Rationale Acetazolamide and atomoxetine-plus-oxybutynin (‘AtoOxy’) can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone. Methods In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions. Outcomes were assessed at baseline and night 3 of each treatment period. Mixed model analysis compared the reduction in Apnoea-Hypopnoea Index (AHI) from baseline between AtoOxy-plus-acetazolamide and AtoOxy (primary outcome). Secondary outcomes included hypoxic burden and arousal index. Results Although AtoOxy lowered AHI by 49 (33, 62)%baseline (estimate (95% CI)) vs placebo, and acetazolamide lowered AHI by+34 (14, 50)%baseline vs placebo, AtoOxy-plus-acetazolamide was not superior to AtoOxy alone (difference: −2 (−18, 11)%baseline, primary outcome p=0.8). Likewise, the hypoxic burden was lowered with AtoOxy (+58 (37, 71)%baseline) and acetazolamide (+37 (5, 58)%baseline), but no added benefit versus AtoOxy occurred when combined (difference: −13 (−5, 39)%baseline). Arousal index was also modestly reduced with each intervention (11%baseline–16%baseline). Mechanistic analyses revealed that similar traits (ie, higher baseline compensation, lower loop gain) were associated with both AtoOxy and acetazolamide efficacy. Conclusions While AtoOxy halved AHI, and acetazolamide lowered AHI by a third, the combination of these leading experimental interventions provided no greater efficacy than AtoOxy alone. Failure of acetazolamide to further increase efficacy suggests overlapping physiological mechanisms. Trial registration number [NCT03892772][1]. Data are available on reasonable request. Individual patient signals and summary data will data be made available after publication to researchers who provide a methodologically sound 1-page proposal; requestors will be asked to sign a data use agreement. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03892772&atom=%2Fthoraxjnl%2F79%2F3%2F259.atom

中文翻译：

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针对睡眠呼吸暂停多种机制的联合药物治疗：一项随机对照交叉试验

基本原理 乙酰唑胺和阿托莫西汀加奥昔布宁 (AtoOxy) 可以分别通过稳定通气控制和改善扩张肌反应性来改善阻塞性睡眠呼吸暂停 (OSA)。鉴于每种干预措施针对的病理生理机制不同，我们测试了 AtoOxy 加乙酰唑酰胺是否比单独使用 AtoOxy 更有效。方法 在一项多中心随机交叉试验中，19 名中重度 OSA 患者在睡前服用 AtoOxy（80/5 mg）、乙酰唑胺（500 mg）、AtoOxy 加乙酰唑胺或安慰剂，连续三个晚上（第一天剂量减半）晚上），条件之间有 4 天的冲洗。在基线和每个治疗期的第三晚评估结果。混合模型分析比较了 AtoOxy 加乙酰唑酰胺和 AtoOxy 之间呼吸暂停低通气指数 (AHI) 从基线的降低情况（主要结果）。次要结局包括缺氧负担和觉醒指数。结果 尽管与安慰剂相比，AtoOxy 使 AHI 降低了 49 (33, 62)% 基线（估计值 (95% CI)），乙酰唑胺与安慰剂相比使 AHI 降低了 +34 (14, 50)% 基线，但 AtoOxy 加乙酰唑酰胺并不优于安慰剂单独使用 AtoOxy（差异：−2 (−18, 11)%基线，主要结果 p=0.8）。同样，AtoOxy（+58 (37, 71)% 基线）和乙酰唑胺（+37 (5, 58)% 基线）降低了缺氧负担，但组合使用时，与 AtoOxy 相比没有带来额外的益处（差异：-13 (- 5, 39)%基线)。每次干预后，唤醒指数也略有降低（11% 基线 - 16% 基线）。机制分析表明，相似的特征（即较高的基线补偿、较低的环路增益）与 AtoOxy 和乙酰唑胺的功效相关。结论 虽然 AtoOxy 将 AHI 减半，乙酰唑胺将 AHI 降低三分之一，但这些领先的实验干预措施的组合并没有比单独使用 AtoOxy 提供更大的疗效。乙酰唑胺未能进一步提高功效表明存在重叠的生理机制。试验注册号[NCT03892772][1]。可根据合理要求提供数据。个体患者信号和摘要数据将在发表后提供给提供方法上合理的单页提案的研究人员；请求者将被要求签署数据使用协议。 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03892772&atom=%2Fthoraxjnl%2F79%2F3%2F259.atom