Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials

Hao Niu; Judith Sanabria-Cabrera; Ismael Alvarez-Alvarez; Mercedes Robles-Diaz; Simona Stankevičiūtė; Guruprasad P Aithal; Einar S Björnsson; Raul J Andrade; M Isabel Lucena

doi:10.1016/j.phrs.2020.105404

Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials

Pharmacol Res. 2021 Feb:164:105404. doi: 10.1016/j.phrs.2020.105404. Epub 2020 Dec 24.

Authors

Hao Niu¹, Judith Sanabria-Cabrera², Ismael Alvarez-Alvarez¹, Mercedes Robles-Diaz³, Simona Stankevičiūtė⁴, Guruprasad P Aithal⁵, Einar S Björnsson⁶, Raul J Andrade³, M Isabel Lucena⁷

Affiliations

¹ Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain.
² Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain; Platform for Clinical Research and Clinical Trials IBIMA, Plataforma ISCiii de Investigación Clínica, Madrid, Spain.
³ Servicio de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
⁴ Lithuanian University of Health Sciences, Institute of Physiology and Pharmacology, Kaunas, Lithuania.
⁵ NIHR Nottingham Biomedical Research Centre, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, United Kingdom.
⁶ Department of Internal Medicine, Section of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland.
⁷ Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain; Platform for Clinical Research and Clinical Trials IBIMA, Plataforma ISCiii de Investigación Clínica, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. Electronic address: lucena@uma.es.

PMID: 33359912
DOI: 10.1016/j.phrs.2020.105404

Abstract

Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and findings of RCTs in the prevention and management of idiosyncratic DILI. A systematic literature search up to January 31^st, 2020 was performed. Recognised scales were used to assess methodological bias and quality of the studies. Quantitative and qualitative analyses were performed. Heterogeneity was assessed with I² statistic. Overall, 22 RCTs were included: 12 on prevention (n = 2,471 patients) and 10 in management (n = 797) of DILI/non-acetaminophen DILI-related acute liver failure (ALF). Silymarin (eight studies), bicyclol (four), magnesium isoglycyrrhizinate (three), N-acetylcysteine (three), tiopronin (one), L-carnitine (one), and traditional Chinese medicines (two) were tested in the intervention arm, while control arm mostly received standard supportive care or placebo. Main efficacy criteria in the prevention RCTs was DILI incidence or peak of liver enzymes value. In management RCTs, the efficacy parameter was usually 50 % decrease or normalisation of liver enzymes, or survival rate in DILI-related ALF patients. Overall, 15 trials described the randomisation method, eight were double-blind (n = 672) and nine had sample size estimation (n = 880). Four RCTs involving 377 patients used an intention-to-treat analysis. Based on the scarce number of trials available, tested agents showed limited efficacy in DILI prevention and management and a favourable safety profile. In conclusion, heterogeneity among studies in DILI case qualification and methodologic quality was evident, and the RCTs performed demonstrated limited efficacy of specific interventions. International research networks are needed to establish a framework on RCTs design and therapeutic endpoints.

Keywords: Acute liver failure; Clinical trial; Drug-induced liver injury; Management; Prevention; Systematic review.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Chemical and Drug Induced Liver Injury / drug therapy*
Chemical and Drug Induced Liver Injury / prevention & control*
Humans
Protective Agents / adverse effects
Protective Agents / therapeutic use*
Randomized Controlled Trials as Topic

Substances

Protective Agents