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Precision medicine in variceal bleeding: Are we there yet?

  • Author Footnotes
    † Both authors share first authorship
    Marta Magaz
    Footnotes
    † Both authors share first authorship
    Affiliations
    Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain
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  • Author Footnotes
    † Both authors share first authorship
    Anna Baiges
    Footnotes
    † Both authors share first authorship
    Affiliations
    Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
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  • Author Footnotes
    ‡ Virginia Hernández-Gea was the recipient of the EASL Young Investigators' Award 2019.
    Virginia Hernández-Gea
    Correspondence
    Corresponding author. Address: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain.
    Footnotes
    ‡ Virginia Hernández-Gea was the recipient of the EASL Young Investigators' Award 2019.
    Affiliations
    Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
    Search for articles by this author
  • Author Footnotes
    † Both authors share first authorship
    ‡ Virginia Hernández-Gea was the recipient of the EASL Young Investigators' Award 2019.
Published:January 22, 2020DOI:https://doi.org/10.1016/j.jhep.2020.01.008

      Summary

      Variceal bleeding is one of the most feared complications of portal hypertension in patients with cirrhosis because of its deleterious impact on prognosis. Adequate management of patients at risk of developing variceal bleeding includes the prevention of the first episode of variceal bleeding and rebleeding, and is crucial in modifying prognosis. The presence of clinically significant portal hypertension is the main factor determining the risk of development of varices and other liver-related decompensations; therefore, it should be carefully screened for and monitored. Treating patients with clinically significant portal hypertension based on their individual risk of portal hypertension-related bleeding undoubtedly improves prognosis. The evaluation of liver haemodynamics and liver function can stratify patients according to their risk of bleeding and are no question useful tools to guide therapy in an individualised manner. That said, recent data support the idea that tailoring therapy to patient characteristics may effectively impact on prognosis and increase survival in all clinical scenarios. This review will focus on evaluating the available evidence supporting the use of individual risk characteristics for clinical decision-making and their impact on clinical outcome and survival. In primary prophylaxis, identification and treatment of patients with clinically significant portal hypertension improves decompensation-free survival. In the setting of acute variceal bleeding, the risk of failure and rebleeding can be easily predicted, allowing for early escalation of treatment (i.e. pre-emptive transjugular intrahepatic portosystemic shunt) which can improve survival in appropriate candidates. Stratifying the risk of recurrent variceal bleeding based on liver function and haemodynamic response to non-selective beta-blockers allows for tailored treatment, thereby increasing survival and avoiding adverse events.

      Keywords

      Introduction

      Advanced chronic liver disease (cALD) is a progressive disease that impairs liver function and decreases life expectancy.
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      The development of gastroesophageal varices (GEVs) is a hallmark in the natural history of cALD. GEVs represent the clinical confirmation of portal hypertension and increase the risk of decompensation. Acute variceal bleeding (AVB) is due to the rupture of GEVs, severely impacting on prognosis and increasing the risk of death. Although the prognosis of AVB has significantly improved over the last decades due to better management of the haemorrhage itself and its associated complications, mortality is still as high as 15–20%.
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      Portal hypertension is defined as an increase of HVPG >5 mmHg; when HVPG reaches the 10 mmHg threshold, varices usually appear and the risk of developing complications increases – hence this threshold is used to define clinically significant portal hypertension (CSPH). Although measurement of portal pressure is the most useful tool for predicting prognosis in the setting of AVB,
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      there are other known prognostic factors, mainly liver function, that are useful in stratifying risk. In fact, both Child-Pugh score and model for end-stage liver disease (MELD) score were initially developed to assess prognosis in patients with cirrhosis and severe portal hypertension (including variceal bleeding and refractory ascites) that were treated with surgery or transjugular intrahepatic portosystemic shunt (TIPS).
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      That said, HVPG has better diagnostic accuracy for the prediction of decompensation than the MELD or Child-Pugh score,
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      recognition of different stages of risk in patients with cirrhosis is key in order to optimise allocation of therapies with the final aim of improving prognosis. Based on the individual risk of presenting with AVB, 4 stages are defined with a clearly different outcome and risk of death (Fig. 1):
      • Patients without CSPH. Patients with non-CSPH have a very low risk of developing GEVs and other complications of portal hypertension. Close follow-up is recommended as CSPH may appear as the disease progresses.
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      • Patients with CSPH at risk of developing GEV and first variceal bleeding. Once the threshold of HVPG ≥10 mmHg is reached, the risk of developing GEV appears and AVB may occur, therefore specific therapies to prevent AVB should be implemented.
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        Patients with CSPH without varices have a very low risk of decompensation, whereas once varices appear the risk of decompensation increases.
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        Two subgroups of patients should be carefully differentiated:
        • CSPH and no varices/small varices.
        • CSPH and high-risk varices.
      • Patients with AVB. When AVB occurs, the risk of mortality increases and management in referral centres significantly improves prognosis.
      • Patients at risk of recurrent variceal bleeding. Patients overcoming an AVB remain at high risk of further bleeding and decompensation. Prevention of rebleeding should be promptly initiated.
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      Figure thumbnail gr1
      Fig. 1Stages of cALD according with individual risk of presenting with AVB.
      AVB, acute variceal bleeding; cALD, chronic advanced liver disease; CSPH, clinically significant portal hypertension; GEV, gastroesophageal varices; PH, portal hypertension.
      In this review we aimed to evaluate the available evidence supporting individual risk-based treatments and their impact on prognosis. Based on the available evidence, we propose the following treatment strategy based on individual risk.

