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Terlipressin in Hepatorenal Syndrome

Article in Annals of Pharmacotherapy · March 2011

DOI: 10.1345/aph.1P195 · Source: PubMed

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Nephrology

Terlipressin in Hepatorenal Syndrome

Joseph E Mazur, Tanna B Cooper, and Joseph F Dasta

asopressin (8-arginine vasopressin) is

V a nonapeptide that is not protein
bound, has an elimination half-life of 24
OBJECTIVE: To compare the pharmacology, dosing, and adverse reactions of
vasopressin and terlipressin for the treatment of hepatorenal syndrome (HRS)
minutes, and is cleared by renal elimina- and assess the efficacy of the investigational drug terlipressin for HRS.
tion (65%) and metabolized (35%) by tis- DATA SOURCES: Articles evaluating prospective studies for vasopressin and
sue peptidases. This agent has been used terlipressin were discussed after being identified through PubMed (1966-
historically as one of the drugs of choice November 2010), International Pharmaceutical Abstracts (1970-November 2010),
to enhance urine output and serve as a and EMBASE (1985-November 2010) with combinations of the following terms:
vasopressin, terlipressin, and hepatorenal syndrome. In addition, reference citations
bridge for patients to liver transplantation.
from publications identified were reviewed. Thirteen studies were identified for
Vasopressin is a direct systemic vasocon- terlipressin, along with 4 meta-analyses and 1 case report. For vasopressin, 2
strictor (mediated by V1 receptors). studies were identified.
Several studies have recently high- STUDY SELECTION AND DATA EXTRACTION: Prospective clinical studies directly
lighted terlipressin as a novel agent for comparing terlipressin and vasopressin were evaluated, as well as prospective
hepatorenal syndrome (HRS).1,2 Terli- clinical studies and meta-analyses for terlipressin in HRS.
pressin is a long-acting analog of vaso- DATA SYNTHESIS: No randomized, placebo-controlled trials using vasopressin for
pressin, in which lysine is substituted for the treatment of type I HRS have been published, and 4 randomized studies
arginine at position 8 and the N-triglycyl involving 197 patients provide the most current outcome data for use of
terlipressin in HRS. Terlipressin differs significantly from vasopressin with regard
residue is cleaved by endothelial pepti-
to its pharmacology, dosing, and adverse drug reaction profile. There is a paucity
dases, releasing the active drug. The of data on vasopressin for HRS.
pharmacologic half-life of terlipressin is CONCLUSIONS: No definitive recommendations can be made for the use of
6 hours, while its elimination half-life is terlipressin for this indication until further, well-conducted studies are performed.
50 minutes.1 Terlipressin is also a potent KEY WORDS: hepatorenal syndrome, terlipressin, vasopressin.
vasoconstrictor, acting predominantly on
Ann Pharmacother 2011;45:380-7.
V1 receptors found on vascular smooth
Published Online, 8 Mar 2011, theannals.com, DOI 10.1345/aph.1P195
muscle. Its activity on V2 receptors is re-
nal and extrarenal. Activation of V2 re-
ceptors located on the basolateral mem-
brane of the distal tubule can potentiate the antidiuretic ef- Both vasopressin and terlipressin have been used in var-
fect of vasopressin. Extrarenal effects of V2 stimulation ious critical care disease states, such as septic shock,
result in increased factor VIII concentrations and von esophageal variceal bleeding, and, pertinent to this discus-
Willebrand factor.2 Furthermore, increases in cerebral sion, type I and type II HRS.3 In type I HRS, serum creati-
blood flow may occur through stimulation of V2 receptors. nine concentrations increase greater than 2.5 mg/dL in less
Terlipressin is under review by the Food and Drug Admin- than 2 weeks. In type II HRS, renal function deteriorates
istration (FDA) for treatment of type I HRS. more slowly, with a serum creatinine concentration less
than 2.5 mg/dL. Patients with type I HRS have an overall
poor prognosis and an increased mortality rate compared
Author information provided at end of text. with patients with type II HRS.4 The majority of studies re-

