What does the literature say regarding terlipressin for the treatment of hepatorenal syndrome (HRS) compared to other vasoactive agents (e.g., norepinephrine, vasopressin)?

Literature evaluation of terlipressin for the treatment of hepatorenal syndrome (HRS) compared to other vasoactive agents (e.g., norepinephrine, vasopressin) on clinically relevant outcomes (e.g., reversal of HRS, mortality, recurrence of HRS, rates of renal replacement therapy compared to SOC, hospital LOS)

Comment by InpharmD Researcher

The 2021 updated AASLD guidelines recommend using terlipressin as the first-line agent in combination with albumin for the treatment of hepatorenal syndrome (HRS)-acute kidney injury (AKI). Norepinephrine may be administered if terlipressin is unavailable. Multiple meta-analyses provide direct and indirect comparisons between terlipressin and norepinephrine, generally revealing no significant differences in mortality, reversal of HRS, recurrence of HRS, or renal function change. However, terlipressin occasionally was found to improve the reversal of HRS or mortality. A 2020 RCT also observed terlipressin to be associated with a significantly lower requirement of renal replacement therapy than norepinephrine in patients with acute on chronic liver failure. While no significant difference between terlipressin and other vasoactive drugs was noted for the incidence of serious adverse events, norepinephrine was found to be associated with a lower risk of overall or any non-serious adverse events than terlipressin. When compared to octreotide plus midodrine, meta-analyses consistently reported higher rates of HRS reversal in the terlipressin groups; however, terlipressin’s mortality benefits remain inconsistent. Other secondary outcomes, such as health-related quality of life and length of stay remain unexamined in medical literature.

Background

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 hepatorenal syndrome (HRS)-acute kidney injury (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. [1]

A recent meta-analysis that compared the effectiveness of inpatient treatments for hepatorenal syndrome included 26 randomized controlled trials (RCTs; N= 1,736). Terlipressin improved the reversal of HRS compared to midodrine + octreotide (72.5 more reversals per 1,000; 95% CI > 198 to <12) and norepinephrine (30.4 more reversals per 1,000; 95% CI > 83 to <14.6). Terlipressin also reduced mortality compared with midodrine + octreotide (194 fewer deaths per 1,000; 95% CI <352 to > 36) and norepinephrine (66 fewer deaths per 1,000; 95% <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. [2]

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. However, for the outcome of recovery from HRS, albumin plus midodrine plus octreotide regimen (hazard ratio [HR] 0.04; 95% credible interval [CrI] 0.00 to 0.25) and albumin plus octreotide (HR 0.26; 95% CrI 0.07 to 0.80) had significantly lower rates of recovery compared to albumin plus terlipressin. Yet, the difference between albumin plus norepinephrine and albumin plus terlipressin was insignificant (HR 0.85; 95% 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. [3]

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 hepatorenal syndrome. Based on data available from 6 RCTs, the hepatorenal reverse rates were 39.8% with terlipressin compared to 15.4% with placebo (OR 4.96, 95% CI 2.23 to 11.0, p= 0 .001, I2 = 57%). Renal function change, evaluated in 5 studies, was achieved in 50.0% and 23.6% of terlipressin and placebo patients, respectively (risk ratio [RR] 6.48, 95% CI 2.17 to 19.35, p= 0.0008). Based on data from 7 RCTs, the overall rate of mortality was 45.2% in the terlipressin group and 55.7% in the placebo group (RR 0.63, 95% CI 0.44 to 0.91, p= 0.01, I2= 36%). No significant difference was reported between terlipressin and placebo with respect to hepatorenal syndrome recurrence and adverse events based on evaluable studies. [4]

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 hepatorenal syndrome 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%). [4]

