Terlipressin does not reverse hepatorenal syndrome but improves survival

Treating patients with hepatorenal syndrome type 1 (HRS-1) with the synthetic vasopressin analogue terlipressin (Lucassin) and albumin does not improve the chances of reversal of hepatorenal syndrome compared with albumin alone, but could improve survival, the results of a multicenter, randomized, double-blind, placebo-controlled trial suggest.

Reporting the latest findings from the REVERSE trial, Dr. Thomas D. Boyer of the Liver Research Institute at the University of Arizona, Tucson, and colleagues said previous studies, including one by their team, had shown that terlipressin together with albumin was more effective at reversing hepatorenal syndrome type 1 (HRS-1) and improving serum creatinine compared with placebo.

However, they noted that while terlipressin was approved for treating HRS-1 in several countries, it was not approved in the United States or Canada. European guidelines also recommended terlipressin plus albumin as a first-line treatment in these patients.

In the current phase III, randomized double-blind, placebo-controlled trial, 196 patients with cirrhosis, ascites, and HRS-1 were enrolled from 50 centers in the United States and two centers in Canada (Gastroenterology 2016. doi: 10.1053/j.gastro.2016.02.026). Study participants were randomly assigned to terlipressin 1 mg (n = 97) or placebo (n = 99) with albumin every 6 hours.

Treatment continued for 14 days unless the patient had met the study primary endpoint of a confirmed HRS reversal defined by the authors as two serum creatinine levels less than 1.5 mg/dL at least 40 hours apart on treatment without renal replacement therapy or transplant, or serum creatinine (sCr) levels at or above baseline on day 4.

Results showed that confirmed HRS reversal occurred in 19 of 97 patients on terlipressin plus albumin (20%) and 13 of 99 patients on albumin plus placebo (13%) (P = .22), a difference that was not statistically significant.

The secondary outcome of reversal of HRS-1 (defined as at least 1 sCr value less than or equal to 1.5 mg/dL while on treatment) was reached by 23 patients on terlipressin and 15 patients on albumin alone (23.7 vs. 15.2%, P = .13), a finding that again was not statistically significant.

However, the research team observed significant improvements in serum creatinine in the patients treated with terlipressin that correlated with survival. For example, sCr decreased by 1.1 mg/dL in patients receiving terlipressin compared to 0.6 mg/dL in patients receiving placebo.

“While all patients with [confirmed HRS reversal] had a more than 20% decrease in sCr from baseline, the majority with a greater than 20% decrease in sCr did not achieve [confirmed HRS reversal] and yet appeared to have an improved survival compared with patients with less than or equal to 20% improvement,” the study authors wrote.

There were no significant differences in adverse events or overall survival and transplant-free survival rates between the groups.

According to the researchers, the reasons for a “lower than expected treatment effect of terlipressin” were likely due to a combination of factors.

For example, the response rate to active treatment was lower in females (15.6%) than in males and significantly more female patients had been randomized to terlipressin.

Three patients treated with terlipressin who had HRS reversal were also discharged before obtaining the second serum creatinine measurement required to confirm they had met the study’s primary endpoint.

Furthermore, one-third of patients had received less than 3 days of active treatment, which could have also contributed to the lower response rate.

“Overall, the safety profile observed in the study reflects the known pharmacodynamic properties of terlipressin and is consistent with the scientific literature. Terlipressin is an effective therapy for the treatment of HRS-1, with a favorable benefit-risk profile,” the researchers concluded.

Several of the authors are consultants of Ikaria Therapeutics LLC/a Mallinckrodt Company, which sponsored the study and participated in its design, interpretation of data, and writing.

Treating patients with hepatorenal syndrome type 1 (HRS-1) with the synthetic vasopressin analogue terlipressin (Lucassin) and albumin does not improve the chances of reversal of hepatorenal syndrome compared with albumin alone, but could improve survival, the results of a multicenter, randomized, double-blind, placebo-controlled trial suggest.

Reporting the latest findings from the REVERSE trial, Dr. Thomas D. Boyer of the Liver Research Institute at the University of Arizona, Tucson, and colleagues said previous studies, including one by their team, had shown that terlipressin together with albumin was more effective at reversing hepatorenal syndrome type 1 (HRS-1) and improving serum creatinine compared with placebo.

However, they noted that while terlipressin was approved for treating HRS-1 in several countries, it was not approved in the United States or Canada. European guidelines also recommended terlipressin plus albumin as a first-line treatment in these patients.

In the current phase III, randomized double-blind, placebo-controlled trial, 196 patients with cirrhosis, ascites, and HRS-1 were enrolled from 50 centers in the United States and two centers in Canada (Gastroenterology 2016. doi: 10.1053/j.gastro.2016.02.026). Study participants were randomly assigned to terlipressin 1 mg (n = 97) or placebo (n = 99) with albumin every 6 hours.

Treatment continued for 14 days unless the patient had met the study primary endpoint of a confirmed HRS reversal defined by the authors as two serum creatinine levels less than 1.5 mg/dL at least 40 hours apart on treatment without renal replacement therapy or transplant, or serum creatinine (sCr) levels at or above baseline on day 4.

Results showed that confirmed HRS reversal occurred in 19 of 97 patients on terlipressin plus albumin (20%) and 13 of 99 patients on albumin plus placebo (13%) (P = .22), a difference that was not statistically significant.

