Comparative Efficacy of Terlipressin and Norepinephrine for Treatment of Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI): A Systematic Review and Meta-analysis

doi:10.21203/rs.3.rs-2252558/v1

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Comparative Efficacy of Terlipressin and Norepinephrine for Treatment of Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI): A Systematic Review and Meta-analysis

https://doi.org/10.21203/rs.3.rs-2252558/v1

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The treatment of choice for hepatorenal syndrome-acute kidney injury (HRSAKI) is vasoconstrictor therapy in combination with albumin, preferably norepinephrine or terlipressin as recommended by recent guidelines. However, larger head-to-head trials comparing the efficacy of terlipressin and norepinephrine have not been completed. Evaluation of smaller studies can provide insights needed to understand the comparative effects of these 2 medications. In this meta-analysis, we aimed to assess HRS reversal and 1-month mortality in subjects receiving terlipressin or norepinephrine for the management of HRSAKI. We searched literature databases, including PubMed, Cochrane EMBASE, and ResearchGate, for randomized controlled trials (RCTs) published in the last 15 years (2007–2022) that compare terlipressin plus albumin to norepinephrine plus albumin for the treatment of HRS-AKI in adults. We identified 7 RCTs that included a total of 376 subjects with HRSAKI or HRS type 1 and performed pairwise meta-analysis and network meta-analysis with the random effects model to estimate odds ratios (OR) for HRS reversal and 1-month mortality. We also examined additional outcomes of HRS recurrence, predictors of response, and incidence of adverse events (AEs). Network

meta-analysis favored terlipressin for HRS reversal (OR 1.33, 95% confidence interval [CI]; [0.81–2.18] P = 0.2532) and short-term survival (OR 1.43, 95% CI [0.68–3.02]; P = 0.3450) though this benefit did not reach statistical significance. Terlipressin was associated with AEs such as abdominal pain and diarrhea, whereas norepinephrine was associated with cardiovascular AEs such as chest pain and ischemia. Most of the AEs were reversible with reduction in dose or discontinuation of therapy across both arms. Of the terlipressin-treated subjects, 5.3% discontinued therapy due to serious AEs compared to 2.7% of the norepinephrine-treated subjects. Although this analysis favors terlipressin, future studies can provide additional insight into the comparative efficacy of norepinephrine and terlipressin in the treatment of HRS-AKI, especially in the setting of acute-on-chronic liver failure.

Terlipressin

noradrenaline

norepinephrine

meta-analysis

HRS-1

HRS AKI

Hepatorenal syndrome (HRS) is a functional renal failure resulting from hemodynamic changes occurring in cirrhotic patients with ascites and portal hypertension.¹ The diagnosis and staging of HRS has changed in recent guidelines by the American Association for the Study of Liver Diseases (AASLD) to align with the European Association for the Study of the Liver (EASL).^1,2 There are 2 types of HRS: hepatorenal syndrome-acute kidney injury (HRSAKI) and hepatorenal syndrome-chronic kidney disease (HRSCKD).^1,2 HRS-AKI, previously known as HRS type 1

(HRS-1), occurs in patients with cirrhosis in the absence of hypovolemia or significant abnormalities in kidney histology and in the absence of parenchymal renal disease.¹ The primary difference between the definitions of HRS-1 and HRSAKI is the elimination of an absolute serum creatinine (SCr) threshold in the latter.^1,3 HRS-CKD, previously known as HRS type 2 (HRS2), involves a more gradual impairment in kidney function that is less severe than HRS-AKI.^1,2

The prevalence of HRS-AKI in hospitalized patients with decompensated cirrhosis ranges between 27% and 53%, and the development of acute kidney injury (AKI) is associated with a poor prognosis and high 30-day mortality ranging from 29–44%.¹ Vasoconstrictor drugs in combination with albumin are the treatment of choice for HRS to counteract the splanchnic arterial vasodilation and improve effective circulating volume with resultant improvement in renal perfusion.^1,2

Several studies have shown that vasoconstrictors, specifically terlipressin or norepinephrine, in combination with albumin are effective in improving kidney function in patients with HRSAKI.^1,2 However, large head-to-head trials comparing the efficacy of norepinephrine and terlipressin have not been conducted,¹ making it difficult to evaluate the comparative efficacy of the 2 vasoconstrictors. Both AASLD¹ and EASL² guidelines list terlipressin as the preferred treatment for HRS-AKI and recommend norepinephrine as an alternative, while the American College of Gastroenterology guidelines⁴ recommend either terlipressin or norepinephrine as first-line treatment options.

