Terlipressin versus Norepinephrine in the Treatment of Hepatorenal Syndrome: A Systematic Review and Meta-Analysis

Abstract

Background
Hepatorenal syndrome (HRS) is a severe and progressive functional renal failure occurring in patients with cirrhosis and ascites. Terlipressin is recognized as an effective treatment of HRS, but it is expensive and not widely available. Norepinephrine could be an effective alternative. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of norepinephrine compared to terlipressin in the management of HRS.

Methods
We searched the Medline, Embase, Scopus, CENTRAL, Lilacs and Scielo databases for randomized trials of norepinephrine and terlipressin in the treatment of HRS up to January 2014. Two reviewers collected data and assessed the outcomes and risk of bias. The primary outcome was the reversal of HRS. Secondary outcomes were mortality, recurrence of HRS and adverse events.

Results
Four studies comprising 154 patients were included. All trials were considered to be at overall high risk of bias. There was no difference in the reversal of HRS (RR = 0.97, 95% CI = 0.76 to 1.23), mortality at 30 days (RR = 0.89, 95% CI = 0.68 to 1.17) and recurrence of HRS (RR = 0.72; 95% CI = 0.36 to 1.45) between norepinephrine and terlipressin. Adverse events were less common with norepinephrine (RR = 0.36, 95% CI = 0.15 to 0.83).

Conclusions
Norepinephrine seems to be an attractive alternative to terlipressin in the treatment of HRS and is associated with less adverse events. However, these findings are based on data extracted from only four small studies.

Full text

Terlipressin versus Norepinephrine in the Treatment of
Hepatorenal Syndrome: A Systematic Review and Meta-
Analysis
Antonio Paulo Nassar Junior
1
*, Alberto Queiroz Farias
2
, Luiz Augusto Carneiro d’ Albuquerque
3
, Flair
Jose
´Carrilho
2
, Luiz Marcelo Sa
´Malbouisson
1
1Intensive Care Unit, Department of Gastroenterology, University of Sao Paulo. Sao Paulo, SP, Brazil, 2Discipline of Gastroenterology, Department of Gastroenterology.
University of Sao Paulo. Sao Paulo, SP, Brazil, 3Liver and Gastrointestinal Transplant Division, Department of Gastroenterology. University of Sa
˜o Paulo, Sa
˜o Paulo, SP,
Brazil
Abstract
Background:
Hepatorenal syndrome (HRS) is a severe and progressive functional renal failure occurring in patients with
cirrhosis and ascites. Terlipressin is recognized as an effective treatment of HRS, but it is expensive and not widely available.
Norepinephrine could be an effective alternative. This systematic review and meta-analysis aimed to evaluate the efficacy
and safety of norepinephrine compared to terlipressin in the management of HRS.
Methods:
We searched the Medline, Embase, Scopus, CENTRAL, Lilacs and Scielo databases for randomized trials of
norepinephrine and terlipressin in the treatment of HRS up to January 2014. Two reviewers collected data and assessed the
outcomes and risk of bias. The primary outcome was the reversal of HRS. Secondary outcomes were mortality, recurrence of
HRS and adverse events.
Results:
Four studies comprising 154 patients were included. All trials were considered to be at overall high risk of bias.
There was no difference in the reversal of HRS (RR = 0.97, 95% CI = 0.76 to 1.23), mortality at 30 days (RR = 0.89, 95% CI = 0.68
to 1.17) and recurrence of HRS (RR = 0.72; 95% CI = 0.36 to 1.45) between norepinephrine and terlipressin. Adverse events
were less common with norepinephrine (RR = 0.36, 95% CI = 0.15 to 0.83).
Conclusions:
Norepinephrine seems to be an attractive alternative to terlipressin in the treatment of HRS and is associated
with less adverse events. However, these findings are based on data extracted from only four small studies.
