Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2015 Ago;15(Suppl 2):e6235 doi: 10.5867/medwave.2015.6235
Noradrenaline or terlipressin for hepatorenal syndrome?
Pilar Celis, Gabriel Rada
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Abstract

Hepatorenal syndrome is a condition associated with very high mortality that may be reverted in some cases with vasoconstrictors. Terlipressin has generally been considered standard treatment, but noradrenaline has been postulated as alternative. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including four pertinent randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded noradrenaline and terlipressin probably have similar effects on reverting hepatorrenal syndrome and decreasing mortality, but noradrenaline is associated with less adverse effects, and has lower costs.


 
Problem

Hepatorenal syndrome is a condition associated with very high mortality. It is caused by intense renal vasoconstriction consequence of systemic and portal hemodynamic disturbances, particularly splacnic system vasodilation. Intravascular volume expansion and prolonged treatment with vasoconstrictors can revert kidney failure in some patients. Terlipressin improves renal function and decreases mortality, however it has frequent adverse effects, high cost, and it is not widely available. The use of alternative vasoconstrictors has been proposed, such as noradrenaline, which is widely available and has a lower cost.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 databases, to identify systematic reviews and their included primary studies. With this information, we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • Noradrenaline and terlipressin probably have similar effects on reverting hepatorenal syndrome and decreasing mortality.
  • Noradrenaline is associated with less adverse effects than terlipressin.
  • Noradrenaline probably has a more favorable risk/benefit and cost/benefit ratio. 
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found six systematic reviews [1],[2],[3],[4],[5],[6]  including four randomized controlled trials, reported in five references [7],[8],[9],[10],[11].

What types of patients were included

The studies included adults with advanced liver disease (Child Pugh C). One study [8] included patients with type 2 hepatorenal syndrome,  one did not limit by hepatorenal type [7]  and two studies included type 1 hepatorenal syndrome [9],[11].

MELD score ranged between 20 and 30 points in three studies [7],[9],[11] and more than 30 in one [8].

Average creatinine level ranged between 2 and 3 mg/dl in all of the studies.

What types of interventions were included

All studies compared terlipressin to noradrenaline.

Noradrenaline dose ranged from 0.5 to 3 mg/hr. Terlipressin dose was 0.5 to 2 mg every 6 hours in three studies [8],[9],[11] and 1 to 2 mg every 4 hours in one [7].

What types of outcomes
were measured

Mortality, renal function recovery and adverse events.

Summary of findings

The information on the effects of noradrenaline compared to terlipressin is based on four randomized trials including 154 patients. All studies reported the outcomes: mortality, hepatorenal syndrome reversal and adverse effects. 

  • Noradrenaline and terlipressin probably have similar effects on reverting hepatorenal syndrome. The certainty of the evidence is moderate.
  • Noradrenaline and terlipressin probably have similar effects on decreasing mortality in hepatorenal syndrome. The certainty of the evidence is moderate.
  • Noradrenaline is associated with less adverse effects than terlipressin. The certainty of the evidence is high.


Other considerations for decision-making

To whom this evidence does and does not apply

  • Included studies evaluated patients with advanced cirrhosis with high Meld or Child-Pugh scores, with type 1 or 2 hepatorenal syndrome, so this evidence can be applied to the majority of patients presenting with this condition.
About the outcomes included in this summary
  • The outcomes included are those considered critical for decision-making by the authors of this summary: mortality, hepatorenal syndrome reversal and adverse effects. These coincide with those mentioned in the main guidelines [12],[13]
Balance between benefits and risks, and certainty of the evidence
  • Existing evidence shows equivalent benefit, but less adverse effects, so probably the benefit/risk ratio is favorable to noradrenaline.
  • However, it is important to mention the difference in adverse effects is not given by severe adverse effects, which are similar for both terlipressin and noradrenaline, but mainly by the higher frequency of abdominal pain and an increase in stool frequency.
What would patients and their doctors think about this intervention
  • Terlipressin is considered standard treatment for hepatorenal syndrome, and consequently the main guidelines recommended it. Despite the existing evidence favoring noradrenaline there should be resistance from clinicians to adopt this therapy, at least while guidelines do not recommend it explicitly.
Resource considerations
  • Noradrenaline has lower cost, so if we consider there is no difference in efficacy, it is probably a cost-effective intervention. 

Differences between this summary and other sources

  • The conclusions of this summary are in agreement with the more recent systematic review that includes all of the studies identified [4].
  • The main guidelines differ in their recommendations. The European guideline recommends terlipressin as first line therapy, but mentions noradrenaline as an alternative [12],[13]. The American guideline recommends using vasoactive agents, mainly octeotride or midodrine (terlipressin is not available in the United States), but recognizes the role of noradrenaline, limiting its use to critical care units.
Could this evidence change in the future?
  • The probability of future evidence changing the conclusion of this summary is low, because of the certainty of the evidence.
  • There are no other completed or ongoing studies evaluating this question, at least according to the International Controlled Trials Registry Platform of World Health Organization.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Matrix of evidence (static version).

