What is the supportive evidence for terlipressin compared to norepinephrine in HRS-AKI reversal?

What evidence showing that terlipressin is superior to norepinephrine in HRS-AKI reversal?

Comment by InpharmD Researcher

Across comparative randomized data, terlipressin and norepinephrine generally demonstrate similar efficacy for HRS-AKI reversal when used with albumin, with most analyses showing no statistically significant differences in renal recovery or short-term survival. However, pooled trial data and select comparative analyses suggest a consistent numerical trend favoring terlipressin, with slightly higher rates of HRS reversal and, in some analyses, improved survival outcomes, although these findings do not consistently reach statistical significance. Overall, the evidence does not establish clear superiority of terlipressin over norepinephrine, but the directionality of results across several datasets has led to a perception of a modest clinical advantage for terlipressin despite low-to-moderate certainty of evidence.

Background

According to the 2024 American Gastroenterological Association (AGA) Clinical Practice Update on the Use of Vasoactive Drugs and Intravenous Albumin in Cirrhosis, terlipressin is considered the vasoactive drug of choice for hepatorenal syndrome (HRS)-acute kidney injury (AKI) based on the available evidence, primarily from placebo-controlled randomized trials demonstrating improved renal function and reduced need for renal replacement therapy, although without a mortality benefit. Evidence directly comparing terlipressin with norepinephrine is limited; however, the largest randomized trial (n=120) reported higher rates of HRS-AKI reversal and improved survival with terlipressin administered as a continuous infusion compared with norepinephrine (Table 1). A network meta-analysis also suggested a possible slight advantage of terlipressin, although with low certainty. [1]

Per 2021 updated American Association for the Study of Liver Diseases (AASLD) guidelines, vasoconstrictor drugs in combination with albumin are the treatment of choice for HRS-AKI. Terlipressin, given either as an intravenous (IV) bolus or continuous IV infusion, is a preferred drug (dose unspecified). A response to terlipressin is defined by decreases of creatinine to <1.5 mg/dL or a return to within 0.3 mg/dL of baseline over a maximum of 14 days. The therapy should be discontinued if creatinine remains at or above the treatment level past 4 days despite a maximally tolerated dose of terlipressin. If terlipressin is unavailable, norepinephrine may be given. If neither terlipressin nor norepinephrine can be administered, a trial of oral midodrine (5 to 15 mg Q8H) in combination with octreotide (100 to 200 mcg Q8H or 50 mcg/hour IV) may be considered; however, the efficacy remains relatively low. [2]

A 2024 meta-analysis synthesized data from seven randomized controlled trials (RCTs) involving 376 adults with HRS-AKI or HRS type 1 (HRS-1). The investigators aimed to compare the efficacy and safety of terlipressin versus norepinephrine, both administered alongside albumin, for the treatment of HRS-AKI. The primary outcomes evaluated were HRS reversal and 1-month mortality, with secondary endpoints including HRS recurrence, predictors of response, and adverse event (AE) profiles. Using a random effects model with Knapp-Hartung adjustment to account for clinical and methodological heterogeneity, terlipressin was numerically associated with higher rates of HRS reversal (47.9% vs 39.9%; odds ratio [OR] 1.33, 95% confidence interval [CI] 0.80 to 2.22; p= 0.22) and improved 1-month survival (mortality rate 50.7% vs 63.5%; OR 1.50; 95% CI 0.64 to 3.53; p= 0.26) compared to norepinephrine, though results did not reach statistical significance. Adverse event profiles differed between agents, with terlipressin more commonly linked to gastrointestinal AEs such as abdominal pain and diarrhea, and norepinephrine more frequently associated with cardiovascular complications, including chest pain and ischemia. Discontinuation due to serious AEs was modest in both cohorts (5.3% for terlipressin vs 2.7% for norepinephrine). Despite the lack of statistical significance, the directionality of the findings and the consistency of numerically favorable outcomes with terlipressin suggest a potential clinical advantage, particularly in light of its usability outside the intensive care unit setting. [3]

