Poor Evidence Underpins Treatments for Hepatorenal Syndrome

By Marilynn Larkin

October 30, 2019

NEW YORK (Reuters Health) - Because almost all studies of treatments for hepatorenal syndrome (HRS) are flawed, one cannot be recommended over another, a systematic review and meta-analysis concludes.

"I am surprised by the lack of good quality evidence to treat a condition that carries such a high risk of death," Dr. Kurinchi Selvan Gurusamy of University College London told Reuters Health by email. "Low-certainty evidence indicates that noradrenaline and terlipressin may increase resolution from hepatorenal syndrome when used in addition to albumin and supportive treatment, although there is no evidence that they decrease deaths."

Dr. Gurusamy and colleagues searched the literature through 2018 for randomized clinical trials of treatments for HRS in adults with cirrhosis who had not undergone liver transplant.

As reported online September 12 in the Cochrane Library, 25 trials (1,263 participants; 12 interventions) were included the review. Two trials were funded by pharmaceutical companies; five were funded by parties who had no vested interest in the results; and 18 did not report the source of funding.

All trials were at high risk of bias, and all the evidence was of low or very low certainty.

For example, the trials included participants with liver cirrhosis of varied etiologies and a mixture of type 1 HRS only, type 2 HRS only, or both types. Ages ranged from 42 to 60, and the proportion of women, when reported, ranged from 5.8% to 61.5%.

Follow-up ranged from one week to six months. Overall, 59% of participants died during this period and about 35% recovered. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone.

No difference in mortality at maximal follow-up emerged between the different interventions. No trials included health-related quality of life as an outcome.

There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants); number of serious adverse events per participant (two trials; 166 participants); proportion of participants with any adverse events (four trials; 402 participants); proportion of people who underwent liver transplantation at maximal follow-up (four trials; 342 participants); or other features of decompensation at maximal follow-up (one trial; 466 participants).

Five trials (293 participants) reported the number of any adverse events, and five (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51).

Eighteen trials (1,047 participants) reported recovery from HRS. In the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery than albumin plus terlipressin (HR 0.04 and HR 0.26, respectively). There was no evidence of differences between the groups in any other direct comparisons.

In the network meta-analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from compared with albumin plus terlipressin.

Dr. Gurusamy said, "Until new high-quality evidence becomes available, one cannot make any strong recommendations. However, if one wants to use any drugs in addition to albumin and supportive treatment, noradrenaline, which has fewer adverse events and is cheaper than terlipressin, may be preferable to other drugs."

Dr. Priya Grewal, Associate Professor of Liver and Medicine, Icahn School of Medicine at Mount Sinai in New York City, commented in an email to Reuters Health, "This is a well-conducted meta-analysis of appropriately selected published studies. However, in clinical practice...HRS type 1 typically carries a very high mortality without transplant at three months, and the results showing lack of benefit on mortality between different treatments arms is expected."

Patients had both type 1 and type 2 HRS, she noted, "and hence the trend to benefit in the albumin and terlipressin arm may be less than reported in large randomized multicenter trials on type 1 HRS patients published in the US," she said.

"Since there are very few treatment options available to these patients, most of which include albumin combined with either midodrine and octreotide or noradrenaline or terlipressin (not currently approved in the U.S.), any reversal of HRS, be it at the cost of some side effects, is acceptable in clinical practice," she said.

"The negative results of this review should be taken in the context of patients with type 1 HRS who are gravely ill, hospitalized, and likely to die without a liver transplant," she said. "Conducting studies in (these) very sick patients is difficult, leading to smaller single studies, and accounts for the high dropout rates in various treatment trials."

"Treatments, specifically terlipressin plus albumin, showing improvement in renal function, are much needed in the U.S., even in the absence of a survival benefit or improvement in health-related quality of life," Dr. Grewal concluded.

SOURCE: http://bit.ly/2WhV6kO

Cochrane Libr 2019.

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