What are current guideline recommendations for use of terlipressin in hepatorenal syndrome?

Introduction
Hepatorenal syndrome (HRS) is a form of acute kidney injury (AKI) that occurs in patients with decompensated cirrhosis and ascites.¹ Acute kidney injury occurs in up to 20% to 50% of patients with cirrhosis who are admitted to a hospital with complications of cirrhosis. The prognosis of patients with HRS is poor; 3-month survival is estimated at 20% to 40%.²

Terlipressin, a synthetic vasopressin receptor agonist, has been approved for use in Europe for treatment of HRS for more than 30 years.^3,4 Without access to terlipressin in the US, management of HRS has often involved off-label use of vasoconstrictors and albumin, as well as renal replacement therapy (RRT) in more severe cases.⁵ These treatments can serve as a bridge to definitive therapy with liver transplantation.

In 2021, the phase 3 CONFIRM trial reported outcomes of treatment with terlipressin compared with placebo in patients with HRS.⁶ In 2022, terlipressin became the first US Food and Drug Administration (FDA)-approved agent indicated to improve kidney function in adults with HRS with rapid reduction in kidney function.³ Given the long-standing treatment of HRS with other agents in the US, considerations regarding the study supporting its FDA approval, and various international guidelines, questions may arise regarding current recommendations on use of terlipressin in HRS. This review describes the recent CONFIRM trial and guideline recommendations for medical management of HRS.

HRS pathophysiology and terlipressin mechanism

The pathogenesis of HRS involves arterial vasodilation in the splanchnic circulation that is triggered by portal hypertension.¹ A rise in cardiac output and fall in systemic vascular resistance occur as disease progresses, which activates the renin-angiotensin and sympathetic nervous systems. This results in a decline in kidney perfusion, reduced glomerular filtration rate, and decreases in mean arterial pressure (MAP) and effective blood volume. Terlipressin is thought to increase renal blood flow in HRS by reducing portal hypertension and blood circulation in portal vessels, as well as increasing effective arterial volume and MAP, addressing these abnormalities in systemic and renal hemodynamics.³

The FDA-approved indication of terlipressin is in HRS with rapid reduction in kidney function.³ This corresponds to historical definitions of HRS Type 1, which has been defined as a sudden impairment of kidney function, specifically a 100% increase in serum creatinine to a value >2.5 mg/dL within <2 weeks.⁷ According to recent guidelines that rely on International Club of Ascites definitions of AKI, HRS Type 1 is now referred to as HRS-AKI and is characterized by cirrhosis with ascites in the presence of stage 2 or 3 AKI, non-response to 2 consecutive days of diuretic withdrawal and plasma volume expansion, and an absence of shock, recent use of nephrotoxic drugs, or signs of structural kidney injury.^5,8 Hepatorenal syndrome Type 2, now classified as HRS-non-AKI (HRS-NAKI), is a less severe form of HRS characterized by a steady and progressive decline in kidney function, refractory ascites, and sodium retention.

CONFIRM trial
The CONFIRM trial was the major phase 3 trial supporting FDA approval of terlipressin.⁶ In CONFIRM, 300 patients with HRS-AKI were randomized to double-blind terlipressin 1 mg or placebo every 6 hours; on day 4, eligible patients without a decrease in serum creatinine ≥30% could receive 2 mg every 6 hours. Albumin was strongly recommended in all patients, and was administered to 83% and 91% of patients treated with terlipressin and placebo, respectively. The primary efficacy end point was verified reversal of HRS, defined as 2 consecutive serum creatinine measurements of ≤1.5 mg/dL at least 2 hours apart up to day 14 and survival without RRT for at least an additional 10 days. Secondary efficacy endpoints included HRS reversal (serum creatinine ≤1.5 mg/dL while receiving assigned treatment), 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.

Major results of the CONFIRM trial are presented in Table 1.⁶ Terlipressin demonstrated significant improvement in the primary efficacy endpoint and all secondary efficacy endpoints, except for verified HRS reversal without recurrence through day 30. Safety outcomes, while not statistically compared between groups, demonstrated that patients treated with terlipressin experienced numerically higher incidences of death by 90 days and respiratory failure, as well as lower incidence of liver transplant by 90 days.

