Skip to main content

Advertisement

SpringerLink
Log in

Treatment with carvedilol improves survival of patients with acute-on-chronic liver failure: a randomized controlled trial

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background and aims

In addition to the portal pressure reducing effect, non-selective beta blockers (NSBBs) have possible immunomodulatory and effect in reducing bacterial translocation. Recently, it has been shown that patients who are already on NSBBs should be continued on them (if feasible), if acute-on-chronic liver failure (ACLF) develops. It, however, remains unknown if patients with ACLF and no or small esophageal varices at presentation will benefit from the use of NSBBs. We studied the efficacy and safety of carvedilol in patients with ACLF in reducing mortality, variceal bleeding and non-bleeding complications.

Methods

136 patients with ACLF (with no or small esophageal varices and HVPG ≥ 12 mmHg) were randomized to either carvedilol (n = 66) or placebo arms (n = 70).

Results

Within 28 days, 7 (10.6%) of 66 patients in the carvedilol group and 17 (24.3%) of 70 in the placebo group died (p= 0.044). Fewer patients in the carvedilol compared to placebo group developed acute kidney injury (AKI) (13.6% vs 35.7%, p = 0.003 and spontaneous bacterial peritonitis (SBP) (6.1% vs 21.4%, p= 0.013). Significantly, more patients in the placebo group had increase in APASL ACLF Research Consortium-ACLF grade (22.9% vs 6.1%, p= 0.007). There was no significant difference in the 90-day transplant-free survival rate and development of AKI, SBP, non-SBP infections (including pneumonia) and variceal bleed within 90 days, between the two groups.

Conclusions

In ACLF patients with either no or small esophageal varices and HVPG ≥ 12 mmHg, carvedilol leads to improved survival and fewer AKI and SBP events up to 28 days.

ClinicalTrials.gov identifier number

NCT02583698.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AARC:

APASL ACLF Research Consortium

ACLF:

Acute-on-chronic liver failure

AKI:

Acute kidney injury

APASL:

Asian Pacific Association for the Study of the Liver

CLIF-C:

Chronic Liver Failure Consortium

DILI:

Drug-induced liver injury

FHVP:

Free hepatic venous pressure

HBV:

Hepatitis B virus

HE:

Hepatic encephalopathy

HEV:

Hepatitis E virus

HVPG:

Hepatic venous pressure gradient

INR:

International normalized ratio

LT:

Liver transplantation

NASH:

Non-alcoholic steatohepatitis

NSBB:

Non-selective beta blocker

WHVP:

Wedged hepatic venous pressure

References

  1. Lebrec D, Nouel O, Bernuau J, Bouygues M, Rueff B, Benhamou JP. Propranolol in prevention of recurrent gastrointestinal bleeding in cirrhotic patients. Lancet. 1981;1:920–1.

    Article  CAS  Google Scholar 

  2. de Montmollin E, Aboab J, Mansart A, Annane D. Bench-to-bedside review: betaadrenergic modulation in sepsis. Crit Care. 2009;13:230.

    Article  Google Scholar 

  3. Perez-Paramo M, Munoz J, Albillos A, Freile I, Portero F, Santos M, et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology. 2000;31:43–8.

    Article  CAS  Google Scholar 

  4. Reiberger T, Ferlitsch A, Payer BA, Mandorfer M, Heinisch BB, Hayden H, et al. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol. 2013;58:911–21.

    Article  CAS  Google Scholar 

  5. Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology. 2003;37:902–8.

    Article  Google Scholar 

  6. D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. HVPG reduction and prevention of variceal bleeding in cirrhosis. A systematic review. Gastroenterology. 2006;131:1611–24.

    Article  Google Scholar 

  7. Senzolo M, Cholongitas E, Burra P, Leandro G, Thalheimer U, Patch D, et al. Beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int. 2009;29:1189–93.

    Article  CAS  Google Scholar 

  8. Kumar A, Das K, Sharma P, Mehta V, Sharma BC, Sarin SK. Hepatic venous pressure gradient, systemic and pulmonary hemodynamics in patients with acute-on-chronic liver failure. Dig Dis Sci. 2009;54:869–78.

    Article  Google Scholar 

  9. Garg H, Kumar A, Garg V, Kumar M, Kumar R, Sharma BC, et al. Hepatic and systemic hemodynamic derangements predict early mortality and recovery in patients with acute-on-chronic liver failure. J Gastroenterol Hepatol. 2013;28(8):1361–7.

    Article  Google Scholar 

  10. Mookerjee RP. Acute-on-chronic liver failure: liver and portal haemodynamics. Curr Opin Crit Care. 2011;17(2):170–6.

    Article  Google Scholar 

  11. Mookerjee RP, Pavesi M, Thomsen KL, Mehta G, Macnaughtan J, Bendtsen F, et al. Treatment with non-selective beta-blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol. 2016;64:574–82.

    Article  CAS  Google Scholar 

  12. Sarin SK, Kedarisetty CK, Abbas Z, Amarapurkar D, Bihari C, Chan AC, et al. APASL ACLF Working Party. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014. Hepatol Int. 2014;8(4):453–71.

    Article  Google Scholar 

  13. Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007;45:1348–54.

    Article  CAS  Google Scholar 

  14. Choudhury A, Jindal A, Maiwall R, Sharma MK, Sharma BC, Pamecha V, et al. Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models. Hepatol Int. 2017;11(5):461–71.

    Article  CAS  Google Scholar 

  15. http://www.aclf.in/?page=doctor_aarc_grade_cal.

  16. Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Ginès P, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol. 2014;61:1038–47.

    Article  Google Scholar 

  17. https://www.clifresearch.com/ToolsCalculators.aspx.