380 n The Annals of Pharmacotherapy n 2011 March, Volume 45 theannals.com

Downloaded from aop.sagepub.com by guest on October 11, 2013
viewed here used vasopressin or terlipressin for type I decreasing serum creatinine concentration to reflect im-
HRS. proved renal function.7,8 The reasons that these 2 major
studies were reviewed are that they are the largest studies
Data Sources conducted to date, they were randomized and prospective,
and they involved multicenters.
Articles evaluating prospective studies for vasopressin In the study by Sanyal and colleagues, 56 patients were
and terlipressin were identified through PubMed (1966- randomized to terlipressin or placebo.7 The study popula-
November 2010), International Pharmaceutical Abstracts tion included patients with a diagnosis of type I HRS and ex-
(1970-November 2010), and EMBASE (1985-November cluded those with severe cardiovascular disease. Patients re-
2010), using combinations of the following terms: vaso- ceived either terlipressin 1 mg every 6 hours or placebo (with
pressin, terlipressin, and hepatorenal syndrome. Reference both groups receiving albumin 100 g intravenously, then 25 g
citations from publications identified were reviewed. Thir- daily). The interventions were continued until treatment fail-
teen studies were identified for terlipressin, along with 4 ure or liver transplantation occurred or until 14 days had
meta-analyses and 1 case report. For vasopressin, 2 studies passed. The primary outcome was type I HRS reversal, with
were identified. secondary outcomes of change in serum creatinine, treatment
failure, adverse events, combined incidence of treatment suc-
Literature Review cess and partial response, and transplant-free survival and
overall survival at 60 and 180 days. HRS resolution was
CLINICAL STUDIES OF VASOPRESSIN AND TERLIPRESSIN
serum creatinine less than or equal to 1.5 mg/dL on 2 occa-
Hadengue and colleagues investigated the effects of ter- sions at least 48 hours apart without death, dialysis, or recur-
lipressin administered for 2 days on glomerular filtration rence before day 14. A total of 112 patients were enrolled,
rate in patients with cirrhosis and type I HRS.5 Nine patients with 56 assigned to treatment and 56 assigned to placebo.
received intravenous terlipressin 2 mg once daily for 2 days Baseline characteristics were similar between groups: mean
and a placebo in a randomized, double-blind, crossover age was 51 years, the majority were white males, and alco-
study. Results indicated that terlipressin statistically in- holic hepatitis was present in 52% of patients. Treatment suc-
creased creatinine clearance (from mean [SEM] 15.2 [2] cess with terlipressin was double that with placebo (25% vs
mL/min to 27 [4] mL/min) and urine output (from 628 [67] 12.5%; p = 0.093). Although not statistically significant, it
mL/day to 811 [76] mL/day). Urinary sodium excretion was can be viewed as a clinically significant treatment effect. This
not statistically different after placebo (0.6 [0.1] mEq/L/24 was indicated by serum creatinine concentrations improving
h) versus terlipressin (9.3 [7.2] mEq/L/24 h). This was a hy- from baseline to day 14 with terlipressin (–0.7 mg/dL) com-
pothesis-generating pilot study, with improvement in renal pared with placebo (0 mg/dL; p < 0.009). However, overall
hemodynamics in the short term suggesting a long-term and transplantation-free survival was similar between groups.
study be conducted. No adverse drug events were noted. Various reasons may explain the primary endpoint not reach-
Solanki and colleagues, in a prospective, randomized, ing statistical significance, such as strict endpoints of HRS re-
single-blind trial, assigned 24 consecutive patients with versal, large placebo effect, and a too short duration that pa-
type I HRS to intravenous terlipressin 1 mg every 12 hours tients were on terlipressin. Limitations to this study were lack
(n = 12) or placebo at 12-hour intervals.6 They studied the of statistical power and time it took for patients to reverse
endpoint of improvement in renal function as defined by their HRS (often >3 days).
reversal of HRS and survival at 15 days. Statistically sig- Martin-Llahi and colleagues studied 46 patients with
nificant improvements in urine output, creatinine clear- cirrhosis and types I and II HRS.8 Patients were treated
ance, mean arterial pressure, and decreases in blood urea with intravenous terlipressin 1 mg every 4 hours or no ter-
nitrogen concentrations were reported. Five of 12 patients lipressin for up to 15 days, with all patients receiving albu-
receiving terlipressin survived to day 15 and had reversal min titrated to a targeted central venous pressure. The re-
of HRS (p < 0.05). This study neither permitted titration of sults indicated improvement or complete response in the
higher doses of terlipressin nor addressed its long-term use. terlipressin plus albumin group (9 vs 1, p value not noted).
Each patient received the combination of fresh frozen plas- Treatment durations were similar in both groups. When re-
ma 150 mL every 8 hours plus albumin 20 g daily. All pa- sponse rates were assessed in patients with type I versus
tients received dopamine 4 µg/kg/min for the initial 24 to those with type II HRS, patients with type II HRS had a
48 hours, which was unique compared with other terli- greater response rate (67% vs 35%). Unlike in other stud-
pressin studies. This study only demonstrated positive re- ies, arterial pressures were linked to improvements in renal
sults with terlipressin up to 15 days. function in the group responding to terlipressin plus albu-
Two recent prospective studies evaluating the use of ter- min. Ten of 23 patients (43.5%) treated with terlipressin
lipressin plus albumin compared with albumin alone and albumin compared with 2 patients (8.7%) treated with
showed positive results using the surrogate endpoints of albumin alone showed improvement in renal function (p =

theannals.com The Annals of Pharmacotherapy n 2011 March, Volume 45 n 381

JE Mazur et al.

