Hepatology. 2015 Jan 16. doi: 10.1002/hep.27709.
Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial.
Cavallin M1, Kamath PS, Merli M, Fasolato S, Toniutto P, Salerno F, Bernardi M, Romanelli RG, Colletta C, Salinas F, Di Giacomo A, Ridola L, Fornasiere E, Caraceni P, Morando F, Piano S, Gatta A, Angeli P; for the Italian Association for the Study of the Liver Study Group on Hepatorenal Syndrome.
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Background
Renal dysfunction is a challenging complication of liver cirrhosis.
Revised consensus recommendations on diagnosis and management of AKI in patients with cirrhosis have been recently published and nicely covered by David Baird on the Renal Fellows Network.
Potential causes of AKI may include structural renal diseases and more importantly the hepatorenal syndrome (HRS).
HRS is a type of functional renal failure: renal vasoconstriction leads to a severe reduction in GFR with minimal renal histologic abnormalities.
HRS is a life-threatening condition with critically poor prognosis unless liver transplantation can be immediately performed.
There are two types of HRS.
- Type 1 HRS is characterized by a doubling of the initial serum creatinine to a level higher than 221 μmol/L [2.5 mg/dL] in less than 2 weeks. The median survival time is less than 2 weeks and practically all patients die within 8–10 weeks after the onset of renal failure.
- Type 2 HRS is characterized by a less progressive course with initial serum creatinine levels less than 221 μmol/L [2.5 mg/dL]. The main clinical consequence of type 2 HRS is diuretic-resistant ascites. Patients have a longer median survival time of approximately 6 months.
New pharmacological treatments may significantly improve short-term outcome, enhancing the feasibility of performing liver transplantation.
Systemic vasoconstrictors with plasma expansion are now the standard therapy. However, most of the experts do not agree on the best vasoconstrictor to use.
Terlipressin is the most widely used vasoconstrictor in Europe. It is a vasopressin derivative that has been shown to improve renal function in 40%-50% of patients.
In countries where terlipressin is not available (e.g. United States), either norepinephrine or midodrine and octreotide with albumin have been used.
The study we will discuss at the next #NephJC is a randomized controlled trial, in which the authors compared the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS.
Methods
Design: randomized controlled trial
Setting: Hepatology Units from 8 hospitals in Italy
Participants: Adults with cirrhosis and type 1 or severe type 2 HRS.
Exclusion criteria:
- hepatocellular carcinoma outside Milan criteria,
- septic shock,
- cardiac or respiratory failure,
- stroke, or
- coronary artery disease.
Intervention:
All patients received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter.
- TERLI group: terlipressin was administered initially by continuous intravenous infusion at an initial dose of 3 mg/24 hours. If there was no response after 48 hours, the dose of terlipressin was progressively increased to 12 mg/24 hours.
- MID/OCT group: midodrine was administered orally at a starting dose of 7.5 mg every 8 hours along with octreotide administered subcutaneously at a starting dose of 100 mcg every 8 hours. If there was no response after 48 hours, the dose of midodrine was progressively increased to 12.5 mg every 8 hours and octreotide to 200 mcg every 8 hours.
Patients were treated until serum creatinine decreased to < 1.5 mg/dL or for a maximum of 14 days.
Definitions of response to treatment:
- Complete response: a decrease in serum creatinine to <133 µmol/L (<1.5 mg/dL).
- Partial response: a <50% serum creatinine decrease from baseline to a final value >133 mmol/L (>1.5 mg/dL).
- No response: a serum creatinine decrease of <50% from baseline.
- Primary endpoint: complete response at completion of treatment.
Results:
Twenty-seven patients were randomized to the TERLI group and 22 to the MID/OCT group.
At the baseline, there were no significant differences between the two groups.
Mean arterial pressure (MAP) was significantly higher in the TERLI group vs. the MID/OCT
There was a significantly higher percentage of response to treatment in the TERLI group than in the MID/OCT group:
- TERLI group 70.4%
- MID/OCT group 28.6%
Discussion
In both groups, improvement in renal function was associated with a significant increase in mean arterial pressure
The response to treatment was found to be an independent predictor of survival.
Serious adverse events were not significantly different in the two groups, but stroke and arterial hypertension were observed only in the TERLI group.
Interestingly, 50% of nonresponders in the MID/OCT group received terlipressin plus albumin as a rescue treatment: an improvement of renal function was observed in 83.3% of patients