A 2024 systematic review and meta-analysis evaluated the efficacy and safety of terlipressin plus albumin compared to noradrenaline plus albumin in the treatment of HRS in adult patients with cirrhosis. The analysis incorporated data from nine prospective clinical trials encompassing 486 patients—244 treated with terlipressin and 242 with noradrenaline. Outcomes analyzed spanned both clinical efficacy endpoints—such as serum creatinine, urine output, creatinine clearance, and reversal of HRS—and hemodynamic or biochemical markers, including mean arterial pressure (MAP), plasma renin activity, plasma aldosterone levels, and urine sodium concentration. Results from the pooled analysis demonstrated no statistically significant differences between the terlipressin and noradrenaline groups for serum creatinine (mean difference [MD] 0.03 mg/dL; 95% CI -0.07 to 0.13; p= 0.6), urine output (MD 32.75 mL/24 hours; 95% CI -93.94 to 159.44; p= 0.6), MAP (MD 1.40 mmHg; 95% CI -1.17 to 3.96; p= 0.27), urinary sodium (MD −1.02 mEq/L; 95% CI -5.15 to 3.11; p= 0.63), plasma renin activity, or aldosterone levels (p>0.05 for all). The reversal rate of HRS (risk ratio [RR] 1.15; 95% CI 0.96 to 1.37; p= 0.12) and overall mortality (RR 0.87; 95% CI 0.74 to 1.01; p= 0.08) also did not differ significantly between the two treatment arms. However, noradrenaline demonstrated a statistically significant advantage in creatinine clearance compared to terlipressin (MD 4.22 mL/min; 95% CI 0.4 to 8.05; p= 0.03). Subgroup analyses based on terlipressin dosing and timing of outcome assessments reinforced the overall findings. Risk of bias evaluation using Cochrane methodology indicated generally low risk across domains, though blinding of participants and personnel was limited in most trials. Collectively, these findings support noradrenaline as a clinically effective and safe alternative to terlipressin for the management of HRS, with the added benefits of greater availability and lower cost. [4]

A 2022 meta-analysis that compared the effectiveness of inpatient treatments for HRS included 26 randomized controlled trials (RCTs; N= 1,736). Terlipressin improved the reversal of HRS compared to norepinephrine (30.4 more reversals per 1,000; 95% CI >83 to <14.6). Terlipressin also reduced mortality compared with norepinephrine (66 fewer deaths per 1,000; 95% CI <142.5 to >24). Terlipressin did not significantly increase the risk of serious adverse events (20.4 more adverse events per 1,000; 95% CI -5.1 to 51). Based on these results, it was suggested that until access to terlipressin improves, initial norepinephrine administration may be more appropriate than the initial trial with midodrine plus octreotide. [5]

A 2019 meta-analysis examined RCTs comparing the risk versus benefits of treatment regimens for HRS in patients with decompensated cirrhosis. A total of 23 trials (N= 1,185) were included in one or more outcomes, and studies with participants who had previously undergone liver transplantation were excluded. When comparing various regimens to albumin plus terlipressin, there was no statistically significant difference in all-cause mortality rates at maximal follow-up. The difference between albumin plus norepinephrine and albumin plus terlipressin on the outcome of recovery from HRS was insignificant (hazard ratio 0.85; 95% credible interval [CrI] 0.58 to 1.28). Pooled data from 5 trials reporting the number of any adverse events found albumin plus norepinephrine to be associated with a lower risk of any adverse events compared to albumin plus terlipressin (rate ratio 0.51; 95% CrI 0.28 to 0.87) by direct comparison. Although researchers indicated length of hospital stay as an exploratory outcome, none of the trials included in the analysis reported it. As all examined studies were at high risk of bias, and all the evidence was of low or very low certainty, the robustness of this analysis remains low. [6]

A 2018 systematic review and meta-analysis (N= 18 RCTs, 1,011 patients) also compared the safety and efficacy of terlipressin for the reversal of HRS to placebo and other vasoactive agents used in clinical practice. When comparing terlipressin to norepinephrine, data from 8 RCTs indicated an overall rate of 53.5% in the terlipressin group and 52.9% in the norepinephrine group, with no significant difference between the two. Similarly, renal function change (60.3% terlipressin vs. 61.8% norepinephrine), mortality (61.7% vs. 62.0%), and HRS recurrence found no significant differences; however, the incidence of total adverse events was higher with terlipressin than norepinephrine (25.4% vs. 10.6%, RR 2.72; 95% CI 1.33 to 5.55; p= 0.006, I2= 4%). Based on type 1 HRS subgroup analysis between terlipressin and norepinephrine, reverse rate, renal function change rate, mortality, and adverse events were all similar. Overall, results demonstrated the superiority of terlipressin compared to placebo as well as other vasoconstrictor drugs, with the exception of norepinephrine. [7]