0.017). Six (26%) patients in the terlipressin plus albumin The results indicated a pooled frequency of responder pa-
group were alive at 3 months versus 4 (17%) in the albu- tients with reversal HRS of 0.52 (95% CI 0.42 to 0.61; p =
min group (p = 0.7) Survival differences at 3 months 0.0001), with HRS recurrence after terlipressin discontinu-
should not be extrapolated to a broader base of cirrhotic ation of 0.55 (95% CI 0.40 to 0.69; p = 0.00001). The
patients with HRS since there was insufficient power to pooled rate of patients with adverse effects of terlipressin
form statistically significant conclusions. As well, the therapy was 0.29 (95% CI 0.17 to 0.42; p ≤ 0.00001). This
study lacked a double-blind design. Finally, it did not in- meta-analysis did not identify factors that could predict
vestigate the role of terlipressin in recurrences of HRS and which patients would respond to terlipressin. The analysis
its role in patients ineligible for transplantation. All 4 of should be viewed with caution regarding the role of terli-
these studies are summarized in Table 1. pressin for HRS reversal. For example, the meta-analysis
Terlipressin has recently been administered intraopera- involved a small number of patients and contained only 1
tively in patients undergoing liver transplantation in an at- prospective study. It can be inferred that the studies were
tempt to provide stable hemodynamics during surgery and not homogeneous by addressing various secondary out-
to minimize postoperative acute kidney injury.9 A total of comes (eg, HRS recurrence after terlipressin withdrawal in
30 patients received either terlipressin (loading dose and responder patients). No adverse effects were reported,
continuous infusion) or saline starting during surgery and which is rare, and only 5 trials specifically investigated
continued for 48 hours. During surgery, portal venous pres- type I HRS. Furthermore, no mortality rates were reported,
sure decreased, while mean arterial pressures were higher in which limits extrapolation to larger populations.
the treatment group without changes in cardiac output. On The Cochrane Collaboration identified 6 randomized tri-
day 4, creatinine clearance was significantly lower in the als for inclusion in a meta-analysis exploring the beneficial
control group versus in patients receiving terlipressin; how- and harmful effects of terlipressin for HRS.11 Three trials as-
ever, there were no changes in renal function at discharge. sessed 51 patients who received terlipressin 1 mg twice daily
Hence, terlipressin may have a role in preserving short-term from 2 to 15 days with cointerventions of albumin, fresh
postoperative renal function in patients undergoing liver frozen plasma, and cimetidine 800 mg daily. Terlipressin re-
transplantation without causing splanchnic hypoperfusion. duced the mortality rate by 34% (risk difference –0.34, 95%
CI –0.56 to –0.12) and improved renal function via creati-
META-ANALYSES
nine clearance (weighted mean difference [WMD] 21
mL/minute, 95% CI 17 to 24; serum creatinine WMD –2.5
In the first meta-analysis, 10 clinical trials (154 pa- mg/dL , 95% CI –244 to –194; and urine output WMD 707
tients), with 2 (20%) being randomized controlled trials, mL/day, 95% CI –212 to 1675). Statistical analysis for inter-
were analyzed.10 Data were extracted independently by 2 trial heterogeneity was not statistically significant (χ2, p =
investigators. Tests for heterogeneity were performed, as 0.12) for mortality, but was significant when other tests were
well as a sensitivity analysis, using a fixed-effects model. used. For fixed-effect meta-analysis, terlipressin increased re-

Table 1. Terlipressin Studies for Hepatorenal Syndrome

HRS
Reference Type Design/Regimen Results

Hadengue Type I Cohort, double-blind, crossover, randomized Increased creatinine clearance and urine output; no
(1998)5 (N = 9) Terlipressin 2 mg daily, then placebo for 2 days; changes in urinary sodium excretion; hypothesis-generating
no plasma expanders pilot for larger studies
Solanki Type I Cohort, prospective HRS reversal in 5 pts. in terlipressin group; 5 pts. in terlipressin
(2003)6 (N = 24) Terlipressin 2 mg daily for 15 days (12 pts. per group); group survived; urine output, creatinine clearance
albumin 20 g daily plus fresh frozen plasma for 15 days significantly improved, while serum creatinine decreased
(not significant)
Sanyal Type I Cohort, prospective, randomized, double-blind HRS reversal in 19 pts. vs 7 pts. on placebo; follow-up 180
(2008)7 (N = 112) Terlipressin 1-2 mg 4 times per day for 14 days (56 pts. days with mean duration of terlipressin 6.3 days; overall
per group) and transplant-free survival equal between groups
Cointerventions: albumin 100 g/day on day 1, then 25 g Serum creatinine improved; statistically significant
daily for 13 days
Martin-Llahi Type I Nonblinded, randomized HRS reversal in 9 pts. vs 2 pts. on placebo; follow-up 90 days
(2008)8 (n = 35) Terlipressin 1-2 mg every 4 h for 15 days (23 pts. per with mean duration of 7 days; overall survival equal between
Type II group) groups at 90 days
(n = 11) Cointerventions: albumin 1 g/kg on day 1, then 40 g/day
for 14 days

HRS = hepatorenal syndrome.