      Patients without CSPH

      GEVs are frequently found in patients with poor liver function (in up to 85% of patients with Child-Pugh C and in up to 40% of patients with Child-Pugh A
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      • Luca A.
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      ). The strongest predictor of GEV development is portal hypertension. It is well known that GEVs develop when patients have an HVPG ≥10 mmHg. Therefore, identification of patients with cALD and CSPH is the mainstay of management in this subgroup.
      Patients without CSPH and without varices should undergo close follow-up to periodically reassess their risk of decompensation.
      Available data in patients with non-CSPH (HVPG >5 and <10 mmHg) comes from the seminal study from Groszmann et al. conducted in 79 patients with HVPG <10 mmHg without varices (41 of them treated with timolol). The authors could not demonstrate the benefit of treatment with a non-selective beta-blocker (NSBB) to prevent development of GEVs or AVB, probably because of the low risk of decompensation in this subpopulation
      • Groszmann R.J.
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      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in cirrhosis.
      (Table S1).
      Treating the underlying aetiology of liver disease and promoting a healthy lifestyle should be implemented in all patients with cALD regardless of the stage. Alcohol abstinence decreases portal hypertension and improves the prognosis of patients with alcohol-related liver disease
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      and should always be recommended. Hepatitis virus suppression significantly impacts survival by reducing portal hypertension-related decompensation and liver-related mortality.
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      Direct-acting antivirals (DAAs) reduce HVPG and are safe in all stages of chronic liver disease. Obesity increases the risk of decompensation in patients with cALD independent of the aetiology of cirrhosis.
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      • Morillas R.
      • et al.
      Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis.
      Lifestyle intervention (caloric reduction and moderate physical exercise) decreases HVPG and should always be recommended.
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      • Augustín S.
      • et al.
      Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study.
      Close follow-up is recommended in these patients to periodically reassess risk, as portal hypertension will increase with disease progression.
      Non-invasive methods can be useful for identifying patients at high risk of CSPH, especially in centres where HVPG measurement is not available. Large spontaneous portosystemic shunts are frequently found in patients with severe portal hypertension
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      and may help identify patients at high risk of decompensation and poor outcome.
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      • Low G.
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      Association between portosystemic shunts and increased complications and mortality in patients with cirrhosis.
      However, most evidence has come from studies evaluating liver stiffness. Liver stiffness measurement (LSM) by transient elastography (TE) correlates with the risk of presenting with CSPH.
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      Baveno VI Faculty
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      Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.
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      Values below 13.6 kPa rule out CSPH while values above the ≥21 kPa cut-off are highly specific for CSPH and can be used to identify patients at risk of decompensation. However, data generated in the era of DAA treatment indicate that even after viral suppression, portal hypertension progression and development of GEV can occur.
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      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV–cirrhotic patients.
      HVPG maintains its prognostic accuracy after viral suppression and is the only tool that can adequately monitor changes in portal hypertension.
      • Mandorfer M.
      • Kozbial K.
      • Schwabl P.
      • Chromy D.
      • Semmler G.
      • Stättermayer A.F.
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      Changes in HVPG predict hepatic decompensation in patients who achieved SVR to IFN-free therapy.
      • Lens S.
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      • Mariño Z.
      • Londoño M.-C.
      • LLop E.
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      Effects of all-oral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis.
      • Mandorfer M.
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      Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension.
      As a matter of fact, CSPH may be present in almost half of patients with LSM <13.6 KPa after a sustained virologic response (SVR).
      • Lens S.
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      • Mariño Z.
      • Londoño M.-C.
      • LLop E.
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      This demonstrates the limited value of thresholds generated in patients with active HCV infection. In fact, the correlation between TE and HVPG after SVR seems to be limited to patients without CSPH.
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      Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension.
      Spleen stiffness may also be useful for detecting CSPH at a threshold of >50.7 kPa,
      • Zykus R.
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      and has been suggested to correlate better with CSPH than LSM.
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      • Sahara A.
      • Takabatake H.
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      However, this technique has the drawback of being technically more challenging than LSM and is still not sufficiently validated to replace HVPG nor guide clinical decisions.

      Patients with CSPH at risk of developing GEV and first variceal bleeding

      Patients with CSPH and no varices/small varices

      Although traditionally GEVs were treated according to the presence of high-risk rupture criteria (size, red spot signs – or any varix in Child-Pugh C), recent data suggest that treatment should be considered in a broader fashion
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • 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.
      (Fig. 2). Indeed, the final aim of treatment in patients with CSPH with or without GEV is prevention of AVB and portal hypertension-related decompensation.
      Figure thumbnail gr2
      Fig. 2Treatment strategy for primary prophylaxis based on an individual risk-based approach.
      CSPH, clinically significant portal hypertension; EBL, endoscopic band ligation; NSBB, non-selective beta blocker.
      In patients with CSPH, the risk of developing varices reaches 57% at 5 years.
      • Merli M.
      • Nicolini G.
      • Angeloni S.
      • Rinaldi V.
      • De Santis A.
      • Merkel C.
      • et al.
      Incidence and natural history of small esophageal varices in cirrhotic patients.
      Recent data show
      • Villanueva C.
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      • Genescà J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • 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.
      that decreasing HVPG by >10% from baseline, or to absolute values <10 mmHg, reduces the risk of varices and AVB regardless of the presence of varices. The benefit of primary prophylaxis in the subgroup of patients with CSPH without varices or with small varices was specifically addressed in a randomised, double-blind, placebo-controlled, multicentre trial,
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • 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.
      enrolling 201 patients with compensated cirrhosis and CSPH, 87 of them without varices and 114 with small varices. Patients were randomised to receive placebo or NSBB (either propranolol or carvedilol based on haemodynamic response). A haemodynamic response to NSBBs was defined as a decrease in HVPG ≥10% or <10 mmHg 20 min after intravenous propranolol (0.15 mg/kg) (acute haemodynamic response). Patients treated with NSBBs had a significantly lower rate of portal hypertension-related decompensation (ascites, variceal bleeding and encephalopathy) and mortality. This composite endpoint (decompensation or mortality) occurred in 16% of patients in the beta-blocker group vs. 27% in the placebo group (hazard ratio [HR] 0.51; 95% CI 0.26–0.97; p = 0.041).
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      • Aracil C.
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      β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      In agreement with previous studies,
      • Mandorfer M.
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      treatment with NSBBs had a beneficial impact despite not being able to prevent progression to high-risk varices, suggesting that NSBB treatment may have additional beneficial effects. NSBBs reduced the risk of ascites development from 20% to 9% (HR 0.42; 95% CI 0.19–0.92; p = 0.030). In a post hoc analysis, the authors demonstrated that the subgroup of patients who achieved an acute haemodynamic response benefited the most from treatment with NSBBs, with better outcomes and a lower rate of decompensation (9% vs. 29% at 1 year; HR 0.32; 95% CI 0.13–0.75; p = 0.0077). No patient with Child-Pugh class C was included in the study but previous data recommend considering small varices as high risk in patients with Child-Pugh C,
      • de Franchis R.
      Baveno VI Faculty
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      ,
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      suggesting that the benefit may also apply to patients at higher risk (those with Child-Pugh C).
      These data further reinforce the idea that HVPG responses to NSBBs clearly differentiate 2 groups of patients with distinct prognosis and represent the sole prognostic tool able to guide risk-based tailored treatment (Fig. 2). Specific data on patients with CSPH, no/small varices and non-responders to NSBBs are lacking and endoscopic band ligation (EBL) has not been tested. Although NSBBs may also be beneficial,
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • 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.
      no formal recommendation can be given.
      Patients with CSPH and without varices or with small varices and haemodynamic response benefit from treatment with NSBBs.

      Patients with cALD and high-risk varices (always with CSPH)