A 2017 Cochrane review and meta-analysis evaluated the beneficial and harmful effects of terlipressin compared to other vasoactive drugs for patients with hepatorenal syndrome. A total of 10 randomized clinical trials were included (N= 474 participants). The included trials compared terlipressin versus norepinephrine (7 trials), octreotide (1 trial), midodrine and octreotide (1 trial), or dopamine (1 trial). All participants in both groups received albumin as a cointervention. Primary outcomes evaluated included mortality, persistent HRS, and serious adverse events. No significant difference was found between terlipressin and other vasoactive drugs for mortality. Two comparisons were conducted, one with all 10 trials (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%), and another with only 2 trials with a low risk of bias (RR 0.92, 95% CI 0.63 to 1.36; 94 participants); results were similar in both analyses. For the persistence of HRS, an analysis of 9 trials found significant beneficial effects of terlipressin versus other vasoactive drugs (RR 0.79, 95% CI 0.63 to 0.99; 394 participants; I² = 26%). There was no significant difference between terlipressin and other vasoactive drugs for the incidence of serious adverse events. Additionally, no evidence was found suggesting differences between terlipressin and other included drugs regarding the overall risk of non-serious adverse events, except for the increased risk of diarrhea or abdominal pain associated with terlipressin (RR 3.50, 95% CI 1.19 to 10.27; 221 participants; 5 trials; I² = 0%). Health-related quality of life, a secondary outcome, was not evaluated in any included trials. All analyses were determined to be based on very low-quality evidence, and ultimately, it was concluded that there was insufficient evidence to support or refute the beneficial or harmful effects of terlipressin compared to other vasoactive agents. [8]

