Assessment of Ototoxicity in Patients With Heart Failure Receiving High-Dose IV Loop Diuretics

Importance: Concern for ototoxicity hinders loop diuretic (LD) dosing in heart failure (HF); given the mechanism by which LDs affect the ear, high-dose LDs should produce transient, not permanent, hearing changes. Objective: To measure the association of LD dose with permanent and temporary ototoxicity. Design, Setting, and Participants: Cohort 1 received a randomized sequence of LD doses (bumetanide, 1.25-10 mg) across study visits with serial audiometry assessments. Cohort 2 received serial LD up to furosemide 500-mg doses during a HF hospitalization with audiometry at baseline and prior to discharge. Cohort 3 retrospectively characterized clinically diagnosed ototoxicity in HF hospitalizations was defined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes. Cohorts 1 and 2 were single center, while cohort 3 was multicenter. Cohort 1 studied outpatient participants with stable HF, while cohort 2 (n = 40) and cohort 3 studied hospitalized patients with acute HF. Exposure: Intravenous LD. Main Outcomes and Measures: The primary outcomes were clinically diagnosed ototoxicity and hearing changes via audiometry. Results: Cohort 1 contained 50 participants, cohort 2 contained 40 participants, and cohort 3 contained 22 656 participants. In cohort 1, mean (SD) participant age was 63.2 (10.4) years, and 21 of 50 participants (42%) were women. In cohorts 1 and 2, clinically diagnosed ototoxicity was not observed. In cohort 1, at peak diuretic concentration, worsening hearing shifts were infrequent (24 ears of 400 doses [6%]) but were more common with higher doses (odds ratio [OR], 1.99; 95% CI, 1.21-3.28 per doubling dose; P = .007). Within hours, hearing shifts largely resolved and were absent in 98% of measurements (393 ears of 400 doses). No significant association between LD dose and hearing shifts was present at any time aside from peak LD concentration. In cohort 2, hearing shifts were not different across groups divided by the median daily LD dose and were not associated with LD dose (OR, 1.19; 95% CI, 0.71-1.98 per doubling dose; P = .52). In cohort 3, 608 HF hospitalizations (2.7%) had clinically diagnosed ototoxicity. In multivariable analyses, peak dose of 160 mg furosemide equivalents or greater (OR, 0.83; 95% CI, 0.52-1.31; P = .43) and 400 mg furosemide equivalents or greater (OR, 1.28; 95% CI, 0.71-2.31; P = .41) were not associated with greater clinically diagnosed ototoxicity risk relative to less than 160 mg. Conclusions and Relevance: In this analysis of 2 small HF cohorts, short-term exposure to high-dose LD was not associated with permanent ototoxicity, although concomitant ototoxin use was excluded. Future studies are needed to understand the risk of ototoxicity with repeated LD exposure and in broader HF populations. Trial Registration: ClinicalTrials.gov Identifiers: NCT04481919 and NCT05323487.