Two meta-analysis articles in 2017 addressed comparative efficacy of norepinephrine and terlipressin. Facciorusso et al conducted a systematic review to compare various randomized controlled trials (RCTs) to evaluate the efficacy of vasoactive drugs such as terlipressin, midodrine, octreotide, noradrenaline, and dopamine, alone or in combination for the treatment of HRS-1.⁵ Their data suggest the use of either terlipressin plus albumin or norepinephrine plus albumin over midodrine and octreotide plus albumin for reversal of HRS. Furthermore, they found that terlipressin may reduce short-term mortality compared to placebo.⁵ Similarly, Zheng et al conducted a network meta-analysis to compare vasoconstrictor therapies such as terlipressin, norepinephrine, and midodrine plus octreotide for the treatment of HRS-1.⁶ They found terlipressin to be the most efficacious vasoconstrictor in comparison to other therapies, but it was associated with a higher risk of adverse events (AEs).⁶ Meanwhile, norepinephrine appeared to be an appropriate alternative with a lower rate of AEs.⁶ Additionally, another systematic review published in 2018 by Wang et al included a

meta-analysis to estimate the safety and efficacy of terlipressin compared to placebo, albumin, a combination of placebo and albumin, or other available vasoconstrictor therapies such as dopamine, norepinephrine, octreotide alone, or a combination of midodrine and octreotide for treatment of either HRS-1 or HRS-2.⁷ The data from Wang et al indicated that terlipressin was comparable to norepinephrine for the reversal of HRS and was favorable compared to placebo or octreotide.⁷ The number of included studies were too small for a comparative analysis of terlipressin, dopamine, midodrine and octreotide to draw definitive conclusions.

Since the recent meta-analyses,^5–7 additional studies that may shed light on the comparative efficacy of the 2 treatments have been published.^8–10 With the addition of this new evidence, we conducted a meta-analysis to compare the reported efficacy of terlipressin and norepinephrine for the treatment of HRS.

Search strategy and selection criteria

We conducted literature searches of PubMed, Cochrane EMBASE, and ResearchGate databases for RCTs published between 2007 to 2022. The major outcomes assessed were HRS reversal and

short-term mortality for patients with HRS-AKI. Additional outcomes assessed were HRS recurrence, predictors of response, and safety. The search strategy included the terms “HRS-1 or HRS-AKI,” “norepinephrine or noradrenaline,” and “terlipressin.” We included for evaluation all RCTs with adults aged ≥ 18 years who were diagnosed with HRS-1 or HRS-AKI and treated with either norepinephrine or terlipressin in combination with albumin. We excluded

meta-analysis or systematic reviews, observational studies, retrospective studies, trials with subjects who had dual diagnosis such as sepsis or cardiopulmonary diseases in addition to HRS, as well as any study published in languages other than English. Two independent reviewers carried out our search strategy. We manually evaluated the titles and abstracts of trials to exclude those that did not meet the inclusion criteria. Two independent reviewers evaluated the eligibility of the remaining trials.

Data extraction and outcomes

Three reviewers extracted the data independently from each study. We evaluated outcomes related to HRS reversal and short-term mortality. The primary outcome in each trial was reversal of HRS as defined by complete response. Five of the 7 trials defined complete response as a decrease in SCr to a value of 1.5 mg/dL or lower during treatment.^10–14 One trial, Indrabi et al,¹⁵ did not define complete response in the abstract. The Arora et al⁹ trial defined complete response as return of SCr to a value within 0.3 mg/dL of baseline as reflected in the new AASLD guidelines.

Reported short-term mortality ranged from 14 days to 90 days in all trials. We opted to assess 1-month mortality, defined as either 28-day or 30-day mortality. We excluded trials from our assessment that did not evaluate mortality at 1 month. We also evaluated other outcomes in this meta-analysis that were reported as secondary outcomes in the trials, such as recurrence of HRS after initial reversal, predictors of response, and incidence of AEs. When trials included subjects with HRS-1 and HRS-2, we selectively extracted data for subjects with HRS-1 where reported.