      Patients with medium/large varices are at an increased risk of AVB, and the reported 2-year bleeding incidence is 25–30%.
      • Polio J.
      • Groszmann R.
      Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment.
      ,
      • Bosch J.
      • García-Pagán J.
      Prevention of variceal rebleeding.
      Although aetiological treatments
      • Mandorfer M.
      • Kozbial K.
      • Schwabl P.
      • Chromy D.
      • Semmler G.
      • Stättermayer A.F.
      • et al.
      Changes in HVPG predict hepatic decompensation in patients who achieved SVR to IFN-free therapy.
      ,
      • Lens S.
      • Alvarado-Tapias E.
      • Mariño Z.
      • Londoño M.-C.
      • LLop E.
      • Martinez J.
      • et al.
      Effects of all-oral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis.
      and/or lifestyle interventions (sport, diet, alcohol avoidance…) may reduce portal hypertension and improve prognosis, NSBBs and EBL represent the mainstay of primary prophylaxis in patients with CSPH.
      Both treatments are effective at reducing the risk of the first AVB and are equally recommended.
      • 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.
      However, recent data from a meta-analysis evaluating 32 RCTs, including 3,362 patients receiving primary prophylaxis with NSBBs or EBL, showed that, although equally effective in terms of reducing the risk of AVB, NSBBs demonstrated a better safety profile and a decrease in all-cause mortality.
      • Sharma M.
      • Singh S.
      • Desai V.
      • Shah V.H.
      • Kamath P.S.
      • Murad M.H.
      • et al.
      Comparison of therapies for primary prevention of esophageal variceal bleeding: a systematic review and network meta-analysis.
      These data suggest that NSBBs, probably due to their additional beneficial effects on portal hypertension, should be the treatment of choice in patients without contraindications.
      Carvedilol more potently reduces HVPG and improves outcomes in non-responders to propranolol.
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • Payer B.A.
      • Schwabl P.
      • Pinter M.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      Achieving either an acute or chronic haemodynamic response translates into clinically meaningful benefits, as it not only reduces the risk of variceal bleeding but also of ascites onset/worsening, decreasing markers of intestinal permeability and bacterial translocation, as well as the incidence of spontaneous bacterial peritonitis and the need for liver transplant, thereby improving survival.
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • Payer B.A.
      • Schwabl P.
      • Pinter M.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      • Groszmann R.J.
      • Bosch J.
      • Grace N.D.
      • Conn H.O.
      • Garcia-Tsao G.
      • Navasa M.
      • et al.
      Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage.
      • 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.
      • Bureau C.
      • Péron J.M.
      • Alric L.
      • Morales J.
      • Sanchez J.
      • Barange K.
      • et al.
      “A la carte” treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding.
      • Turnes J.
      • Garcia-Pagan J.C.
      • Abraldes J.G.
      • Hernandez-Guerra M.
      • Dell'Era A.
      • Bosch J.
      Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis.
      • Villanueva C.
      • Aracil C.
      • Colomo A.
      • Hernández-Gea V.
      • López-Balaguer J.M.
      • Alvarez-Urturi C.
      • et al.
      Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.
      • La Mura V.
      • Abraldes J.G.
      • Raffa S.
      • Retto O.
      • Berzigotti A.
      • García-Pagán J.C.
      • et al.
      Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension.
      • Hernández-Gea V.
      • Aracil C.
      • Colomo A.
      • Graupera I.
      • Poca M.
      • Torras X.
      • et al.
      Development of ascites in compensated cirrhosis with severe portal hypertension treated with β-blockers.
      Moreover, once achieved, haemodynamic responses are maintained over long periods of times.
      • 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 cirrhosis.
      ,
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • 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.
      ,
      • Kirnake V.
      • Arora A.
      • Gupta V.
      • Sharma P.
      • Singla V.
      • Bansal N.
      • et al.
      Hemodynamic response to carvedilol is maintained for long periods and leads to better clinical outcome in cirrhosis: a prospective study: acute hemodynamic response to carvedilol.
      ,
      • Augustin S.
      • González A.
      • Badia L.
      • Millán L.
      • Gelabert A.
      • Romero A.
      • et al.
      Long-term follow-up of hemodynamic responders to pharmacological therapy after variceal bleeding.
      Therefore, treatment allocation based on an acute or chronic haemodynamic response to NSBBs improves prognosis and limits side effects in a personalised way.
      • Kamath P.S.
      • Mookerjee R.P.
      Individualized care for portal hypertension: not quite yet.
      Studies evaluating the usefulness of haemodynamic response in the setting of primary prophylaxis are listed in Table S2.
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • Payer B.A.
      • Schwabl P.
      • Pinter M.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      • Groszmann R.J.
      • Bosch J.
      • Grace N.D.
      • Conn H.O.
      • Garcia-Tsao G.
      • Navasa M.
      • et al.
      Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage.
      • 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.
      • Bureau C.
      • Péron J.M.
      • Alric L.
      • Morales J.
      • Sanchez J.
      • Barange K.
      • et al.
      “A la carte” treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding.
      • Turnes J.
      • Garcia-Pagan J.C.
      • Abraldes J.G.
      • Hernandez-Guerra M.
      • Dell'Era A.
      • Bosch J.
      Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis.
      • Villanueva C.
      • Aracil C.
      • Colomo A.
      • Hernández-Gea V.
      • López-Balaguer J.M.
      • Alvarez-Urturi C.
      • et al.
      Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.
      • La Mura V.
      • Abraldes J.G.
      • Raffa S.
      • Retto O.
      • Berzigotti A.
      • García-Pagán J.C.
      • et al.
      Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension.
      • Hernández-Gea V.
      • Aracil C.
      • Colomo A.
      • Graupera I.
      • Poca M.
      • Torras X.
      • et al.
      Development of ascites in compensated cirrhosis with severe portal hypertension treated with β-blockers.
      ,
      • Bosch J.
      • Garcia-Pagán J.C.
      • Berzigotti A.
      • Abraldes J.G.
      Measurement of portal pressure and its role in the management of chronic liver disease.
      ,
      • Seijo-Ríos S.
      • García-Pagán J.C.
      Trombosis portal.
      Based on the available data, there are no clear advantages of one NSBB over another and the selection may be driven by the particularities of each drug and patient preferences (Table 1).
      Table 1Possible drugs and approaches available for (pre)primary prophylaxis in patients with clinically significant portal hypertension.
      TreatmentType effectHalf-life and metabolismRecommended dosage and frequencyApproximate

      cost
      Adverse effectsBeneficial additional effects
      PropranololAdrenergic blockade in β1 (decrease cardiac output) and in β2 receptors (reduce splanchnic blood flow)Peak plasma concentration: 1-2 hours

      Liver metabolism (eliminates up to 90% of an oral dose) Renal excretion in 3-6 hours
      20–40 mg orally twice a day, Maximal dosage: 320 mg/dayBetween 3–

      6 €/month
      Bradycardia, fatigue, bronchoconstriction, cardiac failure, cold extremities, intermittent claudication, dizziness, hypoglycaemia, functional impotenceReduced risk of bacterial translocation, ascites, SBP, HRS, and also improvement in survival
      TimololAdrenergic blockade in β1 and even higher affinity in β2 receptorsPeak plasma concentration 1-2 hours. Renal excretionInitiation dose 5 mg

      Maximal dosage: 80 mg/day
      5 €/monthBradycardia, fatigue, wheezing or shortness of breath, syncope, intermittent claudication, impotenceNo long-term studies
      NadololAdrenergic blockade in β1 (decrease cardiac output) and in β2 receptors (reduce splanchnic blood flow)Peak plasma concentration: 2-4 hours.

      No hepatic first pass effect.

      75% Renal excretion
      20–40 mg orally once a day. Maximal dosage: 160 mg/day (no/mild ascites present)Between 8–16 €/month.Bradycardia, fatigue, bronchoconstriction, cardiac failure, cold extremities, intermittent claudication, dizziness, hypoglycaemia, functional impotenceReduced risk of bacterial translocation, ascites, SBP, HRS, and also improvement in survival
      Carvedilolβ1, β2 and α1-blockade and NO production (decrease intrahepatic resistance and produces intrahepatic and systemic vasodilatation)Peak plasma concentration: 1 hour

      Biliary metabolism

      Faecal excretion
      Start with 6.25 mg once a day. Maximal dosage: 12.5 mg/day6 €/monthFatigue, Initial exacerbation of heart failure, renal failureReduced risk of bacterial translocation, ascites, SBP, HRS, and also improvement in survival
      EBLLocal effectOne session every 2–4 weeks until the varices are eradicated4,500€/month
      Extracted from Imperiale TF et al. Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding. Hepatology 2007;45. HRS, hepatorenal syndrome; NO, nitric oxide; SBP, spontaneous bacterial peritonitis.
      Deep sedation side effects, oesophageal ulcerations, scars bleeding, dysphagia or even stricturesNo additional effects
      Extracted from Imperiale TF et al. Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding. Hepatology 2007;45. HRS, hepatorenal syndrome; NO, nitric oxide; SBP, spontaneous bacterial peritonitis.
      The best approach in non-haemodynamic responders is still a matter of debate. There are no studies evaluating the benefit of changing from NSBBs to EBL. The best therapeutic strategy in non-responders to any NSBB remains to be found – both NSBBs and EBL are valid options. The decision to choose one over another has to be discussed with patients after carefully describing not only the main effect of the therapy but also side effects, severity of the most frequent side effects and importantly additional benefits of the treatment, mainly the impact on survival and other portal hypertension-related complications (Table 1).

