Effects of the Combination of Atomoxetine and Oxybutynin on OSA Endotypic Traits

BACKGROUND: We recently showed that administration of the combination of the noradrenergic drug atomoxetine plus the antimuscarinic oxybutynin (ato-oxy) prior to sleep greatly reduced OSA severity, likely by increasing upper airway dilator muscle activity during sleep. In patients with OSA who performed the ato-oxy trial with an esophageal pressure catheter to estimate ventilatory drive, the effect of the drug combination (n = 17) and of the single drugs (n = 6) was measured on the endotypic traits over a 1-night administration and compared vs placebo. This study also tested if specific traits were predictors of complete response to treatment (reduction in apnea-hypopnea index [AHI] > 50% and < 10 events/h). METHODS: The study was a double-blind, randomized, placebo-controlled trial. The arousal threshold, collapsibility (ventilation at eupneic drive [Vpassive]), ventilation at arousal threshold, and loop gain (stability of ventilatory control, LG1), were calculated during spontaneous breathing during sleep. Muscle compensation (upper airway response) was calculated as a function of ventilation at arousal threshold adjusted for Vpassive. Ventilation was expressed as a percentage of the eupneic level of ventilation (%(eupnea)). Data are presented as mean [95% CI]. RESULTS: Compared with placebo, ato-oxy increased Vpassive by 73 [54 to 91]%(eupnea) (P<.001) and muscle compensation by 29 [8 to 51] %eupnea (P=.012), reduced the arousal threshold by-9 [-14 to -3]% (P=.022) and LG1 by -11 [-22 to 2]% (P=.022). Atomoxetine alone significantly reduced arousal threshold and LG1. Both agents alone improved collapsibility (Vpassive) but not muscle compensation. Patients with lower AHI, higher Vpassive, and higher fraction of hypopneas over total events had a complete response with ato-oxy. FINDINGS: Ato-oxy markedly improved the measures of upper airway collapsibility, increased breathing stability, and slightly reduced the arousal threshold. Patients with relatively lower AHI and less severe upper airway collapsibility had the best chance for OSA resolution with ato-oxy.