382 n The Annals of Pharmacotherapy n 2011 March, Volume 45 theannals.com

 Terlipressin in Hepatorenal Syndrome

nal marker endpoints, and the intertrial heterogeneity was sta- terlipressin benefit, with or without albumin, compared
tistically significant (p < 0.001). Overall, limitations to this with placebo (OR 7.47; 95% CI 3.17 to 17.56; p < 0.0001).
meta-analysis were small sample size (n = 51) and inability There was mild, nonsignificant heterogeneity (χ2 = 3.96, I2
to capture clinical heterogeneity, which is important in this = 24%; p = 0.27). Survival rates could not be analyzed in
type of analysis. this meta-analysis. Differences in adverse effects were seen
Adverse effects were limited and rated nonserious (only between terlipressin and norepinephrine at the end of the
abdominal cramps and cardiac arrhythmias). None of the study, with no heterogeneity between the trials (χ2 = 0.39,
trials reported adverse effects in the control groups, which I2 = 0%; p = 0.53). Adverse effects (abdominal cramps)
is another weakness. were reported in 4 patients, and 1 patient had ST-segment
Sagi and colleagues recently conducted a meta-analysis depression. As shown with other meta-analyses reviewed,
of studies evaluating terlipressin in reversal of type I HRS the study methodology, with no data extraction, was good,
(serum creatinine <1.5 mg/dL).12 Included studies were plus it had 2 independent reviewers. The weaknesses were
randomized controlled trials of terlipressin and albumin the size of the trials reviewed; type of HRS studied (only
treatment for at least 3 days in a total of 223 patients from type I); and small numbers of adverse effects reported,
4 different trials. Pooled relative risks were used in the sta- with short study durations.
tistical analysis portion, with assessment of interstudy het- Two studies showed modest benefit with the use of vas-
erogeneity by χ2 tests and I2 measurements. The primary opressin in HRS. The first was a prospective, open-label
outcome was reversal of type I HRS. Secondary outcomes study of 18 patients, which showed that very low-dose
evaluated included incidence of adverse effects, recurrence of vasopressin (1 unit/hour or around 0.02 units/min) signifi-
HRS (defined as increase in serum creatinine ≥1.5 mg/dL in cantly improved urine output.14 Before treatment, mean
patients responding), and transplant-free survival. Rate of re- (SD) urine output was 155 (9) mL per day. At 24, 48, and
versal of type I HRS was 46% versus 11.6% in the control 72 hours, urine output improved to 1067 (87), 1020 (501),
group (relative risk 3.66; 95% CI 2.15 to 6.23; p < 0.00001). and 1311 (988) mL per day, respectively (p < 0.0001). Al-
Transplant-free survival was 24.8% versus 12.4% in favor of though urine output improved, creatinine clearance did not
terlipressin at 90 days, with patients receiving terlipressin be- increase, and the overall mortality rate was 39% at 72
ing 1.85 times more likely to be alive at 90-days follow-up hours. Severe limitations to this study included failure of
(95% CI 1.00 to 3.41; p = 0.05). Adverse effects were limit- the authors to state the type of HRS studied, no reporting
ed, with an overall incidence of 45.3%. Severe adverse ef- of adverse effects or concomitant medications, no detail on
fects requiring discontinuation of therapy were seen in 6.8% creatinine clearance calculations, and the rationale as to
of patients, and 10.3% of patients experienced ischemic ef- why the low dose of vasopressin was used.
fects from terlipressin. This analysis was well conducted con- A retrospective observational study addressed a cohort of
sidering the patient population studied (type I HRS, majority 43 patients (8 received vasopressin, 16 received octreotide,
with alcoholic hepatitis), duration of therapies (>3 days of ter- and 19 received both).15 Recovery rates were evaluated by
lipressin and albumin), and evaluation at 90 and 180 days in improvements in serum creatinine concentrations, and those
3 of the 4 studies. Overall, the statistical analysis was accept- with “responses” had lower mortality rates. Clinical re-
able, but the number of studies was small. Publication bias sponse rates were better with vasopressin plus octreotide
was a possible limitation, with no negative trials reported and (8/19 patients, 42%) versus vasopressin monotherapy (3/8
analyzed. patients, 38%) versus octreotide monotherapy (0%; p =
In the most recent meta-analysis, by Dobre and col- 0.01). The mean vasopressin dosage was 0.23 (0.19)
leagues, 2 independent reviewers extracted 8 eligible trials units/minute, and the authors reported no adverse effects
of terlipressin in HRS, involving 320 patients.13 The prima- with vasopressin and 1 case of diarrhea with octreotide. A
ry outcome measure was decreased serum creatinine (≤1.5 limitation of this observational study was the potential for
mg/dL) during treatment. The secondary outcome mea- selection bias since this was not a randomized controlled
sures were survival at 30, 60, 90, and 180 days, changes in trial. There was an unexpectedly low incidence of adverse
serum creatinine at the end of the study, and changes in drug reactions with vasopressin at the dosages used, which
mean arterial pressure and urine output at the end of the is another limitation, knowing that vasopressin in septic
study, with analysis of major adverse events (ischemia and shock can cause mesenteric ischemia at higher doses. Over-
arrhythmia). Acceptable heterogeneity statistical tests and all, the clinical applicability of the studies for terlipressin
sensitivity analyses were both performed. Three of the 6 and the meta-analysis should be viewed with caution.
studies compared terlipressin plus albumin alone, 2 studies
compared terlipressin plus albumin with albumin plus TERLIPRESSIN DOSING REGIMENS
placebo, and 1 crossover study compared terlipressin with
placebo. Two studies compared terlipressin plus albumin Since terlipressin has a longer half-life than vasopressin,
with norepinephrine plus albumin. The results indicated dosing is based on scheduled intermittent intravenous in-

theannals.com The Annals of Pharmacotherapy n 2011 March, Volume 45 n 383

JE Mazur et al.

