Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure

Abstract

Background & aims: N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure.

Methods: In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation.

Results: A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I-II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III-IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031).

Conclusions: Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.

Trial registration: ClinicalTrials.gov NCT00004467.

Figure 1

Study design. A total of 820 patients were screened, leading to 173 patients enrolled in the final study.

Figure 2

Kaplan-Meier curve for each group (treatment by coma category) was used to show overall survival to 365 days. In separate analyses, patients in the NAC I–II group demonstrated significantly higher survival than either Placebo III–IV (p = 0.012) or NAC III–IV (p = 0.002). Number of patients with censored data prior to 365 days: 14 in NAC I–II, 5 in NAC III–IV, 12 in Placebo I–II, 7 in Placebo III–IV.

Figure 3

Kaplan-Meier curves for each group (treatment by coma category) showing transplant-free survival to 365 days. Patients in the NAC I–II group demonstrated significantly higher transplant-free survival than the other three groups (largest p = 0.017). Number of patients with censored data prior to 365 days: 10 in NAC I–II, 2 in NAC III–IV, 5 in Placebo I–II, 2 in Placebo III–IV. Note: 2 patients in the NAC III–IV group were censored, one at day34 and the other at day 58.

Figure 4

Kaplan-Meier curves for each group (treatment by coma category) showing number of days to transplantation to 365 days. Patients in the NAC I–II group demonstrated significantly longer time to transplantation than the other three groups (largest p = 0.032). Number of patients with censored data prior to 365 days: 10 in NAC I–II, 2 in NAC III–IV, 5 in Placebo I–II, 3 in Placebo III–IV. Note: 2 patients in the NAC III–IV group were censored, one at day34 and the other at day 58.