bosch J.
        • et al.
        Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
        N Engl J Med. 2005; 353: 2254-2261
        • Mandorfer M.
        • Hernández-Gea V.
        • Reiberger T.
        • et al.
        Hepatic venous pressure gradient response in non-selective beta-blocker treatment—is it worth measuring?.
        Curr Hepatol Rep. 2019; 18: 174-186
        • Villanueva C.
        • López-Balaguer J.M.
        • Aracil C.
        • et al.
        Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis.
        J Hepatol. 2004; 40: 757-765
        • Merkel C.
        • Bolognesi M.
        • Berzigotti A.
        • et al.
        Clinical significance of worsening portal hypertension during long-term medical treatment in patients with cirrhosis who had been classified as early good-responders on haemodynamic criteria.
        J Hepatol. 2010; 52: 45-53
        • Villanueva C.
        • Aracil C.
        • Colomo A.
        • et al.
        Acute hemodynamic response to β-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.
        Gastroenterology. 2009; 137: 119-128
        • Reiberger T.
        • Ferlitsch A.
        • Payer B.A.
        • et al.
        Noninvasive screening for liver fibrosis and portal hypertension by transient elastography—a large single center experience.
        Wien Klin Wochenschr. 2012; 124: 395-402
        • Colecchia A.
        • Montrone L.
        • Scaioli E.
        • et al.
        Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis.
        Gastroenterology. 2012; 143: 646-654
        • Abraldes J.G.
        • Bureau C.
        • Stefanescu H.
        • et al.
        Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study.
        Hepatology. 2016; 64: 2173-2184
        • Berzigotti A.
        • Seijo S.
        • Arena U.
        • et al.
        Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.
        Gastroenterology. 2013; 144: 102-111.e1
        • Ferlitsch M.
        • Reiberger T.
        • Hoke M.
        • et al.
        Von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.
        Hepatology. 2012; 56: 1439-1447
        • Augustin S.
        • Millán L.
        • González A.
        • et al.
        Detection of early portal hypertension with routine data and liver stiffness in patients with asymptomatic liver disease: a prospective study.
        J Hepatol. 2014; 60: 561-569
        • Choi S.-Y.
        • Jeong W.K.
        • Kim Y.
        • et al.
        Shear-wave elastography: a noninvasive tool for monitoring changing hepatic venous pressure gradients in patients with cirrhosis.
        Radiology. 2014; 273: 917-926
        • Kim H.Y.
        • So Y.H.
        • Kim W.
        • et al.
        Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices.
        J Hepatol. 2019; 70: 412-422
        • Palaniyappan N.
        • Cox E.
        • Bradley C.
        • et al.
        Non-invasive assessment of portal hypertension using quantitative magnetic resonance imaging.
        J Hepatol. 2016; 65: 1131-1139
        • Trebicka J.
        • von Heydebrand M.
        • Lehmann J.
        • et al.
        Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients.
        J Hepatol. 2016; 64: 1265-1273
        • Reverter E.
        • Lozano J.J.
        • Alonso C.
        • et al.
        Metabolomics discloses potential biomarkers to predict the acute HVPG response to propranolol in patients with cirrhosis.
        Liver Int. 2019; 39: 705-713
        • Reiberger T.
        • Ferlitsch A.
        • Payer B.A.
        • et al.
        Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
        J Hepatol. 2013; 58: 911-921https://doi.org/10.1016/j.jhep.2012.12.011
        • Mookerjee R.P.
        • Pavesi M.
        • Thomsen K.L.
        • et al.
        Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure.
        J Hepatol. 2016; 64: 574-582
        • Angeli P.
        • Bernardi M.
        • Villanueva C.
        • et al.
        EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
        J Hepatol. 2018; 69: 406-460
        • Garcia-Tsao G.
        • Abraldes J.G.
        • Berzigotti A.
        • et al.
        Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
        Hepatology. 2017; 65: 310-335
        • Villanueva C.
        • Graupera I.
        • Aracil C.
        • et al.
        A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.
        Hepatology. 2017; 65: 1693-1707
        • Villanueva C.
        • Albillos A.
        • Genescà J.
        • et al.
        β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
        Lancet. 2019; 393: 1597-1608
        • Merkel C.
        • Marin R.
        • Angeli P.
        • et al.
        A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis 1.
        Gastroenterology. 2004; 127: 476-484
        • Sarin S.K.
        • Mishra S.R.
        • Sharma P.
        • et al.
        Early primary prophylaxis with beta-blockers does not prevent the growth of small esophageal varices in cirrhosis: a randomized controlled trial.
        Hepatol Int. 2013; 7: 248-256
        • Qi X.-S.
        Nonselective beta-blockers in cirrhotic patients with no or small varices: a meta-analysis.
        World J Gastroenterol. 2015; 21: 3100
        • Mandorfer M.
        • Peck-Radosavljevic M.
        • Reiberger T.
        Prevention of progression from small to large varices: are we there yet? An updated meta-analysis.
        Gut. 2017; 66: 1347-1349
        • Bhardwaj A.
        • Kedarisetty C.K.
        • Vashishtha C.
        • et al.
        Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial.
        Gut. 2017; 66: 1838-1843
        • D’Amico G.
        • Pagliaro L.
        • Bosch J.