The secondary outcome of reversal of HRS-1 (defined as at least 1 sCr value less than or equal to 1.5 mg/dL while on treatment) was reached by 23 patients on terlipressin and 15 patients on albumin alone (23.7 vs. 15.2%, P = .13), a finding that again was not statistically significant.

However, the research team observed significant improvements in serum creatinine in the patients treated with terlipressin that correlated with survival. For example, sCr decreased by 1.1 mg/dL in patients receiving terlipressin compared to 0.6 mg/dL in patients receiving placebo.

“While all patients with [confirmed HRS reversal] had a more than 20% decrease in sCr from baseline, the majority with a greater than 20% decrease in sCr did not achieve [confirmed HRS reversal] and yet appeared to have an improved survival compared with patients with less than or equal to 20% improvement,” the study authors wrote.

There were no significant differences in adverse events or overall survival and transplant-free survival rates between the groups.

According to the researchers, the reasons for a “lower than expected treatment effect of terlipressin” were likely due to a combination of factors.

For example, the response rate to active treatment was lower in females (15.6%) than in males and significantly more female patients had been randomized to terlipressin.

Three patients treated with terlipressin who had HRS reversal were also discharged before obtaining the second serum creatinine measurement required to confirm they had met the study’s primary endpoint.

Furthermore, one-third of patients had received less than 3 days of active treatment, which could have also contributed to the lower response rate.

“Overall, the safety profile observed in the study reflects the known pharmacodynamic properties of terlipressin and is consistent with the scientific literature. Terlipressin is an effective therapy for the treatment of HRS-1, with a favorable benefit-risk profile,” the researchers concluded.

Several of the authors are consultants of Ikaria Therapeutics LLC/a Mallinckrodt Company, which sponsored the study and participated in its design, interpretation of data, and writing.

Treating patients with hepatorenal syndrome type 1 (HRS-1) with the synthetic vasopressin analogue terlipressin (Lucassin) and albumin does not improve the chances of reversal of hepatorenal syndrome compared with albumin alone, but could improve survival, the results of a multicenter, randomized, double-blind, placebo-controlled trial suggest.

Reporting the latest findings from the REVERSE trial, Dr. Thomas D. Boyer of the Liver Research Institute at the University of Arizona, Tucson, and colleagues said previous studies, including one by their team, had shown that terlipressin together with albumin was more effective at reversing hepatorenal syndrome type 1 (HRS-1) and improving serum creatinine compared with placebo.

However, they noted that while terlipressin was approved for treating HRS-1 in several countries, it was not approved in the United States or Canada. European guidelines also recommended terlipressin plus albumin as a first-line treatment in these patients.

In the current phase III, randomized double-blind, placebo-controlled trial, 196 patients with cirrhosis, ascites, and HRS-1 were enrolled from 50 centers in the United States and two centers in Canada (Gastroenterology 2016. doi: 10.1053/j.gastro.2016.02.026). Study participants were randomly assigned to terlipressin 1 mg (n = 97) or placebo (n = 99) with albumin every 6 hours.

Treatment continued for 14 days unless the patient had met the study primary endpoint of a confirmed HRS reversal defined by the authors as two serum creatinine levels less than 1.5 mg/dL at least 40 hours apart on treatment without renal replacement therapy or transplant, or serum creatinine (sCr) levels at or above baseline on day 4.

Results showed that confirmed HRS reversal occurred in 19 of 97 patients on terlipressin plus albumin (20%) and 13 of 99 patients on albumin plus placebo (13%) (P = .22), a difference that was not statistically significant.

The secondary outcome of reversal of HRS-1 (defined as at least 1 sCr value less than or equal to 1.5 mg/dL while on treatment) was reached by 23 patients on terlipressin and 15 patients on albumin alone (23.7 vs. 15.2%, P = .13), a finding that again was not statistically significant.

However, the research team observed significant improvements in serum creatinine in the patients treated with terlipressin that correlated with survival. For example, sCr decreased by 1.1 mg/dL in patients receiving terlipressin compared to 0.6 mg/dL in patients receiving placebo.

“While all patients with [confirmed HRS reversal] had a more than 20% decrease in sCr from baseline, the majority with a greater than 20% decrease in sCr did not achieve [confirmed HRS reversal] and yet appeared to have an improved survival compared with patients with less than or equal to 20% improvement,” the study authors wrote.

There were no significant differences in adverse events or overall survival and transplant-free survival rates between the groups.

According to the researchers, the reasons for a “lower than expected treatment effect of terlipressin” were likely due to a combination of factors.

For example, the response rate to active treatment was lower in females (15.6%) than in males and significantly more female patients had been randomized to terlipressin.

Three patients treated with terlipressin who had HRS reversal were also discharged before obtaining the second serum creatinine measurement required to confirm they had met the study’s primary endpoint.

Furthermore, one-third of patients had received less than 3 days of active treatment, which could have also contributed to the lower response rate.

“Overall, the safety profile observed in the study reflects the known pharmacodynamic properties of terlipressin and is consistent with the scientific literature. Terlipressin is an effective therapy for the treatment of HRS-1, with a favorable benefit-risk profile,” the researchers concluded.

Several of the authors are consultants of Ikaria Therapeutics LLC/a Mallinckrodt Company, which sponsored the study and participated in its design, interpretation of data, and writing.