In 1 study comparing terlipressin and octreotide, renal function improved in both groups, but the terlipressin group had a greater hepatorenal syndrome reverse rate than the octreotide group (55% vs 20%, p= 0 .01). Incidence rate of hepatorenal syndrome recurrence and adverse events were not reported in this study. Another RCT compared terlipressin to dopamine, finding improvement in 24-hour urine output and plasma renin activity in both groups, as well as similar one-month mortality. One RCT compared terlipressin with the combination of octreotide and midodrine, finding that terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in a reversal of renal failure (55.5% vs 4.8%, p <0 .001) and renal function improvement (70.4% vs 28.6%, p= 0 .01) in hepatorenal syndrome patients. [4]

A subgroup analysis between terlipressin and placebo for type 1 hepatorenal syndrome found a higher hepatorenal syndrome reverse rate (RR 4.92, 95% CI 1.60 to 15.09, p = 0 .005, I2 = 70%) and higher renal function change rate (RR 3.77, 95% CI 1.54 to 9.27, p = 0 .004, I2 = 52%) compared to placebo, with similar rates of hepatorenal syndrome recurrence, mortality, and adverse events. Based on type 1 hepatorenal syndrome 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. [4]

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 hepatorenal syndrome, 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 hepatorenal syndrome, 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. [5]

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 hepatorenal syndrome. A total of 13 randomized control trials (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 (odds ratio [OR] 0.93, 95% CI 0.43 to 1.98) or reversing hepatorenal syndrome (OR 0.99, 95% CI 0.43 to 2.33). Additionally, low-quality evidence found no significant difference between dopamine plus furosemide and terlipressin in improving short-term mortality (OR 1.00, 95% CI 0.18 to 5.67). Compared to midodrine plus octreotide, terlipressin was not associated with short-term mortality benefits based on very low-quality evidence (OR 1.14, 95% CI 0.39 to 3.33). However, moderate-quality evidence indicates significantly higher ORs of reversing hepatorenal syndrome in those receiving terlipressin than midodrine plus octreotide (OR 26.25, 95% CI 3.07-225.21). 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 hepatorenal syndrome. Moderate-quality evidence supports the use of terlipressin over midodrine plus octreotide for the reversal of hepatorenal syndrome. [6]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

Please see Tables 1-5 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:

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:

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:

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:

