Hepatotoxicity Score: A New Method to Adjust for Use of Potentially Hepatotoxic Medications by Chronic Liver Disease Status

Abstract

Background: Studies evaluating the hepatic safety of medications have been limited by the inability to control for confounding from receipt of other hepatotoxic drugs.

Objective: The objective of this study was to develop an index (Hepatotoxicity Score) to adjust for concomitant hepatotoxic medication exposure within pharmacoepidemiology studies.

Methods: We identified 193 medications with ≥ 4 reports of hepatotoxicity and created cohorts of outpatient initiators in the Veterans Health Administration (2000-2021). Exposure occurred from initiation through 30 days after discontinuation or up to 1 year. We measured age-/sex-adjusted rates of hospitalization for severe acute liver injury (ALI) by chronic liver disease (CLD), identified drugs with high rates, and used these rates as weights in the score. To demonstrate real-world use, we calculated the score for proton pump inhibitor (PPI) initiators. We summed the weights of the drugs dispensed within 90 days prior to PPI initiation. Hazard ratios (HRs) of severe ALI (95% confidence intervals) were measured with and without adjustment for Hepatotoxicity Score.

Results: Among 89 512 PPI initiators with CLD, HRs of severe ALI were higher for lansoprazole (HR = 2.17 [95% CI, 1.24-3.82]), but not pantoprazole (HR = 0.83 [95% CI, 0.61-1.13]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.99 [95% CI, 1.13-3.50]). Among 2 462 414 PPI initiators without CLD, HRs were not significantly higher for lansoprazole (HR = 1.66 [95% CI, 0.99-2.77]) but were significantly lower for pantoprazole (HR = 0.59 [95% CI, 0.37-0.95]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.52 [95% CI, 0.91-2.54]).

Conclusions: The Hepatotoxicity Score provides a tool to adjust for confounding due to concomitant hepatotoxic drug exposure within hepatic safety studies.

Keywords: acute liver injury; confounding; hepatotoxicity.

FIGURE 1

Selection flow for the evaluation of the Hepatotoxicity Score as a confounder among initiators of proton pump inhibitors. ^*Baseline severe acute liver injury defined by either of the following definitions within the first two days of hospital admission: 1) alanine aminotransferase > 120 U/L (3 times upper limit of normal, 40 U/L) + total bilirubin > 2.0 mg/dL (2 times upper limit of normal, 1.0 mg/dL) (definition 1), or 2) international normalized ratio ≥ 1.5 + total bilirubin > 2.0 mg/dL (definition 2). ^†Other baseline evidence of liver injury defined as any of the following during the baseline period: (1) one alanine aminotransferase > 100 U/L, (2) two alanine aminotransferases ≥ 40 U/L separated by at least 6 months, or (3) or one alkaline phosphatase > 172 mg/dL (1.5 times the upper limit of normal).

FIGURE 2

Hazard ratios with 95% confidence intervals of severe acute liver injury for category of Hepatotoxicity Score among initiators of proton pump inhibitors, adjusted for age, sex, obesity (body mass index ≥ 30 kg/m²), diabetes mellitus, hyperlipidemia, and heart failure. CI = confidence interval; HR = hazard ratio.