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

Abstract

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.

Keywords: OSA pharmacotherapy; OSA phenotypes; noradrenergic and antimuscarinic.

Figure 1

Consolidated Standards of Reporting Trials diagrams of the clinical trial testing ato-oxy (A) and of the trial testing the effects of the drugs administered alone (B). Results of the primary outcome analysis were previously published in Taranto-Montemurro et al. ato-oxy = combination of atomoxetine and oxybutynin.

Figure 1

Consolidated Standards of Reporting Trials diagrams of the clinical trial testing ato-oxy (A) and of the trial testing the effects of the drugs administered alone (B). Results of the primary outcome analysis were previously published in Taranto-Montemurro et al. ato-oxy = combination of atomoxetine and oxybutynin.

Figure 2

Individual data showing the effect of ato-oxy on the endotypic traits assessed during spontaneous breathing during NREM (A) and REM (B). Vpassive and Vactive were increased with ato-oxy. The arousal threshold and LG were reduced on ato-oxy. LG of the respiratory system was calculated here at the frequency of one cycle/min. Lines indicate mean values. AHI = apnea-hypopnea index; NREM = non-rapid eye movement sleep; %_eupnea = percentage of the eupneic level of ventilation; REM = rapid eye movement sleep; Vactive = ventilation at the arousal threshold; Vpassive = ventilation at eupneic drive. See Figure 1 legend for expansion of other abbreviation.

Figure 3

Group data showing the effects of atomoxetine, oxybutynin, and ato-oxy (in combination) on the endotypic traits in all patients during NREM sleep. Only the patients who performed the study with the P_es measurement were included in the analysis: n = 17 for placebo and ato-oxy in combination; n = 6 for atomoxetine and oxybutynin administered alone. The Consolidated Standards of Reporting Trials diagrams in Figure 1 also provide more details. Lines represent means, and the boxes indicate 95% CIs from mixed effects model analysis (Model 2, Table 3). Muscle compensation data illustrate the model-estimated underlying effects of interventions on Vactive adjusting for Vpassive (equivalent to Vactive minus Vpassive but accounting for floor/ceiling effects). ∗P < .05, ^†P < .01, ^‡P < .001 vs placebo. P_es = esophageal pressure. See Figure 1 and 2 legends for expansion of other abbreviations.

Figure 4

Endograms of three representative patients on placebo and on ato-oxy. A, A patient with a severe OSA characterized by a bad anatomy (low Vpassive, blue dot), moderate muscle compensation (Vactive, red dot > Vpassive), and low arousal threshold (orange line) on placebo shows an impressive improvement in Vpassive and Vactive on the drugs; arousal threshold is slightly reduced. B, The patient has a good anatomy (Vpassive approximately 90%) on placebo but bad muscle compensation (Vactive is much lower than Vpassive), meaning that he cannot activate the upper airway dilator muscles during sleep despite an increase in ventilatory drive to > 200%_eupnea (negative effort dependence with high arousal threshold). On the drug, the negative effort dependence is greatly reduced, and the ventilation remains close to eupneic values even when the ventilatory drive is high. C, Patient with severe anatomy (low Vpassive), high arousal threshold, and very good muscle compensation (Vactive is much higher than Vpassive) on placebo. Vpassive is highly increased on ato-oxy, and ventilation remains close to eupnea even at higher ventilatory drive levels. Shaded areas indicate the interquartile range. See Figure 1 and 3 legends for expansion of abbreviations.

Figure 5

These plots show a significant direct relation between residual AHI (on ato-oxy) and AHI on placebo (left panel) and an inverse relation between residual AHI and the F_hypopneas (center panel). The right panel shows an inverse relation between the residual AHI and the ventilation when ventilatory drive is at eupneic level on placebo (Vpassive, right panel). Shaded blue areas include patients with a complete response on ato-oxy (> 50% reduction in AHI from placebo and AHI on drug < 10 events/h). Vertical dotted lines represent cutoff values between responders and nonresponders for each independent variable AHI: apnea-hypopnea index. Only 14 patients with P_es measurements and a baseline AHI > 10 events/h were included in this analysis. F_hypopneas = fraction of hypopneas (numbers of hypopneas/total obstructive events). See Figure 1 and 2 legends for expansion of abbreviations.