Abstract：
BACKGROUND: 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.
BACKGROUND: NCT03892772.
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.
BACKGROUND: NCT03892772.
摘要：
背景：乙酰唑胺和托莫西汀联合奥昔布宁（AtoOxy）可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）。鉴于每种干预措施所针对的病理生理机制不同，我们测试了AtoOxy加乙酰唑胺是否比单独的AtoOxy更有效。
方法：在一项多中心随机交叉试验中，19例中度至重度OSA患者接受了AtoOxy（80/5mg），乙酰唑胺（500毫克），联合AtoOxy-plus-acetazolazamide或安慰剂在睡前三个晚上（第一个晚上的一半剂量），并在条件之间进行4天的冲洗。在基线和每个治疗期的第3晚评估结果。混合模型分析比较了AtoOxy加乙酰唑胺和AtoOxy之间的呼吸暂停-呼吸不足指数（AHI）从基线的降低（主要结果）。次要结果包括缺氧负荷和唤醒指数。
结果：尽管与安慰剂相比，AtoOxy将AHI降低了49（33，62）％的基线（估计值（95％CI）），与安慰剂相比，乙酰唑胺使AHI基线降低+34(14，50)%，AtoOxy加乙酰唑胺并不优于单独的AtoOxy（差异：-2（-18，11）％基线，主要结果p=0.8)。同样，用AtoOxy（+58（37，71）％基线）和乙酰唑胺（+37（5，58）％基线）降低低氧负荷，但与AtoOxy相比，合并时没有增加益处（差异：-13（-5，39）％基线）。每次干预时，唤醒指数也略有降低（基线11％-基线16％）。机理分析显示，相似的特征(即，较高的基线补偿，较低的环增益）与AtoOxy和乙酰唑胺疗效相关。
结论：虽然AtoOxy将AHI减半，乙酰唑胺将AHI降低了三分之一，这些主要的实验干预措施的组合没有比单独的AtoOxy提供更大的疗效。乙酰唑胺不能进一步增加功效提示重叠的生理机制。
背景：NCT03892772。
方法：在一项多中心随机交叉试验中，19例中度至重度OSA患者接受了AtoOxy（80/5mg），乙酰唑胺（500毫克），联合AtoOxy-plus-acetazolazamide或安慰剂在睡前三个晚上（第一个晚上的一半剂量），并在条件之间进行4天的冲洗。在基线和每个治疗期的第3晚评估结果。混合模型分析比较了AtoOxy加乙酰唑胺和AtoOxy之间的呼吸暂停-呼吸不足指数（AHI）从基线的降低（主要结果）。次要结果包括缺氧负荷和唤醒指数。
结果：尽管与安慰剂相比，AtoOxy将AHI降低了49（33，62）％的基线（估计值（95％CI）），与安慰剂相比，乙酰唑胺使AHI基线降低+34(14，50)%，AtoOxy加乙酰唑胺并不优于单独的AtoOxy（差异：-2（-18，11）％基线，主要结果p=0.8)。同样，用AtoOxy（+58（37，71）％基线）和乙酰唑胺（+37（5，58）％基线）降低低氧负荷，但与AtoOxy相比，合并时没有增加益处（差异：-13（-5，39）％基线）。每次干预时，唤醒指数也略有降低（基线11％-基线16％）。机理分析显示，相似的特征(即，较高的基线补偿，较低的环增益）与AtoOxy和乙酰唑胺疗效相关。
结论：虽然AtoOxy将AHI减半，乙酰唑胺将AHI降低了三分之一，这些主要的实验干预措施的组合没有比单独的AtoOxy提供更大的疗效。乙酰唑胺不能进一步增加功效提示重叠的生理机制。
背景：NCT03892772。