Citation: Nassar Junior AP, Farias AQ, d’ Albuquerque LAC, Carrilho FJ, Malbouisson LMS (2014) Terlipressin versus Norepinephrine in the Treatment of
Hepatorenal Syndrome: A Systematic Review and Meta-Analysis. PLoS ONE 9(9): e107466. doi:10.1371/journal.pone.0107466
Editor: Helge Bruns, University Hospital Heidelberg, Germany
Received May 12, 2014; Accepted August 12, 2014; Published September 9, 2014
Copyright: ß2014 Nassar Junior et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.
Funding: The authors have no support or funding to report.
Competing Interests: The authors have declared that no competing interests exist.
* Email: paulo_nassar@yahoo.com.br
Introduction
Hepatorenal syndrome (HRS) is a severe functional renal failure
occurring in patients with cirrhosis and ascites. It develops as a
consequence of the severe reduction in the renal perfusion
secondary to splanchnic arterial vasodilation. Arterial vasodilation
leads to a decrease in the effective blood volume, homeostatic
activation of vasoactive systems (renin-angiotensin-aldosterone
system [RAAS], antidiuretic hormone [ADH] and sympathetic
nervous system) and, consequently, renal vasoconstriction [1].
HRS is sub-classified into types 1 and 2. Type 1 HRS is
characterized by rapid progressive renal failure, usually accompa-
nied by multiorgan failure. Type 2 HRS manifests itself as a slowly
progressive functional renal failure associated with refractory
ascites [1]. A 40% premature mortality rate has been reported in
type 1 HRS [2], but may be as high as 83% [3]. Mortality
associated with type 2 HRS ranges from 20% to 60% [2,3]. Since
the arterial vasodilation seems to be a key mechanism in the
pathogenesis of HRS, vasoconstrictors have been used as a
bridging therapy leading up to the definitive treatment; liver
transplantation. The vasopressin analog terlipressin is the most
widely studied drug, especially in type 1 HRS [4]. However, it is
expensive and unavailable in many countries. Norepinephrine, a
catecholamine with predominantly alpha-adrenergic activity, is
widely available, inexpensive and has been used for the treatment
of HRS type 1 since 2002 [5].
With the ominous prognosis of HRS and the high cost
associated with terlipressin in mind, we performed a systematic
review and meta-analysis to evaluate the efficacy and safety of
norepinephrine compared to terlipressin in the treatment of HRS.
Methods
Literature Search
Studies were identified through a search of the Medline,
EMBASE, Scopus, Cochrane Central Register of Controlled
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Trials (CENTRAL), Lilacs (Literatura Latino-Americana e do
Caribe em Cieˆncias da Sau´de) and Scielo (Scientific Eletronic
Library Online) databases. A sensitive search strategy was used,
combining the following Medical Subject Headings and keywords:
‘‘terlipressin’’ and ‘‘norepinephrine’’ or ‘‘noradrenalin’’ in combi-
nation with ‘‘hepatorenal syndrome’’. References of the included
studies were also searched. The search strategy was restricted to
randomized clinical trials performed on adult subjects and
published before 14 January 2014. There was no language
restriction. Titles and abstracts were assessed for eligibility and
full-text copies of all articles deemed to be potentially relevant
were retrieved. A standardized eligibility assessment was per-
formed independently by two reviewers (APNJ and LMSM).
Disagreements were resolved by consensus.
The PRISMA statement was used for guidance [6] and the
meta-analysis was registered on the PROSPERO database
(CRD42013006723).
Study selection
Studies that fulfilled the following criteria were included:
1. Compared terlipressin to norepinephrine in the treatment of
type 1 or type 2 HRS;
2. Reported at least one of the following outcomes: reversal of
HRS, effect on mortality, recurrence rates after cessation of the
treatment or assessment of adverse events on both arms of the
study.
Data extraction and quality assessment
A data extraction sheet was developed. Two authors (APNJ and
LMSM) independently extracted the following data from included
studies, as available: year of publication, number of patients
designated to terlipressin or norepinephrine, methods of random-
ization, allocation concealment, blinding method, age, type of
HRS, etiology of cirrhosis and duration of treatment. Child-Pugh
and MELD scores, serum creatinine and mean arterial pressure
(MAP) were recorded at baseline. Authors of the included studies
were contacted by email to complete the missing data that was
required for characterizing the studies.
