Introduction

Type 1 hepatorenal syndrome (HRS-1) is a rapidly progressing kidney failure that occurs in patients with decompensated cirrhosis and ascites. Left untreated, HRS-1 is often fatal, with a median survival of weeks to months. Pharmacotherapy with vasopressors, such as terlipressin, has shown potential in reversing hemodynamic abnormalities associated with advanced cirrhosis and improving renal perfusion and function in patients with HRS-1. Terlipressin’s vasoconstrictor activity reduces portal blood inflow and portal hypertension, leading to improved systemic hemodynamics and increased renal perfusion pressure. The CONFIRM Study aimed to confirm the efficacy and safety of terlipressin combined with albumin compared to placebo plus albumin in treating HRS-1 in adults with cirrhosis.

Methods

Trial Design:

• Randomized, double-blind, placebo-controlled trial.
• Developed under a special protocol assessment agreement with the Food and Drug Administration as a phase 3 registration trial.
• Approved by the research ethics board at each participating institution.
• Trial designed by the sponsor and the second author, with all investigators contributing and vouching for the data.
• Statistician employed by the sponsor analyzed the data and vouched for the analysis.
• All authors had access to the data and vouched for the trial’s adherence to the protocol.

Patients:

• Eligible patients had HRS-1, cirrhosis, ascites, and rapidly progressive kidney failure.
• Serum creatinine level doubled to at least 2.25 mg per deciliter (199 μmol per liter) within 14 days before randomization.
• Patients excluded if they had sustained reduction in serum creatinine level of more than 20% or a decrease to below 2.25 mg per deciliter at least 48 hours after diuretic withdrawal and albumin infusions.
• Major exclusion criteria included a serum creatinine level greater than 7.0 mg per deciliter (619 μmol per liter), large-volume paracenteses of 4 liters or more within 2 days before randomization, sepsis or uncontrolled bacterial infection for which antibiotic treatment had been administered for less than 2 days, severe cardiovascular disease, recent renal-replacement therapy (within 4 weeks before randomization), or discontinuation of midodrine and octreotide before randomization.

Randomization and Clinical Regimen:

• Patients randomly assigned in a 2:1 ratio to receive terlipressin plus albumin or placebo plus albumin.
• Stratification factors were qualifying serum creatinine level and preenrollment large-volume paracentesis.
• Terlipressin or placebo administered intravenously every 5.5 to 6.5 hours.
• Strongly recommended that all patients receive albumin.
• Dosage adjustments permitted based on the patient’s response and clinical conditions.

Efficacy End Points:

• Primary efficacy end point: Verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart up to day 14 and survival without renal-replacement therapy for at least an additional 10 days.
• Clinical failure classified if patients received renal-replacement therapy, underwent transjugular intrahepatic portosystemic shunt placement, received open-label vasopressor therapy before day 14, serum creatinine level did not improve by day 4, or serum creatinine level did not decrease to 1.5 mg per deciliter or less by day 14.
• Secondary efficacy end points: HRS reversal (serum creatinine level of 1.5 mg per deciliter or less), durability of HRS reversal, HRS reversal among patients with systemic inflammatory response syndrome, and verified reversal of HRS without recurrence of HRS by day 30.

Safety:

• Data on nonserious adverse events collected up to 7 days after the end of the treatment period.
• Data on serious adverse events collected up to 30 days after the end of the treatment period.
• Mortality documented up to 90 days after the first dose of terlipressin or placebo.

Statistical Analysis:

• Efficacy analyses performed in the intention-to-treat population.
• Sample size of 300 patients to provide 90% power to detect significant differences in the primary efficacy end point between the terlipressin and placebo groups.
• Multiple imputation used to account for missing end-point data in the intention-to-treat analysis.
• Hochberg procedure used to adjust for multiple testing of secondary end points.

Results

• Terlipressin demonstrated a higher rate of HRS reversal during the first 14 days, with 39% of patients achieving serum creatinine ≤ 1.5 mg/dL, compared to 18% in the placebo group (P<0.001).
• Durability of HRS reversal without renal replacement therapy up to day 30 was better in the terlipressin group (34% vs. 17% in placebo; P=0.001).
• Among patients with systemic inflammatory response syndrome, terlipressin showed superior efficacy for HRS reversal (37% vs. 6% in placebo; P<0.001).
• Verified reversal of HRS without recurrence by day 30 was observed in 26% of terlipressin patients and 17% in placebo (P=0.08).
• 90-day overall or transplantation-free survival did not differ significantly between the terlipressin group (51%) and placebo group (45%) (difference: 6 percentage points; 95% CI: -6 to 18).
• Adverse events were more common in the terlipressin group compared to placebo (88% vs. 89%).
• Abdominal pain, nausea, diarrhea, and respiratory failure occurred more frequently with terlipressin.
• Deaths due to respiratory disorders were higher in the terlipressin group (11%) compared to placebo (2%).
• Liver transplantations were performed in 23% of terlipressin patients and 29% in placebo by day 90.
• The study suggests that terlipressin with albumin is effective in reversing HRS-1 in cirrhosis patients but carries an increased risk of adverse events, particularly respiratory complications.

Discussion and Conclusion

Terlipressin as a potential treatment option for this serious condition. The current study, being a phase 3 trial, further strengthened the existing evidence base by employing rigorous methods and a larger sample size.

However, despite the promising efficacy of terlipressin in improving renal function and reversing HRS-1, the study acknowledged that the treatment did not significantly impact overall or transplantation-free survival up to 90 days. This finding was important to note as it indicated that although terlipressin improved the acute condition of HRS-1, it might not be sufficient to alter the long-term outcomes or survival rates significantly. This limitation raised questions about the need for a more comprehensive approach in managing patients with HRS-1, considering other aspects of their liver disease and overall clinical condition.

One of the study’s limitations that the study openly acknowledged was that the trial was not specifically powered to assess differences in survival between the two groups. Powering a study means ensuring that the sample size is large enough to detect statistically significant differences in the primary outcome. As survival is a complex endpoint influenced by multiple factors, including liver disease severity, comorbidities, and access to liver transplantation, conducting a study solely to assess survival would require a much larger sample size and a longer follow-up period. Despite this limitation, the study still provided valuable insights into the short-term efficacy of terlipressin in improving renal function.

Additionally, the study acknowledged that their study lacked detailed follow-up beyond the 90-day period. A longer follow-up could have provided more information on the durability of treatment effects and the potential impact of terlipressin on patient outcomes beyond the initial recovery period. Long-term follow-up data are essential for understanding the sustained benefits or possible late effects of the treatment and for evaluating the potential impact on liver transplantation rates over an extended period.

In conclusion, the study provided a thorough discussion of their findings, emphasizing the strengths and limitations of the study. The results supported the use of terlipressin as an effective option for improving renal function in patients with HRS-1. However, the study’s results also highlighted the need for further research to understand the impact of terlipressin on long-term outcomes and survival rates, as well as its potential role in influencing liver transplantation decisions.

The full journal can be found on the NEJM website: https://www.nejm.org/doi/full/10.1056/NEJMoa2008290

Reference:

1. Wong F, Pappas SC, Curry MP, Reddy KR, Rubin RA, Porayko MK, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med. 2021;384(8):818-828. doi:10.1056/NEJMoa2008290