stead of continuous intravenous infusion with vasopressin. verse events; 3 of those patients withdrew (nonfatal my-
Most studies have used fixed dosages of terlipressin. Ex- ocardial infarction, livedo reticularis, cyanosis of the fin-
amples include 1-2 mg every 4 hours, 0.5-2 mg every 4-6 gers).7 In the study by Martin-Llahi et al., 10 patients treated
hours, 1-2 mg every 6 hours, and 1 mg every 12 hours.16-19 with terlipressin and albumin developed serious complica-
For patients with type I HRS who received terlipressin, tions (myocardial infarction, intestinal ischemia, and/or cir-
it appears that, to achieve endpoints of decreased serum culatory overload).8 From these 3 studies, no treatments
creatinine or increased urine output, the dose should be in- specific to terlipressin-induced myocardial infarction or is-
creased at various intervals. The concept of hepatorenal re- chemia were outlined, other than stopping the agent. Based
sistance to vasoconstrictors was introduced in 2 studies on various case reports, it has been postulated that possible
with different dosing regimens. Neri and colleagues used risk factors for ischemia include hypovolemia, concomi-
intermittent intravenous terlipressin 1 mg every 8 hours for tant administration of vasopressors and terlipressin, and
5 days, followed by 0.5 mg every 8 hours for 2 weeks plus continuous intravenous administration.21 No antidotes are
intravenous boluses of albumin. If patients did not respond known to reverse the cutaneous necrosis induced by either
to this initial treatment, the terlipressin and albumin regi- terlipressin or vasopressin.
mens were repeated.18 Kalil et al. dose adjusted their terli- Intravenous N-acetylcysteine (NAC) was used in 1 case
pressin regimen based on reversal of renal failure, starting of HRS with terlipressin-induced vasoconstriction. NAC
at 0.5 mg intravenous bolus every 4 hours, with incremen- 150 mg/kg administered over 2 hours improved cardiac
tal dosage increases after 3 days of treatment to a final dose output and decreased systemic vascular resistance and
of 2 mg every 4 hours. When reversal was obtained, there mean arterial pressure.22 In patients with acute liver failure
was a gradual reduction in dosage until interruption was with severe encephalopathy, worsening intracranial hyper-
performed in a 3-day period.19 Studies indicate that an in- tension has been identified. Six mechanically ventilated
travenous dose of 2 mg every 4 hours was the highest dos- patients with acute liver failure and grade IV hepatoen-
age used. Also, there are differences in mean daily dose at cephalopathy were administered a single dose of intra-
the end of treatment, ranging from 4.9 mg to 7.8 mg in the venous terlipressin 0.005 mg/kg followed by serial cerebral
2 previous studies.7,8 perfusion pressure measurements. Intracranial pressure in-
The idea of administering terlipressin by continuous in- creased significantly at 1 hour, from a median of 69
fusion has been recently introduced.20 Gerbes and col- mL/100 g/min (range 48-83 mL/100 g/min) to 81 mL/100
leagues retrospectively assessed 32 consecutive patients g/min (range 62-97 mL/100 g/min; p = 0.016). The cere-
with HRS treated with terlipressin.20 The starting dose was bral perfusion pressure then returned to baseline at 2 hours.
3 mg daily (with a possible addition of 1 mg/day in pa- The mechanism is thought to be stimulation of the V2 re-
tients not responding) and albumin (20-30 g/day) for 11 ceptors in the cerebral vasculature. Therefore, caution
(2) days. They used treatment endpoints of reversing HRS should be used in even low doses of terlipressin in patients
via decreased serum creatinine (<1.5 mg/dL) and minimal with acute liver failure and hepatic encephalopathy.23 Since
adverse drug reactions (3 patients developed arrhythmias). cerebral hemodynamic studies with intracranial pressure
This small case series demonstrated good efficacy and monitoring are not done often in patients with HRS unless
minimal adverse effects, but is limited by its retrospective transplantation is to occur, it is difficult to determine the
design. Efficacy was defined as HRS reversal with serum clinical significance of these measurements. Other case re-
creatinine values of less than 1.5 mg/dL in 42% of cases. ports associated with terlipressin use in HRS were noted in
To achieve predefined endpoints for patients with type I Table 2.24,25
HRS receiving terlipressin, doses in the majority of studies
should be titrated to effect. The major unknown from the PRACTICAL CONSIDERATIONS
dosing strategies used is the point at which optimal phar-
macologic effects best correlate with the surrogate end- There are some practical considerations regarding terli-
points. Physiologic surrogate endpoints such as decreases pressin that center on dosing, efficacy as outlined by clini-
in serum creatinine and increases in urine output were de- cal responses, and toxicity. If terlipressin becomes ap-
pendent on differing terlipressin dosages, which varied proved for use in the US, contraindications for use could
considerably in clinical trials.5-8 comprise history of coronary artery disease, dilated and
nondilated cardiomyopathies, arrhythmias, cerebrovascular
disease, obliterative arterial disease of the lower limbs, ar-
ADVERSE EFFECTS
terial hypertension, asthma and chronic obstructive pul-
One of the original terlipressin studies for treatment of monary disease, and age greater than 70 years.26 The rea-
HRS reported cardiovascular complications such as ar- sons that such low rates, or in some cases absence, of ad-
rhythmias, as well as crampy abdominal pain.6 In the verse drug reactions were reported with terlipressin may
Sanyal et al. study, 5 patients on terlipressin had serious ad- include the fact that patients with these disease states were