      Patients with AVB

      Most of the evidence available regarding the benefits of risk stratification comes from studies performed in the clinical scenario of AVB, where the higher mortality risk concentrates and prognosis significantly differs among patients. AVB treatment should aim to achieve haemodynamic stabilisation, haemostasis and prevent complications.
      Basic resuscitation measures should be applied as in any critically ill patient but AVB requires a careful volume restitution allowing perfusion but avoiding overexpansion.
      • 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.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • Bosch J.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      Red blood cells should be transfused in a restrictive fashion when haemoglobin (Hb) drops below 7 g/dl
      • Villanueva C.
      • Colomo A.
      • Bosch A.
      • Concepcion M.
      • Hernandez-Gea V.
      • Aracil C.
      • et al.
      Transfusion strategies for acute upper gastrointestinal bleeding.
      (Fig. 3).
      Figure thumbnail gr3
      Fig. 3Management of acute variceal bleeding.
      AVB, acute variceal bleeding; EBL, endoscopic band ligation; TIPS, transjugular intrahepatic shunt; HE, hepatic encephalopathy.
      Haemostatic treatment should combine vasoactive agents and endoscopic treatment. Terlipressin, somatostatin and octreotide have all shown similar efficacy
      • Villanueva C.
      • Planella M.
      • Aracil C.
      • López-Balaguer J.M.J.
      • González B.
      • Miñana J.
      • et al.
      Hemodynamic effects of terlipressin and high somatostatin dose during acute variceal bleeding in nonresponders to the usual somatostatin dose.
      and should be started as soon as AVB is suspected, and maintained for up to 5 days. Once endoscopic haemostasis is achieved, shorter regimens of vasoactive drugs have been suggested although no clear general recommendation can be given based on the available data.
      • Azam Z.
      • Hamid S.
      • Jafri W.
      • Salih M.
      • Abbas Z.
      • Abid S.
      • et al.
      Short course adjuvant terlipressin in acute variceal bleeding: a randomized double blind dummy controlled trial.
      • Lo G.-H.
      The use of vasoconstrictors in acute variceal bleeding: how long is enough?.
      • Yan P.
      • Tian X.
      • Li J.
      Is additional 5-day vasoactive drug therapy necessary for acute variceal bleeding after successful endoscopic hemostasis? A systematic review and meta-analysis.
      EBL should be the treatment of choice for oesophageal varices whereas gastric varices require glue injection. Bacterial infection and renal failure are the most feared complications of AVB and should be prophylactically treated with antibiotics and careful replacement of fluids and electrolytes.
      • 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.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • Bosch J.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.

      Identification of patients at risk of a poor outcome during AVB

      Patients admitted with AVB do not benefit equally from standard of care as not all patients carry the same risk of treatment failure and death.
      HVPG measured within 24 hours of the bleeding episode is a strong prognostic factor of outcome after AVB. Patients with HVPG ≥20 mmHg are 5 times more likely to experience failure to control AVB or early rebleeding, requiring more blood transfusions and a longer stay in the intensive care unit than patients with HVPG <20 mmHg, and contributing to a higher mortality rate.
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • Bosch J.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      ,
      • Moitinho E.
      • Escorsell A.
      • Bandi J.
      • Salmerón J.
      • García-Pagán J.
      • Rodés J.
      • et al.
      Prognostic value of early measurements of portal pressure in acute variceal bleeding.
      • Abraldes J.G.
      • Villanueva C.
      • Bañares R.
      • Aracil C.
      • Catalina M.V.
      • García-Pagán J.C.
      • et al.
      Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy.
      • Villanueva C.
      • Ortiz J.
      • Minana J.
      • Soriano G.
      • Sabat M.
      • Boadas J.
      • et al.
      Somatostatin treatment and risk stratification by continuous portal pressure monitoring during acute variceal bleeding.
      Child-Pugh score is widely used to estimate prognosis in patients with cirrhosis. Although its utility as a risk prediction tool has been questioned,
      • Kok B.
      • Abraldes J.G.
      Child-pugh classification: time to abandon?.
      several studies in the setting of AVB support its value as a decision-making tool. Child-Pugh assessment during the acute bleeding episode predicts outcome. Survival in Child-Pugh A patients is near 100% while mortality is common in patients with Child-Pugh C >13 points.
      Recalibrated MELD is an accurate continuous model for early mortality estimation after AVB. Reverter et al.
      • Reverter E.
      • Tandon P.
      • Augustin S.
      • Turon F.
      • Casu S.
      • Bastiampillai R.
      • et al.
      A MELD-based model to determine risk of mortality among patients with acute variceal bleeding.
      showed that an MELD score of 19 or higher was associated with a high mortality risk (20%). The utility of recalibrated MELD in predicting outcome has recently been validated in 2 observational studies.
      • Rudler M.
      • Bureau C.
      • Carbonell N.
      • Mathurin P.
      • Saliba F.
      • Mallat A.
      • et al.
      Recalibrated MELD and hepatic encephalopathy are prognostic factors in cirrhotic patients with acute variceal bleeding.
      ,
      • Conejo I.
      • Guardascione M.A.
      • Tandon P.
      • Cachero A.
      • Castellote J.
      • Abraldes J.G.
      • et al.
      Multicenter external validation of risk stratification criteria for patients with variceal bleeding.
      Recalibrated MELD was not specifically focused on providing specific subgroup risk estimates for the use of early TIPS. Therefore, until more studies specifically addressing the role of MELD in decision-making are performed, its use cannot be recommended to tailor therapy.
      The presence of further decompensation, mainly ascites, worsens the prognosis in patients with AVB. Patients with AVB and ascites have a significantly higher 1-year death risk than patients without ascites, independently of Child-Pugh or MELD score. Therefore the presence of ascites should be carefully assessed in patients with AVB in order to stratify patients and select patients with a poor outcome,
      • D'Amico G.
      • Pasta L.
      • Morabito A.
      • D'Amico M.
      • Caltagirone M.
      • Malizia G.
      • et al.
      Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.
      although its role in clinical decision-making is not established.

      Risk-based treatment strategy

      HVPG-based therapy

      Placing a pre-emptive TIPS (p-TIPS) in high-risk patients selected based on an HVPG >20 mmHg during AVB reduces treatment failure and mortality.
      • Monescillo A.
      • Martínez-Lagares F.
      • Ruiz-del-Arbol L.
      • Sierra A.
      • Guevara C.
      • Jimenez E.
      • et al.
      Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding.
      p-TIPS, also called early TIPS, refers to a TIPS placed as early as possible (between the first 24–72 h after admission) in a patient at high-risk of failure/rebleeding and bleeding-related mortality, before failure arises and after achieving haemodynamic stability and after the initial treatment with vasoactive drugs and EBL. This study included patients not treated with the recommended gold standard method (sclerotherapy, non-covered stents) and this may explain why mortality in the control group was higher than reported in most recent trials. Despite the ground-breaking data, no other study has been conducted with the aim of validating these findings.
      Both in primary and secondary prophylaxis, patients that achieve an adequate HVPG response have lower rates of bleeding and improved survival.

