Clin Mol Hepatol > Volume 30(4); 2024 > Article
Brujats and Villanueva: Examining the therapeutic landscape of beta-blockers in portal hypertension
Graphical Abstract
Advanced chronic liver disease (ACLD) progresses over time, from a compensated stage (cACLD) to development of decompensation (dACLD), markedly declining life expectancy [1,2]. Portal hypertension (PH), usually estimated by the hepatic-venous pressure gradient (HVPG), is the main determinant leading to decompensation [2-4]. Variceal bleeding, overt ascites (or pleural effusion), and/or overt encephalopathy define decompensation [2]. An HVPG ≥10 mmHg defines clinically significant PH (CSPH), the main substage of cACLD, since varices and decompensating events develop above this threshold [2]. The presence of varices identifies a substage of cACLD with CSPH, since patients with varices have an increased risk of decompensation [5,6].
Increased hepatic vascular resistance is the primary factor leading to PH in early cACLD, and is related to liver fibrosis with architectural distortion, endothelial dysfunction, and vascular occlusion [7,8]. At this stage, mild increases in portal pressure activate vasodilatory and angiogenic signals, developing portosystemic collaterals and progressive splanchnic vasodilatation. The ensuing increase in portal blood flow leads to hyperdynamic circulation, exacerbating PH [6-8]. The persistence of etiological/co-etiological factors, such as obesity, diabetes or alcohol consumption, by facilitating systemic delivery of PAMPs and DAMPs, as well as bacterial translocation induced by PH, may favor the release of pro-inflammatory cytokines [9]. This may further increase intrahepatic vascular resistance and exacerbate splanchnic vasodilatation and hyperdynamic circulation, worsening PH and eventually leading to decompensation [8-10]. Cardiac output progressively increases until the advanced stages of dACLD, when cardiac compensatory reserve may be reduced, mainly in stressful situations such as severe bacterial infections or acute-on-chronicl iver failure, which may negatively impact survival [11,12].
Among patients with cACLD, hyperdynamic circulation is more developed in those with CSPH than in those with mild PH (HVPG between 5 and 10 mmHg) [6], and among patients with CSPH is more accentuated in those with varices [6,12]. Non-selective beta-blockers (NSBBs) decrease PH by β1-adrenergic blockade (reducing heart rate and cardiac output) and by β2-adrenergic blockade, causing splanchnic vasoconstriction due to unopposed adrenergic tone [13-15]. NSBBs have a portal-pressure-decreasing effect once CSPH has developed, but have a minimal effect in patients with mild PH, when hyperdynamic circulation is poorly developed [6]. The HVPG-lowering effect of NSBBs is also smaller in decompensated vs. compensated patients [11]. This may be related to vascular dysfunction in dACLD, with hypo-contractility induced by dysregulation of vasoactive proteins [16]. Altogether, indicates that patients with cACLD and CSPH may benefit the most from NSBBs.
Preventing complications of PH is the goal of therapy in cACLD. This is particularly relevant in patients with CSPH and mainly in those with varices, due to their higher risk of decompensation [2]. Strong evidence supports the efficacy of NSBBs to prevent bleeding in cirrhosis with high-risk varices [13-18]. Furthermore, the PREDESCI study demonstrated that NSBBs can also prevent decompensation in cACLD with CSPH, with a 50% risk reduction. This was mainly achieved by preventing ascites, the most frequent and severe decompensation in cACLD [19]. Subsequent studies reinforce the value of NSBBs to prevent decompensation [20,21]. At present, CSPH can be confirmed non-invasively, mainly relying on liver stiffness measurement (LSM) by transient elastography [18,22]. LSM ≤15 KPa plus platelets ≥150x109/L rule-out CSPH, and LSM of ≥25 KPa rule it in quite accurately [18,22]. Detecting varices by endoscopy or collateral circulation by imaging also identifies patients with CSPH [2]. In the PREDESCI study, the benefit of NSBBs in cACLD was consistent in patients either with or without small varices, but was more apparent with small varices, probably due to the higher risk of decompensation [19].