The results of CONFIRM were received with some controversy. For example, some experts expressed concern over the risk of death and the lower rate of liver transplant with terlipressin in CONFIRM, stating that the trial is unlikely to change their practice of off-label use of norepinephrine and albumin.⁹ The adverse respiratory events were also a concern for FDA during review of the product’s New Drug Application.¹⁰ Some experts have proposed these respiratory effects may be attributable to potential terlipressin-induced pulmonary arterial dilation, pulmonary venoconstriction, and increased permeability of the alveolar capillary barrier, all of which may be aggravated by concomitant administration of albumin.⁹ The FDA review document describes the manufacturer’s mitigation strategy, which is rooted in post-hoc analyses of CONFIRM that used a “Mitigated Population” (ie, patients in CONFIRM without the following high-risk characteristics: Grade 3 acute-on-chronic liver failure, serum creatinine ≥5 mg/dL, or listed for transplant with a Model for End-Stage Liver Disease score ≥35).¹⁰ Primary and secondary efficacy results in the Mitigated Population were generally consistent with those in the main CONFIRM analysis; however, the risk of serious or fatal respiratory failure in patients treated with terlipressin compared with placebo was reduced (10% vs 7%).

The FDA review concluded that although the mitigation strategy has not been prospectively tested, it is reasonable to believe that risk of terlipressin can be effectively mitigated by close monitoring of respiratory status and avoiding its use in patients at significant risk of respiratory failure.¹⁰ Terlipressin was ultimately approved, with 8 “Yes” and 7 “No” votes cast by the Cardiovascular and Renal Drugs Advisory Committee of the FDA Center for Drug Evaluation and Research. The current terlipressin prescribing information includes a boxed warning instructing against its initiation in patients experiencing hypoxia and requiring monitoring for hypoxia in treated patients; a limitation of use also states that patients with a serum creatinine >5 mg/dL are unlikely to experience benefit. A warning in the label also indicates that terlipressin-induced adverse events may make a patient ineligible for liver transplant.

Guideline recommendations
Several guidelines from various US and international societies have provided recommendations for the medical management of HRS, which are summarized in Table 2. When provided by the guideline, categorizations of the strength of the recommendation and quality of supporting evidence are indicated. Generally, all guidelines acknowledge the role of terlipressin in management of HRS, considering it a first-line agent. When terlipressin is unavailable, most guidelines indicate that norepinephrine can be used as an alternative. Recommendations for these two treatments generally differ by the quality of supporting evidence, with evidence in support of terlipressin being considered of higher quality.

Conclusion
The FDA approval of terlipressin in 2022 represents the first product approval in the US for treatment of HRS-AKI and the availability of a treatment that has long been available for this condition 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. Current US and international guidelines consider terlipressin a first-line option for treatment of HRS-AKI; while norepinephrine may be considered an alternative where terlipressin is unavailable, the quality of supporting evidence is generally considered greater for terlipressin. Given the residual safety concerns demonstrated with terlipressin in the CONFIRM trial, it remains to be seen whether US practice will shift from the long-standing use of off-label norepinephrine and albumin for treatment of HRS-AKI.

References

1. Sole C, Pose E, Sola E, Gines P. Hepatorenal syndrome in the era of acute kidney injury. Liver Int. 2018;38(11):1891-1901. doi:10.1111/liv.13893
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3. Terlivaz. Package insert. Mallinckrodt Pharmaceuticals; 2022.
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5. Buccheri S, Da BL. Hepatorenal Syndrome: Definitions, Diagnosis, and Management. Clin Liver Dis. 2022;26(2):181-201. doi:10.1016/j.cld.2022.01.002
6. 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
7. 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
8. Bajaj JS, O’Leary JG, Lai JC, et al. Acute-on-Chronic Liver Failure Clinical Guidelines. Am J Gastroenterol. 2022;117:225-252. doi:10.14309/ajg.0000000000001595
9. Pichler RH, Swenson ER, Leary PJ, Paine CH. Terlipressin: Hopes Fulfilled or Dashed? Clin J Am Soc Nephrol. 2022;17:140-142. doi:10.2215/CJN.06710521
10. US Food and Drug Administration. Center for Drug Evaluation and Research Terlipressin Integrated Review. US Food and Drug Administration. Published September 12, 2022. Accessed December 16, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/022231Orig1s000IntegratedR.pdf
11. Sarin SK, Choudhury A, Sharma MK, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hepatol Int. 2019;13:353-390. doi:10.1007/s12072-019-09946-3
12. European Assocation for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-460. doi:10.1016/j.jhep.2018.03.024

Prepared by:
Ryan Rodriguez, PharmD, MS, BCPS
Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

January 2023

The information presented is current as December 16, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.