Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure
Lee WM, Hynan LS, Rossaro L, et al; Acute Liver Failure Study Group.
Summary by Camille Boustani
Acetaminophen is one of the most common etiologies of acute liver failure and its management with N-acetylcysteine (NAC) is well established. Some preliminary work had shown NAC may benefit those with other forms of acute liver failure; however, up to this point there had not never been a clinical trial evaluating this.
Some proposed mechanisms for NAC being effective in non-acetaminophen acute liver failure include improved tissue oxygen delivery as well as systemic hemodynamics. Lee et al. aimed to establish, in a prospective, randomized, double blind placebo trial, whether patients receiving NAC for non-acetaminophen acute liver failure have improved, overall and transplant-free survival at 3 weeks.
Adults age >18 with evidence of acute liver failure (INR >1.5, encephalopathy with <24 weeks duration) were eligible. Patients were excluded if they had known or suspected acetaminophen overdose, previously received NAC, had ischemic hepatic injury, liver failure due to pregnancy or cancer, refractory hypotension, septic shock, were expected to undergo transplant in <8 hours, or were older that 70 yr.
Of the 820 potentially eligible patients screened for inclusion, 558 (68%) met the exclusion criteria. Of the 262 remaining patients, a total of 89 were excluded because either they refused to or were unable to consent. As a result, the final study group was comprised of 173 patients. Of those 173, 92 received placebo (5% dextrose) and 81 received NAC (loading dose of 150 mg/kg/h of NAC over 1 hour, followed by 12.5 mg/kg/h for 4 hours, then continuous infusions of 6.25 mg/kg NAC for the remaining 67 hours).
The primary outcome of the trial is overall survival at three weeks. Secondary outcomes included transplant-free survival, transplant rate, length of hospital stay, and composite of the number of organ systems failing.
The authors note that the difference in size between the two groups (92 vs. 81) was a result of the randomization process that stratified patients by site, as well as standard encephalopathy (coma) grades – coma grade I-II, and coma grade III-IV.
At baseline the placebo group had a higher percentage of females (68% vs 47%, p=0.004) and a longer median duration between jaundice and encephalopathy than the treated group (12 vs 7 days, p=0.026).
The etiologies of the acute liver failure across the study groups were similar and consisted of DILI (n=45), autoimmune hepatitis (n=26), hepatitis B (n=37), and indeterminate (n=41).
With regards to the primary outcome, the overall survival at 3 weeks was similar between the two groups – 70% (95% CI=60 – 81%) for NAC and 66% (95% CI=56 – 77%) for placebo (one-sided p=0.283). Notably, as a secondary outcome, transplant-free survival was significantly higher at 40% (95% CI=28 – 51%) in the NAC group as compared to 27% for placebo (95% CI=18 – 37%, one-sided p=0.043).
Further stratifying transplant free survival by comparing patients with coma grade (I-II vs. II-IV) revealed an even more significant difference. In those patients with coma grade I–II: 52% (95% CI=38 – 65%, n=58) survived in the NAC group as compared to 30% (95% CI=17 – 43%, n=56) in the placebo group (one-sided p=0.01). However, in those with coma grade III–IV, transplant-free survival was only 9% (95% CI=0 – 22%, n=23) with NAC vs. 22% (95% CI=7 – 37%, n=36) with placebo (one-sided p=0.912). The odds ratios comparing the treatment groups for transplant-free survival were 2.46 (95% CI= 1.14, 5.30) for coma category I–II and 0.33 (95% CI=0.06, 1.74) for coma category III–IV.
Another important secondary outcome of this study was rates of transplant. Overall transplantation rates were 32% (95% CI= 21 – 43%, n=81) for NAC vs. 45% (95% CI= 34 – 55%, n=92) for placebo, p=0.093.
Acute liver failure is still associated with a high mortality despite available therapies and developments in transplant surgery. Enrollment difficulties, due to both the rarity and mortality of the condition, have made it difficult to study therapeutic options reliably. The aim of this study was to establish if NAC benefited patients with non-acetaminophen related liver failure. The authors found no difference in the primary outcome – overall survival. They did observe as a secondary outcome that NAC improves transplant-free survival at 3 weeks and 1 year in these patients. The subgroup with advanced coma grades (III-IV) did not benefit from this therapy. Several factors may have confounded observing a treatment effect – a smaller treatment group, faster time to transplant, and a high early mortality.
One limitation is that it had twice the number of patients with coma grades I-II compared to those with coma grades III-IV. This was due to the enrollment exclusion criteria, which omitted a larger proportion of patients with advanced encephalopathy due to pre-terminal patient status and those about to be transplanted.
Larger trials with broader inclusion are needed to further elucidate which patient populations may benefit most from NAC. But based on this study, NAC treatment could be initiated in patients with early hepatic encephalopathy, especially given it has minimal associated adverse effects. This article has changed practice guidelines for non-acetaminophen related acute liver failure.