A 2016 meta-analysis compared the effectiveness of various doses of terlipressin to norepinephrine, midodrine plus octreotide, and dopamine plus furosemide in patients with type 1 HRS. A total of 13 RCTs (N= 739) were eligible for inclusion. In a comparison between terlipressin and norepinephrine, low-quality evidence found no significant differences in terlipressin improving short-term mortality over its comparators (OR 0.93, 95% CI 0.43 to 1.98) or reversing hepatorenal syndrome (OR 0.99, 95% CI 0.43 to 2.33). Overall, very low-quality evidence is available to support terlipressin for a reduction in mortality rates over other commonly used agents in the treatment of type 1 HRS. [9]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What evidence showing that terlipressin is superior to norepinephrine in HRS-AKI reversal?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure
Design	Open-label randomized controlled trial N= 120
Objective	To compare reversal of hepatorenal syndrome-acute kidney injury (HRS-AKI) at day 14 and to compare early response of noradrenaline and terlipressin at day 4 and 7, and to assess 28-day survival
Study Groups	Terlipressin (n= 60) Noradrenaline (n= 60)
Inclusion Criteria	Patients diagnosed with acute on chronic liver failure (ACLF; acute hepatic insult manifesting as jaundice [serum bilirubin ≥5 mg/dL] and coagulopathy [INR ≥1.5] complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease or cirrhosis, and is associated with high 28-day mortality)
Exclusion Criteria	Aged < 18 years, decompensated cirrhosis, patients on renal replacement therapy, renal or liver transplantation, history of coronary artery disease, ischemic cardiomyopathy, ventricular arrhythmia, peripheral vascular disease, chronic kidney disease, obstructive uropathy, or lack of informed consent
Methods	Eligible patients were randomized to receive either continuous infusion of terlipressin at 2 mg/24h or noradrenaline starting at 0.5 mg/h. Dosage of terlipressin was doubled every 48 hours in case of no response (< 25% of pre-treatment value) to the maximum dosage of 12 mg/24h. Dosage of noradrenaline was doubled every 4 hours, at increments of 0.5 mg/h up to 3 mg/h, to achieve an increase in mean arterial pressure (MAP) of at least 10 mmHg or an increase in 4h urine output >200 mL. All patients received standard management based on the hospital protocol and received plasma expansion with albumin for initial 2 days (1 g/kg/day dose titrated as per signs of volume overload). Daily albumin (20-40 g/day) was given in both groups until the end of reversal of HRS-AKI or evidence of volume overload (central venous pressure [CVP] > 18 cm of H20) or inferior vena cava [IVC] > 22 mm) or requirement of renal replacement therapy (RRT). Staging of AKI and response to treatment were defined as per the ICA-AKI criteria, and response was assessed every 48 hours. Complete and partial response was defined as the return of serum creatinine (SCr) to a value within 0.3 mg/dL of the baseline and regression of AKI stage with a reduction of SCr to ≥ 0.3 mg/dL above baseline, respectively. No response was defined as no regression of AKI.
Duration	Follow-up: 28 days
Outcome Measures	Primary: reversal of HRS-AKI at day 14 Secondary: early response of noradrenaline and terlipressin at days 4 and 7, 28-day survival, adverse events (AEs)
Baseline Characteristics		Terlipressin (n= 60)	Noradrenaline (n= 60)
	Age, years	40.26 ± 6.25	38.80 ± 6.95
	Male	96%	92%
	Etiology Alcohol Reactivation of hepatitis B Drug-induced liver injury Hepatitis E infection	73% 8.3% 6.7% 6.7%	71.7% 11.7% 8.3% 3.3%
	Stage of acute kidney injury Stage II Stage III	51.6% 48.3%	53.3% 46.66%
	Clinical/biochemical parameters Total bilirubin, mg/dL Aspartate transaminases, IU/mL Alanine transaminase, IU/mL Serum creatinine, mg/dL International normalized ratio Model for end-stage liver disease (MELD) Baseline urine flow rate, mL/hour	22.15 ± 9.71 130 54 1.79 2.80 ± 0.64 33.27 ± 4.98 24.34 ± 2.02	22.96 ± 8.44 116 55 2.02 2.79 ± 0.726 33.75 ± 5.00 23.64 ± 2.68
Results	Endpoint	Terlipressin (n= 60)	Noradrenaline (n= 60)	p-value
	Reversal of hepatorenal syndrome at day 14	24 (40%)	10 (16.7%)	0.004
	Response day 4 (partial response; complete response)	16/60 (26.7%) (5;11)	7/60 (11.7%) (7;0)	0.03
	Response day 7 (partial response; complete response)	25/60 (41.7%) (4;21)	12/60 (20%) (7:5)	0.01
	Overall survival	29/60 (48.3%)	12/60 (20%)	0.001
	Requirement of RRT 14-day mortality 28-day mortality	34 (56.66%) 35% (21/34) 91.2% (31/34)	48 (80%) 65% (39/48) 100%	0.006 0.05 0.07
	Median dose of IV albumin (interquartile range [IQR]), g/day	60 (60 to 80)	60 (60 to 75)	0.81
	Mean dose of study medication, mg/day	2.02 ± 0.70	1.11 ± 0.40	-
	Both drugs caused a significant increase in urine flow in patients with AKI-HRS from baseline. In the terlipressin arm, urine flow rate increased from 24.34 ± 2.02 to 47.21± 2.48 mL/hour (p< 0.01), and in the noradrenaline group, from 23.68 ± 2.68 to 35.46 ± 2.97 mL/hour (p< 0.001).
Adverse Events	Common Adverse Events: Diarrhea more than 4 times/day (terlipressin vs. noradrenaline 8.3% vs. 0), abdominal pain (1.6% vs. 0), atrial fibrillation
	Serious Adverse Events: atrial fibrillation (3.3% vs. 0), cyanosis (6.6% vs. 0), chest pain (3.3% vs. 0), ventricular premature complex (0 vs. 5%), hypertension (0 vs. 3.3%)
	Percentage that Discontinued due to Adverse Events: 9 patients vs. 5 patients
Study Author Conclusions	Acute kidney injury in ACLF carries a high mortality. Infusion of terlipressin gives an earlier and higher response than noradrenaline, with improved survival in ACLF patients with HRS-AKI.
InpharmD Researcher Critique	As the study included a relatively sick cohort of patients at baseline (MELD > 20), the mortality benefits of terlipressin compared to noradrenaline may not apply to other patient populations. The open-label design may also increase the risk of bias while interpreting study results.