384 n The Annals of Pharmacotherapy n 2011 March, Volume 45 theannals.com

 Terlipressin in Hepatorenal Syndrome

excluded or that poor documentation failed to capture these cerns related to serious adverse effects with terlipressin as
events. Titrating dosages of terlipressin to determine well as poor outcomes not previously reported in studies.
changes in urine output or serum creatinine may be appro- Therefore, terlipressin appears to be a reasonable option
priate. Optimal duration of therapy is unknown in patients for treatment of HRS, although definitive recommenda-
being treated with terlipressin. Since the majority of pa- tions are difficult given the currently available literature
tients with type I or type II HRS may require more intense and the difficulty in conducting trials in these desperately
hemodynamic monitoring, patients receiving any vaso- ill patients.
pressin analog should be monitored in an intensive care
unit (ICU) or a step-down unit. There is a strong likelihood Joseph E Mazur PharmD BCPS BCNSP, Clinical Pharmacy Man-
ager, Clinical Specialist, Medical Intensive Care Unit, Department
that these patients may be on renal replacement therapies, of Pharmacy Services, Medical University of South Carolina,
constituting ICU levels of care. Vasopressin may appear to Charleston, SC
be a better agent than octreotide, given the results from 1 Tanna B Cooper PharmD BCPS, Clinical Specialist, Medical/Sur-
gical Intensive Care Unit, Clinical Coordinator, Digestive Diseases
retrospective study, but the data for these agents, as well as Service Line, Department of Pharmacy Services, Medical Universi-
vasoactive agents, are weak. A recent review still suggests ty of South Carolina
liver transplantation as the most viable option in patients Joseph F Dasta MSc FCCM FCCP, Professor Emeritus, The Ohio
State University, Columbus, OH; Adjunct Professor, College of Phar-
with type I HRS.27 macy, University of Texas, Austin, TX
Correspondence: Dr. Mazur, [email protected]
Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1P195
Summary
Conflict of interest: Authors reported none
Overall, there are minor pharmacologic differences be-
tween vasopressin and terlipressin, except that terlipressin References
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before liver transplantation is the main indication for the 1. Kam PC, Williams S, Yoong FF. Vasopressin and terlipressin: pharma-
cology and its clinical relevance. Anaesthesia 2004;59:993-1001.
use of vasopressin or terlipressin. These agents are also DOI 10.1111/j.1365-2044.03877.x
used in the treatment of esophageal variceal bleeding and 2. Pesaturo AB, Jennings HR, Voils SA. Terlipressin: vasopressin analog
septic shock. There are large variations in the way that and novel drug for septic shock. Ann Pharmacother 2006;40:2170-7.
DOI 10.1345/aph.1H373
these medications are used clinically for the treatment of
3. Asfar P, Radermacher P, Calès P, Oberti F. The effects of vasopressin and
HRS, and the data for terlipressin are better reported from its analogues on the liver and its disorders in the critically ill. Curr Opin
randomized studies. Recent case reports have outlined con- Crit Care 2010;16:148-52. DOI 10.1097/MCC.Ob013e328335a35b

Table 2. Terlipressin Adverse Drug Reactions from Hepatorenal Syndrome Studies and Case Reports
Reference Study/Case Report/ADRs Treatment Modalities

Hadengue Study; none

(2004)5
Solanki Study; 5/12 pts. (abdominal pain 2, self-limiting arrhythmias 3) None noted
(2003)6
Sanyal Study; 7/56 pts. with ADRs deemed serious (nonfatal myocardial None noted; terlipressin withdrawn
(2008)7 infarction 1, respiratory acidosis 1, respiratory distress 2,
arrhythmia 2, livedo reticularis 1)
Martin-Llahl Study; 18/23 pts. (gastrointestinal bleed 4, myocardial infarction None noted; possible withdrawal of terlipressin
(2008)8 1, suspected intestinal ischemia 3, arrhythmia 2, circulatory
overload 7, arterial hypertension 1)
Kalil (2009)19 Case series; 5/7 pts. (sudden death 1, end-stage liver failure 2, None noted
sepsis 2)
Sen (2002)22 Case report; severe peripheral ischemia N-acetylcysteine 150 mg/kg over 2 h; improved peripheral pulses
Megarbane Case report (2 pts.); cutaneous necrosis Terlipressin discontinued in both cases; pts. died
(2009)21
Shawcross Case series; increased intracranial pressures in 6 pts. Returned to baseline after 2 h
(2004)23
Posada Case report; cutaneous necrosis Lowered dose of terlipressin; no changes
(2009)24
DiMicoli Case report; ischemia of breast skin Stopped terlipressin; complete recovery in a few days
(2007)25

ADR = adverse drug reaction.

theannals.com The Annals of Pharmacotherapy n 2011 March, Volume 45 n 385

JE Mazur et al.

