Evaluating Updated Hepatorenal

Syndrome Guidance: Is Now the Time

for Terlipressin?
Chaeyeong Jang, PharmD l PGY1 Pharmacy Resident
April 19, 2022
Speaker Disclosure 
 I have no actual or potential conflicts of interest to disclose
 Terlipressin is not an FDA-approved medication

2
Objectives
 Recall the diagnostic criteria for hepatorenal syndrome (HRS-AKI and HRS-CKD)
 Discuss the 2021 American Association for the Study of the Liver Diseases (AASLD) Guidance
updates for the management of hepatorenal syndrome
 Evaluate current literature on the use of terlipressin in the management of hepatorenal syndrome

3
 Hepatorenal Syndrome Pathophysiology

Portal hypertension

Splanchnic arterial vasodilation

Arterial hypovolemia

Activation of vasoconstrictor factors

Renal hypoperfusion
4

Portal Venous Pressure. Science Direct.

Hepatorenal Syndrome Pathophysiology
Portal hypertension Cirrhosis-associated
cardiomyopathy

Splanchnic arterial vasodilation

Systemic Decreased cardiac

Arterial hypovolemia
inflammation output

Activation of vasoconstrictor factors

Renal hypoperfusion

5
 HRS Background

Definition: renal dysfunction in chronic liver disease

Diagnosis of exclusion

Incidence: 27%-53% of patients with cirrhosis

30-day mortality: 29%-44%

Risk factors: hyponatremia, high plasma activity, liver size, severity of ascites
6
Biggins SW. Hepatology. 2021;74(2):1014-1048.
 HRS Criteria
Diagnostic Criteria
Cirrhosis with ascites
Acute kidney disease (AKI) or chronic kidney disease (CKD) (as defined on the next slide)
No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with
albumin infusion
Absence of shock
No current or recent use of nephrotoxic drugs (antibiotics, contrast, NSAIDs)
No signs of structural kidney injury as indicated by proteinuria (>500 mg/day), microhematuria
(>50 RBCs/high-power yield), and/or abnormal renal ultrasonography

7
Gupta K. World J Gastroenterol. 2021;27(26):3984-4003.
Biggins SW. Hepatology. 2021;74(2):1014-1048.
 HRS Classifications
Prior Definitions
HRS type 1: rapid renal injury defined by 2x
increase from baseline serum creatinine (SCr)
to a value >2.5 mg/dL or 50% reduction in
creatinine clearance
HRS type 2: moderate renal failure with
creatinine ranging from 1.5 to 2.5 mg/dL that
occurs progressively
Gupta K. World J Gastroenterol. 2021;27(26):3984-4003.
Biggins SW. Hepatology. 2021;74(2):1014-1048.
Current Definitions
HRS-AKI: patients with HRS criteria with an
increase in SCr >0.3 mg/dL within 48 hours
or >50% increase from baseline SCr within
the last 7 days*
HRS-CKD: patients with HRS criteria and
estimated GFR <60 mL/min/
1.73 m2 for >3 months in absence of other
potential causes of kidney disease
*Definitions of AKI according to the International Club of Ascites
(ICA) updated in 2015
8
 HRS Classifications
Prior Definitions
HRS type 1: rapid renal injury defined by 2x
increase from baseline serum creatinine (SCr)
to a value >2.5 mg/dL or 50% reduction in
creatinine clearance
HRS type 2: moderate renal failure with
creatinine ranging from 1.5 to 2.5 mg/dL that
occurs progressively
Gupta K. World J Gastroenterol. 2021;27(26):3984-4003.
Biggins SW. Hepatology. 2021;74(2):1014-1048.
Current Definitions
HRS-AKI: patients with HRS criteria with an
increase in SCr >0.3 mg/dL within 48 hours
or >50% increase from baseline SCr within
the last 7 days*
HRS-CKD: patients with HRS criteria and
estimated GFR <60 mL/min/
1.73 m2 for >3 months in absence of other
potential causes of kidney disease
*Definitions of AKI according to the International Club of Ascites
(ICA) updated in 2015
9
Assessment Question #1
 Which of the following patients with cirrhosis and ascites, without evidence of shock, and no
improvement after an albumin challenge would meet the criteria for HRS-AKI?
A) A patient with SCr 0.6 increase over the last 24 hours and received IV contrast one day ago
B) A patient with SCr 2.2 increased from baseline SCr 1.3 over the last 3 days and has spontaneous
bacterial peritonitis
C) A patient with SCr 0.2 increase over the last 48 hours and has gastric varices
D) A patient with SCr 1.8 increased from baseline SCr 1.4 over the last 5 days and has normal renal
ultrasound 

