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Assessment of the Frequency, Phenotypes, and Outcomes of Acute Liver Injury Associated with Amoxicillin/Clavulanate in 1.4 Million Patients in the Veterans Health Administration

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Abstract

Introduction

Drug-induced liver injury is a significant health issue, yet the exposure-based incidence remains to be characterized.

Objective

We aimed to assess the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate using a large electronic health record system.

Methods

Using the Veterans Health Administration electronic health record system, we developed the framework to identify unexplained acute liver injury, defined by alanine aminotransferase and/or alkaline phosphatase elevation temporally linked to prescription records of amoxicillin/clavulanate, a major culprit of clinically significant drug-induced liver injury, excluding other competing causes. The population was subcategorized by pre-existing liver conditions and inpatient status at the time of exposure for the analysis.

Results

Among 1,445,171 amoxicillin/clavulanate first exposures in unique individuals [92% men; mean age (standard deviation): 59 (15) years], 6476 (incidence: 0.448%) acute liver injuries were identified. Of these, 4427 (65%) had alternative causes, yielding 2249 (incidence: 0.156%) with unexplained acute liver injuries. The incidence of unexplained acute liver injury was lowest in outpatients without underlying liver disease (0.067%) and highest in inpatients with pre-existing liver conditions (0.719%). Older age, male sex, and American Indian or Alaska Native (vs White) were associated with a higher incidence of unexplained acute liver injury. Cholestatic injury affected 74%, exhibiting a higher frequency with advanced age, inpatient exposure, and pre-existing liver conditions. Hepatocellular injury with bilirubin elevation affected 0.003%, with a higher risk at age >45 years. During a 12-month follow-up, patients with unexplained acute liver injury had a higher adjusted overall mortality risk than those without evident acute liver injury.

Conclusions

This framework identifies unexplained acute liver injury following drug exposure in large electronic health record datasets. After validating in other systems, this framework can aid in deducing drug-induced liver injury in the general patient population and regulatory decision making to promote drug safety and public health.

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Acknowledgements

The authors thank Drs. Teresa Hudson (Central Arkansas Veterans Healthcare System, Little Rock, AR, USA), Susan Theus (Memphis VA, Memphis, TN, USA), and Dawn Provenzale (in memoriam: VA Cooperative Studies Program Epidemiology Center (CSPEC)-Durham, Durham, NC, USA) for their administrative support, Ms. Kate Dishongh (Central Arkansas Veterans Healthcare System, Little Rock, AR, USA) and Mrs. Marsha Turner (CSPEC, Durham, NC, USA) for their contribution to research coordination and assistance for regulatory oversight, and Andrew Thompson Jr, MS (Statistician, VA CSPEC-Durham, Durham, NC, USA) and Thomas S Redding IV, MS (Statistician, VA CSPEC-Durham, Durham, NC, USA) for their coding advice.

Author information

Authors and Affiliations

  1. Gastroenterology, Durham Veterans Affairs Health Care System, Durham VA Medical Center, 40 Duke Medicine Cir, Suite DUMC 3913, Durham, NC, 27710, USA

    Ayako Suzuki & Christine M. Hunt

  2. Gastroenterology, Duke University, Durham, NC, USA

    Ayako Suzuki & Christine M. Hunt

  3. Specialty Clinics, Greenville VA Healthcare Center, Greenville, NC, USA

    Hans Tillmann

  4. Gastroenterology, Hepatology and Nutrition, East Carolina University, Greenville, NC, USA

    Hans Tillmann

  5. HSR&D, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA

    James Williams

  6. Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA

    Ronald G. Hauser

  7. Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA

    Ronald G. Hauser

  8. Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Julie Frund & Fred Prior

  9. Brody School of Medicine, East Carolina University, Greenville, NC, USA

    Mizuki Suzuki

  10. National Institute for Health Research (NIHR) Nottingham Biomedical Research Center at the Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK

    Guruprasad P. Aithal

  11. Servicio de Aparato Digestivo y Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA_Plataforma Bionand), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain

    M. Isabel Lucena & Raúl J. Andrade

  12. CIBERehd, Madrid, Spain

    M. Isabel Lucena & Raúl J. Andrade

  13. Bioinformatics and Biostatistics, National Center for Toxicological Research, Jefferson, AR, USA

    Weida Tong

  14. VA Cooperative Studies Program Epidemiology Center-Durham, Durham, NC, USA

    Christine M. Hunt

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  1. Ayako Suzuki
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Corresponding author

Correspondence to Ayako Suzuki.

Ethics declarations

Funding

The present study was supported by grants of the HSR&D VA Merit Review Award Pilot Project Program (PPO 15-155: 2016-2017). This work was also partly supported with resources and the use of facilities at the Durham VA Medical Center, the Center of Innovation for Health Services and Research in Primary Care (CIN 13‐410), and Cooperative Studies Program Epidemiology Center (CSPEC) at the Durham VA Medical Center, and the Division of Gastroenterology, Duke University.

Conflicts of interest/competing interests

The authors have no conflicts of interest that are directly relevant to the content of this study.

Ethics approval

The study was approved by the Institutional Review Board and the Research and Development Committee of Central Arkansas Veterans Healthcare System (FWA: 00002261) and Durham Veterans Affairs Health Care System (FWA:00001600).

Consent to participate

The Institutional Review Boards at the Central Arkansas Veterans Healthcare System and Durham Veterans Affairs Health Care System determined that this study met exempt human subjects research criteria Category 4 (i.e., use of existing data) and an informed consent form is not applicable.

Consent for publication

Not applicable.

Availability of data and material

The US Department of Veterans Affairs (VA) places legal restrictions on access to veteran’s healthcare data, which includes both identifying data and sensitive patient information. The analytic data sets used for this study are not permitted to leave the VA firewall without a Data Use Agreement, per VA privacy and data security policies and regulatory constraints. This limitation is consistent with other studies based on VA data. However, VA data are made freely available to researchers behind the VA firewall with an approved VA study protocol. For more information, please visit https://www.virec.research.va.gov or contact the VA Information Resource Center at vog.av@CeRIV.

Code availability

Coding strategies used in this study are available upon request.

Authors’ contributions

Conceptualization: AS, CMH, HT, FP, GPA, MIL, RJA, WT; data curation: JW, RGH; analysis: AS, JW; coding/code validation: JF, MS; funding acquisition: AS; methodology: AS, CMH, HT, JW, RGH, FP; project administration: AS, CMH; supervision: AS; validation: AS, MS; writing original draft: AS; writing, review and editing: AS, HT, JW, RGH, JF, MS, FP, GPA, MIL, RJA, WT, CMH. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. The corresponding author further affirms that the article is an honest, accurate, and transparent account of the study. All the authors and acknowledged individuals in the paper read and approved the final version.

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The views expressed in this article are those of the authors and do not necessarily represent the policies, position of, nor imply endorsement from the Department of Veterans Affairs or the US Government.

FDA disclaimer

This article reflects the views of the authors and does not necessarily reflect those of the US Food and Drug Administration.

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Suzuki, A., Tillmann, H., Williams, J. et al. Assessment of the Frequency, Phenotypes, and Outcomes of Acute Liver Injury Associated with Amoxicillin/Clavulanate in 1.4 Million Patients in the Veterans Health Administration. Drug Saf 46, 129–143 (2023). https://doi.org/10.1007/s40264-022-01255-3

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