        Pharmacological treatment of portal hypertension: an evidence-based approach.
        Semin Liver Dis. 1999; 19: 475-505
        • Kalambokis G.N.
        • Christodoulou D.
        • Baltayiannis G.
        • et al.
        Propranolol use beyond 6 months increases mortality in patients with Child-Pugh C cirrhosis and ascites: correspondence.
        Hepatology. 2016; 64: 1806-1808
        • Kalambokis G.N.
        • Baltayiannis G.
        • Christou L.
        • et al.
        Red signs and not severity of cirrhosis should determine non-selective β-blocker treatment in Child-Pugh C cirrhosis with small varices: increased risk of hepatorenal syndrome and death beyond 6 months of propranolol use.
        Gut. 2016; 65: 1228-1230
        • Gluud L.L.
        • Krag A.
        Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults.
        Cochrane Database Syst Rev. 2012; (Cochrane Hepato-Biliary Group, ed) (CD004544)
        • Sharma M.
        • Singh S.
        • Desai V.
        • et al.
        Comparison of therapies for primary prevention of esophageal variceal bleeding: a systematic review and network meta-analysis.
        Hepatology. 2019; 69: 1657-1675
        • Lo G.-H.
        Letter to the editor: beta-blockers are preferable to banding ligation for primary prophylaxis of variceal bleeding?.
        Hepatology. 2019; 70: 1876
        • Bosch J.
        Carvedilol: the β-blocker of choice for portal hypertension?.
        Gut. 2013; 62: 1529-1530
        • Sinagra E.
        • Perricone G.
        • D’Amico M.
        • et al.
        Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis.
        Aliment Pharmacol Ther. 2014; 39: 557-568
        • Shah H.A.
        • Azam Z.
        • Rauf J.
        • et al.
        Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial.
        J Hepatol. 2014; 60: 757-764
        • Lo G.-H.
        • Chen W.-C.
        • Wang H.-M.
        • et al.
        Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding: prevention of variceal rebleeding.
        J Gastroenterol Hepatol. 2012; 27: 1681-1687
        • Stanley A.J.
        • Dickson S.
        • Hayes P.C.
        • et al.
        Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding.
        J Hepatol. 2014; 61: 1014-1019
        • Thiele M.
        • Krag A.
        • Rohde U.
        • et al.
        Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices.
        Aliment Pharmacol Ther. 2012; 35: 1155-1165
        • Puente A.
        • Hernández-Gea V.
        • Graupera I.
        • et al.
        Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review.
        Liver Int. 2014; 34: 823-833
        • Patch D.
        • Sabin C.A.
        • Goulis J.
        • et al.
        A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis.
        Gastroenterology. 2002; 123: 1013-1019
        • Téllez L.
        • Ibáñez-Samaniego L.
        • Pérez del Villar C.
        • et al.
        Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.
        J Hepatol. 2020; 73: 1404-1414
        • Madsen B.S.
        • Nielsen K.F.
        • Fialla A.D.
        • et al.
        Keep the sick from harm in spontaneous bacterial peritonitis: dose of beta blockers matters.
        J Hepatol. 2016; 64: 1455-1456
        • D’Amico G.
        • Malizia G.
        • Bosch J.
        Beta-blockers in 2016: still the safest and most useful drugs for portal hypertension? D’Amico et al.
        Hepatology. 2016; 63: 1771-1773
        • Garcia-Tsao G.
        Beta blockers in cirrhosis: the window re-opens.
        J Hepatol. 2016; 64: 532-534
        • Bossen L.
        • Krag A.
        • Vilstrup H.
        • et al.
        Nonselective β-blockers do not affect mortality in cirrhosis patients with ascites: post hoc analysis of three randomized controlled trials with 1198 patients: liver Failure/Cirrhosis/Portal Hypertension.
        Hepatology. 2016; 63: 1968-1976
        • Leithead J.A.
        • Rajoriya N.
        • Tehami N.
        • et al.
        Non-selective β-blockers are associated with improved survival in patients with ascites listed for liver transplantation.
        Gut. 2015; 64: 1111-1119
        • Sersté T.
        • Gustot T.
        • Rautou P.-E.
        • et al.
        Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites.
        J Hepatol. 2012; 57: 274-280
        • Llach J.
        • Ginès P.
        • Arroyo V.
        • et al.
        Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites.
        Gastroenterology. 1988; 94: 482-487
        • Krag A.
        • Bendtsen F.
        • Henriksen J.H.
        • et al.
        Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
        Gut. 2010; 59: 105-110
        • Ruiz-del-Arbol L.
        Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
        Hepatology. 2003; 38: 1210-1218
        • Feu F.
        • García-Pagán J.C.
        • Bosch J.
        • et al.
        Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.
        Lancet. 1995; 346: 1056-1059
        • La Mura V.
        • Abraldes J.G.
        • Raffa S.
        • et al.
        Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension.
        J Hepatol. 2009; 51: 279-287
        • Reiberger T.
        • Bucsics T.
        • Paternostro R.
        • et al.
        Small esophageal varices in patients with cirrhosis-should we treat them?.
        Curr Hepatol Rep. 2018; 17: 301-315
        • Reiberger T.
        • Püspök A.
        • Schoder M.
        • et al.
        Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III).
        Wien Klin Wochenschr. 2017; 129: 135-158