4. Arroyo V, Terra C, Gines P. Advances in the pathogenesis and treatment syndrome? Gastroenterology 2002;123:2161-2.
of type-1 and type-2 hepatorenal syndrome. J Hepatol 2007;46:935- 46. DOI 10.1053/gast.2002.37303
DOI 10.1016/j.jhep.2007.02.001 23. Shawcross DL, Davies NA, Mookerjee RP, et al. Worsening of cerebral
5. Hadengue A, Gadano A, Moreau R, et al. Beneficial effects of the 2-day hyperemia by the administration of terlipressin in acute liver failure with
administration of terlipressin in patients with cirrhosis and hepatorenal severe encephalopathy. Hepatology 2004;39:471-5.
syndrome. J Hepatol 1998;29:565-70. DOI 10.1002/hep.20044
6. Solanki P, Chawla A, Garg R, et al. Beneficial effects of terlipressin in 24. Posada C, Feal C, Garcia-Cruz A, et al. Cutaneous necrosis secondary to
hepatorenal syndrome: a prospective, randomized placebo-controlled terlipressin therapy. Acta Derm Vencreol 2009;89:434-5.
clinical trial. J Gastroenterol Hepatol 2003;18:152-6. DOI 10.2340.00015555-0651
DOI 10.1046/j.1440-1746. 2003.02934.x 25. DiMicoli A, Bracci E, Mirici Cappa F, et al. Terlipressin infusion induces
7. Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, ischemia of breast skin in a cirrhotic patient with hepatorenal syndrome.
double-blind, placebo-controlled trial of terlipressin for type 1 hepatore- Dig Liver Dis 2008;40:304-5. DOI 10.1016/j.did.2007.11.009
nal syndrome. Gastroenterology 2008;134:1360-8. 26. Moreau R, Lebrec D. The use of vasoconstrictors in patients with cirrho-
DOI 10.1053/j.gastro.2008.02.014 sis: type I HRS and beyond. Hepatology 2006;43:385-94.
8. Martin-Llahi M, Pepin M, Guevara M, et al. Terlipressin and albumin vs DOI 10.1002/hep.21094
albumin in patients with cirrhosis and hepatorenal syndrome: a random- 27. Kiser TH, MacLaren R, Fish DN. Treatment of hepatorenal syndrome.
ized study. Gastroenterology 2008;134:1352-9. Pharmacotherapy 2009;29:1196-121
DOI 10.1053/j.gastrol.2008.02.024
9. Mukhtar A, Salah M, Aboulfetouh F, et al. The use of terlipressin during
living donor liver transplantation: effects on systemic and splanchnic
hemodynamics and renal function. Crit Care Med 2011 (in press). DOI
10.1097/CCM.0b013e3182120842 El Uso de la Terlipresina en el Tratamiento del Síndrome
10. Fabrizi F, Dixit V, Martin P. Meta-analysis: terlipressin therapy for the Hepatorrenal
hepatorenal syndrome. Aliment Pharmacol Ther 2006;24:935- 44.
DOI 10.111/j.1365-2036.2006.03086.x
11. Gluud LL, Kjaer MS, Christensen E. Terlipressin for hepatorenal syn- JE Mazur, TB Cooper, y JF Dasta
drome. Cochrane Database Syst Rev 2006;4:CD005162.
Ann Pharmacotheri 2011;45:380-7.
DOI 10:1002/14651858.CD005162.pub2
12. Sagi SV, Mittal S, Kasturi KS, Sood GK. Terlipressin therapy for reversal
of type 1 hepatorenal syndrome: a meta-analysis of randomized con- EXTRACTO
trolled trials. J Gastroenterol Hepatol 2010;25:880-5. OBJETIVO: Comparar la diferencias en la farmacología, dosificación, y
DOI 10.1111/j.1440-1746.2009.06132.x reacciones adversas entre la vasopresina y terlipresina en el tratamiento
13. Dobre M, Demirjian S, Schgal AR, Navaneethan SD. Terlipressin in del síndrome hepatorrenal (SHR). También se evalúa la eficacia del
hepatorenal syndrome: a systematic review and meta-analysis. Int Urol fármaco en investigación, terlipresina, en el tratamiento del SHR.
Nephrol Epub 2010 Mar 20. DOI 10.1007/s11255-010-9725-8 FUENTES DE INFORMACIÓN: Se identificó estudios prospectivos de
14. Eisenman A, Armali Z, Enat R, Bankir L, Baruch Y. Low-dose vaso- vasopresina y terlipresina por medio de una búsqueda en PubMed (1966
pressin restores diuresis both in patients with hepatorenal syndrome and a noviembre de 2010) Abstractos Farmacéuticos Internacionales (1970
in anuric patients with end-stage heart failure. J Internal Med 1999;246: - noviembre 2010), y EMBSASE (1985 a noviembre de 2010) usando
183-90. una combinación de los siguientes términos: vasopresina, terlipresina, y
15. Kiser TH, Fish DN, Obritsch MD, et al. Vasopressin, not octreotide, may síndrome hepoutorrenal. Además, se revisó las referencias de las
be beneficial in the treatment of hepatorenal syndrome: a retrospective publicaciones identificadas.
study. Nephrol Dial Transplant 2005:20:1813-20. SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: Estudios clínicos
DOI 10.1093/ndt/gfh930 prospectivos que compararon directamente la terlipresina y vasopresina
16. Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenalin vs fueron evaluados, así como estudios clínicos prospectivos y meta-
terlipressin in patients with hepatorenal syndrome: a prospective, ran- análisis que describieron el uso de terlipresina en el SHR.
domized, unblended, pilot study. J Hepatol 2007;47:499-505. SÍNTESIS DE DATOS: Trece estudios de terlipresina fueron identificados
DOI 10.1016/j.jhep.2007.04.010 junto con 4 meta-análisis y reporte de un caso. Se identificó 2 estudios
17. Sharma P, Kumar A, Shrama BC, Sarin SK. An open-label pilot, ran- que reportaron el uso de vasopresina. No existen estudios aleatorios de
diseño controlado con placebo de vasopresina para el tratamiento del
domized controlled trial of noradrenaline versus terlipressin in the treat-
SHR tipo 1, mientras que había 4 estudios aleatorios que contenían un
ment of type I hepatorenal syndrome and predictors of response. Am J
total de 197 pacientes que proveyeron datos más recientes sobre el uso
Gastroenterol 2008;103:1689-97. de terlipresina en el tratamiento de SHR. Los datos demuestran que la
DOI 10.1111/j.1572-0241.2008.01828.x terlipresina es significativamente diferente de vasopresina en cuanto a su
18. Neri S, Pulvirenti D, Malaguarnera M, et al. Terlipressin and albumin in farmacología, dosificación, y efectos adversos. Existe una escasez de
patients with cirrhosis and type I hepatorenal syndrome. Dig Dis Sci datos sobre el uso de vasopresina para el tratamiento de SHR.
2008;53:830-5. DOI 10.1007/s10620-007-9919-9 CONCLUSIONES: La terlipresina y vasopresina difieren en su
19. Kalil JR, Cerqueira LA, Barbosa DS, et al. Poor outcomes with treatment farmacología, dosificación, y efectos adversos. Se ha sugerido que la
of hepatorenal syndrome type I with splanchnic vasoconstrictors and al- terlipresina es una otra opción para vasopresina, pero la terlipresina
bumin: report of seven cases and review of the literature. Arq Gastroen- sigue siendo un medicamento de investigación en los Estados Unidos.
terol 2009;46:214-8. DOI 10.1590/S0004-28032009000300014 Históricamente, resultados positivos han sido demostrados con la
20. Gerbes AL, Huber E, Gulberg V. Terlipressin for hepatorenal syndrome: terlipresina en la reversión del SHR tipo 1 con un mínimo de eventos
continuous infusion as an alternative to iv bolus administration. Gas- adversos. Sin embargo, informes recientes que describen reacciones
troenterology 2009;137:1179-89. DOI 10.1053/j.gastro.2009.03.064 adversas y falta de resultados en el tratamiento del SHR han generado
21. Megarbane H, Barete S, Khosrotehrani K, et al. Two observations raising
cierta preocupación con este medicamento. Como resultado, no se
puede proveer recomendaciones definitivas para el uso de terlipresina
questions about risk factors of cutaneous necrosis induced by terlipressin
para esta indicación hasta que se lleven a cabo nuevos estudios bien
(Glypressin). Dermatology 2009;219:334-7. DOI 10.1159/000195676
realizados.
22. Sen S, Mookerjee RP, Jalan R. Terlipressin-induced vasoconstriction re-
versed with N-acetylcysteine: a case for combined use in hepatorenal Traducido por Carlos da Camara

