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 servo-ventilation (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 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). 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 sound-abatement 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 2·8–3·7 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 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77–1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66–1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68–1·46; p=0·98) and for CSA was 0·74 (0·44–1·23; p=0·25). 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.

中文翻译：

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适应性伺服通气治疗射血分数降低心力衰竭患者的睡眠呼吸障碍 (ADVENT-HF)：一项多中心、多国、平行组、开放标签、3 期随机对照试验

背景

在心力衰竭和射血分数降低的患者中，睡眠呼吸障碍（包括阻塞性睡眠呼吸暂停（OSA）和中枢性睡眠呼吸暂停（CSA））与发病率、死亡率和睡眠中断增加相关。我们假设用峰值流量触发自适应伺服通气（ASV）装置治疗睡眠呼吸障碍将改善心力衰竭和射血分数降低患者的心血管结局。

方法

我们对 18 岁或以上患有心力衰竭且射血分数降低（左心室射血分数≤45%）的患者进行了一项多中心、多国、平行组、开放标签、3 期随机对照试验，研究对象为峰值流量触发 ASV。并存的睡眠呼吸障碍（呼吸暂停低通气指数 [AHI] ≥ 15 次/小时睡眠）经过最佳药物治疗后稳定下来，并进行了隐藏分配和盲法结果评估。该试验在 9 个国家的 49 家医院进行。睡眠呼吸障碍被分为主要为 OSA（Epworth 嗜睡量表评分为 10 或更低）或主要为 CSA。参与者被随机分配接受单独标准最佳治疗或标准最佳治疗加 ASV (1:1)，按研究地点和睡眠呼吸暂停类型（即 CSA 或 OSA）分层，随机排列大小为 4 和 6 的块命令。在随机分组后的第 1、3 和 6 个月以及此后每 6 个月进行一次临床评估，最多持续 5 年。主要终点是全因死亡率、因心血管原因首次入院、新发心房颤动或扑动以及适当的心脏复律除颤器电击的综合累积发生率。全因死亡率是次要终点。主要结局分析是在意向治疗人群中进行的。该试验已在ClinicalTrials.gov（ NCT01128816）和国际标准随机对照试验编号登记册（ISRCTN67500535）注册，试验已完成。

发现

首次和最后一次注册时间为 2010 年 9 月 22 日和 2021 年 3 月 20 日。由于与 COVID-19 相关的限制，注册提前终止。筛选了 1127 名患者，其中 731 名 (65%) 患者被随机分配接受标准护理（n=375；每小时睡眠平均 AHI 42·8 事件 [SD 20·9]）或标准护理加 ASV（n= 356；每小时睡眠 43·3 个事件 [20·5]）。所有患者的随访最迟于 2021 年 6 月 15 日结束，当时试验因电机消声材料可能崩解而召回 ASV 装置而提前终止。在试验过程中，41 名（6%）参与者撤回同意，34 名（5%）参与者失访。在 ASV 组中，在试验过程中，平均 AHI 下降至每小时 2·8–3·7 次事件，随机分组后 1 个月评估睡眠质量的相关改善。在平均 3·6 年 (SD 1·6) 的随访期内，ASV 对主要复合结局没有影响（对照组有 180 起事件，ASV 组有166 起事件；风险比 [HR] 0·95 ，95% CI 0·77–1·18；p=0·67）或全因死亡率的次要终点（对照组死亡 88 例，ASV组死亡 76 例；0·89、0·66– 1·21；p=0·47)。对于 OSA 患者，全因死亡率的 HR 为 1·00 (0·68–1·46；p=0·98)，CSA 患者的全因死亡率 HR 为 0·74 (0·44–1·23；p=0 ·25）。未发现与 ASV 使用相关的安全问题。

解释

对于患有心力衰竭、射血分数降低和睡眠呼吸障碍的患者，ASV 对主要复合结局或死亡率没有影响，但安全地消除了睡眠呼吸障碍。

资金

加拿大健康研究院和飞利浦 RS 北美公司。