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

Ayako Suzuki (), Hans Tillmann, James Williams, Ronald G. Hauser, Julie Frund, Mizuki Suzuki, Fred Prior, Guruprasad P. Aithal, M. Isabel Lucena, Raúl J. Andrade, Weida Tong and Christine M. Hunt
Additional contact information
Ayako Suzuki: Durham Veterans Affairs Health Care System, Durham VA Medical Center
Hans Tillmann: Greenville VA Healthcare Center
James Williams: HSR&D, Central Arkansas Veterans Healthcare System
Ronald G. Hauser: Veterans Affairs Connecticut Healthcare System
Julie Frund: University of Arkansas for Medical Sciences
Mizuki Suzuki: Brody School of Medicine, East Carolina University
Fred Prior: University of Arkansas for Medical Sciences
Guruprasad P. Aithal: National Institute for Health Research (NIHR) Nottingham Biomedical Research Center at the Nottingham University Hospital NHS Trust and University of Nottingham
M. Isabel Lucena: Universidad de Málaga
Raúl J. Andrade: Universidad de Málaga
Weida Tong: National Center for Toxicological Research
Christine M. Hunt: Durham Veterans Affairs Health Care System, Durham VA Medical Center

Drug Safety, 2023, vol. 46, issue 2, No 3, 129-143

Abstract: 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. Graphical Abstract

Date: 2023
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DOI: 10.1007/s40264-022-01255-3

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