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Three Part Question

[In patients with elevated risk of liver injury with paracetamol overdose] is [the addition of calmangafodipir better than standard care with NAC at standard dose] at ]decreasing incidence of liver injury, decreasing incidence of liver failure, decreasing length of hospital stay, decreasing incidence of death and improving patient experience]

Clinical Scenario

A 35 year old man attends the emergency department having taking a staggered paracetamol overdose. He reports taking 72x500mg tablets over the past two days. He is suffering from persistent vomiting with increasing abdominal pain. His examination reveals right upper quadrant tenderness. He is acidotic on his blood gas. You start him on IV acetylcysteine as per the SNAP protocol immediately. Blood investigations are taken which reveal a raised ALT and INR. You are concerned that he is at risk of developing serious liver injury and wonder if there is any other treatment that could be initiated in addition to NAC to minimise this risk.

Search Strategy

Medline from 1966 to 2022 using pubmed interface.
Results were filtered to include only papers that were full text, English and involved humans.


(Paracetamol OR acetaminophen OR paracetamol sulphate OR paracetamol derivative) AND (drug overdose OR overdose OR poisoning OR suicide) AND (calmangafodipir) AND (toxicity OR hepatotoxicity OR liver injury OR liver failure)

Search Outcome

This search returned 7 results of which 1 was relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Morrison et al 2019 UK	24 Patients aged 16 or older admitted with paracetamol overdose deemed to required treatment with NAC (as per toxbase)	Randomised open label, safety and tolerability study	Occurrence of adverse events (AE) or serious adverse events (SAE)	No AE or SAE judged probably or definitely related to calmangafodipir	Small phase 1 study. No blinding of study participants or clinicians. Study groups not evenly matched in relation to risk factors for liver injury.
			Haematological and clinical biochemistry parameters of liver injury.	Reduction in significant ALT rise: 2 in 6 (NAC alone) vs 1 in 18 (calmangafodipir + NAC)
			Need for further NAC	Patients needing further NAC treatment: 3 in 6 (NAC alone) vs 0 (calmangafodipir + NAC)

Comment(s)

The only currently licensed treatment for paracetamol overdose is NAC which replenishes hepatocellular glutathione to increase the detoxification of paracetamol metabolites. While it is very effective at preventing livery injury when started within 8 hours of the overdose, its benefits are reduced after this point. It also commonly causes adverse drug reactions and basic administration can take 21 hours. Calmangafodipir is a superoxide dismutase mimetic that is thought to reduce liver injury during the oxidative phase of toxicity which develops around 8 hours after ingestion. Calmangafodipir has only recently been developed and therefore has limited evidence in clinical practice. This phase 1 trial primarily aimed to assess the safety and tolerability of this novel treatment along side routine care with NAC utilising the SNAP protocol. While it was small study, recruiting 24 patient in 4 arms, none had a serious adverse or adverse event linked to calmangafodipir. It concluded that NAC and calmangafodipir was safe and tolerated. However none of the patients included developed severe liver toxicity so calmangafodipir’s safety in this context has not yet been fully established. While this trial was not primarily aimed at detecting benefits in outcomes, there was a suggestion that when used in combination with NAC there was a reduction in markers of liver injury compared to treatment with NAC alone. Calmangafodipir use in routine clinical practice remains some way off, but this study supports further research that would evaluate the effectiveness of calmangafodipir in paracetamol overdose.

Clinical Bottom Line

NAC remains the only licensed treatment for paracetamol overdose but it has recognised limitations. This trial suggests a novel treatment that initially appears to be safe and tolerated but efficacy requires further work to establish.

References

1. Morrison EE, Oatey K, Gallagher B, Grahamslaw J, O’Brien R, Black P, et al. Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12 h regimen of N-acetylcysteine for paracetamol overdose (POP) EBioMedicine 2019 Aug 1;46:423–30.