In patients with high-risk varices, both NSBBs and endoscopic variceal ligation (EVL) have similar efficacy to prevent a first bleeding in RCTs [13,14,17]. A recent individual patient data (IPD) meta-analysis (MA) of RCTs comparing NSBBs vs. EVL for primary prophylaxis, stratified risk according to cirrhosis decompensation [23]. This IPD-MA, by optimizing the assessment of cirrhosis as a multistate disease and that of outcomes as time-dependent events, demonstrated a significant reduction of mortality risk by half in cACLD favoring NSBBs over EVL [23]. This was mainly due to a decreased risk of ascites, while the risk of bleeding was similar. The benefit did not improve by adding EVL to NSBBs [23]. These results strongly support for the preference of NSBBs over EVL in cACLD with high-risk varices, because NSBBs further reduce the risk of ascites and improve survival, in addition to a similar bleeding risk.
Carvedilol is the preferred NSBB in cACLD. It has anti-αadrenergic activity and also enhances intrahepatic NO release, inducing a decrease in intra-hepatic vascular-resistance [24], a key factor leading to inducing PH in cACLD [6,8]. Carvedilol has a greater portal-pressure-decreasing effect than classical-NSBBs, such as propranolol or nadolol, and may achieve a hemodynamic response in previous non-responders to classical-NSBBs [24,25]. Furthermore, carvedilol has additional antioxidant, anti-inflammatory, and antifibrotic effects [26,27]. A recent IPD-MA has investigated the efficacy of carvedilol in cACLD with CSPH, including RCTs comparing carvedilol with a control group receiving no active therapy (in patients with small varices or without varices) or EVL (if high-risk varices) [28]. This IPD-MA has demonstrated that carvedilol can effectively prevent decompensation and significantly improves survival in cACLD with CSPH [28]. This supports the strategy of screening patients with cACLD for CSPH to start therapy with carvedilol, as suggested in the last Baveno meeting.
The goal of treatment in dACLD is to prevent death. This implies preventing further decompensation, which is closely related to death. Whether NSBBs may be effective in dACLD without varices has not been clarified. In patients with dACLD and high-risk varices, NSBBs are no better than EVL to prevent first bleeding, according to a previously commented IPD-MA [23]. After variceal bleeding, current guidelines advise combining NSBBs and EVL to prevent rebleeding [2,3]. According to another IPD-MA, adding NSBBs to EVL significantly decreases rebleeding risk and improves survival compared with EVL monotherapy, particularly in Child-Pugh B/C [29]. In this IPD-MA, NSBBs monotherapy performed as well as combined therapy [29], suggesting that NSBBs are the cornerstone of treatment in patients with previous bleeding. The benefit of NSBBs is particularly relevant in patients with a marked decrease in HVPG [30,31], and guiding therapy based on HVPG response has been suggested to potentially improve efficacy [32]. Nevertheless, the limited availability and invasiveness limit such strategy [33]. Identifying non-responders using non-invasive tools is an unmet clinical need, since this is a promising strategy to guide therapy, particularly in the high-risk setting of dACLD [18,22].
In patients with advanced ascites, NSBBs should be dose-reduced or discontinued if persistently low arterial pressure (systolic <90 mmHg), or if renal impairment [2]. This is also the case in patients with intercurrent conditions determining hemodynamic instability, such as bleeding, SBP or other severe infections [13,14]. After recovery, NSBBs should be re-started at lower doses and under close monitoring. Carvedilol, given its non-selective vasodilatory effect, may increase sodium and water retention in patients with advanced ascites, when classical NSBBs may be preferable [24]. Patients with dACLD and contraindication/intolerance to NSBBs should be considered for trans-jugular intrahepatic porto-systemic shunt [34-36], particularly those with uncontrolled ascites or recurrent decompensation.