Two authors (APNJ and LMSM) assessed the risk of bias of
individual trials using the Cochrane risk of bias tool [7]. For the
outcomes in each included trial, the risk of bias was reported as
‘low risk’, ‘unclear risk’, or ‘high risk’ in the following domains:
random sequence generation; allocation concealment; blinding of
participants and personnel; blinding of outcome assessment;
incomplete outcome data; selective reporting; or other bias.
Disagreements were resolved by consensus.
Outcome measurements
The primary outcome was the reversal of HRS, defined as a
decrease in the serum creatinine value to 133 mmol/l (1.5 mg/dl)
or lower during the treatment. Secondary outcomes were
mortality, recurrence of HRS and adverse effects.
Statistical Analysis
Heterogeneity was assessed by the I
2
statistic. A random-effects
model was employed due to the anticipated variability between
trials in terms of patient populations, interventions, and concom-
itant interventions. The effect of the treatment on the defined
outcome measures was calculated from the raw data using random
effects models. Differences observed between the treatment groups
were expressed as the pooled risk ratio (RR) with a 95%
confidence interval (CI). A priori subgroup analysis was performed
to assess reversal, mortality and recurrence of type 1 and type 2
HRS. All analyses were performed using STATA version 13.0
(STATA Corporation, College Station, TX, USA) and Open
Meta Analyst [8].
Results
Trial identification
The search yielded 77 publications. Four randomized controlled
trials were selected for the analysis (Figure 1) [9,10,11,12].
Trial characteristics
Table 1 summarizes the details of included studies. One study
was performed in Italy [9] and the remaining three were
performed at the same center in India [10,11,12]. Two studies
included patients with type 1 HRS [10,11], one with type 2 HRS
[12] and one with both types of HRS [9]. The studies performed
by Singh et al. [11] and Ghosh et al. [12] were actually a single
center trial which randomized patients with HRS type 1 and HRS
type 2 to terlipressin or norepinephrine and the results to each
condition were published in separated papers. Two studies [9,10]
classified the patients according to the first version of the
International Ascites Club criteria [13] and the remaining
[11,12] by the updated criteria [14].
In all studies, the norepinephrine infusion was adjusted to reach
an increase of at least 10 mmHg in MAP. In three studies,
norepinephrine infusion was also adjusted in order to reach a urine
output of over 200 ml [10,11,12]. Norepinephrine infusion was
increased every 4 h to reach these targets in all studies.
Terlipressin was administered in fixed doses which could be
increased every 3 days to decrease basal value of creatinine by at
least 25% [9] or at least 1 mg/dl [10,11,12]. Norepinephrine and
terlipressin were administered until the reversal of HRS or for a
maximum of 15 days. In all studies, patients were administered
intravenous albumin and had central venous pressure (CVP)
measurements. Albumin was used to maintain a CVP of 10–15 cm
H
2
O in the Italian study [9]. In the Indian studies, patients were
given 20–40 g of albumin per day, which was discontinued if CVP
was more than 18 cm H
2
O [10,11,12].
Table 2 shows the characteristics of the patients in each study.
Risk of bias
In table 3, the methodology of the quality assessment for each
trial is reported using the Cochrane risk of bias tool. All studies
were unblinded and eventually met the overall criteria for high risk
of bias.
Outcomes
Reversal of HRS was assessed in 154 patients. There was no
difference in the reversal of HRS between norepinephrine or
terlipressin (RR = 0.97, 95% CI = 0.76 to 1.23; p = 0.800; I
2
= 0%)
(Figure 2). Ninety-five patients with type 1 HRS were included in
three studies. There was also no difference in the reversal of HRS
between norepinephrine and terlipressin in these patients
(RR = 1.01, 95% CI = 0.69 to 1.49; p = 0.943; I
2
= 0%). Fifty-nine
patients with type 2 HRS were included in two trials and no
difference between treatments could be demonstrated (RR = 0.95,
95% CI = 0.70 to 1.28; p = 0.717; I
2
= 0%).
