What are the Effects of Terlipressin When Treating HRS-1?

When people think of cirrhosis, the liver is often the only organ that comes to mind. However, if left untreated, the disease can quickly lead to other conditions throughout the body, like type 1 hepatorenal syndrome, or HRS-1.  

"HRS-1 usually shows up in patients who have severe liver damage caused by cirrhosis," says Pratima Sharma, M.D., an associate professor of medicine and transplant hepatologist at Michigan Medicine. "When the kidneys are no longer functioning properly due to decompensated cirrhosis, toxins will accumulate within the body and can ultimately lead to death because of multi-organ failure."

Sharma adds that the average survival rate for individuals diagnosed with HRS-1 is "usually only weeks to months in the absence of liver transplantation."

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The drug terlipressin is used to increase blood pressure in patients through its ability to constrict blood vessels in the 'splanchnic circulation,' which means the blood supply that goes to the gastrointestinal tract, liver, spleen and pancreas. It may also improve blood flow to the kidneys. So, this vasoconstrictor is routinely used in both Europe and Asia to treat HRS-1. However, terlipressin is not currently approved by the FDA in the United States.

"Because terlipressin plus albumin is used to treat HRS-1 in many parts of the world, our clinical trial aimed to confirm its efficacy and safety in adults with this condition in North America," says Sharma. "Terlipressin selectively causes splanchnic and extra-renal vasoconstriction by stimulation of 'V1 receptors,' which are predominantly located in the smooth muscles of the arterial vasculature in the splanchnic region. They reduce splanchnic blood flow and portal pressure, which may subsequently improve the blood flow to kidneys."

Sharma was the lead investigator at Michigan Medicine for the registration clinical trial for terlipressin and albumin for HRS-1. The results of this industry-funded study were recently published in The New England Journal of Medicine.

"A total of 300 patients were randomly assigned to receive terlipressin or the placebo for 14 days," says Sharma. "We also recommended that both groups take albumin alongside their assigned drugs."

The team wanted to see if HRS-1 was reversed in any of their patients. This was not an easy task, given that these patients were very sick and traditionally have high mortality rates.  

"Ultimately, we would verify the reversal of HRS-1 by testing the serum creatinine levels in the patients' blood and maintaining that they could survive without renal-replacement therapy for at least ten days after they completed treatment," says Sharma. "A total of 199 individuals were assigned to the terlipressin group, while 101 were in the placebo group."

The team found that 32% of the terlipressin group and 17% of the placebo group showed signs of verified HRS-1 reversal.

"We were able to see that serum creatinine levels were at 1.5 milligrams per deciliter (or less) for the first 14 days of monitoring in 78 patients, or 39% of the terlipressin group, and 18% of the placebo group," says Sharma. "We also observed that in 34% and 17%, respectively, there were no cases of HRS-1 reversal by day 30."

After 90 days had passed, Sharma and her the team observed that 23% of the terlipressin group underwent liver transplantations, while 29% of the placebo group did. In addition, 51% of the terlipressin group and 45% of the placebo group died within that timeframe.  

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 "It should also be noted that adverse effects, such as abdominal pain, diarrhea, nausea and respiratory failure, more frequently occurred within the terlipressin group," says Sharma. "And death within 90 days due to respiratory-related conditions occurred in 11% of the terlipressin group and only 2% of the placebo group."

The study team concluded that while terlipressin is effective in improving kidney function within individuals with cirrhosis and HRS-1, it is also highly associated with adverse – and oftentimes severe – effects, like respiratory failure.

"Patients with HRS-1 are incredibly sick without any available treatment options, but terlipressin and albumin may serve as a bridge to liver transplantation for these individuals," says Sharma. "We hope to expand upon our knowledge of effective treatments for HRS-1 in the future."

Paper cited: "Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome," The New England Journal of Medicine. DOI: 10.1056/NEJMoa2008290