FOOTNOTES

Authors’ contribution
A.B. manuscript writing and approval.
C.V. concept of the work, manuscript writing and approval.
Conflicts of Interest
The authors have no conflicts to disclose.


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Abbreviations

CI
confidence interval
CSPH
clinically significant portal hypertension
FU
follow-up
HVPG
hepatic venous pressure gradient
INR
international normalized ratio
MELD
model for end stage liver disease
NSBBs
non-selective β-blockers
OLT
orthotopic liver transplantation
PH
portal hypertension
RCT
randomized controlled trial
SD
standard deviation
SHR
subdistribution hazard ratio

REFERENCES

1. D’Amico G, Morabito A, D’Amico M, Pasta L, Malizia G, Rebora P, et al. Clinical states of cirrhosis and competing risks. J Hepatol 2018;68:563-576.
crossref pmid
2. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol 2022;76:959-974.
pmid
3. Kaplan DE, Ripoll C, Thiele M, Fortune BE, Simonetto DA, Garcia-Tsao G, et al. AASLD Practice Guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology 2024;79:1180-1211.
crossref pmid
4. Garcia-Tsao G, Abraldes JG, 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. Hepatology 2017;65:310-335.
crossref pmid pdf
5. 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. Aliment Pharmacol Ther 2014;39:1180-1193.
crossref pmid
6. Villanueva C, Albillos A, Genescà J, Abraldes JG, Calleja JL, Aracil C, et al. Development of hyperdynamic circulation and response to β-blockers in compensated cirrhosis with portal hypertension. Hepatology 2016;63:197-206.
crossref pmid pdf
7. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69:406-460.
crossref pmid
8. Felli E, Nulan Y, Selicean S, Wang C, Gracia-Sancho J, Bosch J. Emerging therapeutic targets for portal hypertension. Curr Hepatol Rep 2023;22:51-66.
crossref pmid pmc pdf
9. Albillos A, Martin-Mateos R, Van der Merwe S, Wiest R, Jalan R, Álvarez-Mon M. Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol 2022;19:112-134.
crossref pmid pdf
10. Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015;63:1272-1284.
crossref pmid
11. Alvarado-Tapias E, Ardevol A, Garcia-Guix M, Montañés R, Pavel O, Cuyas B, et al. Short-term hemodynamic effects of β-blockers influence survival of patients with decompensated cirrhosis. J Hepatol 2020;73:829-841.
crossref pmid
12. Turco L, Garcia-Tsao G, Magnani I, Bianchini M, Costetti M, Caporali C, et al. Cardiopulmonary hemodynamics and C-reactive protein as prognostic indicators in compensated and decompensated cirrhosis. J Hepatol 2018;68:949-958.
crossref pmid
13. Rabiee A, Garcia-Tsao G, Tapper EB. Nonselective beta-blockers in portal hypertension: Why, when, and how? Clin Liver Dis (Hoboken) 2022;19:118-123.
crossref pmid pmc pdf
14. Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: Evidence-based indications and limitations. JHEP Rep 2019;2:100063.
crossref pmid pmc
15. Albillos A, Krag A. Beta-blockers in the era of precision medicine in patients with cirrhosis. J Hepatol 2023;78:866-872.
crossref pmid
16. Trebicka J, von Heydebrand M, Lehmann J, Tofteng F, Busk T, Jensen HL, 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.
crossref pmid
17. Sharma M, Singh S, Desai V, Shah VH, Kamath PS, Murad MH, et al. Comparison of therapies for primary prevention of esophageal variceal bleeding: A systematic review and network meta-analysis. Hepatology 2019;69:1657-1675.
crossref pmid pdf
18. Abraldes JG, Caraceni P, Ghabril M, Garcia-Tsao G. Update in the treatment of the complications of cirrhosis. Clin Gastroenterol Hepatol 2023;21:2100-2109.
crossref pmid
19. Villanueva C, Albillos A, Genescà J, Garcia-Pagan JC, Calleja JL, 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. Lancet 2019;393:1597-1608.
crossref pmid
20. Rowe IA, Villanueva C, Shearer JE, Torres F, Albillos A, Genescà J, et al. Quantifying the benefit of nonselective beta-blockers in the prevention of hepatic decompensation: A Bayesian reanalysis of the PREDESCI trial. Hepatology 2023;78:530-539.
crossref pmid
21. Serper M, Kaplan DE, Taddei TH, Tapper EB, Cohen JB, Mahmud N. Nonselective beta blockers, hepatic decompensation, and mortality in cirrhosis: A national cohort study. Hepatology 2023;77:489-500.
crossref pmid pdf
22. Wong YJ, Zhaojin C, Tosetti G, Degasperi E, Sharma S, Agarwal S, et al. Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patients. Clin Mol Hepatol 2023;29:135-145.
crossref pmid pdf
23. Villanueva C, Sapena V, Lo GH, Seo YS, Shah HA, Singh V, et al. Improving primary prophylaxis of variceal bleeding by adapting therapy to the clinical stage of cirrhosis. A competing-risk meta-analysis of individual participant data. Aliment Pharmacol Ther 2024;59:306-321.
crossref pmid
24. Villanueva C, Tripathi D. Carvedilol, probably the β-blocker of choice for everyone with cirrhosis and portal hypertension: But not so fast! Liver Int 2023;43:1154-1156.
crossref pmid
25. Gillespie SL, Hanrahan TP, Rockey DC, Majumdar A, Hayes PC. Review article: controversies surrounding the use of carvedilol and other beta blockers in the management of portal hypertension and cirrhosis. Aliment Pharmacol Ther 2023;57:454-463.
crossref pmid pdf
26. McDowell HR, Chuah CS, Tripathi D, Stanley AJ, Forrest EH, Hayes PC. Carvedilol is associated with improved survival in patients with cirrhosis: a long-term follow-up study. Aliment Pharmacol Ther 2021;53:531-539.
crossref pmid
27. Turco L, Reiberger T, Vitale G, La Mura V. Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension. Liver Int 2023;43:1183-1194.
crossref pmid pdf
28. Villanueva C, Torres F, Shah HA, Tripathi D, Sarin SK, Brujats A, et al. Carvedilol improves risk of decompensation and survival in compensated cirrhosis. A competing-risk meta-analysis of individual patient data. J Hepatol 2021;75:S378-S380.

