The combination of terlipressin and albumin was more effective in improving renal function in patients with cirrhosis and hepatorenal syndrome type I vs. albumin alone, according to data from a phase 3 clinical trial.
“[Hepatorenal syndrome] is one of the most challenging complications of advanced liver disease; acute kidney injury, including [hepatorenal syndrome type I], is a significant predictor of mortality risk in these patients. …Terlipressin is the most widely investigated drug in the treatment of [hepatorenal syndrome type I]. In combination with albumin, terlipressin has been shown to lead to greater improvement in renal function compared with albumin alone,” Thomas D. Boyer, MD, director of the Liver Research Institute, University of Arizona, and colleagues wrote.
Thomas D. Boyer
The researchers evaluated patients with ascites, cirrhosis and hepatorenal syndrome type 1 (HRS-I) from 50 clinical sites in the U.S. and Canada; randomly assigning patients 1 mg IV terlipressin (n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through 14 days unless the patient experienced HRS reversal or serum creatinine was at or above baseline at 4 days after initiation of treatment.
The primary endpoint of the research was the percentage of patients with confirmed HRS reversal. The mean duration of treatment was 5.6 days in the terlipressin group and 6.2 days in the placebo group.
Results showed 19.6% of patients treated with terlipressin plus albumin had confirmed HRS reversal (n = 19) compared with 13.1% of patients treated with placebo plus albumin (n = 13; P = .22). This, however, did not reach statistical significance.
“There was no significant difference in the incidence of [confirmed HRS reversal] between [the two] groups,” the researchers wrote. “The incidence of HRS reversal in the current study was lower than in our previous study (23.7% vs. 33.9%) and in other studies, which in part explains why we failed to achieve our primary endpoint.”
Incidence of HRS reversal was 23.7% for patients treated with terlipressin (n = 23) compared with 15.2% for patients who received placebo plus albumin (n = 15; P = .13).
The mean time to confirmed HRS reversal was 8.5 days for patients treated with terlipressin and 8.5 days for patients treated with placebo.
In the terlipressin group, serum creatinine decreased by 1.1 mg/dL vs. 0.6 mg/dL in the placebo group (P < .001). Further, the researchers found that the decreases in serum creatinine and survival were correlated (r2 = 0.882; P < .001).
Overall and transplant-free survival rates were similar between the two groups. Kaplan-Meier analysis showed more patients treated with terlipressin with confirmed HRS reversal were still alive at 90 days (100%) compared with patients treated with placebo with confirmed HRS reversal (69.2%).
In the terlipressin-treated group, survival was longer in patients with confirmed HRS reversal compared with those without (P < .001).
“This difference was not observed in patients who did vs. did not have [confirmed HRS reversal] after receiving placebo (P = .28),” the researchers wrote.
During treatment, the cumulative incidence of renal replacement therapy was higher among patients treated with terlipressin compared with patients treated with placebo (15.5% vs. 10.1%) at 9 days. However, the incidence of renal replacement therapy was slightly higher in patients treated with placebo at all subsequent follow-up points, according to the research.
The number of adverse events were similar in each group, but patients in the terlipressin group experienced more ischemic events. Further, in the terlipressin-treated group, 20.4% discontinued treatment due to adverse events compared with 6.3% of patients who received placebo.
The researchers concluded: “The reasons for the low response rate are numerous, but it is important to note that all trials of terlipressin plus albumin vs. albumin alone have shown that patients receiving terlipressin are more likely to achieve HRS reversal. … The results show a clear correlation between change in [serum creatinine] value and survival, and suggest a survival benefit accruing with a more than 20% decrease in [serum creatinine] value.” – by Melinda Stevens
Disclosure: Boyer is a consultant for Ikaria Therapeutics, LLC. Please see the full study for a list of all other researchers’ relevant financial disclosures.