10
Assessment Question #1
 Which of the following patients with cirrhosis and ascites, without evidence of shock, and no
improvement after an albumin challenge would meet the criteria for HRS-AKI?
A) A patient with SCr 0.6 increase over the last 24 hours and received IV contrast one day ago
B) A patient with SCr 2.2 increased from baseline SCr 1.3 over the last 3 days and has
spontaneous bacterial peritonitis
C) A patient with SCr 0.2 increase over the last 48 hours and has gastric varices
D) A patient with SCr 1.8 increased from baseline SCr 1.4 over the last 5 days and has normal renal
ultrasound 

11
 AASLD 2021 Guidance Update on HRS-AKI
AASLD 2012 Practice
Guidelines
-Albumin + vasoconstrictor
-Midodrine + octreotide
-Norepinephrine
-Response to therapy not defined
-Duration not defined
Runyon BA. Hepatology. 2013;57(4):1651-1653. Biggins
SW. Hepatology. 2021;74(2):1014-1048.
AASLD 2021 Practice
Guidance
-Albumin + vasoconstrictor
-Preferred: terlipressin
-Alternative: norepinephrine
-Can consider: midodrine + octreotide
-Response to therapy: SCr ↓ to <1.5 or
return to <0.3 of baseline ~14 days max
-Discontinue therapy: SCr >the
pretreatment level ~4 days with the max
tolerated vasoconstrictor
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 Pending FDA approval
Terlipressin
 Mechanism: V1 and V2 receptor agonist
⎻V1 receptors cause splanchnic and extrarenal vasoconstriction
⎻V2 receptors increase water reabsorption in the kidneys
 Dosing: IV bolus or continuous IV infusion 2 mg/day, increased q24-48 hr up to 12 mg/day until
creatinine decrease
 Duration: up to 14 days or longer
 Adverse events:
 Common: diarrhea, abdominal pain
 Serious: peripheral ischemia, dysrhythmia, pulmonary edema
 As of February 2022, FDA has issued a Complete Response Letter regarding the New Drug
Application for terlipressin and required an inspection of the new facility for terlipressin

13
Biggins SW. Hepatology. 2021;74(2):1014-1048.
Magan AA. World J Gastroenterol. 2010;16(41):5139-5147.
 Other Vasoconstrictors
Norepinephrine
• Alpha-1 adrenergic receptor agonist
• Continuous IV infusion starting at 0.5 mg/hr to achieve an increase in MAP
of at least 10 mm Hg or an increase in UOP >200 mL/4 hr; increase q4h in
increments of 0.5 mg/hr up to a max of 3 mg/hr

Midodrine
• Alpha-1 adrenergic receptor agonist
• 5 to 15 mg PO q8h

Octreotide
• Somatostatin analog
• 100 to 200 mcg q8h or 50 mcg/hr IV
14

Biggins SW. Hepatology. 2021;74(2):1014-1048.

 Albumin 25%
 Mechanism: expands volume; deactivates vasoconstrictor systems; increases arterial pressure; may
counteract the decrease in cardiac output; may lower serum bile acid concentration; may have
benefits from antioxidant and anti-inflammatory properties
 Dosing:
 Albumin challenge for HRS: 1 g/kg/day x 2 days with max 100 g/day
 Treatment: IV infusion 1 gm/kg on day 1 of vasoconstrictor therapy, followed by 20-50 gm/day for
the duration of therapy

15

Biggins SW. Hepatology. 2021;74(2):1014-1048.