References:
[1] [1] Arora V, Maiwall R, Rajan V, et al. Terlipressin Is Superior to Noradrenaline in the Management of Acute Kidney Injury in Acute on Chronic Liver Failure. Hepatology. 2020;71(2):600-610. doi:10.1002/hep.30208

Noradrenaline Versus Terlipressin in the Management of Type 1 Hepatorenal Syndrome: A Randomized Controlled Study
Design	Randomized, controlled single-center study N= 60
Objective	To compare noradrenaline and terlipressin in the management of type 1 hepatorenal syndrome (HRS)
Study Groups	Terlipressin (n= 30) Noradrenaline (n= 30)
Inclusion Criteria	Patients with cirrhosis and ascites, serum creatinine > 133 μmol/L (1.5 mg/dL), and no improvement of serum creatinine (decrease to a level of ≤ 133 μmol/L) after at least 2 days of diuretic withdrawal and volume expansion with albumin (1 g/kg of body weight per day up to a maximum of 100 g/day for at least 2 days); absence of shock; no current or recent treatment with nephrotoxic drugs; absence of parenchyma kidney disease
Exclusion Criteria	Patients with improvement in renal function after plasma volume expansion; evidence of sepsis excluding spontaneous bacterial peritonitis; coronary artery disease; obstructive cardiomyopathy; ventricular arrhythmia; obliterative arterial disease
Methods	Patients were randomized to receive either continuous infusion of noradrenaline at an initial dose of 0.5 mg/h or terlipressin as an IV bolus of 0.5 mg every 6 h. For patients taking noradrenaline, if an increase in mean arterial pressure (MAP) of at least 10 mmHg or an increase in 4-h urine output to more than 200 mL was not achieved, the noradrenaline dose was increased every 4-h in steps of 0.5 mg/h, to a maximum dose of 3 mg/h. For patients taking terlipressin, if a significant reduction in serum creatinine level (≥ 1 mg/dL) was not observed during each 3-day period, the dose was increased in a stepwise fashion every 3 days to a maximum of 2 mg every 6 hour (up to 8 mg/day total). Blood samples were taken at baseline and at days 1, 3, 5, 7, and at the end of treatment to measure standard liver and renal function tests. The glomerular filtration rate was assessed by measuring creatinine at baseline at the end of treatment. MAP was measured daily. Patients in both groups were given intravenous (IV) albumin 20-40 g/day through end of study period.
Duration	Intervention: up to 2 weeks of noradrenaline/terlipressin treatment The date range of study was not specified
Outcome Measures	Primary: reversal of type 1 HRS (reflected by decrease in serum creatinine to a value of ≤ 1.5 mg/dL) Secondary: survival at 30 days of therapy
Baseline Characteristics		Noradrenaline (n= 30)	Terlipressin (n= 30)	p-value
	Age, years	51.5 ± 12.8	53.8 ± 8.6	0.418
	Duration of chronic liver disease (CLD), months	20.9 ± 19.3	23.4 ± 14.9	0.574
	Child-Pugh score	12.0 ± 1.3	11.9 ± 1.4	0.782
	Albumin, g/dL	2.4 ± 0.49	2.7 ± 0.6	0.055
	Creatinine, mg/dL	3.3 ± 1.1	3.2 ± 0.9	0.668
	Urine output, mL/day	367.3 ± 175.6	587.0 ± 865.3	0.178
	MAP, mmHg	80.6 ± 10.2	81.3 ± 8.1	0.060
	Median dose and duration	1.5 mg/h x 5 days	3.3 mg/day x 5 days
Results	Endpoint	Noradrenaline (n= 30)	Terlipressin (n= 30)	p-value
	Reversal of HRS*	16 (53%)	17 (57%)	-
	Survival at 30 days	16 (53%)	17 (57%)	-
	*No significant difference was reported between groups for primary outcome or for decreasing serum creatinine and increasing urine output (p > 0.05).
Adverse Events	Treatment with either drug was considered to be well tolerated and safe, without any significant adverse events.
Study Author Conclusions	This randomized controlled trial showed that vasoconstrictors are effective in reversing HRS, have short-term beneficial effect on mortality, and thus may help to buy time to go for liver transplantation. Noradrenaline is effective, safe, and less costly alternative to terlipressin in managing patients with type 1 HRS.
InpharmD Researcher Critique	This study was conducted at a single center in India, where standard of care and costs of medications may differ compared to the United States. The dose utilized within this study was less than other studies, but the authors stated that higher doses of noradrenaline or terlipressin did not significantly impact outcomes in non-responders.

