Terlipressin Shows Some Benefit in Hepatorenal Syndrome

SAN DIEGO – Terlipressin, widely used in Europe for hepatorenal syndrome but not yet approved in the United States, would be a useful option for this difficult-to-treat condition, said transplant hepatologist Dr. James Burton at the annual meeting of the Society of Hospital Medicine.

Currently, U.S. clinicians do their best with albumin and vasoconstrictors such as octreotide and midodrine to counteract the intense splanchnic vasodilatation that causes the condition (J. Clin. Gastroenterol. 2009;43:680-5).

Hepatorenal syndrome is a complication of advanced cirrhosis that can lead to renal failure. Liver transplantation is "the only treatment we currently have available to us that is very effective," especially for rapidly progressing type 1 HRS [hepatorenal syndrome]," said Dr. Burton, associate professor of medicine and the medical director of liver transplantation at the University of Colorado Hospital, Aurora.

The European vasopressin analogue terlipressin (Lucassin) has a long half-life that allows for bolus dosing every 4-6 hours. Several studies found evidence that the drug might be beneficial.

In one study, 56 patients with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) plus albumin. Another 56 patients received placebo plus albumin.

Serum creatinine level decreased to 1.5 mg/dL or less in 14 (25%) terlipressin patients, but in only 7 (12.5%) placebo patients by day 14. This difference was not statistically significant, however. The two groups had similar adverse event rates (Gastroenterology 2008;134:1360-8).

A significant benefit was found in a randomized study of 46 patients. Serum creatinine fell below 1.5 mg/dL or decreased 50% from baseline in 10 (43.5%) patients treated with albumin and terlipressin (1-2 mg/4 hours), vs. 2 (8.7%) patients treated with albumin alone (P = .017). Ten terlipressin patients and four albumin-only patients had cardiovascular complications (Gastroenterology 2008;134:1352-9).

In a third study, which was also randomized, 24 HRS patients received albumin and terlipressin (3 mg/24 hours with escalation based on response) and 17 received standard U.S. treatment – albumin plus midodrine and octreotide, also escalated according to response.

Serum creatinine in that study fell below 1.5 mg/dL in 13 (54%) terlipressin patients and renal function improved in three-quarters. Creatinine fell below 1.5 mg/dL in just 2 (12%) of the standard-treatment patients, and renal function improved in about a third (Angeli et al. The Liver Meeting 2011, American Association for the Study of Liver Diseases).

However, in all three studies, people didn’t live any longer when they were given terlipressin, and this is what is holding up FDA approval, said Dr. Burton, who noted that he and his colleagues are working on a new study "to try to show a survival benefit" for the drug.

He said he hopes the FDA approves terlipressin "because it will be a very effective treatment for hepatorenal syndrome. It would be amazing and wonderful if I could prevent people from going on dialysis" as they wait for a new liver.

Dr. Burton said he has no relevant financial disclosures.

SAN DIEGO – Terlipressin, widely used in Europe for hepatorenal syndrome but not yet approved in the United States, would be a useful option for this difficult-to-treat condition, said transplant hepatologist Dr. James Burton at the annual meeting of the Society of Hospital Medicine.

Currently, U.S. clinicians do their best with albumin and vasoconstrictors such as octreotide and midodrine to counteract the intense splanchnic vasodilatation that causes the condition (J. Clin. Gastroenterol. 2009;43:680-5).

Hepatorenal syndrome is a complication of advanced cirrhosis that can lead to renal failure. Liver transplantation is "the only treatment we currently have available to us that is very effective," especially for rapidly progressing type 1 HRS [hepatorenal syndrome]," said Dr. Burton, associate professor of medicine and the medical director of liver transplantation at the University of Colorado Hospital, Aurora.

The European vasopressin analogue terlipressin (Lucassin) has a long half-life that allows for bolus dosing every 4-6 hours. Several studies found evidence that the drug might be beneficial.

In one study, 56 patients with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) plus albumin. Another 56 patients received placebo plus albumin.

Serum creatinine level decreased to 1.5 mg/dL or less in 14 (25%) terlipressin patients, but in only 7 (12.5%) placebo patients by day 14. This difference was not statistically significant, however. The two groups had similar adverse event rates (Gastroenterology 2008;134:1360-8).