 Renal Replacement Therapy for HRS-AKI
 Renal replacement therapy
 The optimal timing for initiation has not been studied
 Usually reserved as a bridge to liver transplant
 Extremely high mortality rates in patients not listed for liver transplant who receive RRT
regardless of the etiology of the AKI

16
Biggins SW. Hepatology. 2021;74(2):1014-1048.
Assessment Question #2
 Which of the following is the correct update regarding HRS-AKI treatment included in the AASLD
2021 Guidance?
A) Norepinephrine and albumin are the first-line therapy for treatment of HRS-AKI.
B) Albumin should only be considered for treatment with terlipressin.
C) Terlipressin and norepinephrine are similar in terms of their efficacy.
D) A trial of midodrine and octreotide may be considered as last-line therapy.

17
Assessment Question #2
 Which of the following is the correct update regarding HRS-AKI treatment included in the AASLD
2021 Guidance?
A) Norepinephrine and albumin are the first-line therapy for treatment of HRS-AKI.
B) Albumin should only be considered for treatment with terlipressin.
C) Terlipressin and norepinephrine are similar in terms of their efficacy.
D) A trial of midodrine and octreotide may be considered as last-line therapy.

18
 HRS Treatment Timeline

Angeli REVERSE El-Desoki

1999 Singh 2012 2016 2021
(M+O vs. (Terlipressin (Terlipressin (Terlipressin
dopamine) vs. NE) vs. placebo) vs. M+O)

Guevara Cavallin Arora 2020 CONFIRM

2003 2015 (Terlipressin 2021
(Ornipressin (Terlipressin vs. NE) (Terlipressin
vs. placebo) vs. M+O) vs. placebo)

NE = norepinephrine
M+O = midodrine and octreotide
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 Terlipressin vs. Placebo Trials: REVERSE
 Randomized, prospective, double-blind, placebo-controlled
 Objective: to evaluate the efficacy and safety of terlipressin plus albumin vs placebo plus albumin for HRS-1
patients
 Drug administration: Terlipressin 1 mg IV over 2 min q6hr + albumin
 Primary outcome: HRS resolution at day 14 defined as SCr <1.5 mg/dl on 2 occasions, at least 40 hr apart, without
RRT or liver transplant

Outcomes Terlipressin (n = 97) Placebo (n = 99) P-value

Primary outcome 19 (19.6%) 13 (13.1%) 0.22
Change in SCr from -1.1 -0.6 <0.001
baseline (mg/dl)
90-day survival 56 (57.7%) 54 (54.5%) 0.60

20

Boyer TD. Gastroenterology. 2016;150(7):1579-1589.e2.

 Terlipressin vs. Placebo Trials: CONFIRM
 Randomized, prospective, double-blind, placebo-controlled
 Objective: to confirm the efficacy and safety of terlipressin plus albumin, as compared with placebo plus albumin,
in adults with cirrhosis and HRS-1
 Drug administration: Terlipressin 1 mg IV over 2 min q5.5-6.5hr + albumin
 Primary outcome: HRS reversal with two consecutive SCr <1.5 mg/dl at least 2 hr apart up to day 14 and survival
without RRT for at least an additional 10 days

Outcomes Terlipressin (n = 199) Placebo (n = 101) P-value

Primary outcome 63 (32%) 17 (17%) 0.006
90-day mortality 101 (51%) 45 (45%) Not reported

21

Wong F. N Engl J Med. 2021;384(9):818-828.

 Terlipressin vs. Placebo Trials Summary
REVERSE
Included: HRS-1
N = 196
Terlipressin intermittent bolus
Primary outcome: SCr <1.5 mg/dl x 2, at least
40 hr apart, without RRT or transplant at day
14
Adverse events:
-Any: Terlipressin 96.8% vs. Placebo 92.7%
-Pulmonary edema:
Terlipressin 10.8% vs. Placebo 7.4%
Terlipressin is effective in SCr improvement for patients with HRS-AKI
Boyer TD. Gastroenterology. 2016;150(7):1579-1589.e2.
Wong F. N Engl J Med. 2021;384(9):818-828.
CONFIRM
Included: HRS-1
N = 300
Terlipressin intermittent bolus
Primary outcome: SCr <1.5 mg/dl x 2, at least
2 hr apart, up to day 14 days and survival
without RRT for an additional 10 days
Adverse events:
-Any: Terlipressin 88% vs. Placebo 89%
-Respiratory failure:
Terlipressin 10% vs. Placebo 3%
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 Terlipressin vs. Norepinephrine Trials: Singh 2012
 Randomized, open-label, single-center
 Objective: to evaluate the safety and efficacy of terlipressin and norepinephrine (NE) in the treatment of HRS
 Drug administration:
 Terlipressin bolus 0.5 mg q6h with increase q3days to achieve SCr reduction <1 mg/dl (max 2 mg q6h)
 NE continuous infusion standard dosing
 Primary outcome: HRS reversal = SCr <1.5 mg/dl