      Child-Pugh score-based therapy

      Although 3 groups can be clearly differentiated (Child-Pugh A/B/C), patients at medium risk (Child-Pugh B) can be further stratified based on the presence of early bleeding during the diagnostic endoscopy. Child-Pugh B patients with active bleeding have a worse prognosis than Child-Pugh B without active bleeding. Data generated by 2 RCTs suggest that Child-Pugh B + AB & Child-Pugh C are able to identify and select a population with poor outcomes; reported 1-year mortality when treated with the standard of care treatment is 39–40%
      • Lv Y.
      • Yang Z.
      • Liu L.
      • Li K.
      • He C.
      • Wang Z.
      • et al.
      Early TIPS with covered stents versus standard treatment for acute variceal bleeding in patients with advanced cirrhosis: a randomised controlled trial.
      ,
      • García-Pagán J.C.
      • Caca K.
      • Bureau C.
      • Laleman W.
      • Appenrodt B.
      • Luca A.
      • et al.
      Early use of TIPS in patients with cirrhosis and variceal bleeding.
      and the 1-year risk of failure or rebleeding is 50–66%.
      Therefore 2 groups of risk can be distinguished: low risk (Child-Pugh A & Child-Pugh B without AB) and high risk (Child-Pugh B + AB & Child-Pugh C) although it is widely recognised that better tools are needed.
      • 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.

      High-risk patients (Child-Pugh B + AB & Child-Pugh C)

      Mortality in Child-Pugh C 14 & 15 points is extremely high during the AVB episode and available data suggest futility of TIPS in this very high-risk population if not followed by rapid liver transplantation.
      • Rudler M.
      • Rousseau G.
      • Thabut D.
      Salvage transjugular intrahepatic portosystemic shunt followed by early transplantation in patients with Child C14-15 cirrhosis and refractory variceal bleeding: a strategy improving survival.
      Among high-risk patients, accurate selection of candidates for p-TIPS is key to enhancing its beneficial effect. Indeed, patients older than 75 years, with creatinine >3 mg/dl (265 μmol/L), hepatocellular carcinoma outside the Milan criteria and total portal vein thrombosis have been excluded from all the studies stratifying therapy.
      Two RCTs
      • Lv Y.
      • Yang Z.
      • Liu L.
      • Li K.
      • He C.
      • Wang Z.
      • et al.
      Early TIPS with covered stents versus standard treatment for acute variceal bleeding in patients with advanced cirrhosis: a randomised controlled trial.
      ,
      • García-Pagán J.C.
      • Caca K.
      • Bureau C.
      • Laleman W.
      • Appenrodt B.
      • Luca A.
      • et al.
      Early use of TIPS in patients with cirrhosis and variceal bleeding.
      and several observational studies
      • Lv Y.
      • Zuo L.
      • Zhu X.
      • Zhao J.
      • Xue H.
      • Jiang Z.
      • et al.
      Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study.
      • Thabut D.
      • Pauwels A.
      • Carbonell N.
      • Remy A.J.
      • Nahon P.
      • Causse X.
      • et al.
      Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results.
      • Garcia-Pagán J.C.
      • Di Pascoli M.
      • Caca K.
      • Laleman W.
      • Bureau C.
      • Appenrodt B.
      • et al.
      Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study.
      • Hernández-Gea V.
      • Procopet B.
      • Giráldez Á.
      • Amitrano L.
      • Villanueva C.
      • Thabut D.
      • et al.
      Preemptive-TIPS improves outcome in high-risk variceal bleeding: an observational study.
      support the beneficial effect of treating high-risk patients with p-TIPS and are summarised in Table S3. Pre-emptive TIPS decreases rates of failure or rebleeding and improves ascites control in high-risk patients without worsening hepatic encephalopathy.
      • Lv Y.
      • Zuo L.
      • Zhu X.
      • Zhao J.
      • Xue H.
      • Jiang Z.
      • et al.
      Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study.
      • Thabut D.
      • Pauwels A.
      • Carbonell N.
      • Remy A.J.
      • Nahon P.
      • Causse X.
      • et al.
      Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results.
      • Garcia-Pagán J.C.
      • Di Pascoli M.
      • Caca K.
      • Laleman W.
      • Bureau C.
      • Appenrodt B.
      • et al.
      Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study.
      • Hernández-Gea V.
      • Procopet B.
      • Giráldez Á.
      • Amitrano L.
      • Villanueva C.
      • Thabut D.
      • et al.
      Preemptive-TIPS improves outcome in high-risk variceal bleeding: an observational study.
      Moreover, treating Child-Pugh B + AB & Child-Pugh C patients with pre-emptive TIPS reduces 1-year mortality from 30–41% to 14–22%.
      • Lv Y.
      • Zuo L.
      • Zhu X.
      • Zhao J.
      • Xue H.
      • Jiang Z.
      • et al.
      Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study.
      • Thabut D.
      • Pauwels A.
      • Carbonell N.
      • Remy A.J.
      • Nahon P.
      • Causse X.
      • et al.
      Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results.
      • Garcia-Pagán J.C.
      • Di Pascoli M.
      • Caca K.
      • Laleman W.
      • Bureau C.
      • Appenrodt B.
      • et al.
      Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study.
      • Hernández-Gea V.
      • Procopet B.
      • Giráldez Á.
      • Amitrano L.
      • Villanueva C.
      • Thabut D.
      • et al.
      Preemptive-TIPS improves outcome in high-risk variceal bleeding: an observational study.
      The role of p-TIPS in Child-Pugh B + AB patients has been challenged
      • Conejo I.
      • Guardascione M.A.
      • Tandon P.
      • Cachero A.
      • Castellote J.
      • Abraldes J.G.
      • et al.
      Multicenter external validation of risk stratification criteria for patients with variceal bleeding.
      due to the limited number of patients included in the studies and the differential effect of p-TIPS on survival. Detailed information regarding Child-Pugh B + AB patients was available in 2 observational studies
      • Lv Y.
      • Zuo L.
      • Zhu X.
      • Zhao J.
      • Xue H.
      • Jiang Z.
      • et al.
      Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study.
      ,
      • Hernández-Gea V.
      • Procopet B.
      • Giráldez Á.
      • Amitrano L.
      • Villanueva C.
      • Thabut D.
      • et al.
      Preemptive-TIPS improves outcome in high-risk variceal bleeding: an observational study.
      and 1 RCT.
      • Lv Y.
      • Yang Z.
      • Liu L.
      • Li K.
      • He C.
      • Wang Z.
      • et al.
      Early TIPS with covered stents versus standard treatment for acute variceal bleeding in patients with advanced cirrhosis: a randomised controlled trial.
      Survival was significantly improved in the largest observational study available, including 244 Child-Pugh B + AB patients (53 treated with TIPS) from 73% to 91% at 1 year. However, p-TIPS did not impact on mortality in the 27 patients included in the RCT from the same authors, and another large European study evaluating 237 Child-Pugh B + AB patients (19 treated with TIPS). Therefore, the available evidence does not permit definitive conclusions regarding survival in this subgroup of patients. Although no benefit in survival has been demonstrated so far, p-TIPS prevents failure/rebleeding and ascites without increasing the risk of developing hepatic encephalopathy in all the available studies and its use may be considered in Child-Pugh B + AB patients (Table S3). Therefore until new stratification tools and more data are available, pre-emptive TIPS should be considered in Child-Pugh C patients.
      • 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.

