Most Potentially Hepatotoxic Meds Revealed

TOPLINE:

An analysis of real-world evidence identified 17 medications, many not previously regarded as potentially hepatoxic, that have high incidence rates of patient hospitalization for acute liver injury (ALI), offering insights on how to better determine which drugs carry the most significant risk and warrant liver monitoring.

METHODOLOGY:

• Without a systematic approach to classifying medications’ hepatoxic risk, researchers have used case reports published on the National Institutes of Health’s LiverTox, which doesn’t account for the number of people exposed, to categorize drugs’ likelihood of causing ALI. The objective was to identify the most potentially hepatotoxic medications using real-world incidence rates of severe ALI.
• Researchers analyzed US Department of Veterans Affairs electronic health record data for almost 7.9 million individuals (mean age, 64.4 years; 92.5% men)without preexisting liver or biliary disease who were initiated in an outpatient setting on any one of 194 medications with four or more published reports of hepatotoxicity. Drugs delivered by injection or intravenously, prescribed for alcohol use disorder or liver disease treatment, or used as an anticoagulant were not included in the study.
• The primary outcome measured was hospitalization for severe ALI, defined by alanine aminotransferase levels > 120 U/L and total bilirubin levels > 2.0 mg/dL or the international normalized ratio ≥ 1.5 and total bilirubin levels > 2.0 mg/dL within the first 2 days of admission.
• Researchers organized the medications into groups on the basis of observed rates of severe ALI per 10,000 person-years and classified drugs with 10 or more hospitalizations (group 1) and 5-9.9 hospitalizations (group 2) as the most potentially hepatotoxic. The study period was October 2000 through September 2021.

TAKEAWAY:

• Among the study population, 1739 hospitalizations for severe ALI were identified. Incidence rates of severe ALI varied widely by medication, from 0 to 86.4 events per 10,000 person-years.
• Seventeen medications were classified as the most potentially hepatotoxic (groups 1 and 2). Seven of them (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) had incidence rates of ≥ 10 events per 10,000 person-years. The other 10 medications (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) showed incidence rates of 5-9.9 events per 10,000 person-years.
• Of the 17 most hepatotoxic medications, 11 (64%) were not classified as highly hepatotoxic in the published case reports, suggesting a discrepancy between real-world data and case report categorizations.
• Similarly, several medications, including some statins, identified as low-risk in this study were classified as among the most hepatotoxic in the published case reports.

IN PRACTICE:

“Categorization of hepatotoxicity based on the number of published case reports did not accurately reflect observed rates of severe ALI (acute liver injury),” the researchers wrote. “This study represents a systematic, reproducible approach to using real-world data to measure rates of severe ALI following medication initiation among patients without liver or biliary disease…Patients initiating a medication with a high rate of severe ALI might require closer monitoring of liver-related laboratory tests to detect evolving hepatic dysfunction earlier, which might improve prognosis.”

The study illustrates the potential to use electronic health record data to “revolutionize how we characterize drug-related toxic effects,” not just on the liver but other organs, Grace Y. Zhang, MD, and Jessica B. Rubin, MD, MPH, of the University of California, San Francisco, wrote in an accompanying editorial. “If curated and disseminated effectively…such evidence will undoubtedly improve clinical decision-making and allow for more informed patient counseling regarding the true risks of starting or discontinuing medications.

SOURCE:

The study, led by Jessie Torgersen, MD, MHS, MSCE, of the Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, was published online in JAMA Internal Medicine.

LIMITATIONS:

The researchers listed several limitations, including the possibility that reliance on laboratory tests for ascertainment of acute liver injuries could introduce surveillance bias. The study focused on a population predominantly consisting of men without preexisting liver or biliary disease, so the findings may not be generalizable to women or individuals with liver disease. Additionally, researchers did not perform a causality assessment of all outcomes, did not study medications with fewer than four published case reports, and did not evaluate the influence of dosage.

DISCLOSURES:

This study was partly funded by several grants from the National Institutes of Health. Some authors declared receiving grants and personal fees from some of the funding agencies and other sources outside of this work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.