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Deepali Dixit, PharmD, BCPS, BCCCP, FCCM, is a clinical associate professor of pharmacy practice and administration at the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, in Piscataway.
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Terlipressin Has Been Shown to Improve HRS Reversal Outcomes, but Concerns Remain
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Pharmacy Practice in Focus: Health SystemsMarch 2024
Volume 13
Issue 2
The drug is the first FDA-approved agent for treating hepatorenal syndrome.
Image credit: Rasi | stock.adobe.com
Acute kidney injury (AKI) is one of the most frequent complications for patients with advanced cirrhosis. Volume depletion is the most common etiology for AKI, with hepatorenal syndrome (HRS) the second most common cause in these patients.1 Hepatorenal syndrome–acute kidney injury (HRS-AKI), formally known as hepatorenal syndrome type 1 (HRS-1), is a potentially reversible form of AKI in patients with decompensated cirrhosis and ascites.1,2 Studies indicate that up to 50% of patients with advanced cirrhosis require hospitalization because of cirrhosis complications and may experience AKI as a result. Patients with HRS-AKI have a poor prognosis, with an estimated survival rate of 20% to 40% over the course of 3 months.3,4
Although the exact pathogenesis of HRS-AKI is not fully understood, it is believed to result from various factors. HRS-AKI is characterized by advanced liver disease with splanchnic and systemic vasodilation triggered by portal hypertension. An increase in cardiac output and a decrease in systemic vascular resistance occur as the disease progresses, which activates the reninangiotensin and sympathetic nervous systems.5 This results in renal afferent vasoconstriction, leading to a decline in kidney perfusion, reduced glomerular filtration rate, decreased mean arterial pressure, and decreased effective blood volume.5
Diagnostic Criteria and Management of HRS-AKI
Early identification and treatment of AKI in patients with cirrhosis are important to improve clinical outcomes.6,7 For HRS-AKI, AKI is used as a diagnostic parameter. AKI is defined as an increase in serum creatinine of at least 0.3 mg/dL within 48 hours or a 50% or more increase from baseline. This new definition considers even small acute increases in serum creatinine concentrations.6,7
Liver transplantation is the only effective cure for cirrhosis. However, there are pharmacological treatment options that can serve as a bridge to definitive therapy with liver transplantation. As vasodilation plays a crucial role in the development of HRS-AKI, vasoconstrictors and albumin have been studied as treatments.8,9 Data from randomized clinical trials and a meta-analysis have demonstrated that treatment with vasoconstrictors and albumin is effective in improving splanchnic vasoconstriction and renal function, reducing portal pressures, and reducing the risk of mortality in patients with HRS-AKI, compared with albumin alone or no intervention.10
The vasoconstrictor options include terlipressin (Terlivaz; Mallinckrodt), norepinephrine (Levophed; Pfizer), and the combination of octreotide (Sandostatin; Novartis) and midodrine, concomitantly with albumin infusion. Norepinephrine has been shown to cause vasoconstriction with minimal effects on the myocardium, and it corrects the low systemic vascular resistance associated with HRS-AKI.2,3 Midodrine, on the other hand, causes systemic vasoconstriction that, in turn, improves systemic blood pressure and enhances renal perfusion pressure. Additionally, octreotide counteracts the effects of several splanchnic vasodilators and decreases the discrepancy in intravascular volume and arterial vasodilation. Midodrine, octreotide, and albumin can be administered in the general hospital unit but have limited benefits in reversing HRS-AKI. If patients do not respond to this therapy, they may need to be transferred to the intensive care unit (ICU) for vasopressor infusions, requiring ICU monitoring and possibly a central venous catheter.
Albumin is the standard of care for treating HRS-AKI; it should be used with vasoconstrictors. Albumin serves multiple roles in the management of HRS, such as expanding plasma volume and improving cardiac inotropic effects. The dose of albumin is 40 to 50 g/d and is continued for the duration of therapy along with vasoconstrictors.
In 2021, the phase 3 CONFIRM trial (NCT02770716) reported treatment outcomes with terlipressin compared with placebo in patients with HRS-AKI. In 2022, terlipressin became the first FDA-approved agent indicated to improve kidney function in adults with HRS with a rapid reduction in kidney function.11 Terlipressin, a synthetic vasopressin receptor agonist, has been approved for use in Europe for treatment of HRS-AKI for more than 30 years.11 Terlipressin is believed to improve renal blood flow in HRS by decreasing portal hypertension and blood flow in portal vessels while increasing effective arterial volume and mean arterial pressure. This addresses abnormalities in systemic and renal hemodynamics.11
In CONFIRM, 300 patients with HRS-AKI were randomly assigned to terlipressin 1 mg or placebo every 6 hours; on day 4, eligible patients without a decrease in serum creatinine of 30% or more received 2 mg every 6 hours. The administration of albumin was strongly recommended in all patients and was given to 83% of patients treated with terlipressin and 91% of patients treated with placebo. During the study, the primary efficacy end point verified reversal of HRS and was defined as 2 consecutive serum creatinine measurements of 1.5 mg/dL or less at least 2 hours apart up to day 14 and survival without renal replacement therapy (RRT) for at least an additional 10 days. Secondary efficacy end points included HRS reversal (serum creatinine ≤ 1.5 mg/dL while receiving assigned treatment), the durability of HRS reversal (HRS reversal without RRT to day 30), HRS reversal among patients with systemic inflammatory response syndrome, and verified reversal of HRS without recurrence by day 30. Terlipressin improved the primary and secondary efficacy end points except for verified HRS reversal without recurrence through day 30. Although not statistically compared between groups in the study, the safety outcomes showed that patients treated with terlipressin experienced higher incidences of death by 90 days and respiratory failure, as well as lower incidence of liver transplant by 90 days.3,4
Notably, there is ongoing controversy surrounding the use of terlipressin in treating HRS because of the study supporting its FDA approval and several guidelines that endorse its usage. The results of CONFIRM also have contributed to the debate, and current recommendations on using terlipressin in HRS are being scrutinized. For example, concern has been expressed regarding the risk of death and the lower rate of liver transplant with terlipressin shown in the CONFIRM trial. Those who have expressed this concern have noted that it remains unlikely that the practice of off-label use of norepinephrine and albumin would be changed from the trial.12
Furthermore, terlipressin-induced adverse events are of concern. Use of terlipressin heightens the risk of severe or fatal respiratory failure. In CONFIRM, respiratory failure was reported in 14% of patients treated with terlipressin compared with 5% of patients treated with placebo. The terlipressin prescribing information includes a boxed warning instructing against its initiation in patients experiencing hypoxia (eg, oxygen saturation as measured by pulse oximetry, < 90%) and requires monitoring for hypoxia in treated patients; a limitation of use also states that patients with a serum creatinine greater than 5 mg/dL are unlikely to experience benefit. Using a pulse oximeter while receiving this therapy is essential, and clinicians must remain vigilant for patients with respiratory issues.13 Patients with volume overload or with acute-on-chronic liver failure grade 3 are at increased risk.
