52 in 52 – #23: Molecular Adsorbent Recirculating System in Acute Liver Failure

Questions:

1. Does molecular adsorbent recirculating system (MARS) therapy result in improved transplant-free survival (TFS) in patients with acute liver failure (ALF), compared to standard medical therapy (SMT)?
2. Does MARS significantly improve biochemical profiles and hemodynamics compared to SMT?

Wait… What is MARS…?

Before we get into the study design it’s probably worth a brief overview of what in the world MARS is. To put it into its most simple form, one could think of MARS as “liver dialysis”. The cornerstone of MARS therapy is the use of an albumin bath run in series with a standard continuous renal replacement therapy (CRRT) circuit, to remove highly water soluble and protein-bound compounds. Generally, MARS is used as a bridge to transplant or while awaiting native hepatic function to recover.

PICO

Population:

• Enrolled patients treated with MARS in 3 tertiary care transplant hospitals in North America
  • Emory University Hospital, Atlanta, GA
  • University of Alberta Hospital, Edmonton, AB, Canada
  • University of Kansas Medical Center, Kansas City, KS
• Enrolled patients treated with SMT through the Acute Liver Failure Study Group (ALFSG) member institutions
  • SMT patients were identified using propensity matching
    • Age
    • Sex
    • Acetaminophen-induced ALF as etiology
    • Use of CRRT or other renal replacement therapy
    • Use of vasopressors
    • Dependence on mechanical ventilation
    • Presence of grade III/IV hepatic encephalopathy
    • INR
    • Bilirubin
    • Creatinine
    • Kings College Criteria (acetaminophen and non-acetaminophen)
  • Ratio of 1 MARS patient to 4 SMT patients
• Enrollment criteria
  • Diagnosis of ALF by treating provider
    • ALF was defined using the following criteria (must meet all 4):
      • 1) INR greater than or equal to 1.5
      • 2) Hepatic Encephalopathy of any grade based on West Haven Criteria
      • 3) Illness duration less than 26 weeks,
      • 4) Absence of existing cirrhosis (note: patients with liver failure secondary to acute Wilson’s disease or de novo presentation of preexisting subclinical liver disease were considered).
    • Age ≥ 18 years
    • Day 0 is defined as ICU admission date
    • Received MARS or SMT based on institutional standard-of-care and institutional guidelines
  • Subgroup analysis of acetaminophen vs non-acetaminophen ALF
  • Exclusion criteria
    • SMT patients missing any of the following data of the propensity score were excluded
  • Enrollment
    • 520 propensity-matched patients with ALF
      • 104 in MARS Arm
      • 416 in SMT Arm

Intervention:

• MARS therapy

Comparator:

• Standard Medical Therapy

Outcome:

• Positive trial
• 3 sensitivity analyses were conducted to assess the sensitivity based on the inclusion/exclusion of several variables
• Model 1: Primary analysis
  • MARS was significantly associated with 21-day transplant-free survival
    • OR 1.90 (95% CI 1.07 – 3.39), p = 0.030
    • This benefit was largest in the group with acetaminophen ingestion as the cause of ALF (See figure 2)
  • Model 2: adjusted for acetaminophen-induced ALF
    • OR 1.86 (95% CI, 1.05–3.31), p = 0.033
  • Model 3: Adjusted for mechanical ventilation
    • OR,1.91 (95% CI, 1.07–3.41), p = 0.029
  • In acetaminophen-acute liver failure (n= 51), molecular adsorbent recirculating system was associated with significant improvements (post vs pre) in:
    • Mean arterial pressure (92.0 vs 78.0 mm Hg; p≤ 0.002)
    • Creatinine (77.0 vs 128.2 µmol/L; p≤ 0.002)
    • Lactate (2.3 vs 4.3 mmol/L; p≤ 0.002)
    • Ammonia (98.0 vs 136.0 µmol/L; p≤ 0.002).
  • In non-acetaminophen acute liver failure (n= 53), molecular adsorbent recirculating system was associated with significant improvements in
    • Bilirubin (205.2 vs 251.4 µmol/L; p≤ 0.022)
    • Creatinine (83.1 vs 133.5 µmol/L; p≤ 0.022)
    • Ammonia (111.5 vs 140.0 µmol/L; p≤ 0.022)
    • However, there was an increased need for vasopressor support: post 43.4% vs pre 34.0%, p < 0.001

Take Aways:

• This 2022 observational trial displays a potential benefit for the use of MARS therapy in patients with acute liver failure.
• In this study, MARS was used infrequently when compared to SMT (104 vs 1544 over a 10-year period). This may highlight the limited access to this therapy.
  • This was a large study for MARS therapy.
• Many of the outcomes track for disease-oriented outcomes. However, I would argue this is 21-day transplant-free survival is a meaningful patient-oriented outcome with a modest but statistically significant difference.
  • Furthermore, the propensity matching and sensitivity analysis were well-done with relevant co-variates.
• Acetaminophen-associated ALF accounted for close to 50% of the MARS and SMT cohorts, and MARS seems to perform better in this cohort. While acetaminophen-associated ALF is common in the US, Europe, and Australia, acetaminophen toxicity may be less prevalent in other countries.
• The authors clearly outlined exclusion and inclusion criteria.
• Limitations included:
  • The MARS therapy group liver transplant rate was relatively low (22.1%). Does this mean the therapy worked? Maybe. In my mind, this more likely means the patients were more likely carefully selected.
  • MARS and SMT protocols were not standardized amongst facilities.
  • Classification of HE level was calculated retrospectively based on documented GCS scores.