Outcomes Terlipressin (n = 23) NE (n = 23) P-value

Primary outcome 9 (39.1%) 10 (43.4%) 0.764

Serum creatinine Baseline Day 15 P-value Baseline Day 15 P-value -

(mg/dl) 3.26 1.67 0.002 2.82 1.55 0.000 -
30-day survival 7 8 -
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Singh V. J Hepatol. 2012;56(6):1293-1298.
 Terlipressin vs. Norepinephrine Trials: Arora 2020
 Randomized, open-label, single-center
 Objective: to compare the efficacy of continuous infusion of terlipressin with NE in the management of HRS-
AKI in patients with acute on chronic liver failure (ACLF)
 Drug administration:
 Terlipressin continuous infusion starting at 2 mg/24h
 NE continuous infusion standard dosing
 Primary outcome: reversal of HRS-AKI at day 14
 Complete response = return of SCr to within 0.3 mg/dL of baseline

Outcomes Terlipressin (n = NE (n = 60) P-value

60)
Primary outcome 24 (40%) 10 (16.7%) 0.004
28-day survival 29 (48.3%) 12 (20%) 0.001
Dialysis requirement 34 (56.7%) 48 (80%) 0.006 24

Arora V. Hepatology. 2020;71(2):600-610.

 Terlipressin vs. Norepinephrine Trials Summary
Singh 2012
Inclusion criteria: cirrhosis with ascites with
SCr >2.5 mg/dl
Average patient terlipressin group: 51-year-old
male with cirrhosis due to alcohol, MELD
score 26, baseline SCr 3.27 mg/dl
N = 46
Terlipressin intermittent bolus
Primary outcome: reduction in SCr
mg/dl
NE is noninferior to terlipressin
Singh V. J Hepatol. 2012;56(6):1293-1298.
Arora V. Hepatology. 2020;71(2):600-610.
Arora 2020
Inclusion criteria: ACLF and ICA-AKI stage
≥II
Average patient in terlipressin group: 40-year-
old male with cirrhosis due to alcohol, MELD
score 33, baseline SCr 1.79 mg/dl
N = 120
Terlipressin continuous infusion
<1.5
Primary outcome: return to SCr baseline <0.3
mg/dl
Terlipressin is superior to NE
25
 Midodrine + Octreotide vs. Terlipressin: Cavallin 2015
 Multicenter, randomized
 Objective: to compare terlipressin plus albumin vs. midodrine and octreotide plus albumin in the treatment of
HRS in patients with cirrhosis
 Drug administration:
 Terlipressin continuous infusion starting at 3 mg/24hr
 Midodrine PO starting at 7.5 mg q8hr and octreotide SQ starting at 100 mcg q8hr
 Primary outcome:
 Complete response: a decrease in SCr to <1.5 mg/dl

Outcomes Terlipressin Midodrine/octreotide P-value

(n = 27) (n = 21)
Primary outcome 55.5% 4.8% <0.001
90-day survival 59% 43% Nonsignificant
26

Cavallin M. Hepatology. 2015;62(2):567-574.

 Midodrine + Octreotide vs. NE: El-Desoki 2021
 Parallel-group, open-label, randomized
 Objective: to compare the efficacy of midodrine/octreotide to that of norepinephrine for the treatment of patients
with HRS
 Drug administration:
 Norepinephrine continuous infusion starting at 0.5 mg/h (max 3 mg/h)
 Midodrine PO 5 mg TID (max 12.5 mg TID) plus octreotide 100 mcg/6hr SQ (max 200 ug/6hr)
 Primary outcome: full response defined as the return of SCr to <0.3 mg/dl of the baseline up to 10 days

Outcomes Norepinephrine Midodrine/octreotide P-value

(n = 27) (n = 26)
Primary outcome 15 (57.6%) 5 (20%) 0.006
30-day survival 11 (42.3%) 6 (24%) 0.166