References:
[1] [1] Saif RU, Dar HA, Sofi SM, Andrabi MS, Javid G, Zargar SA. Noradrenaline versus terlipressin in the management of type 1 hepatorenal syndrome: A randomized controlled study. Indian J Gastroenterol. 2018;37(5):424-429. doi:10.1007/s12664-018-0876-3

Noradrenaline is as Effective as Terlipressin in Hepatorenal Syndrome Type 1: A Prospective, Randomized Trial
Design	Randomized, open-label, prospective, single-center (India) N= 41
Objective	To compare the efficacy of noradrenaline versus terlipressin in the treatment of hepatorenal syndrome (HRS) type 1
Study Groups	Noradrenaline continuous infusion (0.5-3 mg/hour) (n= 21) Terlipressin (0.5-2 mg/6 hours) (n= 20)
Inclusion Criteria	Patients between 18-70 years old, decompensated cirrhosis with HRS type 1
Exclusion Criteria	Improved renal function after central blood volume expansion; severe sepsis, pancreatitis, or shock; use of nephrotoxic drugs, history of coronary artery disease, obstructive cardiomyopathy, ventricular arrhythmia, or obliterative arterial disease of the limbs
Methods	Eligible patients were randomized to receive either intravenous (IV) noradrenaline infusion (0.5-3 mg/h) or IV terlipressin (0.5-2 mg/6h) for 2 weeks. IV albumin (20 g/day) was given to both groups until the end of the study period. Group noradrenaline received a starting dose of 0.5 mg/hour to achieve a MAP increase of ≥10 mmHg or a 1-hour urine output increase to >40 mL. If either goal was not achieved, the dose was increased by 0.5 mg/hour every 4 hours (maximum dose 3 mg/hour). IV furosemide infusion (0.001 mg/kg/min) was supplemented, if needed, to maintain a urine output of at least 40 mL/1 hour. Group terlipressin received a starting dose of 0.5 mg every 6 hours (IV bolus). If a significant (>25%) reduction in serum creatinine level was not observed at 3 days, the dose was increased by 0.5 mg every 6 hours, up to a (maximum dose 2 mg every 6 hours).
Duration	Intervention infusion: 2 weeks Trial duration: 3 years
Outcome Measures	Primary: complete response (i.e., reversal of HRS) Secondary: completion of 2 weeks of therapy, death
Baseline Characteristics		Noradrenaline (n= 21)	Terlipressin (n= 20)	p-Value
	Age, years	50.16 ± 8.57	55.05 ± 8.6	Not significant (NS)
	Male	84.2%	95.5%	NS
	Alcoholic cirrhosis	47.4%	86.4%	0.0167
	Child-Pugh score	11.21 ± 1.39	10.5 ± 1.99	NS
	Model for end-stage liver disease (MELD) score	27.9 ± 4.8	32.9 ± 5.9	0.0052
	Serum sodium, mEq/L	123.2 ± 29.8	122.5 ± 27.9	NS
	Creatinine, mg/dL	2.57 ± 1.30	3.54 ± 1.79	0.0412
	Urine sodium, mEq/L	19.1 ± 9.1	23.5 ± 18.6	NS
	Mean arterial pressure, mmHg	71.4 ± 18.7	75.3 ± 19.7	NS
Results	Endpoint	Noradrenaline (n= 21)	Terlipressin (n= 20)	p-Value
	HRS reversal	47.6%	45%	1.00
	Decrease in serum creatinine from baseline	3.1 ± 1.4 mg/dL to 2.2±1.3 mg/dL, (p= 0.028)	3.4 ± 1.6 mg/dL to 2.3±1.3 mg/dL, p= 0.035	-
	Increase in MAP	77.3 ± 8.6 mmHg to 103.4 ± 8.3 mmHg, p= 0.0001	76.8 ± 11.6 mmHg to 100±9.4 mmHg, p= 0.0001	-
	Duration of therapy (range), days	9.1 ± 2.8 (5 to 14)	8.3 ± 2.4 (5 to 14)	-
	Death during the study period	52.4%	55%	-
	A lower baseline MELD score was an independent predictor of response to treatment during multivariate analysis.
Adverse Events	Common Adverse Events: Noradrenaline (14.3% mild chest pain) vs. Terlipressin (10.0% mild chest pain, 10.0% loose stools, 5.0% abdominal pain)
	Serious Adverse Events: Death: Noradrenaline 52.4% (7 due to sepsis, 3 liver failure, 1 gastro-intestinal bleed) vs. Terlipressin 55% (8 due to sepsis, 2 liver failure, 1 acute tubular necrosis)
	Percentage that Discontinued due to Adverse Events: Noradrenaline (not disclosed) vs. Terlipressin (5.0% discontinued for loose stools on day 8)
Study Author Conclusions	Noradrenaline and terlipressin had similar response rates for the treatment of type 1 HRS. However, noradrenaline was associated with fewer adverse events. Therefore, noradrenaline can be used as an alternative to terlipressin in treatment of HRS in places where terlipressin is not available.
InpharmD Researcher Critique	The study is limited by its small sample size and lack of power analysis details, indicating that the study is likely insufficient to detect a difference between noradrenaline and terlipressin if one truly exists.