  18. Angeli P, Gines P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol. 2015;62:986-74.

    Article  Google Scholar 

  19. Jindal A, Vashistha C, Sharma MK, Sarin SK. Acute-on-chronic liver failure- does etiology really matter? J Clin Exp Hepatol. 2013;3:S18–20.

    Article  Google Scholar 

  20. Sarin SK, Choudhury A. Acute-on-chronic liver failure: terminology, mechanisms and management. Nat Rev Gastroenterol Hepatol. 2016;13(3):131–4.

    Article  CAS  Google Scholar 

  21. Turnes J, Garcia-Pagan JC, Abraldes JG, Hernandez-Guerra M, Dell’Era A, Bosch J, et al. Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis. Am J Gastroenterol. 2006;101:506–12.

    Article  CAS  Google Scholar 

  22. De Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2005;43:167–76.

    Article  Google Scholar 

  23. Senzolo M, Cholongitas E, Marelli L, Thalheimer U, Patch D, Burroughs AK, et al. The low incidence of bacterial infections could be a protective factor against variceal bleeding per se in hemodynamic responders to propranolol. Am J Gastroenterol. 2006;101:2436–7.

    Article  Google Scholar 

  24. Straub RH, Pongratz G, Weidler C, Linde HJ, Kirschning CJ, Glück T, et al. Ablation of the sympathetic nervous system decreases gram-negative and increases gram-positive bacterial dissemination: key roles for tumor necrosis factor/phagocytes and interleukin-4/lymphocytes. J Infect Dis. 2005;192:560–72.

    Article  CAS  Google Scholar 

  25. Worlicek M, Knebel K, Linde HJ, Moleda L, Schölmerich J, Straub RH, et al. Splanchnic sympathectomy prevents translocation and spreading of E. coli but not S. aureus in liver cirrhosis. Gut. 2010;59:1127–34.

    Article  CAS  Google Scholar 

  26. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52:595–638.

    CAS  PubMed  Google Scholar 

  27. Peuschel KE. Antiviral therapy with non-selective beta blockers: preliminary experimental and clinical corroboration. Med Hypotheses. 2005;64:256–60.

    Article  CAS  Google Scholar 

  28. Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310:1683–91.

    Article  Google Scholar 

  29. Sersté T, Njimi H, Degré D, Deltenre P, Schreiber J, Lepida A, et al. The use of beta-blockers is associated with the occurrence of acute kidney injury in severe alcoholic hepatitis. Liver Int. 2015;35:1974–82.

    Article  Google Scholar 

  30. Umgelter A, Reindl W, Franzen M, Lenhardt C, Huber W, Schmid RM. Renal resistive index and renal function before and after paracentesis in patients with hepatorenal syndrome and tense ascites. Intensive Care Med. 2009;35:152–6.

    Article  CAS  Google Scholar 

  31. Rezayat KA, Zeraati AA, Pezeshki Rad M, Chogan J, Davoudian N, Akhavan Rezayat A, et al. Impact of propranolol on preventing renal dysfunction in patients with cirrhosis. Middle East J Dig Dis. 2017;9(4):206–11.

    Article  Google Scholar 

  32. Kastelan S, Ljubicic N, Kastelan Z, Ostojic R, Uravic M. The role of duplex-doppler ultrasonography in the diagnosis of renal dysfunction and hepatorenal syndrome in patients with liver cirrhosis. Hepatogastroenterology. 2004;51:1408–12.

    PubMed  Google Scholar 

  33. Ozcan H, Aytac SK, Yagmurlu B, Erten A. Effect of propranolol on renal hemodynamics in patients with cirrhosis: assessment with Doppler US. Tani Girisim Radyol. 2004;10:230–3.

    PubMed  Google Scholar 

  34. Kumar A, Sharma P, Anikhindi SA, Prajapati R, Agarwal R, Sharma B, Bansal N, Singla V, Arora A. Can non-selective beta-blockers (NSBBs) prevent enlargement of small esophageal varices in patients with cirrhosis? A Meta-analysis. J Clin Exp Hepatol. 2017;7(4):275–83.

    Article  Google Scholar 

Download references

Author information

Author notes

  1. Manoj Kumar and Sumit Kainth contributed equally to this work and are joint first authors.

Authors and Affiliations

  1. Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India

    Manoj Kumar, Sumit Kainth, Ashok Choudhury, Rakhi Maiwall, Saggere Muralikrishna Shasthry, Ankur Jindal & Shiv K. Sarin

  2. Department of Critical Care Medicine, Institute of Liver and Biliary Sciences, New Delhi, India

    Lalita G. Mitra, Vandana Saluja & Prashant Mohan Agarwal

  3. Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India

    Ankit Bhardwaj

  4. Department of Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India

    Guresh Kumar

Authors
  1. Manoj Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sumit Kainth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashok Choudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rakhi Maiwall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lalita G. Mitra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vandana Saluja
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Prashant Mohan Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Saggere Muralikrishna Shasthry
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ankur Jindal
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ankit Bhardwaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Guresh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shiv K. Sarin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

We thank SK, MK and SKS for developing the protocol; SK, MKS, SKS and AB for enrolling participants in the study; RM, AC, LGM, VS, PA, SSM, AJ and SKS for reviewing and providing inputs to the protocol and manuscript; and GK for helping with statistical analysis.

Corresponding author

Correspondence to Manoj Kumar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The study has been approved by the institutional ethics committee of the Institute of Liver and Biliary Sciences (Letter no. F.25/5/80/ILBS/AC/2015/711) and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, M., Kainth, S., Choudhury, A. et al. Treatment with carvedilol improves survival of patients with acute-on-chronic liver failure: a randomized controlled trial. Hepatol Int 13, 800–813 (2019). https://doi.org/10.1007/s12072-019-09986-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-019-09986-9

Keywords

Search

Navigation