NACSTOP

Published

Wong A. "The NACSTOP Trial: A Multicenter, Cluster-Controlled Trial of Early Cessation of Acetylcysteine in Acetaminophen Overdose". Hepatology. 2019. 69(2):774-784.
PubMed • Full text • PDF

Clinical Question

In adult patients that present to the emergency department following acetaminophen toxic exposure and normal ALT and serum creatinine at presentation and at 12 hours, how does a reduced dose (250mg/kg over 12 hours) of N-acetylcysteine compare to standard dose (300mg/kg over 20hours) in terms of liver injury and death.

Bottom Line

In a relatively small pilot study of patients presenting with acetaminophen toxicity without signs of liver toxicity and low acetaminophen levels at 12 hours after initiation of NAC, a 12-hour infusion of N-acetylcysteine was not associated with more hepatic injury when compared to a 20-hour infusion.

Major Points

The treatment of choice following a toxic ingestion of acetaminophen is N-acetylcysteine (NAC), intravenous formulations have been available in much of the world for several decades. The Rumack-Matthew nomogram has been utilized for risk stratification based on time from ingestion and serum concentration. A fixed duration of a 20-hour infusion has been the standard of care for many years but in patients who are at low risk of hepatotoxicity, this may represent over-treatment.

The NACSTOP trial, conducted in 6 centres in Australia, clustered 3 centres to a 12-hour (250mg/kg) infusion to compare to 3 centres with the standard 20-hour (300mg/kg) infusion. No patient reached their primary outcome ALT elevation (hepatic toxicity). There was also no statistical difference between groups for secondary outcomes of elevation of AST, INR, or late presentation for hepatic injury at 14 days. Adverse events were similar between group and were primarily gastrointestinal.

This study was limited in its small size, open label design, and presumably a lack of randomization of the clusters since the 12-hour intervention only occurred at sites with toxicology units. This pilot/feasibility study was not powered for clinical endpoints, but is notable for none of the 100 participants having a hepatic toxicity event. The WJC editors have some reservations about the design of the trial, but note that these findings are consistent with low-risk patients receiving a shorter duration of NAC for acetaminophen toxicity. A larger, randomized study is needed to shore up the evidence base for 12-hour NAC treatments in such a population.

Guidelines

As of July 2022, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, cluster-control, open-label trial. WJC ed note: It is unclear if randomization occurred at the cluster level.
• N=100
  • 12 hour infusion (n=50)
  • 20 hour infusion (n=50)
• Setting: 6 Australian centers
• Enrollment: 2016-2018
• Follow-up: 14 days
• Primary Outcome: Hepatic injury at 20 hours after initiation of NAC infusion (ALT doubling and peak ALT > 100 IU/L)

Population

Inclusion Criteria

All of the following:

• Aged ≥16 years
• At presentation:
  • Single/acute or staggered >1 hour acetaminophen ingestion
  • Serum ALT in normal range
  • Serum creatinine in normal range
• At 4 hours:
  • Acetaminophen serum concentration of 150mg/L (Australian and New Zealand acetaminophen guidelines nomogram)
• After 12 hours of NAC infusion:
  • Serum acetaminophen level below therapeutic upper range of 20 mg/L (132 umol/L)
  • Serum ALT in normal range
  • Serum creatinine in normal range

Exclusion Criteria

• Pregnancy
• Acetaminophen modified-release ingestion, and
• Other supratherapeutic ingestions (i.e., unintentional ingestions of more than 10 g or more than 200 mg/kg over 24 hours, more than 6 g/day over 48 hours). WJC ed note: We are unclear what this means and how it differs from the related inclusion criteria.

Baseline Characteristics

From the 20 hour infusion group.

• Demographics: Median age 22, 80% female
• Ingestion: 60% <8h from ingestion to treatment, 6% EtOH co-ingestion, 26% other drug co-ingestion, 92% single ingestion, 8% staggered ingestion, median ingestion 269 mg/kg,
• Laboratory parameters, median:
  • At presentation: ALT 18 IU/L, AST 21 IU/L, acetaminophen 146 mg/L
• Median time to NAC infusion: 7 hours

Interventions

• All eligible patients were started on an infusion of (1) acetylcysteine 200 mg/kg over 4 hours followed by (2) acetylcysteine 6.25 mg/kg/hr for a total of 100 mg/kg over the next 16 hours.
• Protocol by arm:
  • 12 hour infusion: If stopping criteria met at 8 hours, which was completion of (1) and 4 of the 16 hours of (2), then acetylcysteine was stopped and Ringer’s lactate IV was given for the remaining time of the infusion of (2). This was a total of 250 mg/kg acetylcysteine.
    • Stopping criteria, based upon labs at 12 hours: Normal serum ALT, normal creatinine, acetaminophen <20 mg/L. Participants with these laboratory values were excluded from the study.
  • 20 hour infusion: Continuation of (1) and (2) for a total of acetylcysteine 300 mg/kg over 20 hours.
    • Participants meeting the stopping criteria were similarly excluded from the study.

Outcomes

Comparisons are 12 hour infusion vs. 20 hour infusion.

Primary Outcomes

Hepatic injury at 20 hours after initiation of NAC infusion

Defined as doubling of ALT and peak ALT >100 IU/L

0 vs. 0 (OR 1.0; 95% CI 0.02 to 50)

Secondary Outcomes

Median 20-hour ALT concentration

18 vs. 16 IU/L; P=0.51

Median 20-hour creatinine

61 μmol/L vs. 61 μmol/L; P=0.44

Median 20-hour INR

1.2 vs. 1.2; p = 0.98

Hepatotoxicity (ALT >1000), death, requiring liver transplant

0 vs. 0

Other Outcomes

Duration of acetylcysteine infusion

13 (IQR 13-13.5) vs. 20 (20-20) hours (no P-value provided)

Extension of acetylcysteine infusion

0 vs. 0

Adverse Events

Nonallergic anaphylactic reaction (NAAR)

0 vs. 2% (dyspnea observed in 1 patient)

Any GI symptom

28% vs. 24% (OR 1.23; 95% Ci 0.5 to 3.01; P=0.64)

Nausea: 14% vs. 6%

Vomiting: 10% vs. 14%

Both nausea and vomiting: 4% vs. 4%

Criticisms

• Intervention and control groups were done at separate centers, possible bias in local practice may have occurred.
• Open label so selection bias possible
• The intervention sites (i.e., 12 hour sites) were co-located with inpatient toxicology units, so presumably the sites in this cluster trial (which divvys up participants by site) were not in actuality randomized. This introduces bias in that hospitals with toxicology units may have greater experience with acetaminophen overdoses, which might have introduced an advantage to those at the intervention sites.
• Participants were excluded if they did not meet stopping criteria at 12 hours, so, in effect, the study group was selected based upon response to the intervention itself.

Funding

• Australian National Health and Medical Research Council Postgraduate Scholarship (1114284)
• The Morson Taylor Award, Australasian College for Emergency Medicine