Real-World Data to Evaluate Severe Acute Liver Injury After Outpatient Initiation of Potentially Hepatotoxic Medications: A Series of Nationwide Cohort Studies

Background: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI) reported on the US National Institutes of Health LiverTox website. Real-world evidence on incidence rates of severe ALI after initiation of medications, accounting for period of exposure, are lacking.

Objectives: Estimate observed rates of severe ALI among medications considered potentially hepatotoxic and compare these with toxicity based on case reports.

Methods: We conducted a set of cohort studies of new initiators of potentially hepatotoxic medications (≥4 reports of hepatotoxicity) using US Department of Veterans Affairs (VA) electronic health records. Eligible patients had: 1) a potentially hepatotoxic medication newly dispensed from an outpatient pharmacy from 2000-2021, and 2) ≥365 days in the VA system prior to fill. Patients were excluded if, prior to initiation of the potentially hepatotoxic medication, they had liver/biliary disease (to increase the likelihood that severe ALI events were medication-related) or an oral anticoagulant fill (preventing ascertainment of ALI-induced coagulopathy). The primary outcome was incident hospitalization with severe ALI, defined by inpatient: 1) alanine aminotransferase >120 U/L + total bilirubin >2.0 mg/dL, or 2) international normalized ratio 1.5 + total bilirubin >2.0 mg/dL, within 30 days of each other. Liver/biliary disease diagnosis recorded during follow-up or as a primary/contributory discharge diagnosis of a hospitalized severe ALI resulted in censoring. We calculated age-/sex-adjusted rates of severe ALI and compared observed rates with cumulative reports.

Results: Among 7,912,944 patients within 195 new initiator cohorts, we identified 4,602 incident inpatient severe ALI events. Incidence rates of severe ALI ranged from 6.0 events/1,000 person-years (nevirapine) to 0 events/1,000 person-years (amphetamine, atomoxetine, chlorzoxazone, orlistat, oxaprozin, propafenone, tamoxifen). Eight medications (nevirapine, voriconazole, erlotinib, prochlorperazine, lenalidomide, zidovudine, ritonavir, linezolid) had rates ≥2.0 events/1,000 person-years, and eight (metronidazole, fluconazole, chlorpromazine, rifampin, erythromycin, estrogens, moxifloxacin, mexiletine) had rates between 1.0 and 1.9 events/1,000 person-years. Of these 16 medications with the highest rates of severe ALI, 11 (68.8%) were not included in the highest hepatotoxicity category based on case reports.

Conclusions: Case reports inaccurately reflected observed rates of severe ALI for specific medications. Estimating rates of severe ALI after medication initiation within real-world data could be used to investigate hepatotoxicity safety signals.