Quality assessment

To assess the risk of bias, 2 reviewers independently evaluated the studies using the Cochrane risk of bias assessment tool. This tool evaluated 5 domains of bias for randomized trials: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result.

Data analysis

We performed pairwise meta-analysis and network meta-analysis with a random effects model to calculate 95% confidence intervals (CIs) and pooled estimates of odds ratios (ORs) to evaluate HRS reversal and 1-month mortality outcomes. The RCTs used to conduct this analysis had variation in treatment intensity, length of treatment, and target population. Therefore, due to the anticipated heterogeneity, we used a random effects model with Knapp-Hartung adjustment to evaluate the pooled effect sizes between the trials and their respective standard errors. We also assessed between-study heterogeneity using the I² and τ² statistics to understand how the true effect sizes vary within our meta-analysis study. Additionally, we decided to use the frequentist inference approach since it is more commonly used than the Bayesian counterpart and has better interpretability.

Study characteristics

The database search identified 96 records, 12 of which were duplicates. This resulted in 85 unique records that were individually screened for eligibility. Seven RCTs, with a total of 376 subjects diagnosed with HRS-1 or HRS-AKI, comparing terlipressin and norepinephrine were included in the meta-analysis review (Fig. 1).

Of note, a recent trial by Nayyar et al⁸ met the inclusion criteria for this meta-analysis but was excluded because results fell significantly outside of the normal distribution when plotted on the forest plot matrix. In addition, the 0% HRS reversal rate in the norepinephrine arm prevented calculation of an effect size unless corrections were used.⁸ All trials were open-label RCTs, except Indrabi et al,¹⁵ which provided no information regarding its blinding protocol. All RCTs were conducted exclusively in subjects with HRS-1 or provided data separately for a subset of HRS-1 subjects if the population included subjects diagnosed with both HRS-1 and HRS-2. The duration of treatment ranged from 14 days to 15 days in all trials,^9–14 except for Indrabi et al,¹⁵ which did not disclose the treatment duration in its abstract. All trials reported HRS reversal rate and mortality; however other secondary endpoints such as recurrence of HRS, predictors of response, and incidence of AEs were reported inconsistently. All participants received supportive therapy with albumin. Additionally, 2 trials, Sharma et al¹³ and Goyal et al,¹⁴ administered third-generation cephalosporin prophylactically as supportive therapy. It was also noted that Goyal et al¹⁴ administered furosemide to maintain urine output in norepinephrine-treated subjects only. Terlipressin was administered as intravenous (IV) bolus in 6 trials,^10–15 and as continuous IV infusion in 1 trial,⁹ while Indrabi et al¹⁵ did not specify its route of administration. Table 1 shows the summary of all study parameters included in this