Since all studies reported the mortality rate at 30 days, this end-
point was chosen to perform a pooled estimate. No difference in
mortality at 30 days between norepinephrine and terlipressin
could be found (RR = 0.89, 95% CI = 0.68 to 1.17; p = 0.404;
I
2
= 0%) (Figure 3). There were also no differences in mortality
among subgroups of type 1 (RR = 0.88, 95% CI = 0.66 to 1.15;
Terlipressin vs Noradrenalin for Hepatorenal Syndrome
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p = 0.345; I
2
= 0%) and type 2 HRS patients (RR = 1.12, 95%
CI = 0.44 to 2.83; p = 0.808; I
2
= 0%).
Three studies reported recurrence rates of HRS after the
cessation of the treatment [9,11,12]. There was no difference in
these rates between norepinephrine and terlipressin (RR = 0,72;
95% CI = 0,36 to 1,15; p = 0.357; I
2
= 0%) nor was among the
subgroups of type 1 (RR = 0.71, 95% CI = 0.13 to 3.82; p = 0.688;
I
2
= 0%) and type 2 HRS patients (RR = 0.82, 95% CI = 0.036 to
1.84; p = 0.63; I
2
= 0%).
Adverse events were less common with norepinephrine
(OR = 0.36, 95% CI 0.15 to 0.83; p = 0.017; I
2
= 0%) (Figure 4),
although all adverse events were of minor importance (Norepi-
nephrine: three episodes of chest pain without electrocardiogram
changes or troponin elevation, two episodes of ventricular
extrasystoles, one episode of ST segment depression reversed after
titration of the dose; terlipressin: 17 episodes of abdominal cramps
and increased frequency of stools, two episodes of cyanosis, two
episodes of extrasystoles and one episode of ST segment
depression reversed after a titration of dose).
Figure 1. Search strategy.
doi:10.1371/journal.pone.0107466.g001
Table 1. Included studies.
Study Design Screened patients Included patients Terlipressin dosage Norepinephrine dosage
Alessandria,2007 [9] Single center, unblinded 36 20 1–2 mg every 4 h 0.05–0.7 mcg/kg/min
Sharma, 2008 [10] Single center, unblinded 49 40 0.5–2 mg every 6 h 0.5–3 mg/h
Singh, 2012 [11] Single center, unblinded 60 46 0.5–2 mg every 6 h 0.5–3 mg/h
Ghosh, 2013 [12] Single center, unblinded 58 46 0.5–2 mg every 6 h 0.5–3 mg/h
doi:10.1371/journal.pone.0107466.t001
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Table 2. Characteristics of the included patients.
Study Alessandria et al., 2007 [9] Sharma et al., 2008 [10] Singh et al., 2012 [11] Ghosh et al., 2013 [12]
Norepinephrine
(n = 10)
Terlipressin
(n = 12)
Norepinephrine
(n = 20)
Terlipressin
(n = 20)
Norepinephrine
(n = 23)
Terlipressin
(n = 23)
Norepinephrine
(n = 23)
Terlipressin
(n = 23)
Age (years) 5663556248.2613.4 47.869.8 51.4611.6 48.3611.6 45.869.2 48.2610.5
Etiology, Alcohol 2 (20.0%) 4 (33.3%) 12 (60.0%) 14 (70.0%) 10 (43.4%) 12 (52.1%) 15 (65.2%) 16 (69.6%)
Child Pugh score 1061116111.060.9 10.660.8 10.7062.01 10.4361.72 10.061.77 10.562.35
MELD score 2661266231.666.0 29.666.2 26.3963.13 24.6565.31 21.362.79 21.063.28
Serum creatinine (md/dl) 2.360.2 2.560.3 3.361.3 3.060.5 3.2760.71 3.1060.66 2.1560.21 2.0560.22
MAP (mmHg) 7162746378.265.3 81.4611.4 64.7611.9 65.2610.2 65.367.2 66.269.5
Data are mean 6standard deviation or number (%) of patients; MELD, model for end-stage liver disease; MAP, mean arterial pressure.
doi:10.1371/journal.pone.0107466.t002
Table 3. Risk of bias assessment.
