(B-248) Sacubitril-valsartan and Risk of Ototoxicity: A Disproportionality Analysis

Background: Sacubitril/Valsartan (Sacu-Val), the first angiotensin receptor neprilysin inhibitor, was approved by the FDA in 2015 for the treatment of heart failure with reduced ejection fraction. Following its approval, concerns about potential ototoxicity emerged, but data remain limited.

Objectives: To assess the association between Sacu-Val and the risk of hearing impairment and vestibular disorders compared to Lisinopril and Losartan using data from the FDA Adverse Event Reporting System (FAERS).

Methods: Design and Setting: An active comparator-restricted disproportionality analysis of FAERS data (2015Q3–2023Q3) using MedDRA-v27.1 preferred terms, with analysis restricted to primary suspect cases.
Exposures and Outcome: Sacu-Val was compared to Lisinopril and Losartan as active comparators. The primary outcome was the frequency of hearing impairment and vestibular disorders reports.
Statistical Analysis: We calculated the Reporting Odds Ratios (RORs) adjusting for sex, age, and indication of use. We also calculated the Bayesian Information Component (IC) and Empirical Bayes Geometric Mean (EBGM).

Results: A total of 55,101 individual case safety reports (ICSRs) were analyzed: 28,091 reports for Sacu-Val (51.0%), 18,430 for Lisinopril (33.5%), and 8,580 for Losartan (15.6%). Hearing impairment was more frequently reported with Sacu-Val (1.47%) than with Lisinopril (0.53%) or Losartan (0.93%). The adjusted RORs for hearing impairment associated with Sacu-Val were 2.35 (95% CI, 1.80–3.06) compared to Lisinopril and 1.97 (95% CI, 1.46–2.66) compared to Losartan. For hypoacusis, Sacu-Val reports showed a significantly higher frequency of this adverse event, accounting for 71.91% of all hearing impairment reports. The adjusted ROR for hypoacusis with Sacu-Val was 15.03 (95% CI, 7.48–30.23) compared to Lisinopril and 7.44 (95% CI, 3.91–14.15) compared to Losartan. Bayesian analyses confirmed the findings, with Sacu-Val showing a higher-than-expected frequency of hypoacusis compared to both Lisinopril (EBGM 20.5, 90% CI 18.5–22.5) and Losartan (EBGM 7.97, 90% CI 7.22–8.76). Disproportionality analyses for vestibular disorders also indicated a higher frequency with Sacu-Val (1.47%) than with Lisinopril (0.53%) and Losartan (0.93%). The adjusted RORs for vestibular disorders were 2.58 (95% CI, 2.33–2.86) for Sacu-Val compared to Lisinopril and 1.78 (95% CI, 1.58–2.00) for Sacu-Val compared to Losartan.

Conclusions: Sacu-Val is associated with a higher incidence of reports of hearing impairment, including hypoacusis, and vestibular disorders, compared to Lisinopril and Losartan. Larger pharmacoepidemiologic studies are needed to confirm these findings.