      Low-risk patients (Child-Pugh A & Child-Pugh B without AB)

      Mortality in Child-Pugh A patients ranges from 0 to 3.9% and in Child-Pugh B patients from 8.3 to 12.2 % at 6 weeks.
      • 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.
      ,
      • Rudler M.
      • Bureau C.
      • Carbonell N.
      • Mathurin P.
      • Saliba F.
      • Mallat A.
      • et al.
      Recalibrated MELD and hepatic encephalopathy are prognostic factors in cirrhotic patients with acute variceal bleeding.
      ,
      • Conejo I.
      • Guardascione M.A.
      • Tandon P.
      • Cachero A.
      • Castellote J.
      • Abraldes J.G.
      • et al.
      Multicenter external validation of risk stratification criteria for patients with variceal bleeding.
      ,
      • Lv Y.
      • Zuo L.
      • Zhu X.
      • Zhao J.
      • Xue H.
      • Jiang Z.
      • et al.
      Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study.
      Although low, mortality is not negligible and factors predicting poor outcome remain unknown. Current guidelines recommend the standard of care treatment previously detailed. Data from a single retrospective study showed that bacterial infection in Child-Pugh A patients with AVB is as low as 2% and mortality was not influenced by the use of antibiotics, suggesting that maybe antibiotic treatment would not impact mortality in Child-Pugh A. However until new data confirm this finding in the setting of a prospective RCT, antibiotic prophylaxis should be recommended in all patients with AVB.
      • Tandon P.
      • Abraldes J.
      • Keough A.
      • Bastiampillai R.
      • Jakayumar S.
      • Carbonneau M.
      • et al.
      Risk of bacterial infection in patients with cirrhosis and acute variceal hemorrhage, based on Child-Pugh class and effects of antibiotics.
      The implementation of pre-emptive TIPS has changed the clinical scenario of secondary prophylaxis by improving survival and reducing rebleeding rates.

      Patients at risk of recurrent variceal bleeding

      Patients surviving a first AVB episode are at high risk of rebleeding during follow-up (60% in the first year) if no treatment is given.
      • Bosch J.
      • García-Pagán J.
      Prevention of variceal rebleeding.
      ,
      • D'Amico G.
      Esophageal varices: from appearance to rupture; natural history and prognostic indicators.
      Therapy to prevent rebleeding is mandatory in all patients surviving an AVB episode and should be initiated before the patient is discharged from the hospital. Combination therapy with NSBBs and EBL is significantly more effective than either EBL or drug therapy alone in preventing recurrent AVB.
      • Pagliaro L.
      • Lebrec D.
      • Poynard T.
      • Hillon P.
      • Benhamou J.-P.
      Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis. A controlled study [N Engl J Med 1981;305:1371–1374].
      ,
      • Villanueva C.
      • Balanzó J.
      • Novella M.T.
      • Soriano G.
      • Sáinz S.
      • Torras X.
      • et al.
      Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding.
      Therefore, combination therapy is recommended for all patients recovering from an episode of AVB, irrespective of their cirrhosis stage. Despite correctly applying combination therapy, 21% of patients rebleed and 24% die during the first 6 weeks.
      • Augustin S.
      • Muntaner L.
      • Altamirano J.T.
      • González A.
      • Saperas E.
      • Dot J.
      • et al.
      Predicting early mortality after acute variceal hemorrhage based on classification and regression tree analysis.
      Using risk/benefit analysis to guide secondary prophylaxis based on individualised prognosis may reduce the rebleeding rate.
      HVPG and Child-Pugh score are the 2 main reported prognostic factors that enable a risk-based approach and stratification of patients according to their probability of rebleeding. Consequently, the general recommendation of NSBB + EBL for all patients undergoing secondary prophylaxis should be re-evaluated, taking into account the individualised prognosis and risk. Moreover, the implantation of pre-emptive TIPS may change the characteristics of the population requiring secondary prophylaxis, probably with an overrepresentation of low-risk patients. Studies aiming to stratify risk in the subgroup of non-high-risk patients with AVB who did not receive p-TIPS are urgently required.

      Risk-based secondary prophylaxis strategy

      Child-Pugh score-based therapy

      Recent studies have explored the effect of combination therapy vs. monotherapy depending on Child-Pugh class (A vs. B/C). Overall, the results reinforce the concept that NSBBs are the key element of secondary prophylaxis:
      Child-Pugh A: An individual patient meta-analysis
      • Albillos A.
      • Zamora J.
      • Martínez J.
      • Arroyo D.
      • Ahmad I.
      • De-la-Peña J.
      • et al.
      Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis.
      showed that in patients with Child-Pugh A score, combination therapy (EBL + a NSBB) was better than either of them alone in preventing all-source rebleeding (HR 0.46; 95% CI 0.2–1.04; p = 0.02), supporting combination therapy as the best-known strategy to reduce all-source rebleeding in Child-Pugh A patients. The combination of EBL and a NSBB was associated with a lower mortality rate than an NSBB alone in Child-Pugh A patients, although this effect was not statistically significant (incidence rate ratio [IRR] 0.29; 95% CI 0.06–1.41; p = 0.125).
      A multicentre, placebo-controlled RCT showed that the addition of simvastatin (40 mg/day) to EBL + a NSBB was associated with a significant survival benefit in Child-Pugh class A and B patients, mainly due to a decrease in mortality from rebleeding or infections,
      • Abraldes J.G.
      • Villanueva C.
      • Aracil C.
      • Turnes J.
      • Hernandez-Guerra M.
      • Genesca J.
      • et al.
      Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis.
      while no remarkable benefits were observed in Child-Pugh C patients.
      Therefore, in Child-Pugh A patients, evidence supports the use of combination therapy for secondary prophylaxis. The addition of simvastatin seems beneficial, and although more data are needed to fully support its use, the lack of secondary effects and its safety profile may further support its use.
      Child-Pugh B/C: It has been reported that combination therapy is better than EBL alone in preventing rebleeding (IRR 0.41; 95% CI 0.24–0.70; p = 0.001).
      • Albillos A.
      • Zamora J.
      • Martínez J.
      • Arroyo D.
      • Ahmad I.
      • De-la-Peña J.
      • et al.
      Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis.
      However, when combination therapy is compared with monotherapy with NSBBs, NSBBs alone demonstrated similar rates of rebleeding (IRR 1.36; 95% CI 0.87–2.14; p = 0.18), suggesting that NSBBs alone could be sufficient to prevent rebleeding in Child-Pugh B/C patients. Additionally, this meta-analysis also showed that EBL could have a deleterious effect on mortality compared to combination therapy in the subgroup of Child-Pugh B/C patients (IRR 0.46; 95% CI 0.25–0.85; p = 0.013).
      • Albillos A.
      • Zamora J.
      • Martínez J.
      • Arroyo D.
      • Ahmad I.
      • De-la-Peña J.
      • et al.
      Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis.
      Although mortality was also greater in Child-Pugh B/C patients treated with combination therapy, the difference was not statistically significant (IRR 1.40; 95% CI 0.87–2.27; p = 0.167). Therefore, based on this meta-analysis, the mainstay of therapy in Child-Pugh B/C should be NSBBs.
      Treating patients with CSPH based on their individual risk of portal hypertension-related bleeding improves prognosis and limits side effects of therapy.

