Gastroenterology

Gastroenterology

Volume 137, Issue 3, September 2009, Pages 856-864.e1
Gastroenterology

Clinical Advances in Liver, Pancreas, and Biliary Tract
Intravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure

https://doi.org/10.1053/j.gastro.2009.06.006Get rights and content

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.

Section snippets

Objective

The primary outcome measure for this trial was the overall number of patients surviving at 3 weeks after study admission; our research hypothesis was that patients receiving NAC would have a significantly higher overall survival rate than those receiving the placebo. The secondary outcome measures were the number of patients surviving without transplantation and the number of patients undergoing transplantation at 3 weeks after study admission. Our research hypothesis for transplant-free

Study Population

Among 820 eligible patients at sites with institutional review board approval, 558 (68%) met exclusion criteria (Supplementary Figure 1). Of the remaining 262 patients, 89 were excluded either because consent was refused (46 patients), was unobtainable (34 patients), or, after randomization, because of protocol violations (9 patients). The 9 protocol violations included inadvertent enrollment of 2 prisoners who were removed from consideration once their status was recognized, 1 patient for whom

Discussion

There is no established treatment for non-acetaminophen acute liver failure other than liver transplantation. Our study suggests that transplant-free survival was improved by NAC. However, this improvement in survival was observed primarily in those with early stage hepatic encephalopathy: among those with coma grades I–II at admission, 52% receiving NAC survived without transplantation vs 30% survival for those who received placebo. This finding was supported by the survival analyses (Figure 1

Acknowledgments

The Data and Safety Monitoring Board for the trial included Michael W. Fried, Chair, University of North Carolina, Chapel Hill, NC; Edward Geehan, Georgetown University, Washington, DC; Lewis Tepperman, New York University, New York, NY; Caroline Riely, University of Tennessee, Memphis, TN; Patrick Northup, University of Virginia, Charlottesville, VA; Prashant Pandya, VA Medical Center, Kansas City, MO; and Aynar Unalp-Arida, Johns Hopkins University, Baltimore, MD.

The authors dedicate this

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    Conflict of interest The authors disclose no conflicts. The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety (specifically, serious adverse events as defined in federal guidelines) have been confirmed independently by a biostatistician who is not employed by the corporate entity. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis. This was a randomized clinical trial (ClinicalTrials.gov number NCT00004467).

    Funding The study was supported by the following grants: R-03 DK52827, R-01 DK58369, and U-01 DK58369 from the National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and FD-R-001661 from the Orphan Products Division, United States Food and Drug Administration. Additional funding was provided by the Stephen Tips Fund of the Northwestern Medical Foundation and the Jeanne Roberts and Rollin and Mary Ella King Funds of the Southwestern Medical Foundation. This study was performed under IND #56925, filed with the Food and Drug Administration. The N-acetylcysteine used in the trial was supplied initially by Apothecon/Geneva Pharmaceuticals (Princeton, NJ), a division of Bristol Myers Squibb, and after April 2003 was supplied by Cumberland Pharmaceuticals (Nashville, TN). No additional support, data analysis, or input of any kind was provided by these companies.

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