Terlipressin can be safely administered as an intravenous bolus through a peripheral route. However, it is an expensive option. Unlike norepinephrine, terlipressin can be administered without the need for a central line and is suitable for use outside the intensive care unit. Conversely, norepinephrine is typically administered through a central venous catheter via continuous intravenous infusion, which necessitates intensive care unit–level care. This may be considered cost-effective in the long run. According to US and international guidelines, the recommended first-line agent for managing HRS is terlipressin, with norepinephrine as an alternative if terlipressin is unavailable.
Conclusions
HRS-AKI is a severe complication that occurs in patients with advanced cirrhosis and is associated with a poor prognosis. Recent improvements have been achieved in understanding pathophysiology, diagnosis, and management. The FDA approval of terlipressin represents the first agent available for treating HRS, which has long been available internationally. The CONFIRM trial, which supported this approval, demonstrated that terlipressin improved HRS reversal outcomes but did not improve mortality and increased incidence of respiratory failure. It is uncertain whether the long-standing use of off-label norepinephrine and albumin to treat HRS-AKI will shift providers’ practice because of safety concerns with terlipressin.
References
Solé C, Pose E, Solà E, Ginès P. Hepatorenal syndrome in the era of acute kidney injury. Liver Int. 2018;38(11):1891-1901. doi:10.1111/liv.13893
Angeli P, Ginès P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64(4):531-537. doi:10.1136/gutjnl-2014-308874
Tariq R, Singal AK. Management of hepatorenal syndrome: a review. J Clin Transl Hepatol. 2020;8(2):192-199. doi:10.14218/JCTH.2020.00011
What are current guideline recommendations for use of terlipressin in hepatorenal syndrome? UI Health. January 2023. Accessed October 20, 2023. https://dig.pharmacy.uic.edu/faqs/2023-2/january-2023-faqs/what-are-current-guideline-recommendations-for-use-of-terlipressin-in-hepatorenal-syndrome/
Angeli P, Garcia-Tsao G, Nadim MK, Parikh CR. News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) consensus document. J Hepatol. 2019;71(4):811-822. doi:10.1016/j.jhep.2019.07.002
Angeli P, Ginès P, Wong F,et al. Diagnosis and management of acute kidney injury inpatients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol. 2015;62(4):968-974. doi:10.1116/j.jhep.2014.12.029
Acevedo JG, Cramp ME. Hepatorenal syndrome: update on diagnosis and therapy. World J Hepatol. 2017;9(6):293-299. doi:10.4254/wjh.v9.i6.293
Baraldi O, Valentini C, Donati G, et al. Hepatorenal syndrome: update on diagnosis and treatment. World J Nephrol. 2015;4(5):511-520. doi:10.5527/wjn.v4.i5.511
Dundar HZ, Yılmazlar T. Management of hepatorenal syndrome. World J Nephrol. 2015;4(2):277-286. doi:10.5527/wjn.v4.i2.277
Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology. 2010;51(2):576-584. doi:10.1002/hep.23286
Wong F, Pappas SC, Curry MP, et al; CONFIRM Study Investigators. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med. 2021;384(9):818-828. doi:10.1056/NEJMoa2008290
Pichler RH, Swenson ER, Leary PJ, Paine CH. Terlipressin: hopes fulfilled or dashed? Clin J Am Soc Nephrol. 2022;17(1):140-142. doi:10.2215/CJN.06710521
Terlivaz. Prescribing information. Mallinckrodt Pharmaceuticals; 2022. Accessed October 18, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022231s000lbl.pdf
Articles in this issue
FDA Seeks to Regulate Laboratory-Developed Tests
Securing the Supply Chain: The DSCSA and the New Importation Policy in Florida
Overview of Pharmacological Treatment in Peripheral Artery Disease
Terlipressin Has Been Shown to Improve HRS Reversal Outcomes, but Concerns Remain
Impact of Pharmacist-Led Initiatives on Health Care–Associated Clostridioides difficile Rates
The Psychological Impact of GLP-1 Receptor Agonists: An Ongoing Investigation
A Pharmacist’s Guide to Continuous Glucose Monitoring
Managing Blood Glucose Levels for Expectant Mothers With Diabetes
Unsung Heroes: Recognizing the Vital Role of Pharmacy Informaticists in Health Care
Advancements in Diabetes Management: Harnessing the Power of CGM
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