Terlipressin versus placebo/no intervention for people with cirrhosis and hepatorenal syndrome

Background

Cirrhosis is a chronic disorder of the liver where scar tissue replaces the normal liver. People with cirrhosis can develop a kidney disease known as hepatorenal syndrome. The disease may develop when the blood flow to the kidneys becomes insufficient. Increasing the blood flow to the kidneys may therefore benefit people with hepatorenal syndrome. There are two types of hepatorenal syndrome: type 1 occurs rapidly, and type 2 has a slower onset. Terlipressin is a drug that increases the blood flow to the kidneys by constricting blood vessels. The drug may therefore help people with cirrhosis and hepatorenal syndrome.

Review question

Is terlipressin better than inactive placebo/no treatment for people with hepatorenal syndrome?

Search date

November 2016.

Study characteristics

The review includes nine randomised clinical trials (RCTs) and a total of 534 participants. The trials originated from six countries. Seven trials included only participants with type 1 hepatorenal syndrome. Two trials included a total of 96 participants with type 1 or type 2 hepatorenal syndrome.

Study funding sources

Three RCTs reported funding from a pharmaceutical company. The remaining trials did not report funding or did not receive funding from pharmaceutical companies.

Key results

People who received terlipressin had a lower risk of dying than people who received inactive placebo or no treatment. Terlipressin was also associated with a beneficial effect on renal function. Terlipressin increased the risk of serious circulation and heart problems (so-called cardiovascular events). Other adverse events included diarrhoea and abdominal pain.

The analyses mainly included people with type 1 hepatorenal syndrome. No beneficial or harmful effects of terlipressin were found when analysing participants with type 2 hepatorenal syndrome (possibly due to the small number of participants).

Quality of the evidence

We considered the evidence to be of low quality.

Authors' conclusions: 

This review suggests that terlipressin may be associated with beneficial effects on mortality and renal function in people with cirrhosis and type 1 hepatorenal syndrome, but it is also associated with serious adverse effects. We downgraded the strength of the evidence due to methodological issues including bias control, clinical heterogeneity, and imprecision. Consequently, additional evidence is needed.

Read the full abstract...
Background: 

Hepatorenal syndrome is a potentially reversible renal failure associated with severe liver disease. The disease is relatively common among people with decompensated cirrhosis. Terlipressin is a drug that increases the blood flow to the kidneys by constricting blood vessels. The previous version of this systematic review found a potential beneficial effect of terlipressin on mortality and renal function in people with cirrhosis and hepatorenal syndrome.

Objectives: 

To assess the beneficial and harmful effects of terlipressin versus placebo/no intervention for people with cirrhosis and hepatorenal syndrome.

Search strategy: 

We identified eligible trials through searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, and Science Citation Index Expanded, and manual searches until 21 November 2016.

Selection criteria: 

Randomised clinical trials (RCTs) involving participants with cirrhosis and type 1 or type 2 hepatorenal syndrome allocated to terlipressin versus placebo or no intervention. We allowed co-administration with albumin administered to both comparison groups.

Data collection and analysis: 

Two review authors independently extracted data from trial reports and undertook correspondence with the authors. Primary outcomes were mortality, hepatorenal syndrome, and serious adverse events. We conducted sensitivity analyses of RCTs in which participants received albumin, subgroup analyses of participants with type 1 or type 2 hepatorenal syndrome, and Trial Sequential Analyses to control random errors. We reported random-effects meta-analyses with risk ratios (RR) and 95% confidence intervals (CI). We assessed the risk of bias based on the Cochrane Hepato-Biliary Group domains. We graded the quality of the evidence using GRADE.

Main results: 

We included nine RCTs with a total of 534 participants with cirrhosis and ascites. One RCT had a low risk of bias for mortality and a high risk of bias for the remaining outcomes. All included trials had a high risk of bias for non-mortality outcomes. In total, 473 participants had type 1 hepatorenal syndrome. Seven RCTs specifically evaluated terlipressin and albumin. Terlipressin was associated with a beneficial effect on mortality when including all RCTs (RR 0.85, 95% CI 0.73 to 0.98; 534 participants; number needed to treat for an additional beneficial outcome (NNTB) 10.3 people; low-quality evidence). Trial Sequential Analysis including all RCTs also found a beneficial effect of terlipressin. Additional analyses showed a beneficial effect of terlipressin and albumin on reversal of hepatorenal syndrome (RR 0.63, 95% CI 0.48 to 0.82; 510 participants; 8 RCTs; NNTB 4 people; low-quality evidence). Terlipressin increased the risk of serious cardiovascular adverse events (RR 7.26, 95% CI 1.70 to 31.05; 234 participants; 4 RCTs), but it had no effect on the risk of serious adverse events when analysed as a composite outcome (RR 0.91, 95% CI 0.68 to 1.21; 534 participants; 9 RCTs; number needed to treat for an additional harmful outcome 24.5 people; low-quality evidence). Non-serious adverse events were mainly gastrointestinal, including diarrhoea (RR 5.76, 95% CI 2.19 to 15.15; 240 participants; low-quality evidence) and abdominal pain (RR 1.54, 95% CI 0.97 to 2.43; 294 participants; low-quality evidence).

We identified one ongoing trial on terlipressin versus placebo in participants with cirrhosis, ascites, and hepatorenal syndrome type 1.

Three RCTs reported funding from a pharmaceutical company. The remaining trials did not report funding or did not receive funding from pharmaceutical companies.

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