      HVPG-guided therapy

      Strong evidence stemming from several studies has demonstrated that in secondary prophylaxis, achieving HVPG response is associated with a very low residual risk of bleeding,
      • Ripoll C.
      • Groszmann R.
      • Garcia-Tsao G.
      • Grace N.
      • Burroughs A.
      • Planas R.
      • et al.
      Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
      ,
      • Reiberger T.
      • Ulbrich G.
      • Ferlitsch A.
      • Payer B.A.
      • Schwabl P.
      • Pinter M.
      • et al.
      Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol.
      ,
      • Monescillo A.
      • Martínez-Lagares F.
      • Ruiz-del-Arbol L.
      • Sierra A.
      • Guevara C.
      • Jimenez E.
      • et al.
      Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding.
      ,
      • Augustin S.
      • Muntaner L.
      • Altamirano J.T.
      • González A.
      • Saperas E.
      • Dot J.
      • et al.
      Predicting early mortality after acute variceal hemorrhage based on classification and regression tree analysis.
      ,
      • Albillos A.
      • Zamora J.
      • Martínez J.
      • Arroyo D.
      • Ahmad I.
      • De-la-Peña J.
      • et al.
      Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis.
      ,
      • Villanueva C.
      • López-Balaguer J.M.
      • Aracil C.
      • Kolle L.
      • González B.
      • Miñana J.
      • et al.
      Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis.
      • Turco L.
      • Villanueva C.
      • La Mura V.
      • García-Pagán J.C.
      • Reiberger T.
      • Genescà J.
      • et al.
      Lowering portal pressure improves outcomes of patients with cirrhosis, with or without ascites: a meta-analysis.
      • Garcia-Pagán J.C.
      • Navasa M.
      • Bosch J.
      • Bru C.
      • Pizcueta P.
      • Rodés J.
      Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis.
      • García-Pagán J.C.
      • Feu F.
      • Bosch J.
      • Rodés J.
      Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study.
      • Merkel C.
      • Bolognesi M.
      • Berzigotti A.
      • Amodio P.
      • Cavasin L.
      • Casarotto I.M.
      • 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.
      better survival and lower risk of developing other complications of portal hypertension. Studies evaluating the usefulness of HVPG response in the setting of secondary prophylaxis are listed in Table S4. The use of haemodynamic criteria to individualise treatment of portal hypertension by measuring individual HVPG optimises therapy and may avoid unnecessary procedures, such as EBL, in HVPG responders.
      In this regard, it is important to remark that non-responders to NSBB that finally achieve an adequate haemodynamic response after adding or changing the drug obtain similar survival and rebleeding rates as acute responders to propranolol/nadolol monotherapy.
      • Villanueva C.
      • Graupera I.
      • Aracil C.
      • Alvarado E.
      • Miñana J.
      • Puente Á.
      • et al.
      A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.
      In fact, studies assessing the efficacy of secondary prophylaxis show that patients undergoing HVPG-guided therapy have better long-term survival than those undergoing standard combination therapies (29% vs. 43%). Specifically, this better survival is in relation to a lower rebleeding rate (19% vs. 31%) and to a lower incidence of decompensation during follow-up (55 vs. 72%).
      • Villanueva C.
      • Graupera I.
      • Aracil C.
      • Alvarado E.
      • Miñana J.
      • Puente Á.
      • et al.
      A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.
      In patients who do not initially respond to NSBBs, different approaches aimed at further diminishing their HVPG have been studied:
      • I)
        Adding nitrates (isosorbide-5-mononitrate [ISMN]) to NSBBs. The combination of an NSBB plus low-dose ISMN has been shown to have a greater portal pressure-reducing effect than NSBBs alone,
        • Garcia-Pagán J.C.
        • Navasa M.
        • Bosch J.
        • Bru C.
        • Pizcueta P.
        • Rodés J.
        Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis.
        ,
        • García-Pagán J.C.
        • Feu F.
        • Bosch J.
        • Rodés J.
        Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study.
        ,
        • Villanueva C.
        • Graupera I.
        • Aracil C.
        • Alvarado E.
        • Miñana J.
        • Puente Á.
        • et al.
        A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.
        • Villanueva C.
        • Aracil C.
        • Colomo A.
        • Lopez-Balaguer J.M.
        • Piqueras M.
        • Gonzalez B.
        • et al.
        Clinical trial: a randomized controlled study on prevention of variceal rebleeding comparing nadolol + ligation vs. hepatic venous pressure gradient-guided pharmacological therapy.
        • García-Pagán J.C.
        • Villanueva C.
        • Albillos A.
        • Bañares R.
        • Morillas R.
        • Abraldes J.G.
        • et al.
        Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial.
        • Albillos A.
        • García-Pagán J.
        • Iborra J.
        • Bandi J.
        • Cacho G.
        • Pérez-Paramo M.
        • et al.
        Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension.
        although patients should be tightly monitored for potential side effects.
      • Available studies have shown that the long-term combination of an NSBB with ISMN further decreases HVPG from 10% (propranolol alone) to 19% (propranolol + ISMN)(p <0.01), without adding significant adverse effects.
      • II)
        Adding prazosin (anti-α1-adrenergic) to NSBBs.
        • Villanueva C.
        • Graupera I.
        • Aracil C.
        • Alvarado E.
        • Miñana J.
        • Puente Á.
        • et al.
        A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.
        ,
        • Villanueva C.
        • Aracil C.
        • Colomo A.
        • Lopez-Balaguer J.M.
        • Piqueras M.
        • Gonzalez B.
        • et al.
        Clinical trial: a randomized controlled study on prevention of variceal rebleeding comparing nadolol + ligation vs. hepatic venous pressure gradient-guided pharmacological therapy.
        Prazosin, proven to be effective in diminishing HVPG, leads to a haemodynamic response in patients previously considered non-responders and decreases HVPG by a mean of 22% (vs. 12% in patients treated only with NSBBs; p <0.01). Patients should be carefully chosen, as alpha blockade can be detrimental in this clinical scenario. A few studies support its role in preventing rebleeding in secondary prophylaxis
        • Albillos A.
        • García-Pagán J.
        • Iborra J.
        • Bandi J.
        • Cacho G.
        • Pérez-Paramo M.
        • et al.
        Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension.
        and even suggest that the combination of NSBB + prazosin could be more effective than NSBB + ISMN.
        • Albillos A.
        • Lledó J.L.
        • Rossi I.
        • Pérez-Páramo M.
        • Tabuenca M.J.
        • Bañares R.
        • et al.
        Continuous prazosin administration in cirrhotic patients: effects on portal hemodynamics and on liver and renal function.
      • III)
        Change to carvedilol. There is no evidence supporting the use of carvedilol in secondary prophylaxis. Although carvedilol has shown similar efficacy to EBL
        • Stanley A.J.
        • Dickson S.
        • Hayes P.C.
        • Forrest E.H.
        • Mills P.R.
        • Tripathi D.
        • et al.
        Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding.
        and NSBB + ISMN
        • Lo G.H.
        • Chen W.C.
        • Wang H.M.
        • Yu H.C.
        Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding.
        at preventing rebleeding and improving survival, the combination of carvedilol and EBL in non-HVPG responders has yet to be tested. Due to its anti-α1-adrenergic activity, carvedilol decreases systemic arterial pressure. Generally, patients on secondary prophylaxis are more fragile (hypotension, hyponatremia and refractory/difficult to treat ascites) than those in primary prophylaxis. Carvedilol may not be well tolerated in this clinical scenario.
        • Sinagra E.
        • Perricone G.
        • D'Amico M.
        • Tinè F.
        • D'Amico G.
        Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis.
        Until new data are available, carvedilol cannot be broadly recommended in secondary prophylaxis and efforts to identify the subgroup of patients who may benefit from a more potent portal pressure reduction are strongly needed.
      Interestingly, as performing HVPG measurements is not widely available, it should be noted that non-invasive methods are being studied in order to evaluate the response to NSBBs and to allow for optimisation of medical therapy without the need to perform HVPG measurements,
      • Reverter E.
      • Lozano J.J.
      • Alonso C.
      • Berzigotti A.
      • Seijo S.
      • Turon F.
      • et al.
      Metabolomics discloses potential biomarkers to predict the acute HVPG response to propranolol in patients with cirrhosis.
      ,
      • Trebicka J.
      • von Heydebrand M.
      • Lehmann J.
      • Tofteng F.
      • Busk T.
      • Jensen H.L.
      • et al.
      Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients.
      although none of these methods can replace HVPG at the moment.