Table 1

Parameters of Included Studies
	Study design	Location; year; follow-up length	HRS-1 or HRS-AKI diagnostic criteria	Intervention (no. of participants)	Concomitant therapies	Relevant outcomes reported	No. (%) HRS reversal	No. (%) mortality at 28 days or 30 days
Alessandria et al, 2007¹¹	Single-center, open-label, randomized controlled trial	Italy; NR; 6 months	HRS-1 diagnostic criteria: International Club of Ascites 2007^a	Norepinephrine (continuous infusion) 0.1 µg/kg per min up to 0.7 µg/kg/min until HRS reversal or for a maximum of 14 days (n = 4) Terlipressin (IV bolus) 1 mg every 4 h up to 2 mg every 4 h until HRS reversal or for maximum 14 days (n = 5)	Albumin 20 g/100 mL	HRS reversal^c; 1-month mortality; HRS recurrence; incidence of side effects	Norepinephrine 3/4 (75) Terlipressin 4/5 (80)	Norepinephrine 1/4 (25) Terlipressin 1/5 (20)
Sharma et al, 2008¹³	Single-center, open-label, randomized controlled trial	India; 2005–2006; 15 days	HRS-1 diagnostic criteria: International Club of Ascites 2007^a HRS-1: Defined as SCr level > 2.5 mg/dL or a 24-hour creatinine clearance level < 20 mL/min	Norepinephrine (continuous infusion) 0.5 mg/h up to 3 mg/h for 15 days (n = 20) Terlipressin (IV bolus) 0.5 mg every 6 h up to 2 mg every 6 h for 15 days (n = 20)	Albumin 20–40 g/day Third-generation cephalosporins prophylactically	HRS reversal^d; 1-month mortality; predictors of response; and incidence of side effects	Norepinephrine 10/20 (50) Terlipressin 10/20 (50)	Norepinephrine 9/20 (45) Terlipressin 9/20 (45)
Singh et al, 2012¹²	Single-center, open-label, randomized controlled trial	India; 2009–2011; 30 days	HRS-1 diagnostic criteria: Cirrhosis with ascites with SCr levels ≥ 2.5 mg/dL; absence of shock; fluid losses and treatment with nephrotoxic drugs; no improvement in renal function following diuretic withdrawal and plasma volume expansion; no ultrasound evidence of renal parenchymal disease or obstructive uropathy, and absence of proteinuria more than 500 mg/24 h	Norepinephrine (continuous infusion) 0.5 mg/h up to 3 mg/h until HRS reversal or a maximum of 15 days (n = 23) Terlipressin (IV bolus) 0.5 mg every 6 h up to 2 mg every 6 h until HRS reversal or for a maximum of 15 days (n = 23)	Albumin 20 g/day	HRS reversal^e; 1-month mortality; predictors of response, and incidence of side effects	Norepinephrine 10/23 (43.4) Terlipressin 9/23 (39.1)	Norepinephrine 15/23 (65.2) Terlipressin 16/23 (69.5)
Indrabi et al, 2013¹⁵	Single-center, randomized controlled trial	India; NR; NR	No information provided	Norepinephrine, dose, route of administration, and duration NR (n = 30) Terlipressin, dose, route of administration, and duration not reported (n = 30)	Albumin (dose not reported)	HRS reversal^f; predictors of response, and HRS recurrence	Norepinephrine 16/30 (53) Terlipressin 17/30 (57)	Not available
Goyal et al, 2016¹⁴	Single-center, open-label, randomized controlled trial	India; NR; NR	HRS-1 diagnostic criteria: International Club of Ascites 2007^a HRS-1: Defined as doubling of initial SCr to > 2.5 mg/dL in less than 2 weeks	Norepinephrine (continuous infusion) 0.5 mg/h up to 3 mg/h until HRS reversal or maximum 14 days (n = 21) Terlipressin (IV bolus) 0.5 mg every 6 h up to 2 mg every 6 h until HRS reversal or maximum 14 days (n = 20)	Albumin 20 g/day Furosemide 0.001 mg/kg/min if adequate urine output was not achieved (norepinephrine arm only) Third-generation cephalosporin prophylactically	HRS reversal^d; predictors of response; and incidence of side effects	Norepinephrine 10/21 (47.6) Terlipressin 9/20 (45)	Not available
Saif et al, 2018¹⁰	Single-center, open-label, randomized controlled trial	India; NR; 90 days	HRS-1 diagnostic criteria: International Club of Ascites 2007^a	Norepinephrine (continuous infusion) 0.5 mg/h up to 3 mg/h until HRS reversal or 14 days of therapy (n = 30) Terlipressin (IV bolus) 0.5 mg every 6 h up to 2 mg every 6 h until HRS reversal or 14 days of therapy (n = 30)	Albumin 20–40 g/day	HRS reversal^d; 1-month mortality; predictors of response	Norepinephrine 16/30 (53) Terlipressin 17/30 (57)	Norepinephrine 14/30 (46.7) Terlipressin 13/30 (43.3)
Arora et al, 2020⁹	Single-center, open-label, randomized controlled trial	India; Oct 2015-Dec 2016; NR	HRS-AKI diagnostic criteria: International Club of Ascites 2015^b	Norepinephrine (continuous infusion) 0.5 mg/h up to 3 mg/h until HRS reversal or 14 days of therapy (n = 60) Terlipressin (continuous infusion) 2 mg/day up to 12 mg/day until HRS reversal or 14 days of therapy (n = 60)	Albumin 20–40 g/day	HRS reversal^g; 28-day mortality; predictors of response; incidence of side effects	Norepinephrine 10/60 (16.7) Terlipressin 24/60 (40%)	Norepinephrine 48/60 (80%) Terlipressin 31/60 (51.7)
CVP, central venous pressure; H₂O, water; NR, not reported.
^a Presentation with cirrhosis and ascites, SCr > 1.5 mg/dL, with no improvement of SCr after at least 2 days of diuretic withdrawal and volume expansion with albumin at the dose of 1 g/kg of body weight per day (maximum of 100 g/day), absence of shock, no current or recent treatment with nephrotoxic drugs, and absence of parenchymal kidney disease as indicated by proteinuria > 500 mg/day, microhematuria (> 50 red blood cells per high power field), and/or abnormal renal ultrasonography.
^b Diagnosis of cirrhosis with ascites; diagnosis of AKI according to ICA-AKI (ICA-AKI stage ≥ II); no response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg of body weight per day; absence of shock; no current or recent use or nephrotoxic drugs; no macroscopic signs of structural kidney injury, defined as absence of proteinuria (> 500 mg/day), absence of microhematuria (> 50 red blood cells per high power field), normal findings on renal ultrasonography.¹⁶
^c Defined as decrease of SCr level ≥ 30% compared with the baseline value to a final value of ≤ 1.5 mg/dL during the treatment.
^d Defined as decrease in SCr to a value of ≤ 1.5 mg/dL during the treatment.
^e Defined as SCr < 1.5 mg/dL.
^f No information provided.
^g Defined as return of SCr to a value within 0.3 mg/dL of baseline. Baseline value of SCr obtained in the previous 3 months.

