Tinker Ready

November 12, 2007

November 12, 2007 (Boston) -- The antidote for acetaminophen poisoning can also slow early-stage acute liver failure triggered by other causes, including hepatitis B and drug-induced injury, according to data from an 8-year study released here at the American Association for the Study of Liver Diseases (AASLD) 58th Annual Meeting.

Patients in the early stage of a coma resulting from non--acetaminophen related acute liver failure (NAALF) who received N-acetylcysteine (NAC) had a significantly higher spontaneous survival rate, according to an abstract presented by William Lee, MD, from the University of Texas Southwestern Medical Center in Dallas, Texas, on behalf of the US Acute Liver Failure Study Group. However, the treatment was not useful for coma grade III-IV patients.

There is no treatment for acute liver failure, but in 1991, research suggested that NAC improved hemodynamics in NAALF patients, Dr. Lee said, noting that the drug has a good safety profile and is easy to administer. A subsequent paper found no effect, but it looked at grade IV coma patients who were ventilated and paralyzed, so Lee's group set up a multicenter, randomized controlled clinical trial that screened 848 adult patients over an 8-year period at 25 sites.

The primary endpoint of the trial was overall survival (OS), with spontaneous (transplant-free) survival (SS) and transplant rate as secondary endpoints. The researcher randomized 173 patients and stratified them by site and coma category (I -- II vs III -- IV) to receive either NAC or placebo (PLB). Thirty-seven patients (21%) had hepatitis B virus infection. Forty-five patients (26%) had drug-induced liver injury, and 27 (15%) had autoimmune hepatitis. Liver injury in the rest of the patients had indeterminate or "other" causes.

There were no differences at 3 weeks in OS and SS between groups (OS: NAC, 70.4% [57 of 81 patients] vs PLB, 66.3% [61 of 92 patients]; P = .57; SS: NAC, 39.5% [32 of 81 patients] vs PLB, 27.2% [25 of 92 patients]; P = .09).

However, when broken down by coma categories, (I -- II vs III -- IV), the difference in SS was significant for those with coma grade I to II at randomization (NAC, 51.7% [30 of 58 patients] vs PLB, 30.4% [17 of 56 patients]; P = .021) but not for coma III to IV patients (SS: NAC, 8.7% [2 of 23 patients] vs PLB, 22.2% [8 of 36 patients]; P = .177).

"In light of its good safety profile, [intravenous] NAC should be considered for early-stage ALF but should not be a substitute in the community hospital for early referral for transplantation," Dr. Lee said. "Patients with late-stage disease typically survive only a short period of time. NAC is probably not of value in this setting."

AASLD president Gregory Gores, MD, called the work "a high-profile, landmark study.... If you look at giving this drug early, there appears to be a benefit."

Dr. Lee said a pediatric study of the same approach is still underway. Those researchers reviewed this data and decided to continue, he said.

Dr. Lee has disclosed no relevant financial relationships.

American Association for the Study of Liver Diseases 58th Annual Meeting: Abstract 79. Presented November 5, 2007.

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