Another Measure of Terlipressin Success in Hepatorenal Syndrome

AUSTIN, Texas -- Hepatorenal syndrome (HRS) type 1 patients showed clinically meaningful responses to terlipressin (Terlivaz) under an alternative definition of treatment success, according to a pooled analysis of three phase III studies.

Relative response, defined as more than a 30% reduction in serum creatinine from the start of therapy to the end of treatment, was more likely to be achieved in the terlipressin compared with placebo groups (42.9% vs 23.4%, P<0.001) in the OT-0401, REVERSE, and CONFIRM trials.

This was arguably a meaningful clinical endpoint, as people who achieved a relative response had better odds of survival at 90 days (71.1% vs 41.6%, P<0.001) and a significantly lower incidence of renal replacement therapy by day 90 (15.2% vs 44.6%, P<0.001) compared with nonresponders, reported Muhammad Mujtaba, MD, of the University of Texas Medical Branch in Galveston, and colleagues at the National Kidney Foundation Spring Clinical Meeting.

Thus, relative response may indicate improved renal function even if patients do not meet traditional criteria for a full response or HRS reversal while on terlipressin therapy.

Full response typically requires reducing serum creatinine to within 0.3 mg/dL of the baseline value measured within 3 months of hospital admission, or upon admission if unavailable. Yet historic baseline creatinine levels aren't always available for all patients, Mujtaba's group noted.

As for HRS reversal, serum creatinine needs to be returned to below 1.5 mg/dL.

"We are hoping that physicians start using other criteria and threshold reduction in serum creatinine instead of an arbitrary reduction to 1.5 mg/dL, since the 1.5 mg/dL criteria doesn't apply to a patient with cirrhosis and chronic kidney disease, whereas 30% reduction in serum creatinine can be applied to any patient we treat," Mujtaba told MedPage Today.

"This is an important finding in the context of increasing prevalence of NASH [nonalcoholic steatohepatitis]-related liver disease, as 21% of these patients are reported to have chronic kidney disease, as well. So there are increasing liver disease patient with historic serum creatinine greater than 1.5 mg/dL," he added.

The first drug for treating patients with hepatorenal syndrome, terlipressin has been approved outside the U.S. for more than 3 decades and is endorsed for HRS in guidelines from both the American Association for the Study of Liver Diseases and American College of Gastroenterology.

In the U.S., terlipressin was finally approved in September 2022 after being initially rejected by the FDA back in 2009. The agent works as an injectable synthetic vasopressin analog dosed at 0.85 mg every 6 hours for up to 14 days.

Mujtaba and colleagues noted that the three trials underpinning FDA approval of terlipressin -- OT-0401, REVERSE, and CONFIRM -- had used serum creatinine at the end of treatment of 1.5 mg/dL or less as the threshold of treatment success.

"HRS diagnosis and management has evolved in recent years," Mujtaba said. "In terms of response to treatment, we know that outcomes are better if we are able to improve renal function, irrespective of achieving HRS reversal, which is often used as standard endpoint in clinical trials."

The post hoc pooled analysis of the three trials included 352 individuals who received terlipressin treatment and 256 who received placebo.

Across the pooled patients, 90% where white, the average age was 54, and a third had present alcoholic hepatitis. Alcohol was responsible for most of the participants' cirrhosis (60%), followed by hepatitis C (26%) and NASH (15%).

Average baseline serum creatinine was 3.6 mg/dL and most patients were male.

Notably, FDA does not recommend terlipressin for patients with a serum creatinine over 5 mg/dL.

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