meta-analysis. Baseline characteristics were similar across trials as observed in Table 2.

Table 2

Baseline Characteristics of the Patient Population Across Included Studies
Study	MELD score		MAP (mmHg)		SCr (mg/dL)
	Terlipressin	Norepinephrine	Terlipressin	Norepinephrine	Terlipressin	Norepinephrine
Alessandria et al¹¹	26 ± 2	26 ± 1	74 ± 3	71 ± 2	2.5 ± 0.3	2.3 ± 0.2
Sharma et al¹³	29.6 ± 6.2	31.6 ± 6	81.4 ± 11.4	78.2 ± 5.3	3.0 ± 0.5	3.3 ± 1.3
Singh et al¹²	26.4	24.7	64.7	65.2	3.3	3.1
Indrabi et al¹⁵	No information	No information	No information	No information	No information	No information
Goyal et al¹⁴	30.1 ± 5.9	29.2 ± 6.1	76.8 ± 11.6	77.3 ± 8.6	3.4 ± 1.6	3.1 ± 1.5
Saif et al¹⁰	29.1 ± 5.8	30.4 ± 9.2	81.3 ± 8.1	80.6 ± 10.2	3.2 ± 0.9	3.3 ± 1.1
Arora et al⁹	33.3 ± 5.0	33.8 ± 5.0	68.1 ± 4.6	67.9 ± 4.2	1.8 (1.09, 5.30)	2.0 (1.02–5.10)

MAP, mean arterial pressure; MELD, model for end-stage liver disease.

HRS reversal

The overall HRS reversal rate was higher for subjects treated with terlipressin at 47.9% (90/188) compared to those treated with norepinephrine at 39.9% (75/188). Figures 2a and 2b show the results of direct pairwise meta-analysis and network meta-analysis using OR with 95% CI for HRS reversal. Network meta-analysis results indicate that terlipressin was more favorable for HRS reversal when compared with norepinephrine (OR 1.33; 95% CI [0.81–2.18]; P = 0.2532) based on the 7 RCTs included in the analysis, although statistical significance was not reached. There was no significant heterogeneity between studies as seen by the I² statistic in Fig. 2. We performed both pairwise and network meta-analysis to demonstrate consistency between the assessments.