29. 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. Hepatology 2017;66:1219-1231.
crossref pmid pdf
30. Mandorfer M, Hernández-Gea V, Reiberger T, García-Pagán JC. Hepatic venous pressure gradient response in non-selective beta-blocker treatment—Is it worth measuring? Curr Hepatology Rep 2019;18:174-186.
crossref pdf
31. Turco L, Villanueva C, La Mura V, García-Pagán JC, Reiberger T, Genescà J, 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.
crossref pmid
32. 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. Hepatology 2017;65:1693-1707.
crossref pmid pdf
33. La Mura V, Garcia-Guix M, Berzigotti A, Abraldes JG, García-Pagán JC, Villanueva C, et al. A prognostic strategy based on stage of cirrhosis and HVPG to improve risk stratification after variceal bleeding. Hepatology 2020;72:1353-1365.
crossref pmid pdf
34. Lee EW, Eghtesad B, Garcia-Tsao G, Haskal ZJ, Hernandez-Gea V, Jalaeian H, et al. AASLD Practice Guidance on the use of TIPS, variceal embolization, and retrograde transvenous obliteration in the management of variceal hemorrhage. Hepatology 2024;79:224-250.
crossref pmid
35. Lee HL, Lee SW. The role of transjugular intrahepatic portosystemic shunt in patients with portal hypertension: Advantages and pitfalls. Clin Mol Hepatol 2022;28:121-134.
crossref pmid pdf
36. Larrue H, D’Amico G, Olivas P, Lv Y, Bucsics T, Rudler M, et al. TIPS prevents further decompensation and improves survival in patients with cirrhosis and portal hypertension in an individual patient data meta-analysis. J Hepatol 2023;79:692-703.
crossref pmid

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