SORT 1999: Terlipressin for Hepatorenal Syndrome (1999)

“Terlipressin plus albumin is an effective therapy for hepatorenal syndrome, since it improves renal function and reverses the syndrome in a high proportion of patients.”

— The Sort et al. Study Group

1. Publication Details

  • Trial Title: Terlipressin plus Albumin in the Treatment of Hepatorenal Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.
  • Citation: Sort P, Navasa M, Arroyo V, et al. Terlipressin plus albumin in the treatment of hepatorenal syndrome: a randomized, double-blind, placebo-controlled trial. Hepatology. 1999;30(4):856-861. doi:10.1002/hep.510300409.
  • Published: October 1999, in Hepatology.
  • Author: Pere Sort, M.D.
  • Funding: Spanish Ministry of Health and others.

2. Keywords

Hepatorenal Syndrome (HRS), Liver Cirrhosis, Terlipressin, Vasoconstrictor Agents, Albumin, Acute Kidney Injury.

3. The Clinical Question

In patients with cirrhosis and type 1 hepatorenal syndrome (HRS) (Population), does treatment with terlipressin plus albumin (Intervention) compared to placebo plus albumin (Comparison) improve renal function (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Type 1 hepatorenal syndrome (HRS) is a devastating complication of end-stage liver disease, characterized by rapid and progressive renal failure due to extreme splanchnic and systemic vasodilation. It was considered almost uniformly fatal without a liver transplant.
  • Knowledge Gap: There was no effective medical therapy for HRS. Terlipressin, a long-acting vasopressin analogue, was known to be a potent splanchnic vasoconstrictor. It was unknown if reversing the underlying vasodilation with terlipressin could reverse the renal failure of HRS.
  • Proposed Hypothesis: The authors hypothesized that terlipressin, by correcting splanchnic vasodilation, would improve systemic hemodynamics and reverse the renal failure associated with hepatorenal syndrome.

5. Study Design and Methods

  • Design: A prospective, single-center, randomized, double-blind, placebo-controlled trial.
  • Setting: A single tertiary care university hospital in Spain.
  • Trial Period: Not specified in the publication.
  • Population:
    • Inclusion Criteria: Patients with cirrhosis and type 1 HRS, defined by standard criteria (including a serum creatinine >2.5 mg/dL).
    • Exclusion Criteria: Patients with known ischemic heart disease or peripheral vascular disease.
  • Intervention: Terlipressin, administered as an initial IV bolus of 1 mg every 4 hours, with the dose increased to 2 mg every 4 hours if there was no response. All patients also received IV albumin.
  • Control: Matching placebo (saline) administered in the same manner. All patients also received IV albumin.
  • Management Common to Both Groups: Treatment was continued for a maximum of 15 days or until serum creatinine fell below 1.5 mg/dL.
  • Power and Sample Size: The trial was designed with a sequential statistical design, with a planned maximum of 24 patients.
  • Outcomes:
    • Primary Outcome: Reversal of hepatorenal syndrome, defined as a decrease in serum creatinine to <1.5 mg/dL.
    • Secondary Outcomes: Included changes in renal and systemic hemodynamics, and survival.

