WASHINGTON—Terlipressin can improve disease parameters among patients with hepatorenal syndrome–acute kidney injury, a complication of decompensated cirrhosis. Two novel studies presented at The Liver Meeting 2022 found that giving the drug early or giving it continuously could be safe and effective in this patient group.
In one study, early initiation of terlipressin (Terlivaz, Mallinckrodt) was found to help in early reversal of acute kidney injury (AKI) among patients with HRS-AKI and acute-on-chronic liver failure (ACLF). The drug also yielded improvements in hemodynamic parameters and regression of ACLF stage.
Senior investigator Shiv Kumar Sarin, MD, FAASLD, a senior professor and the vice chancellor at the Institute for Liver and Biliary Sciences, in New Delhi, presented these and other interim results of the randomized controlled eTERLI trial at the meeting (abstract 12).
Previous studies showed that only about one-third of patients with HRS-AKI in ACLF respond to terlipressin, Dr. Sarin said. Typically, the diagnosis of HRS-AKI requires 48 hours of volume repletion with albumin and diuretic withdrawal, he said, but waiting 48 hours before starting vasoconstriction in these patients could lead to rapid disease worsening and high mortality. His center embarked on a study to see if providing the drug earlier would be beneficial.
Dr. Sarin and his co-investigators randomly assigned patients with ACLF and persistent AKI or AKI stage 2/3 despite albumin therapy (40 g) for 12 hours (n=70) into one of two groups. Those in the early treatment arm received injectable terlipressin (2 mg for 24 hours) plus IV albumin (1 g/kg per day for 36 hours and then 20 g per day), while those in the standard treatment arm received IV albumin (1 g/kg per day for the next 36 hours), followed by injectable terlipressin (2 mg for 24 hours) plus IV albumin (20 g per day). The primary end point was reversal of AKI at day 7. Baseline parameters including AKI stage and ACLF scores were comparable.
Full AKI response at day 7 was observed in 24 patients (68.6%) in the early treatment arm versus 11 (31.4%) in the standard arm (P=0.03). After 72 hours, no AKI was detected in 11 patients (31.4%) in the early arm compared with three (8.6%) in the standard arm (P<0.01). Among other notable findings, patients in the early arm showed significant improvement in ACLF grade, mean arterial pressure and urine output at day 3. The total dose of albumin from baseline to day 7 also was lower in the early arm. The mortality rate at 28 days was lower in patients treated earlier (34% vs. 60%; P=0.031).
Treatment with terlipressin at either time point helped decrease complications such as pneumonia, bleeding episodes and urinary tract infections, Dr. Sarin said.
The study indicates that physicians should be able to start terlipressin treatment in as few as 12 hours and not have to wait until 48 hours, Dr. Sarin said. “However, this study is ongoing, and we await further judgment in this trial.”
Continuous Dosing Versus Boluses
The other study demonstrated that continuous terlipressin infusion led to a complete response rate of 59% among 46 patients with HRS-AKI, many of whom were on the liver transplant waitlist, while there were no significant adverse effects. These findings were part of interim results of the InFUSE trial (ClinicalTrials.gov Identifier: NCT04460560), and were presented as a poster of distinction at the meeting (abstract 3656).
Lead researcher K. Rajender Reddy, MD, FAASLD, the Founder’s Professor in Hepatology at the University of Pennsylvania, in Philadelphia, and his co-investigators hypothesized that a continuous infusion strategy might yield greater safety and efficacy.
In this multiple-site trial, investigators enrolled 46 patients with cirrhosis and HRS-AKI. Patients with Model for End-stage Liver Disease (MELD) scores of 35 or greater, ACLF grade 3, and serum creatinine (SCr) higher than 5.0 mg/dL were excluded. The study population’s ages ranged from 28 to 78 years, and slightly more than half identified as male (54%). Half (52%) had alcohol-associated liver disease, and 28% had nonalcoholic steatohepatitis–related cirrhosis. Use of other vasopressors before enrollment was common (63% of patients).
After a 0.5-mg bolus of terlipressin was administered, the drug was given as a continuous infusion (2 mg per day up to 8 mg per day based on SCr response and tolerability) for up to 14 days. Complete response was defined as a 30% reduction in SCr and end-of-treatment SCr of 1.5 mg/dL or less. Partial response was defined as a 30% decrease in SCr and end-of-treatment SCr of more than 1.5 mg/dL, and nonresponse was defined as a less than 30% decrease in SCr.
In results available as of the meeting, 27 patients (59%) had a complete response, eight (17%) had a partial response and 11 (24%) were nonresponders. Most patients (78%) already had been listed or were eligible for liver transplant at enrollment, and seven of 10 not on the list or eligible had a complete response.
The results were impressive considering patients’ level of disease, Dr. Reddy told Gastroenterology & Endoscopy News. Mean baseline MELD score was 26, mean SCr was 2.48 mg/dL, and AKI stages ranged from 1B to 3 among the complete responders.
There were no unexpected drug-related serious adverse events. One patient had hypoxic respiratory failure that was attributed to fluid overload and responded to diuretics. Within 30 days of treatment, there were nine cases that required renal replacement therapy, primarily among nonresponders, and three deaths, two from progressive liver failure and one from progressive renal failure.
The study has since enrolled its 50th patient, Dr. Reddy said, and 12-month follow-up for survival, transplant and kidney-related outcomes is ongoing. “Whether this will lead to a paradigm shift in clinical care needs to be seen, but this is very, very exciting,” he said.
There is now better recognition of the effects of renal dysfunction in patients with liver disease, “and that earlier recognition is really important,” commented Nancy Reau, MD, the Richard B. Capps Chair of Hepatology at Rush Medical College, in Chicago. Guidelines from the American Association for the Study of Liver Diseases recommend the use of norepinephrine or terlipressin over octreotide, and terlipressin is advantageous because it can be offered to patients on the floor versus having to go to the ICU, she said.
Studies showing that terlipressin use at an earlier time point in disease is more effective makes sense, Dr. Reau said. “Is this a game changer and is going to prevent all end-stage renal disease with hepatorenal syndrome? No, absolutely not. But is it a really important opportunity to help some individuals who have renal dysfunction related to liver disease prevent dialysis and improve perioperative outcomes as they go to transplant? Absolutely.”
—Karen Blum
Drs. Reau and Sarin reported no relevant financial disclosures. Dr. Reddy reported financial relationships with several companies including Mallinckrodt, which manufactures Terlivaz.
This article is from the May 2023 print issue.