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

Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial
Design	Randomized controlled trial N= 49
Objective	To compare terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome (HRS) in patients with cirrhosis
Study Groups	Terlipressin with albumin (n= 27) Midodrine and octreotide plus albumin (n= 22)
Inclusion Criteria	Cirrhosis diagnosed by liver biopsy or clinical, biochemical, ultrasound, and/or endoscopic findings; type 1 or severe type 2 HRS as defined by the International Ascites Club criteria of serum creatinine (SCr) level >2.5 mg/dL; age 18-75 years
Exclusion Criteria	Hepatocellular carcinoma outside Milan criteria; septic shock; cardiac or respiratory failure; stroke; coronary artery disease
Methods	Eligible patients were randomized into one of two groups, the terlipressin with albumin (TERLI) group or the midodrine and octreotide plus albumin (MID/OCT) group. For both the TERLI and MID/OCT groups, patients received IV albumin at a dose of 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. In the TERLI group, 27 patients received intravenous (IV) terlipressin at an initial dose of 3 mg/24 hours. The response to treatment was evaluated every 48 hours and if the SCr decreased by < 25% of pretreatment value, the dose was progressively increased to 12 mg/24 hours. In the MID/OCT group, 22 patients received midodrine orally at an initial dose of 7.5 mg every 8 hours. These 22 patients also received octreotide subcutaneously with an initial dose of 100 mcg every 8 hours. If the SCr decreased by < 25%, midodrine was increased to a maximum of 12.5 mg every 8 hours and octreotide was increased to 200 mcg every 8 hours. Treatment in both groups were administered until SCr decreased to ≤ 133 μmol/L (≤ 1.5 mg/dL) or for a maximum duration of 14 days. After a complete or incomplete response, treatment was maintained for 24 hours after. A complete response was defined as a decrease in SCr to ≤ 133 μmol/L (≤ 1.5 mg/dL). A partial response was defined as ≥ 50% decrease in SCr, while a no response was defined as < 50% decrease in SCr. If an adverse effect developed (angina, arrhythmia, peripheral ischemia, severe abdominal pain), treatment was withheld.
Duration	Diagnosed with cirrhosis and HRS between 2008 to 2012 Treatment duration: up to 14 days Follow up: up to 3 months, until liver transplantation, or death
Outcome Measures	Primary outcome: complete response at completion of treatment Secondary outcomes: survival at 1 and 3 months
Baseline Characteristics		TERLI (n= 27)	MID/OCT (n= 21)
	Age, years	60 ± 12	65 ± 12
	Male	21	11
	HRS type 1	25	19
	HRS type 2	2	2
	Viral etiology	10	8
	HRS precipitated by bacterial infections	16	11
	Mean arterial pressure, mm Hg	76.8 ± 10.0	75.2 ± 8.1
	Heart rate, bpm	77.8 ± 11.5	81.1 ± 13.4
	INR	2.0 ± 0.5	1.7 ± 0.5
	Serum bilirubin, µmol/L	201.1 ± 268.3	187.8 ± 252.4
	Serum creatinine, µmol/L	326.8 ± 88.4	343.9 ± 187.5
	Aspartate aminotransferase, U/L	89.0 ± 73.8	68.6 ± 54.6
	Alanine aminotransferase, U/L	43.7 ± 24.6	34.9 ± 31.5
	Gamma-glutamyl transferase, U/L	69.6 ± 70.9	81.7 ± 80.6
	Model for End-Stage Liver Disease	31.2 ± 5.8	29.1 ± 8.1
	Model for End-Stage Liver Disease and Serum Sodium Concentration	32.7 ± 4.4	29.8 ± 6.9
Results	Endpoint	TERLI (n= 27)	MID/OCT (n= 21)	p-Value
	Complete response to treatment	15 (55.5%)	1 (4.8%)	p< 0.001
	Complete or partial response to treatment	19 (70.4%)	6 (28.6%)	p= 0.01
	Reduction of SCr in all responders	323.2 ± 91.1 to 121.6 ± 30.0 μmol/L	332.8 ± 85.1 to 159.8 ± 15.9 μmol/L	p= not significant
	Reduction of SCr in all patients	326.8 ± 88.4 μmol/L to 221.1 ± 162.8 μmol/L	343.9 ± 187.5 to 326.4 ± 273.2 μmol/L	p= 0.035
	Survival at 1 month	19 (70%)	14 (67%)	p= not significant
	Survival at 3 months	16 (59%)	9 (43%)	p= not significant
Adverse Events	Common Adverse Events: abdominal pain (7.4% TERLI vs. 14.3% MID/OCT), diarrhea (7.4% vs. 0), arrhythmia (0 vs. 9.5%), circulatory overload (3.7% vs. 4.8%), arterial hypertension (3.7% vs. 0), stroke (3.7% vs. 0)
	Serious Adverse Events: N/A
	Percentage that Discontinued due to Adverse Events: One patient in the TERLI group discontinued due to stroke (3.7%); this patient eventually died due to stroke. One patient in the MID/OCT group discontinued due to grade 4 bradycardia (4.8%).
Study Author Conclusions	The results of this randomized, comparative study indicate that administration of terlipressin plus albumin is more effective in improving both renal function and survival in patients with cirrhosis and HRS compared with midodrine and octreotide plus albumin. Thus, terlipressin plus albumin should currently be considered the first choice for management of patients with cirrhosis and HRS.
InpharmD Researcher Critique	Nonresponders in this study were permitted to receive rescue treatment, including the ability to cross from one study drug regimen to another. Thus, survival at 1 and 3 months with each individual agent may not have been accurately assessed in this study design.

References:

Cavallin M, Kamath PS, Merli M, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial. Hepatology. 2015;62(2):567-574. doi:10.1002/hep.27709