6. Key Results

  • Enrollment and Baseline: The trial was stopped early after the first interim analysis because of a significant benefit in the intervention group. 19 patients were randomized (9 to terlipressin, 10 to placebo). The groups were well-matched.
  • Trial Status: The trial was stopped early for efficacy.
  • Primary Outcome: Reversal of HRS was significantly more frequent in the terlipressin group than in the placebo group (44% vs 10%; P=0.017).
  • Secondary Outcomes: Patients in the terlipressin group had significant improvements in mean arterial pressure, renal plasma flow, and glomerular filtration rate. While there was a trend toward improved survival, it was not statistically significant in this small study.
  • Adverse Events: Ischemic adverse events were reported in the terlipressin group but were generally manageable with dose reduction.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using Fisher’s exact test.
  • Primary Outcome Analysis: The proportion of patients with reversal of HRS was compared between the two groups.
  • Key Statistic(s) Reported: Reversal of HRS: 4/9 (44%) in the terlipressin group vs 1/10 (10%) in the placebo group; P=0.017.
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk of reversal in Intervention Group) / (Risk of reversal in Control Group).
      • Calculation: RR = 44.4% / 10% = 4.44.
      • Clinical Meaning: An RR of 4.44 means that reversal of HRS was over 4 times more likely in the terlipressin group compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The calculated 95% CI for the RR is approximately 1.1 to 17.8.
      • Clinical Meaning: Since the 95% CI does not cross the line of no effect (1.0), the result is statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.017.
      • Clinical Meaning: The p-value of 0.017 is less than the conventional threshold of 0.05, indicating that the observed difference is unlikely to be due to chance.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Intervention Group) – (Risk in Control Group). Note: Here we calculate Absolute Risk Increase as it’s a positive outcome.
      • Calculation: Absolute Risk Increase = 44.4% – 10% = 34.4%.
      • Clinical Meaning: For every 100 patients with HRS treated with terlipressin and albumin, about 34 additional patients had a reversal of their renal failure.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.344 = 2.9.
      • Clinical Meaning: Approximately 3 patients with type 1 HRS need to be treated with terlipressin and albumin to achieve one additional reversal of the syndrome.
  • Subgroup Analyses: Not applicable due to the small sample size.

8. Strengths of the Study

  • Study Design and Conduct: This was the first randomized, double-blind, placebo-controlled trial to demonstrate a benefit for any medical therapy in type 1 HRS.
  • Physiologic Rationale: The trial was based on a strong understanding of the pathophysiology of HRS and tested a targeted intervention.
  • Large Effect Size: The observed difference in the primary outcome was very large and clinically significant.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The most significant limitation is that this was a small, single-center study. The findings required confirmation in larger, multicenter trials.
  • Other: The trial was stopped early for benefit, which can sometimes lead to an overestimation of the true treatment effect. The primary outcome was a surrogate (renal function) rather than mortality.

10. Conclusion of the Authors

“Terlipressin plus albumin is an effective therapy for hepatorenal syndrome, since it improves renal function and reverses the syndrome in a high proportion of patients. This therapy represents a major advance in the management of this severe complication of cirrhosis.”

11. To Summarize

  • Impact on Current Practice: This was a seminal, practice-changing trial. It was the first study to prove that type 1 HRS was a functional, reversible condition and not an inevitable terminal event. It established the combination of a vasoconstrictor (terlipressin) and albumin as the first-ever effective medical therapy for HRS, creating a new standard of care and a crucial bridge to liver transplantation.
  • Specific Recommendations:
    • Patient Selection: For adult patients with cirrhosis and type 1 hepatorenal syndrome.
    • Actionable Intervention: Promptly initiate treatment with terlipressin and intravenous albumin.
    • Expected Benefit: A dramatic improvement in the likelihood of reversing renal failure, with an NNT of approximately 3.
  • What This Trial Does NOT Mean: This trial does not mean that terlipressin is a cure for the underlying liver disease. It is a bridge to definitive therapy (liver transplantation).
  • Implementation Caveats: Patients treated with terlipressin require close monitoring for ischemic side effects, which can be serious.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a landmark study that provided the first high-quality evidence for a medical therapy for HRS, moving the field beyond supportive care.
  • Influence on Subsequent Research: The findings of this trial have been replicated and confirmed in numerous subsequent studies and meta-analyses. It has spurred research into other vasoconstrictors (e.g., norepinephrine, midodrine/octreotide) and has been a cornerstone of international guidelines for the management of HRS for over two decades. The large, multicenter CONFIRM trial (2021) later confirmed these findings, leading to the approval of terlipressin in the United States.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal dose and duration of terlipressin therapy? How does terlipressin compare to other vasoconstrictor regimens?
  • Future Directions: Research continues to focus on optimizing vasoconstrictor therapy and on developing strategies to improve long-term, transplant-free survival in patients with HRS.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, testing a novel therapy for a previously untreatable and uniformly fatal condition.
  • Methods: The randomized, double-blind, placebo-controlled design was methodologically strong. The main limitation is the small, single-center nature of the study.
  • Results: The trial showed a very large and statistically significant benefit for the primary outcome. The NNT of 3 is a remarkably strong effect size.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. Despite its small size, the dramatic effect size meant the results were highly applicable and practice-changing, establishing the first effective medical treatment for type 1 HRS.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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