27
El-Desoki Mahmoud EI. Front Pharmacol.
2021;12:675948.
 Midodrine and Octreotide Trials Summary
Cavallin 2015
Included: patients with cirrhosis, type 1 or
severe type 2 HRS
N = 48
Terlipressin continuous infusion vs.
midodrine/octreotide
Primary outcome: decrease in SCr to
mg/dl
Terlipressin is more effective than
midodrine/octreotide
El-Desoki Mahmoud EI. Front Pharmacol. 2021;12:675948.
Cavallin M. Hepatology. 2015;62(2):567-574.
El-Desoki 2021
Included: patients with cirrhosis, ascites, and
HRS-AKI based on the 2015 ICA criteria
N = 53
NE vs. midodrine/octreotide
<1.5 Primary outcome: the return of SCr to <0.3
mg/dl of the baseline at the end of the
treatment
NE is more effective than
midodrine/octreotide
28
Assessment Question #3
 According to the primary literature, which of the following is likely to be the biggest benefit
provided by terlipressin for patients with HRS-AKI?
A) Decreased serum creatinine
B) Lower 90-day mortality
C) Improved liver function
D) Delay starting renal replacement therapy

30
Assessment Question #3
 According to the primary literature, which of the following is likely to be the biggest benefit
provided by terlipressin for patients with HRS-AKI?
A) Decreased serum creatinine
B) Lower 90-day mortality
C) Improved liver function
D) Delay starting renal replacement therapy

31
Conclusion
 HRS type 1 has been newly termed as HRS-AKI to allow early diagnosis
 AASLD 2021 Guidance Update on HRS-AKI includes
 Terlipressin plus albumin as the preferred therapy
 Norepinephrine plus albumin is an alternative when terlipressin is unavailable
 Midodrine and octreotide plus albumin as the last-line therapy
 REVERSE and CONFIRM trials showed the efficacy of terlipressin plus albumin in reversing HRS-
AKI when compared to placebo
 Primary literature supports terlipressin’s impact on decreasing serum creatinine but lacks mortality
benefits

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33
References
 Portal Venous Pressure. Science Direct. Accessed April 7 2022. https://www.sciencedirect.com/topics/neuroscience/portal-venous-pressure
 Biggins SW, Angeli P, Garcia-Tsao G, et al. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance
by the American Association for the Study of Liver Diseases. Hepatology. 2021;74(2):1014-1048. doi:10.1002/hep.31884

 Gupta K, Bhurwal A, Law C, et al. Acute kidney injury and hepatorenal syndrome in cirrhosis. World J Gastroenterol. 2021;27(26):3984-4003. doi:10.3748/wjg.v27.i26.3984
 Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis
2012. Hepatology. 2013;57(4):1651-1653. doi:10.1002/hep.26359

 Magan AA, Khalil AA, Ahmed MH. Terlipressin and hepatorenal syndrome: what is important for nephrologists and hepatologists. World J Gastroenterol. 2010;16(41):5139-5147.
doi:10.3748/wjg.v16.i41.5139

 Boyer TD, Sanyal AJ, Wong F, et al. Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal
Syndrome Type 1. Gastroenterology. 2016;150(7):1579-1589.e2. doi:10.1053/j.gastro.2016.02.026

 Wong F, Pappas SC, Curry MP, et al. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. N Engl J Med. 2021;384(9):818-828.
doi:10.1056/NEJMoa2008290

 Singh V, Ghosh S, Singh B, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study. J Hepatol. 2012;56(6):1293-1298.
doi:10.1016/j.jhep.2012.01.012

 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

 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

 El-Desoki Mahmoud EI, Abdelaziz DH, Abd-Elsalam S, Mansour NO. Norepinephrine is More Effective Than Midodrine/Octreotide in Patients With Hepatorenal Syndrome-Acute
Kidney Injury: A Randomized Controlled Trial. Front Pharmacol. 2021;12:675948. Published 2021 Jul 2. doi:10.3389/fphar.2021.675948

34
Evaluating Updated Hepatorenal
Syndrome Guidance: Is Now the Time
for Terlipressin?
Chaeyeong Jang, PharmD l PGY1 Pharmacy Resident
April 19, 2022