RationaleThere are insufficient data to inform the management of central sleep apnea (CSA) in patients with heart failure with reduced ejection fraction (HFrEF). Nocturnal oxygen therapy (NOT) has been postulated to benefit CSA patients with HFrEF but has not been rigorously studied.ObjectivesTo compare NOT with sham NOT (control) in heart failure (HF) patients receiving guideline-based HF therapy on the composite outcome of first occurrence of either mortality due to any cause, a lifesaving cardiovascular intervention, or an unplanned hospitalization for worsening HF, together with other secondary outcomes.MethodsA multisite, double-blind, sham-controlled randomized clinical trial was conducted from September 2019 to December 2021, when the study was terminated prematurely because of slow enrollment. Cox proportional-hazards regression models were used to analyze time-to-event outcomes.ResultsNinety-eight participants (mean left ventricular ejection fraction, 27.8 ± 9.6%; mean central apnea–hypopnea index, 30.6 ± 18.2 events/h) were randomized and followed for an average of 10.8 ± 6.3 months. A total of 22 events met the criteria for the primary composite endpoint. The hazard ratio comparing the NOT group with the control group according to time to first event, adjusted for the stratification factor (hospitalization for HF in the past 12 mo and/or elevated outpatient brain natriuretic peptide or N-terminal pro–B-type natriuretic peptide concentration) was 1.46 (95% confidence interval, 0.65–3.29). No group differences in changes in patient-reported outcomes (HF-specific quality of life [Kansas City Cardiomyopathy Questionnaire], sleep disturbance and sleep-related impairment [Patient-reported Outcomes Measurement Information System], generic health [EQ-5D], or mood [Patient Health Questionnaire-8]) were observed at 6 months. Polysomnography showed improved indices of sleep-disordered breathing (apnea–hypopnea index, central apnea–hypopnea index, and time at oxygen saturation < 90%) with oxygen compared with room air.ConclusionsAlthough NOT improves CSA and overnight oxygenation, this prematurely terminated study does not provide support for the clinical effectiveness of NOT in patients with CSA and HFrEF.Clinical trial registered with www.clinicaltrials.gov (NCT 03745898).