A significant benefit was found in a randomized study of 46 patients. Serum creatinine fell below 1.5 mg/dL or decreased 50% from baseline in 10 (43.5%) patients treated with albumin and terlipressin (1-2 mg/4 hours), vs. 2 (8.7%) patients treated with albumin alone (P = .017). Ten terlipressin patients and four albumin-only patients had cardiovascular complications (Gastroenterology 2008;134:1352-9).

In a third study, which was also randomized, 24 HRS patients received albumin and terlipressin (3 mg/24 hours with escalation based on response) and 17 received standard U.S. treatment – albumin plus midodrine and octreotide, also escalated according to response.

Serum creatinine in that study fell below 1.5 mg/dL in 13 (54%) terlipressin patients and renal function improved in three-quarters. Creatinine fell below 1.5 mg/dL in just 2 (12%) of the standard-treatment patients, and renal function improved in about a third (Angeli et al. The Liver Meeting 2011, American Association for the Study of Liver Diseases).

However, in all three studies, people didn’t live any longer when they were given terlipressin, and this is what is holding up FDA approval, said Dr. Burton, who noted that he and his colleagues are working on a new study "to try to show a survival benefit" for the drug.

He said he hopes the FDA approves terlipressin "because it will be a very effective treatment for hepatorenal syndrome. It would be amazing and wonderful if I could prevent people from going on dialysis" as they wait for a new liver.

Dr. Burton said he has no relevant financial disclosures.

SAN DIEGO – Terlipressin, widely used in Europe for hepatorenal syndrome but not yet approved in the United States, would be a useful option for this difficult-to-treat condition, said transplant hepatologist Dr. James Burton at the annual meeting of the Society of Hospital Medicine.

Currently, U.S. clinicians do their best with albumin and vasoconstrictors such as octreotide and midodrine to counteract the intense splanchnic vasodilatation that causes the condition (J. Clin. Gastroenterol. 2009;43:680-5).

Hepatorenal syndrome is a complication of advanced cirrhosis that can lead to renal failure. Liver transplantation is "the only treatment we currently have available to us that is very effective," especially for rapidly progressing type 1 HRS [hepatorenal syndrome]," said Dr. Burton, associate professor of medicine and the medical director of liver transplantation at the University of Colorado Hospital, Aurora.

The European vasopressin analogue terlipressin (Lucassin) has a long half-life that allows for bolus dosing every 4-6 hours. Several studies found evidence that the drug might be beneficial.

In one study, 56 patients with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) plus albumin. Another 56 patients received placebo plus albumin.

Serum creatinine level decreased to 1.5 mg/dL or less in 14 (25%) terlipressin patients, but in only 7 (12.5%) placebo patients by day 14. This difference was not statistically significant, however. The two groups had similar adverse event rates (Gastroenterology 2008;134:1360-8).

A significant benefit was found in a randomized study of 46 patients. Serum creatinine fell below 1.5 mg/dL or decreased 50% from baseline in 10 (43.5%) patients treated with albumin and terlipressin (1-2 mg/4 hours), vs. 2 (8.7%) patients treated with albumin alone (P = .017). Ten terlipressin patients and four albumin-only patients had cardiovascular complications (Gastroenterology 2008;134:1352-9).

In a third study, which was also randomized, 24 HRS patients received albumin and terlipressin (3 mg/24 hours with escalation based on response) and 17 received standard U.S. treatment – albumin plus midodrine and octreotide, also escalated according to response.

Serum creatinine in that study fell below 1.5 mg/dL in 13 (54%) terlipressin patients and renal function improved in three-quarters. Creatinine fell below 1.5 mg/dL in just 2 (12%) of the standard-treatment patients, and renal function improved in about a third (Angeli et al. The Liver Meeting 2011, American Association for the Study of Liver Diseases).

However, in all three studies, people didn’t live any longer when they were given terlipressin, and this is what is holding up FDA approval, said Dr. Burton, who noted that he and his colleagues are working on a new study "to try to show a survival benefit" for the drug.

He said he hopes the FDA approves terlipressin "because it will be a very effective treatment for hepatorenal syndrome. It would be amazing and wonderful if I could prevent people from going on dialysis" as they wait for a new liver.

Dr. Burton said he has no relevant financial disclosures.