Adaptive Servo-Ventilation for Sleep-Disordered Breathing in Patients with Heart Failure with Reduced Ejection Fraction (ADVENT-HF): a Multicentre, Multinational, Parallel-Group, Open-Label, Phase 3 Randomised Controlled Trial.

Background In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servoventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. Methods We conducted a multicentre, multinational, parallel-group, open -label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction <= 45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] >= 15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all -cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All -cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. Findings The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42 center dot 8 events per h of sleep [SD 20 center dot 9]) or standard care plus ASV (n=356; 43 center dot 3 events per h of sleep [20 center dot 5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor soundabatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2 center dot 8-3 center dot 7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3 center dot 6 years (SD 1 center dot 6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0 center dot 95, 95% CI 0 center dot 77-1 center dot 18; p=0 center dot 67) or the secondary endpoint of all -cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0 center dot 89, 0 center dot 66-1 center dot 21; p=0 center dot 47). For patients with OSA, the HR for all -cause mortality was 1 center dot 00 (0 center dot 68-1 center dot 46; p=0 center dot 98) and for CSA was 0 center dot 74 (0 center dot 44-1 center dot 23; p=0 center dot 25). No safety issue related to ASV use was identified. Interpretation In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. Funding Canadian Institutes of Health Research and Philips RS North America. Copyright (c) 2023 Elsevier Ltd. All rights reserved.