Auditory system adverse events with sacubitril/valsartan: an active-comparator restricted disproportionality analysis using the FDA adverse event reporting system database

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, is used for heart failure with reduced ejection fraction. Emerging evidence suggests potential ototoxicity, including hearing loss and vestibular disorders, which remain underreported and poorly characterized. Our objective was to compare auditory adverse event (AE) reports associated with sacubitril/valsartan versus those associated with lisinopril and losartan. A retrospective active-comparator disproportionality analysis was conducted using individual case safety reports (ICSRs) from the U.S. FDA Adverse Event Reporting System (FAERS) via OpenFDA (2015Q3–2023Q3). The Medical Dictionary for Regulatory Activities (MedDRA) terms identified AEs related to hearing impairment, vestibular disorders, and hypoacusis. Adjusted reporting odds ratios (aRORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for age, sex, hypertension, and heart failure. Bayesian methods complemented the analysis. Among 55,101 ICSRs, 28,091 involved sacubitril/valsartan, with 590 (1.07%) reports of hearing impairment and 4,732 (8.58%) vestibular disorders. Compared to lisinopril, sacubitril/valsartan had higher aRORs for hearing impairment (2.35), vestibular disorders (2.58), and hypoacusis (15.03). Similar elevated risks were found versus losartan. Bayesian analysis confirmed these patterns. Sacubitril/valsartan may be associated with a higher risk of auditory AEs than lisinopril and losartan. These findings warrant further confirmation through pharmacoepidemiologic studies.