O028 Combination Pharmacological Therapy Targeting Multiple Mechanisms of Sleep Apnea

Abstract

Introduction

Currently two leading experimental pharmacological interventions are under investigation for obstructive sleep apnea (OSA). Acetazolamide, which acts to stabilise ventilatory control, lowers the apnea-hypopnea index (AHI) by ∼38%. More recently, atomoxetine-plus-oxybutynin (“AtoOxy”), acting via improvements to dilator muscle responsiveness and baseline tone, was found to lower AHI by >50%. Given that each potential therapy targets a different pathophysiology, we tested whether combined AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone.

Methods

In a multicenter randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5mg respectively), acetazolamide (500mg), AtoOxy-plus-acetazolamide, or placebo at bedtime for 3 nights (half-dose on first night); outcomes were assessed at baseline and night 3 of each treatment period. Primary outcome: mixed model analysis compared the reduction in AHI(3% desaturation or arousal criterion) from baseline between AtoOxy-plus-acetazolamide and AtoOxy. Secondary outcomes included hypoxic burden, arousal index, and visual analog scale for sleep quality.

Results

Compared with placebo, AHI was lowered with AtoOxy by +49 [33, 62] %baseline (estimate [95%CI]), AtoOxy-plus-acetazolamide by +47 [31, 61]%baseline, and acetazolamide by +34 [14, 50]%baseline. However, there was no effect of AtoOxy-plus-acetazolamide vs. AtoOxy alone (−3 [−33, 20]%baseline, P=0.8). Secondary outcomes: AtoOxy, acetazolamide and combined AtoOxy-plus-acetazolamide each lowered hypoxic burden and arousal index, but no differential effect of combination therapy was observed. There was no impact on the visual analog scale for sleep quality.

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.