      Refractory ascites and use of NSBBs

      Some observational studies in patients with refractory ascites reported that the use of NSBBs in this subpopulation was associated with high mortality and a greater incidence of post-paracentesis circulatory dysfunction.
      • Mandorfer M.
      • Bota S.
      • Schwabl P.
      • Bucsics T.
      • Pfisterer N.
      • Kruzik M.
      • et al.
      Nonselective beta-blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.
      • Sersté 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.
      • Sersté 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.
      However, subsequent studies specifically addressing this issue did not confirm this finding,
      • Bossen L.
      • Krag A.
      • Vilstrup H.
      • Watson H.
      • Jepsen P.
      Nonselective beta-blockers do not affect mortality in cirrhosis patients with ascites: post Hoc analysis of three randomized controlled trials with 1198 patients.
      ,
      • Leithead J.A.
      • Rajoriya N.
      • Tehami N.
      • Hodson J.
      • Gunson B.K.
      • Tripathi D.
      • et al.
      Non-selective beta-blockers are associated with improved survival in patients with ascites listed for liver transplantation.
      as long as the doses of NSBB were cautiously titrated and patients were monitored closely. Recently available data compiled in 3,145 patients with cirrhosis and ascites/refractory ascites show that the use of NSBBs does not increase mortality.
      • Chirapongsathorn S.
      • Valentin N.
      • Alahdab F.
      • Krittanawong C.
      • Erwin P.J.
      • Murad M.H.
      • et al.
      Nonselective β-blockers and survival in patients with cirrhosis and ascites: a systematic review and meta-analysis.
      When carvedilol was analysed in a separate analysis, it was not associated with an increased mortality risk in patients with moderate or severe ascites.
      • Sinha R.
      • Lockman K.A.
      • Mallawaarachchi N.
      • Robertson M.
      • Plevris J.N.
      • Hayes P.C.
      Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites.
      This was validated in another recent meta-analysis stratifying patients based on the presence of ascites and showing that achieving a haemodynamic response was associated with significantly lower odds of decompensation, liver transplantation and death, regardless of the presence of ascites.
      • Turco L.
      • Villanueva C.
      • La Mura V.
      • García-Pagán J.C.
      • Reiberger T.
      • Genescà J.
      • et al.
      Lowering portal pressure improves outcomes of patients with cirrhosis, with or without ascites: a meta-analysis.
      In summary, current evidence supports its cautious use. The presence of systolic blood pressure <90 mmHg, serum creatinine >1.5 mg/dl and/or hyponatremia <130 mmol/L should lead to careful monitoring and reduction/stopping of the NSBB,
      • 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.
      with resumption considered once this clinical situation is resolved.

      TIPS

      Patients with contraindications to NSBBs treated only with EBL have a higher mortality (8% vs. 16%, p <0.02) and higher rebleeding rate (12% vs. 31%) than patients treated with NSBB + EBL.
      • Albillos A.
      • Zamora J.
      • Martínez J.
      • Arroyo D.
      • Ahmad I.
      • De-la-Peña J.
      • et al.
      Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis.
      The best strategy to rescue these patients has not been properly addressed and more evidence is required to determine whether TIPS may have a role in this subpopulation. The role of TIPS in secondary prophylaxis is restricted to patients with failure on first-line therapy (NSBB, NSBB + EBL) and recurrent AVB.
      • 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.
      Studies comparing TIPS vs. EBL + NSBB have demonstrated the efficacy of TIPS in reducing rebleeding rates (0% vs. 29%;
      • Holster I.L.
      • Tjwa E.T.T.L.
      • Moelker A.
      • Wils A.
      • Hansen B.E.
      • Vermeijden J.R.
      • et al.
      Covered transjugular intrahepatic portosystemic shunt versus endoscopic therapy + beta-blocker for prevention of variceal rebleeding.
      7% vs. 26%
      • Sauerbruch T.
      • Mengel M.
      • Dollinger M.
      • Zipprich A.
      • Rössle M.
      • Panther E.
      • et al.
      Prevention of rebleeding from esophageal varices in patients with cirrhosis receiving small-diameter stents versus hemodynamically controlled medical therapy.
      ), without improving survival and at the expense of a higher incidence of hepatic encephalopathy. Therefore, TIPS cannot be recommended as a first-line treatment in secondary prophylaxis.
      • Escorsell A.
      • Bañares R.
      • García-Pagán J.C.
      • Gilabert R.
      • Moitinho E.
      • Piqueras B.
      • et al.
      TIPS versus drug therapy in preventing variceal rebleeding in advanced cirrhosis: a randomized controlled trial.
      Future data assessing the individual risk of patients surviving an AVB in the era of p-TIPS may change current treatment recommendations.

      Conclusions

      Individual risk stratification in patients with or at risk of AVB has a significant impact on clinical outcome and survival. HVPG and liver function are able to stratify patients according to individual risk. Tailoring therapy in accordance with the patient's characteristics effectively impacts prognosis and increases survival in all clinical scenarios.

      Abbreviations

      AVB, acute variceal bleeding; cALD, chronic advanced liver disease; CSPH, clinically significant portal hypertension; DAAs, direct-acting antivirals; EBL, endoscopic band ligation; GEV, gastroesophageal varices; HRS, hepatorenal syndrome; HVPG, hepatic venous pressure gradient; LSM, liver stiffness measurement; MELD, model for end-stage liver disease; NO, nitric oxide; NSBB, non-selective beta-blocker; SBP, spontaneous bacterial peritonitis; SVR, sustained virologic response; TE, transient elastography; TIPS, transjugular intrahepatic portosystemic shunt.

      Financial support

      Supported in part by the Instituto de Salud Carlos III ( PI14/00182 and PI17/00298 ); FEDER “Una manera de hacer Europa”). The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III . AB has a Rio Hortega grant from the Instituto de Salud Carlos III . MM is support by the Spanish Association for the Study of the Liver (AEEH).

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors' contribution

      MM & AB: writing original draft. VHG: conceptualisation, supervision, writing original draft, review and editing.

      Acknowledgment

      The authors thank Juan Carlos García-Pagán and Andrés Cárdenas for their scientific and editorial assistance.

      Supplementary data

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