03 Dec Hepato-Renal Syndrome Type 1: Treatment with Terlipressin Reduced Need for Renal Replacement Therapy
MedicalResearch.com Interview with:
Khurram Jamil, MD
Vice President, Clinical Research in Hepatology
Critical Care Division, Mallinckrodt
MedicalResearch.com: What is the background for the new data of terlipressin presented during Kidney Week 2020 Reimagined? Would you briefly describe hepatorenal syndrome type 1? Whom does it affect and how frequently does it progress to ESRD?
Response: Results from two post-hoc analyses of terlipressin, an investigational agent in the U.S. for adults with hepatorenal syndrome type 1 (HRS-1), were presented at Kidney Week 2020 Reimagined, the annual meeting of the American Society of Nephrology. The first was an oral presentation titled, “Terlipressin Improves Renal Replacement Therapy–Free Survival in Hepatorenal Syndrome Type 1” and included a pooled post-hoc analysis to assess the incidence of renal replacement therapy (RRT) and its impact on survival among patients from three Phase 3 trials. The second was a poster presentation titled, “Treatment of Hepatorenal Syndrome Type 1 with Terlipressin Reduces Need for Renal Replacement Therapy After Liver Transplantation,” which focused on a post-hoc analysis of the CONFIRM study and evaluated the need for RRT among patients who had liver transplantation within 90 days of HRS treatment.
HRS-1 is an acute and life-threatening syndrome involving acute kidney failure in people with cirrhosis.[i] HRS-1 can progress to life-threatening renal failure within days,i and has a median survival time of approximately two weeks and greater than 80 percent mortality within three months if left untreated.[ii],[iii] It is often a challenge to effectively diagnose in a timely manner due to its diagnosis of exclusion.iii
In general, the average patient with hepatorenal syndrome (HRS type 1 or type 2) is in their 50s,[iv] and up to 73 percent of HRS patients are men.[v] HRS-1 is estimated to affect between 30,000 and 40,000 patients in the U.S. annually.[vi],[vii]
MedicalResearch.com: What are the main findings? How does terlipressin differ from other treatments (if any) for this condition?
Response: The main findings of the oral presentation were based on pooled analyses of three Phase 3 trials including the pivotal CONFIRM study and found that HRS-1 patients treated with terlipressin (n=52/182) required renal replacement therapy (RRT) (dialysis) less often (p=0.002 at Day 90) and had improved RRT-free survival up to Day 90 compared to placebo (n=130/352) (p=0.03).
In addition, the main findings of the poster presentation, which was a post-hoc analysis of the CONFIRM study and pooled analyses of three Phase 3 trials, including CONFIRM, found that HRS-1 patients treated with terlipressin had a lower rate of RRT following liver transplantation compared to placebo within 90 days of treatment (p=0.036). Renal failure requiring hemodialysis post liver transplant is a major risk factor for death in liver transplant recipients;[viii] patients who require post-transplant dialysis also have significantly worse graft survival compared with those without post-transplant dialysis.[ix]
There are currently no pharmacologic treatments approved in the U.S. for HRS-1. Terlipressin is an investigational agent and its safety and effectiveness have not yet been established by the U.S. Food and Drug Administration (FDA).
The current standard of care for HRS-1 includes vasoconstrictors (agents that constrict or narrow blood vessels thereby increasing blood pressure and allowing greater blood flow into the kidneys) along with concomitant albumin and frequent monitoring.ii
Dialysis (a type of renal replacement therapy, RRT) is sometimes used in hepatorenal syndrome but dialysis is not curative and it can be costly.
MedicalResearch.com: What should readers take away from your report?
Response: The findings presented from the post-hoc and pooled analyses add to the breadth of existing knowledge and data of terlipressin, which has been extensively studied around the world for decades. More specifically, these analyses showed that treatment with terlipressin decreased the rate of renal replacement therapy (RRT) and improved RRT-free survival up to Day 90. These findings are important because they point to the potential for terlipressin to improve patient outcomes by reducing the need for RRT, which poses particular challenges to patients with HRS-1.
These findings also support the results of the Phase 3 CONFIRM trial among HRS-1 patients, the largest prospective trial ever conducted (n=300) in HRS-1 patients.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: My colleagues and I are committed to furthering the understanding of HRS-1, which is typically fatal and marked by rapid decline within three months if left untreated. Terlipressin is approved in many countries outside the United States, where it has been a standard of care for decades in the treatment of patients with HRS-1.[x],[xi]
Any disclosures? Mallinckrodt Pharmaceuticals funded the studies.
 National Organization for Rare Disorders. Hepatorenal Syndrome. Available at: https://rarediseases.org/rare-diseases/hepatorenal-syndrome/. Accessed November 23, 2020.
 Colle I and Laterre PF. Hepatorenal syndrome: the clinical impact of vasoactive therapy. Expert Review of Gastroenterology & Hepatology. (2018) 12:2, 173-188, DOI: 10.1080/17474124.2018.1417034.
 Gines P, Sola E, Angeli P, et al. Hepatorenal syndrome. Nature Reviews. (2018) 4:23.
 Low G, Alexander GJ, Lomas DJ. Hepatorenal syndrome: aetiology, diagnosis, and treatment. Gastroenterol Res Pract. 2015;207012.doi: 10.1155/2015/207012.
 Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008;134:1360-1368.
 C Pant, B S Jani, M Desai, A Deshpande, Prashant Pandya, Ryan Taylor, R Gilroy, M Olyaee. Hepatorenal syndrome in hospitalized patients with chronic liver disease: results from the Nationwide Inpatient Sample 2002–2012. Journal of Investigative Medicine. 2016;64:33–38.
 United States Census Bureau: Quick Facts. Available at: https://www.census.gov/quickfacts/fact/table/US/PST045218. Accessed November 23, 2020.
 Zand MS, Orloff MS, Abt P, et al. High mortality in orthotopic liver transplant recipients who require hemodialysis. Clin Transplant. 2011;25(2):213-21.
 Nagai S, Safwan M, Collin M, et al. Incidence and outcomes of immediate post-operative dialysis in liver transplantation. Am J Transplant. 2017;17:774.
 De Franchis R. Evolving Consensus in Portal Hypertension Report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2005;43:167-176.
 Ioannou GN, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrhage. Cochrane Database of Systematic Reviews. 2003;1. doi: 10.1002/14651858.CD002147.
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