Follow the link to access the interactive version: Terlipressin versus noradrenaline for hepatorenal syndrome

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Matrix of evidence (static version).
Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

El síndrome hepatorrenal es una condición asociada a altísima mortalidad, que puede ser recuperada en ciertos casos con el uso de vasoconstrictores. Generalmente se considera que terlipresina es el tratamiento estándar, pero noradrenalina se ha planteado como una alternativa. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, identificamos seis revisiones sistemáticas que en conjunto incluyen cuatro estudios aleatorizados. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que noradrenalina y terlipresina son probablemente igual de efectivas en lograr mejoría del síndrome hepatorrenal y disminuir la mortalidad, pero que noradrenalina se asocia a menos efectos adversos, y tiene un menor costo.

Authors: Pilar Celis[1,5], Gabriel Rada[1,2,3,4,5]

E-mail: radagabriel@epistemonikos.org

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citation: Celis P, Rada G. Noradrenaline or terlipressin for hepatorenal syndrome?. Medwave 2015 Ago;15(Suppl 2):e6235 doi: 10.5867/medwave.2015.6235

Publication date: 27/8/2015

PubMed record

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  1. Dobre M, Demirjian S, Sehgal AR, Navaneethan SD. Terlipressin in hepatorenal syndrome: a systematic review and meta-analysis. Int Urol Nephrol. 2011 Mar;43(1):175-84. | CrossRef | PubMed |
  2. Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology. 2010 Feb;51(2):576-84. | CrossRef | PubMed |
  3. Hiremath SB, Srinivas LD. Survival benefits of terlipressin and non-responder state in hepatorenal syndrome: a meta-analysis. Indian J Pharmacol. 2013 Jan-Feb;45(1):54-60. | CrossRef | PubMed |
  4. Nassar Junior AP, Farias AQ, D' Albuquerque LA, Carrilho FJ, Malbouisson LM. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PLoS One. 2014 Sep 9;9(9):e107466. | CrossRef | PubMed |
  5. Velez JC, Nietert PJ. Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials. Am J Kidney Dis. 2011 Dec;58(6):928-38. | CrossRef | PubMed |
  6. Zhang ZF, Yang N, Zhao G, Liu LN, Wang YD, Duan ZJ. [Meta-analysis of terlipressin in treatment of hepatorenal syndrome: an update]. Zhonghua Yi Xue Za Zhi. 2009 Jul 28;89(28):1970-4. | PubMed |
  7. Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Cerenzia MT, Martini S, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol. 2007 Oct;47(4):499-505. | PubMed |
  8. Ghosh S, Choudhary NS, Sharma AK, Singh B, Kumar P, Agarwal R, et al. Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study. Liver Int. 2013 Sep;33(8):1187-93. | CrossRef | PubMed |
  9. Sharma P, Kumar A, Shrama BC, Sarin SK. An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. Am J Gastroenterol. 2008 Jul;103(7):1689-97. | CrossRef | PubMed |
  10. Singh V, Ghosh S, Chawla Y, Singh B, Sharma N, Bhalla A, et al. Noradrenaline versus terlipressin in the treatment of hepatorenal syndrome. Gastroenterology. 2011 May;140(5, Suppl 1):s-958. | Link |
  11. Singh V, Ghosh S, Singh B, Kumar P, Sharma N, Bhalla A, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study. J Hepatol. 2012 Jun;56(6):1293-8. | CrossRef | PubMed |
  12. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417. | CrossRef | PubMed |
  13. Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3. | CrossRef | PubMed |
Dobre M, Demirjian S, Sehgal AR, Navaneethan SD. Terlipressin in hepatorenal syndrome: a systematic review and meta-analysis. Int Urol Nephrol. 2011 Mar;43(1):175-84. | CrossRef | PubMed |

Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology. 2010 Feb;51(2):576-84. | CrossRef | PubMed |

Hiremath SB, Srinivas LD. Survival benefits of terlipressin and non-responder state in hepatorenal syndrome: a meta-analysis. Indian J Pharmacol. 2013 Jan-Feb;45(1):54-60. | CrossRef | PubMed |

Nassar Junior AP, Farias AQ, D' Albuquerque LA, Carrilho FJ, Malbouisson LM. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PLoS One. 2014 Sep 9;9(9):e107466. | CrossRef | PubMed |

Velez JC, Nietert PJ. Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials. Am J Kidney Dis. 2011 Dec;58(6):928-38. | CrossRef | PubMed |

Zhang ZF, Yang N, Zhao G, Liu LN, Wang YD, Duan ZJ. [Meta-analysis of terlipressin in treatment of hepatorenal syndrome: an update]. Zhonghua Yi Xue Za Zhi. 2009 Jul 28;89(28):1970-4. | PubMed |

Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Cerenzia MT, Martini S, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol. 2007 Oct;47(4):499-505. | PubMed |

Ghosh S, Choudhary NS, Sharma AK, Singh B, Kumar P, Agarwal R, et al. Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study. Liver Int. 2013 Sep;33(8):1187-93. | CrossRef | PubMed |

Sharma P, Kumar A, Shrama BC, Sarin SK. An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. Am J Gastroenterol. 2008 Jul;103(7):1689-97. | CrossRef | PubMed |

Singh V, Ghosh S, Chawla Y, Singh B, Sharma N, Bhalla A, et al. Noradrenaline versus terlipressin in the treatment of hepatorenal syndrome. Gastroenterology. 2011 May;140(5, Suppl 1):s-958. | Link |

Singh V, Ghosh S, Singh B, Kumar P, Sharma N, Bhalla A, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study. J Hepatol. 2012 Jun;56(6):1293-8. | CrossRef | PubMed |

European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417. | CrossRef | PubMed |

Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3. | CrossRef | PubMed |