Mortality

All 7 trials included in the meta-analysis reported mortality at varying times, ranging from 14 days to 90 days post-treatment initiation. Five of the 7 trials reported 28-day or 30-day mortality and were included in the 1-month mortality assessment (275 subjects). ^9–13 Goyal et al¹⁴ and Indrabi et al¹⁵ trials were not included in the 1-month mortality outcome since they reported mortality at 14 days and 90 days, respectively. The 1-month mortality rate was lower for those receiving terlipressin (50.7% [70/138]) compared to those receiving norepinephrine (63.5% [87/137]) across the 5 trials included.^9–13 Network meta-analysis for short-term survival using OR indicated that terlipressin was more favorable compared to norepinephrine as seen in Fig. 3, (OR 1.43, 95% CI [0.68–3.02]; P = 0.3450). Similar to the HRS reversal assessment, the survival and mortality assessments were consistent across direct pairwise and network

meta-analysis.

Additional endpoints

All trials inconsistently measured additional endpoints. The most common secondary endpoints included HRS recurrence and predictors of response. Out of the 2 trials reporting HRS recurrence, 5 (7.5%) subjects, consisting of 2 (3.0%) subjects from norepinephrine arms and 3 (4.5%) subjects from terlipressin arms, experienced HRS recurrence. ^11,15 Alessandria et al¹¹ defined HRS recurrence as an increase in SCr level of 50% or more than the lowest value after treatment in subjects with complete response with a final value above 1.5 mg/dL during the follow-up period, while Indrabi et al¹⁵ did not define HRS recurrence.

Six of the 7 trials included in this meta-analysis reported predictors of response as an additional outcome.^{9,10, 12–15} Common predictors of response reported for both arms were Child-Turcotte-Pugh score, model for end-stage liver disease (MELD) score, serum urea, serum albumin, and prothrombin time on multivariate analysis for multiple trials.^{9,10, 12–15}

Adverse events

All trials inconsistently reported data for treatment-related AEs. Common AEs reported in the terlipressin arms included abdominal cramps and increased frequency of stools, which improved with a decrease in terlipressin dose. In norepinephrine arms, commonly reported AEs included cardiovascular events such as chest pain and ventricular ectopy without hemodynamic compromise. Across all studies, approximately 5.3% (10/188) of subjects treated with terlipressin required discontinuation of therapy due to serious AEs compared to 2.7% (5/188) of norepinephrine-treated subjects. Three trials reported cardiovascular events such as ST segment depression, chest pain, ventricular ectopy, and peripheral ischemia,^12–14 affecting subjects in both terlipressin and norepinephrine arms.

Quality assessment

Overall, our evaluation indicated that most of the trials included in this meta-analysis were at either “low risk”^9,13 or had “some concerns”^{10–12, 14} of bias using the Cochrane risk of bias assessment tool. Indrabi et al¹⁵ was the only trial determined to be at “high risk” of bias since only the trial abstract was available. One trial¹⁵ did not report its randomization process, and most of the trials^{10,11, 13–15} did not report their allocation concealment methods. Nevertheless, this did not result in high risk of bias since baseline characteristics were evenly distributed between the 2 treatment arms. In most of the trials, participants and healthcare team were aware of the assigned intervention during the trial. However, this did not result in high risk of bias since blinding is unlikely to impact objective outcomes measured in the trials such as HRS reversal (change in SCr) or mortality.

HRS-AKI is characterized by a progressive and rapid deterioration of renal function, which often leads to multiorgan failure and death.¹⁷ Liver transplantation is the optimal treatment for patients with HRS-AKI, even among those who respond to vasoconstrictor therapy.^1,2 The AASLD and EASL guidelines recommend terlipressin as the vasoconstrictor of choice, administered either as IV bolus or continuous IV infusion.^1,2 Alternatively, they recommend norepinephrine in cases where terlipressin is not available.^1,2 Our network meta-analysis data support this recommendation, favoring terlipressin for both HRS reversal and short-term survival benefit, although the observed ORs for these endpoints did not achieve statistical significance. Observed AEs associated with terlipressin in the included trials were abdominal cramps and increased frequency of stools, and the AEs associated with norepinephrine included cardiovascular events such as chest pain and ischemia. The recently published phase 3 CONFIRM trial that examined the efficacy of terlipressin versus placebo for the treatment of HRS also reported these AEs associated with terlipressin.¹⁸ However, in the CONFIRM trial, an additional significant AE of concern was respiratory failure, which was not observed in the included trials. A variety of factors may contribute to this finding, including differences in HRS-AKI diagnostic criteria that delayed the timing of terlipressin administration, the presence of acute-on-chronic liver failure (ACLF) with associated multiorgan dysfunction, and cumulative albumin dosage. Further studies will provide insights into how these factors affect the risk of respiratory failure associated with terlipressin use.