Study
Sequence
generation
Allocation
concealment
Blinding of participants,
personnel and outcome
assessors
Incomplete outcome
data
Selective outcome
reporting
Other source of
bias
Overall risk of
bias
Alessandria, 2007 [9] Unclear Low High Low Low Unclear High
Sharma, 2008 [10] Low Unclear High Low Low Unclear High
Singh, 2012 [11] Low Low High Low Low Low High
Ghosh, 2013 [12] Low Low High Low Low Low High
doi:10.1371/journal.pone.0107466.t003
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Discussion
The results of this review suggest that in patients with HRS,
treatment with norepinephrine is as effective as terlipressin when
used in conjunction with albumin. Additionally, norepinephrine
seems to be associated with less adverse events than terlipressin.
However, these results are based on few trials with a reduced
number of patients included.
In patients with cirrhosis, functional kidney failure is caused by
a severe reduction of the effective circulating volume due to
splanchnic arterial dilation and a reduction in the renal blood flow
due to marked multifactorial intrarenal vasoconstriction [15]. This
particular form of renal dysfunction develops in the later phases of
liver failure and is characterized by low arterial pressure, intense
activation of the renin-angiotensin and sympathetic nervous
systems with an increase in the plasma levels of renin,
norepinephrine, water retention due to increased anti-diuretic
hormone and lowering glomerular filtration rates [1]. Without
treatment, short-term mortality exceeds 50% with a median
survival time of only 2 weeks [16].
Therapy with systemic vasoconstrictors and albumin is a
bridging option to ameliorate renal dysfunction and to improve
survival of patients while waiting for definitive treatment with liver
transplantation. The rationale of associating these two therapies is
to reduce the discrepancy between circulatory capacitance and
intravascular volume, thereby increasing the effective arterial
blood volume. Terlipressin promotes vasoconstriction in both
systemic and splanchnic circulation through activation of V1
receptors of the vascular smooth muscle cells and is reported to
reduce portal inflow, portal systemic shunting [17]; and to dilate
intrahepatic vessels, consequently reducing intrahepatic resistance
to portal inflow [18]. The overall results of the use of terlipressin in
conjunction with albumin in the treatment of HRS are an
improvement in renal function and an increase in the median
survival time as demonstrated in clinical trials and confirmed by at
Figure 2. Reversal of hepatorenal syndrome. P values presented are for heterogeneity. P value for overall effect = 0.792. Chi-square = 0.536
(degrees of freedom = 3).
doi:10.1371/journal.pone.0107466.g002
Figure 3. Mortality rates at 30 days. P values presented are for heterogeneity. P value for overall effect = 0.618. Chi-square = 1.077 (degrees of
freedom = 3).
doi:10.1371/journal.pone.0107466.g003
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least three meta-analyses [4,19,20]. Although terlipressin has
become the vasoactive drug of choice where available, a Cochrane
meta-analysis has pointed out that all randomized controlled
studies that addressed the efficacy of terlipressin were underpow-
ered and at high risk of bias [4]. Additionally, the evidence on the
use of terlipressin in type 2 HRS is scarce since these patients were
included in only one trial [21].
Norepinephrine, an inexpensive a-adrenergic receptor agonist
available worldwide, is a possible alternative treatment for HRS
because its intense vasoconstriction action may increase the
effective arterial blood volume. A pilot single-center study with
12 patients demonstrated the reversal of HRS in 10 (83%) patients
[5]. Since then, according to our literature search, four studies that
aimed to compare norepinephrine and terlipressin in treatment of
HRS have been published [9,10,11,12].
Reversal of HRS occurred in 58% (Figure 2) of type 1 HRS
patients treated with norepinephrine. These figures are very
similar to the response rates reported on terlipressin arms of
randomized controlled trials of this drug compared to placebo [4],
but higher than those found in clinical practice [2,3]. The trial of
Ghosh et al. [12] was the first to randomize type 2 HRS patients
exclusively. Response rates in this trial (74%) were higher than
those found in type 1 HRS patients [12].Type 2 HRS patients
included in the study published by Alessandria et al. also had a
similar response (77%) to both vasoconstrictors [9].
