Use of terlipressin for the treatment of hepatorenal syndrome: “Yes, we can! “

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Evaluated question

Interest of terlipressin in combination with albumin for the treatment of hepatorenal syndrome (HRS).

Type of study

Randomized controlled trial (RCT) versus placebo, double-blind, multicenter North American (60 centers).

Produced with the financial support of the pharmaceutical company producing terlipressin.

Study population
  • Cirrhotic patients presenting the following three criteria:
    • A type 1 SHR
    • Ascites
    • Rapidly progressive acute renal failure defined by a doubling of serum creatinine to a minimum of 199 µmol / L in the 14 days prior to randomization.
  • Non-inclusion criteria:
    • Decrease in serum creatinine by more than 20% or serum creatinine becoming <199 µmol / L after at least 48 hours of stopping diuretics and administration of albumin.
    • Serum creatinine> 619 µmol / L
    • At least one paracentesis ≥ 4 L within 2 days prior to randomization
    • Uncontrolled sepsis and / or bacterial infection treated with antibiotics for ≥ 2 days
    • Severe cardiovascular disease
    • Extra-renal purification within 4 weeks prior to randomization
Method
  • 48h screening phase (stopping diuretics and albumin infusion) to confirm type 1 SHR.
  • Randomization 2: 1 in the “terlipressin + albumin” (G1) or “placebo + albumin” (G2) groups; stratification on serum creatinine <301 μmol / L or ≥ 301 μmol / L and on the need for large volume paracentesis ≥ 4 L between D-14 and D-3 before randomization.
  • IV administration of terlipressin (1mg) or placebo (1mg), every 6 hours until 24 hours after obtaining a serum creatinine ≤ 133 µmol / L, or until D14.
  • Discontinuation of treatment in the event of:
    • Increase in serum creatinine on D4 compared to the initial value.
    • Need for extra-renal purification, introduction of another vasopressor treatment.
    • Liver transplantation.
    • Installation of TIPS.
  • Follow-up visits between J20 and J40, between J46 and J74, between J76 and J104.
  • Intent-to-treat analysis
  • Primary endpoint:
    • “Verified” reversibility of SHR (defined by 2 consecutive measurements of serum creatinine ≤ 133 µmol / L at least 2 hours apart between D0 and D14 and survival without extra-renal purification for at least 10 additional days)
  • Secondary endpoints:
    • Reversibility of SHR (serum creatinine ≤ 133 µmol / L between D0 and D14)
    • Reversibility of SHR without extra-renal purification up to D30
    • Reversibility of SHR in patients with systemic inflammatory response syndrome
    • Reversibility of SHR without recurrence at D30
Essential results
  • 300 patients were randomized including 199 in the G1 and 101 in the G2. The baseline characteristics of the patients were similar between the two groups. Most of them were men, with an average age of 54 years. The cirrhosis was mainly alcoholic. Child-Pugh and MELD scores were 10.0 ± 1.85 (G1) vs 10.2 + 1.89 (G2) and 32.7 + 6.6 (G1) vs 33.1 + 6.2 (G2), respectively.
  • Albumin was administered in 165 patients (83%) in G1 (199.4 + 146.8 g), vs 92 patients (91%) in G2 (239.5 + 183.6 g).
  • Primary endpoint: “verified” reversibility of SHR was significantly more frequent in G1 compared to G2 (32% vs 17%, p = 0.006).
  • Secondary endpoints:
    • Reversibility of SHR: G1: N = 78 (39%) vs G2: N = 18 patients (18%); p <0.001
    • Reversibility of SHR without extra-renal purification up to D30: G1: N = 68 (34%) vs 17 (17%); p = 0.001
    • Reversibility of SHR in patients with systemic inflammatory response syndrome: G1: N = 31 (37%) vs G2: N = 3 (6%); p <0.001
    • Reversibility of SHR without recurrence at D30: G1: N = 52 (26%) vs G2: N = 17 (17%), p = NS
  • At 3 months, 101 patients (51%) had died in the G1, vs 45 patients (45%) in the G2, p = NS.
  • The percentage of patients transplanted between D0 and D90 was lower in G1 compared to G2 (23% vs 29%).
  • Adverse reactions (all stages of severity) were reported in 176 patients (88%) in G1 vs 88 patients (89%) in G2. The proportion of patients in whom treatment had to be permanently discontinued due to adverse effects was higher in G1 (12% vs. 5% in G2). The main cause of death under treatment was respiratory failure (6% in the G1 vs 0% in the G2).
Comments

SHR is the most extreme manifestation of kidney dysfunction in cirrhosis. It is characterized by a decrease in renal perfusion and glomerular filtration rate, following splanchnic and systemic arterial vasodilation. The only curative treatment for SHR is liver transplantation, but several randomized studies have shown that SHR can be reversible following the administration of vasopressor drugs in combination with albumin infusion (1). Terlipressin (a vasopressin analogue with a splanchnic vasoconstrictor effect) is used for this indication in many European and Asian countries. However, it had not been authorized until now in the United States, because a previous North American RCT had failed to demonstrate its superiority over placebo (2). This large RCT confirms the significant superiority of terlipressin compared to placebo (reversibility of SHR in 32% vs 17% of patients, respectively). In addition, this effect is possibly underestimated because the serum creatinine threshold used in the study (199 µmol / L) was higher than in the current definition of SHR (increase of more than 26.5 µmol / L within 48 hours following admission, with no response to volume expansion (3)). Thus, it can be assumed that using this definition, the percentage of patients responding to terlipressin would have been greater (4). This RCT was not sized to show a difference in survival. The percentage of deaths at 3 months identical between the groups could be explained by: 1 / the existence of competitive mortality linked to complications other than SHR, frequent in these patients with advanced liver disease 2 / the occurrence of ‘sometimes fatal cardiorespiratory adverse effects, more numerous in the “terlipressin” group. The authors do not exclude that these complications may partly explain the lesser access to the transplant in patients in the “terlipressin” group. The administration of high doses of albumin in these cirrhotic patients, often having cardiomyopathy, probably contributed to the occurrence of cardiorespiratory events (in particular by pulmonary edema), as had already been suggested in a French RCT (5).

Points forts
  • Multicenter, double-blind, placebo-controlled RCT
  • Large workforce
  • Superiority of terlipressin compared to placebo in obtaining reversibility of SHR.
Weak points
  • Using the old definition of SHR
  • Lack of survival benefit
Implications and conclusions

Terlipressin in combination with albumin is more effective than placebo in achieving reversibility of SHR, but its use is accompanied by sometimes severe side effects. The administration of albumin in high doses can be harmful in the most serious patients: tools for monitoring cardiopulmonary functions should be developed to anticipate the onset of complications (5).

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