We conducted this systematic review because several new studies comparing safety and efficacy of terlipressin and norepinephrine have been published since the last meta-analysis. Facciorusso et al⁵ and Zheng et al⁶ included comparative efficacy trials for all available vasoactive therapies, while Wang et al⁷ compared terlipressin with all available vasoconstrictor therapies as well as placebo and albumin. Additionally, the trial population in these

meta-analyses included patients with both HRS-1 and HRS-2 diagnoses. In contrast, our

meta-analysis assessed only the efficacy of terlipressin and norepinephrine, as they are

guideline-recommended treatments for HRS-AKI with superiority over other vasoconstrictor therapies such as midodrine and octreotide.^1,2 Data from our meta-analysis favor terlipressin use, similar to the conclusion reported by Zheng et al,⁶ whereas other

meta-analyses have found terlipressin and norepinephrine to be comparable.^5,7 The difference in our conclusions can be attributed to the inclusion of newer RCTs in our meta-analysis.

One such publication, a recent trial by Arora et al,⁹ used the updated HRS-AKI definition for diagnosis and restricted the subject population to those experiencing ACLF. ACLF is characterized by acute decompensation of patients with cirrhosis, usually precipitated by an event (commonly bacterial infection) that leads to multiple organ failures, including AKI. ACLF patients are at high risk of short-term mortality.^19,20 ACLF criteria are increasingly being used by hepatologists and critical care specialists for management of patients with chronic liver disease in the critical care setting. In subjects with ACLF enrolled in the trial by Arora et al, terlipressin improved HRS reversal, significantly reduced the need for renal replacement therapy, and improved 28-day survival compared to norepinephrine.⁹ The authors of this study also noted that while there were more AEs limiting the use of the drug in the terlipressin arm, the events were reversible. It is interesting to note that in our pairwise meta-analysis, the HRS reversal results from the Arora et al⁹ trial are the only results for which all values within the margin of error favor terlipressin, indicating that this subject population may experience a clear benefit from treatment with terlipressin over norepinephrine compared to a broader patient population. One hypothesis for this is that terlipressin’s higher selectivity for vasopressin 1 receptors over vasopressin 2 receptors promotes vasoconstriction in both the systemic and splanchnic circulation, making it a better therapeutic option to combat the severe inflammatory response and circulatory impairment in ACLF patients. In addition, in the setting of both systemic and splanchnic vasodilation in ACLF, norepinephrine’s vasoconstrictive efficacy may be more pronounced at the systemic level, thereby limiting its efficacy in reversing splanchnic vasodilation and associated HRS. It should also be noted that another key difference between the Arora et al ⁹ trial and the others included in our analysis is that Arora et al⁹ administered terlipressin as continuous IV infusion as opposed to an IV bolus. Future studies of HRS treatments in the ACLF population could provide valuable data to further characterize the potential superiority of terlipressin over norepinephrine in this specific patient cohort.

While the data presented here favor the use of terlipressin over norepinephrine, it is important to note that there are key differences that may affect the choice of vasoconstrictor for HRS management. Norepinephrine must be given as a continuous IV infusion and typically requires a central venous line and, in most facilities, the transfer of the patient to an intensive care unit (ICU).² In contrast, terlipressin can be given with a peripheral or central line as a bolus or continuous infusion, allowing for use outside of the ICU setting.^2,21,22 Interestingly, most of the trials included in this analysis were conducted on medical floors (non-ICU) with the exception of 2 trials^13,14 that treated all subjects in the ICU from the time HRS-1 diagnosis was suspected. Most of the trials reported higher cost associated with the use of terlipressin^10–14 but did not report costs of hospital admission, albumin, concomitant medications, and subsequent medical treatments after vasoconstrictor therapy.

