Preventive Effect of Angiotensin II Receptor Blockers on High-Dose Methotrexate-Induced Hepatotoxicity Determined Using a Hospital-Based Database Analysis

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Hepatotoxicity is a major adverse effect of high-dose methotrexate (HD-MTX) therapy. Although preclinical studies have highlighted the potential of angiotensin receptor blockers (ARBs) to reduce the risk of MTX-induced hepatotoxicity, their clinical effects remain unknown. Therefore, we aimed to ascertain whether the preventive effect of ARBs on HD-MTX-induced hepatotoxicity is evident in a real-world setting using medical Big Data analysis. This study involved patients who received ≥1.5 g MTX as a single dose by injection between April 1, 2014 and August 31, 2022, and were registered in the JMDC hospital-based database. Factors potentially associated with the development of MTX-induced hepatotoxicity, in addition to concomitant use of ARBs, were selected as explanatory variables and analyzed using a Fine-Gray subdistribution hazard model, accounting for death as a competing event. A total of 243 patients received a single MTX dose of ≥1.5 g during the observation period; among them, 34 patients presented hepatotoxicity grades 3-4. Female sex, concomitant use of anticancer drugs, and a high baseline alanine aminotransferase value were associated with the development of MTX-induced hepatotoxicity. Although concomitant ARB use was associated with a hazard ratio below 1, this was not statistically significant (subdistribution hazard ratio: 0.249, 95% confidence interval: 0.031-1.990). Similar trends were observed in the sensitivity analysis with grade ≥2 hepatotoxicity as the outcome. While the concomitant use of ARBs had a potential preventive effect against HD-MTX-induced hepatotoxicity, its clinical significance appears to be lower than the effect of other known risk factors.