References:
[1] Goyal O, Sidhu SS, Sehgal N, Puri S. Noradrenaline is as Effective as Terlipressin in Hepatorenal Syndrome Type 1: A Prospective, Randomized Trial. J Assoc Physicians India. 2016;64(9):30-35.

Noradrenaline vs. Terlipressin in the Treatment of Type 2 Hepatorenal Syndrome: A Randomized Pilot Study
Design	Randomized, prospective, unblinded, pilot study N= 46
Objective	To evaluate the safety and efficacy of terlipressin and noradrenaline in the management of type 2 hepatorenal syndrome (HRS)
Study Groups	Terlipressin (n= 23) Noradrenaline (n= 23)
Inclusion Criteria	Cirrhosis with ascites with a serum creatinine (SCr) >1.5 mg/dL and <2.5 mg/dL, absence of shock, fluid losses, and treatment with nephrotoxic drug, 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 >500 mg/24 h
Exclusion Criteria	History of coronary artery disease, cardiomyopathy, ventricular arrhythmia, or obstructive arterial disease of limbs
Methods	Patients were randomized using a computer-generated randomization code with 46 envelopes split evenly between terlipressin (group A) and noradrenaline (group B). Patients and investigators were not blinded in this study, and all patients were treated with 20 grams of albumin/day alongside terlipressin or noradrenaline. Albumin was withheld if central venous pressure was more than 18 cm of saline. In group A, patients received terlipressin as an IV bolus of 0.5 mg every 6 hours. If a significant reduction in SCr was not observed in a 3-day period (defined as SCr ≥1 mg/dL), the dose of terlipressin was increased in a setwise fashion every 3 days to a maximum dose of 2 mg every 6 hours. Those in group B received noradrenaline continuous infusion at an initial dose of 0.5 mg/h with a goal to increase the mean arterial pressure (MAP) of at least 10 mmHg or increase in 4-hour urine output to more than 200 mL. When one of these goals weren't achieved, the noradrenaline was increased every 4 hours by 0.5 mg/h up to a maximum dose of 3 mg/h. All patients were hospitalized for 15 days for treatment, during which clinical and biochemical parameters were assessed at baseline and on day 15. During follow-up, patients were treated with diuretics and large-volume paracentesis as needed. If patients experienced a recurrence of HRS, they were treated with the same initial therapy, terlipressin or noradrenaline.
Duration	Between January 2009 to December 2011 Follow-up: until death or 3 months at regular intervals
Outcome Measures	Primary: SCr<1.5 mg/dL Secondary: Death or maximum 15 days of therapy
Baseline Characteristics		Terlipressin (n= 23)	Noradrenaline (n= 23)	p-value
	Age, years	45.8 ± 9.2	48.2 ± 10.5	0.363
	Male	20 (87%)	16 (69.6%)	0.284
	Spontaneous bacterial peritonitis	4 (17.4%)	3 (13%)	0.685
	Child-Pugh Score	10.0 ± 1.77	10.5 ± 2.35	0.561
	Model for end-stage liver disease (MELD) Score	21.3 ± 2.79	21.0 ± 3.28	0.536
	Serum bilirubin, mg/dL	2.38 ± 0.76	2.67 ± 0.86	0.261