Thirty day-mortality rates were around 50%. Two studies that
included only type 1 HRS patients found a 30 day-mortality rate
of over 65% [10,11], which is similar to the ones reported in
randomized controlled trials of terlipressin compared with a
placebo [4,19], but lower than clinical survey data [2,3].
Recurrence rates were around 30%, similar to those found in
observational studies [2,22], but higher than those reported in the
largest study which compared terlipressin and placebo [23].
Norepinephrine was associated with less adverse events than
terlipressin. This difference was related to the frequency of
abdominal cramps and diarrhea found in patients who were given
terlipressin (17 cases in 78 patients). These are common adverse
events related to terlipressin and are usually self-limiting, but were
more common in our meta-analysis than in the Cochrane meta-
analysis of terlipressin compared to placebo [4]. Norepinephrine
and terlipressin both have a safe cardiovascular profile. Only nine
cardiovascular events were found in the included trials and only
two of them (episodes of segment ST depression) led to a change in
therapy (a titration of dose) (10). Cardiovascular adverse effect
rates were lower than those reported for terlipressin in the meta-
analysis previously cited [4].
Although it was not among the outcomes of this review, we
observed all included trials reported lower costs with norepineph-
rine than with terlipressin. However, all of them were performed
in specialized units with a high level of surveillance and only costs
related to the drugs were reported. Although more expensive,
terlipressin has some advantages over norepinephrine. It is given
as an intravenous bolus in a peripheral vein. This means that
terlipressin can be safely used in regular wards. Norepinephrine is
given intravenously as a continuous infusion in a central venous
catheter, usually in the setting of intensive care unit. Therefore, a
comparison of costs between these two treatments must also take
into account intensive care costs.
In spite of an extensive literature search without language
restriction that was conducted, we were not able to identify any
studies published in non-indexed journals or as conference
proceedings. Although included studies had no evidence of
significant heterogeneity, and used similar treatment protocols,
they had small sample sizes and were single-centered. Three of
them were performed at a same center [10,11,12] and they
included patients with different HRS criteria, as these were
updated from 1996 to 2007 [13,14]. Therefore, the first two
studies adopted the first criteria [9,10] and the remaining, the
updated criteria [11,12]. Undoubtedly, these findings reduce
external validity of the results of this meta-analysis. Additionally, it
would be questionable to combine data from patients with patients
with type 1 and type 2 HRS since these two conditions have a
different course and different responses to vasoconstrictors [1,2,3].
Similar limitations were also acknowledged in the meta-analyses of
terlipressin compared to a placebo or other drugs in the treatment
of HRS [4,19]. In order to better address the question of efficacy
and safety of terlipressin and norepinephrine in the treatment of
type 1 and type 2 HRS, we have performed subgroup analysis on
each condition.
Since the largest randomized study published with HRS
patients included only 112 patients [23], a collaborative research
Figure 4. Adverse events. P values presented are for heterogeneity. P value for overall effect = 0.004. Chi-square = 1.901 (degrees of freedom = 3).
doi:10.1371/journal.pone.0107466.g004
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network would be necessary to perform a large clinical trial
comparing norepinephrine to terlipressin in the treatment of HRS.
In conclusion, norepinephrine and terlipressin had similar
response rates for the treatment of type 1 or 2 HRS. However,
norepinephrine was associated with less adverse events than
terlipressin. Nevertheless, these findings are based on small studies,
with a total of only 154 patients. A larger randomized controlled
trial would be needed to draw firm conclusions on the choice of
the vasoconstrictor to treat HRS.
Supporting Information
Checklist S1 PRISMA checklist.
(DOC)
Author Contributions
Conceived and designed the experiments: APNJ AQF LMSM. Performed
the experiments: APNJ LMSM. Analyzed the data: APNJ AQF LMSM.
Contributed to the writing of the manuscript: APNJ AQF LACDA FJC
LMSM.
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Terlipressin vs Noradrenalin for Hepatorenal Syndrome
PLOS ONE | www.plosone.org 7 September 2014 | Volume 9 | Issue 9 | e107466