The quality of evidence in our study was relatively high based on exclusive inclusion of RCTs with objective endpoints such as HRS reversal and mortality. However, most of the trials were open-label^9–14 and did not report allocation concealment methods.^{10,11, 13–15} Nevertheless, blinding is unlikely to impact objective outcome measures such as HRS reversal and mortality. A primary limitation in this analysis is the small number of studies and included subjects. Additionally, each trial had slightly different diagnostic criteria for HRS-1, and throughout the time that these studies were conducted, the definition and nomenclature of HRS-1 changed. While HRS-1 diagnosis depends upon patients reaching a specific SCr threshold, the updated HRS-AKI diagnosis examines the change in SCr as the basis for diagnosis.¹ The updated HRS-AKI diagnostic criteria enable earlier treatment and therefore a better prognosis.²² Because of their timing, all trials, with the exception of Arora et al, did not use the updated definition of

HRS-AKI for diagnosis. An additional limitation is that network meta-analyses can be subject to misinterpretation due to heterogeneity related to considerable differences in the trials, which limit their comparability. We attempted to minimize this by including only RCTs of subjects with HRS-1 or HRS-AKI, which evaluated objective outcomes, and by using the random effects model to compensate for the heterogeneity. As more studies comparing terlipressin and norepinephrine are completed, a clearer understanding of the comparability of these 2 therapies will emerge.

In summary, our network meta-analysis favors terlipressin use for both outcomes of HRS reversal and 1-month mortality for patients with HRS-1 or HRS-AKI when compared to norepinephrine. Additionally, terlipressin was associated with an increased risk of AEs compared to norepinephrine, but discontinuation of therapy due to AEs was uncommon. Large

head-to-head RCTs comparing the efficacy and safety of terlipressin and norepinephrine for the treatment of HRS-AKI as defined by recently revised guidelines would provide valuable insight to guide timely and effective therapy.

AASLD, American Association for the Study of Liver Diseases; ACLF, acute‑on‑chronic liver failure; AE, adverse event; AKI, acute kidney injury; CI, confidence interval; CVP, central venous pressure; EASL, European Association for the Study of the Liver; H₂O, water; HRS, hepatorenal syndrome; HRS‑1, hepatorenal syndrome type 1; HRS‑2, hepatorenal syndrome type 2; HRS‑AKI, hepatorenal syndrome-acute kidney injury; HRS‑CKD, hepatorenal syndrome-chronic kidney disease; ICU, intensive care unit; IV, intravenous; MAP, mean arterial pressure; MELD, model for end‑stage liver disease; NR, not reported; OR, odds ratio; RCT, randomized controlled trial; SCr, serum creatinine; SE, standard error.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable

CONSENT FOR PUBLICATION

Not applicable

AVAILABILITY OF DATA AND MATERIALS

All data generated or analyzed in this meta-analysis are included within this article and cited in the references section.

COMPETING INTERESTS

Both JCO and RMS have served as consultants for Mallinckrodt Pharmaceuticals related to terlipressin.

FUNDING

Not applicable

AUTHORS’ CONTRIBUTIONS

Both JCO and RMS analyzed and interpreted the included trials in this published meta-analysis article as well as the HRS reversal and 1-month mortality data. Both authors contributed to the writing, review, and approval of the final manuscript.

ACKNOWLEDGEMENTS

Medical writing and editorial support, conducted in accordance with the International Committee of Medical Journal Editors (ICMJE) and Good Publication Practice 3 (GPP3) guidelines, were provided by Kim Storvik, PhD, and Sanjna Patel, PharmD, of Red Nucleus, Yardley, PA, USA; funded by Mallinckrodt Pharmaceuticals, plc, Hampton, NJ, USA.

Data extraction and statistical analysis were conducted by Andy Duydang, MS.

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No competing interests reported.

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Comparative Efficacy of Terlipressin and Norepinephrine for Treatment of Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI): A Systematic Review and Meta-analysis

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Abstract

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Introduction

Methods

Search strategy and selection criteria

Data extraction and outcomes

Quality assessment

Data analysis

Results

Study characteristics

HRS reversal

Mortality

Additional endpoints

Adverse events

Quality assessment

Discussion

Abbreviations

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References

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