386 n The Annals of Pharmacotherapy n 2011 March, Volume 45 theannals.com

 Terlipressin in Hepatorenal Syndrome

La Terlipressine dans le Traitement du Syndrome Hépato-Rénal prospectifs comparant la terlipressine et la vasopressine ont été retenus
de même que les articles évaluant la terlipressine dans le SHR.
JE Mazur, TB Cooper, et JF Dasta
RÉSUMÉ: Aucun essai à répartition aléatoire et contrôlé avec placebo
Ann Pharmacotheri 2011;45:380-7. n’est disponible pour évaluer l’utilisation de la vasopressine dans le
traitement du SHR alors qu’une quantité limitée d’informations sur la
terlipressine (n = 197 patients) est publiée. La terlipressine et la
RÉSUMÉ
vasopressine diffèrent par leur pharmacologie, leur profil d’innocuité et
OBJECTIF: Comparer la pharmacologie, le profil d’innocuité, et les leur régime posologique.
régimes posologiques de la vasopressine et de la terlipressine dans le CONCLUSIONS: La vasopressine a été suggérée comme une option
traitement du syndrome hépato-rénal (SHR). Évaluer l’efficacité de la thérapeutique à la terlipressine, qui demeure une molécule encore à l’état
terlipressine dans le traitement du SHR. d’investigation aux États-Unis. Les quelques résultats historiques
SOURCES D’INFORMATION: Une recherche a été effectuée dans les banques disponibles démontrent que la terlipressine peut renverser le SHR avec
de données PubMed (1966 - novembre 2010), International un minimum d’effets indésirables. Toutefois, des rapports récents font
Pharmaceutique Résumé (1970 - novembre 2010), et EMBASE (1985 - état d’une efficacité limitée et d’effets indésirables lors de l’utilisation de
novembre 2010) en utilisant les mots-clés suivants: vasopressine, la terlipressine dans le traitement du SHR. Des essais cliniques
terlipressine, syndrome hépato-rénal. Certaines références citées par les additionnels sont nécessaires avant de formuler des recommandations
articles identifiés par cette recherche ont aussi été considérées. définitives sur ce nouvel agent.
SÉLECTION DE L’INFORMATION: Treize études, 4 méta-analyses et un
Traduit par Sylvie Robert
rapport de cas ont été identifiés pour la terlipressine tandis que 2 études
évaluant la vasopressine étaient disponibles. Les essais cliniques

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