	Blood urea nitrogen, mg/dL	82.7 ± 27.1	80.3 ± 24.3	0.754
	Serum creatinine, mg/dL	2.15 ± 0.21	2.05 ± 0.22	0.106
	Urinary sodium, mEq/mL	24.8 ± 10.5	23.7 ± 9.8	0.725
	Urine output/24 h, mL	717.1 ± 290	670.4 ± 260	0.598
	MAP, mmHg	65.3 ± 7.2	66.2 ± 9.5	0.652
	Plasma renin activity, ng/mL/h	35.2 ± 13.3	33.0 ± 12.3	0.482
	Plasma aldosterone concentration, pg/mL	1,615.6 ± 618.5	1,619.3 ± 668.3	0.985
	Both groups had a similar mean duration of treatment, with 8.6 ± 3.06 days for the terlipressin group and 8.7 ± 3.8 days for the noradrenaline group.
Results	Endpoint	Terlipressin (n=23)	p-value vs. day 1	Noradrenaline (n=23)	p-value vs. day 1
	Primary outcome: Serum creatinine, mg/dL, day 15	1.41 ± 0.58	0.000	1.27 ± 0.23	0.000
	Secondary outcome: Death by a 90-day follow-up	8 (34.7%)	-	9 (39.1%)^#	-
	Urine output, mL/day, day 15	1,287.2 ± 303.7	0.000	1,213.3 ± 312.7	0.000
	Urinary sodium, mEq/L, day 15	60.9 ± 10.2	0.000	62.4 ± 7.2	0.000
	Mean arterial pressure, mmHg, day 15	77.3 ± 5.3	0.000	76.3 ± 4.9	0.000
	Plasma renin activity, ng/mL/h, day 15	12.3 ± 6.9	0.000	10.6 ± 3.92	0.000
	Plasma aldosterone concentration, pg/mL, day 15	647.7 ± 269.0	0.000	597.7 ± 289.1	0.000
	Number of responders (reversal of HRS)	17 (73.9%)	-	17 (73.9%)*	-
	Recurrence of HRS	6 (35.5%)	-	7 (41.2%)	-
	Cost of treatment for 15 days, $	804	-	311^†	-
	^#p> 0.05; *p= 1.0 (group A vs. B); ^†p< 0.05 (group A vs. B)
Adverse Events	In the terlipressin group, two patients developed abdominal cramps and increased frequency of stools, one patient developed cyanosis of their toe, and another developed transient ventricular extrasystole. All of these adverse events were self-limiting. In the noradrenaline group, one patient experienced atypical chest pain with normal cardiac investigations. There were no major adverse events reported requiring therapy discontinuation or dose modification.
Study Author Conclusions	The randomized study results suggest that noradrenaline may be as effective and safe as terlipressin in the reversal of type 2 HRS but at a fraction of the cost. Baseline serum creatinine, urine output, and urinary sodium were found to be the predictors of response.
InpharmD Researcher Critique	Overall, this study is limited by its small sample size, location, and short follow-up though the authors note their results to be comparable to similar studies. The mean dose of terlipressin received was 2.06 ± 0.62 mg/day. In comparison, the mean dose of noradrenaline received was 0.51 ± 0.13 mg/h, which indicates that patients treated with terlipressin required higher doses of therapy compared to the noradrenaline group. Additionally, the cost analysis at a single center in India in 2013 may not present the US healthcare landscape well.

References:
[1] [1] Ghosh S, Choudhary NS, Sharma AK, et al. Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study. Liver Int. 2013;33(8):1187-1193. doi:10.1111/liv.12179