Combination Drug Therapy with Acetazolamide, Eszopiclone +/- Venlafaxine for Obstructive Sleep Apnea (RESCUE-Combo): A Randomized, Double-blind, Placebo-controlled Trial.

Abstract

Introduction: Acetazolamide, eszopiclone, and venlafaxine may target different underlying mechanisms of obstructive sleep apnea (OSA) and individually may partially improve OSA severity in select patients. We tested whether acetazolamide+eszopiclone (DualRx) improves OSA severity. We further explored whether addition of venlafaxine (TripleRx) improves OSA in patients who do not fully respond to DualRx.

Methods: In this double-blind, crossover trial, twenty OSA patients underwent a baseline polysomnography followed by DualRx/Placebo phases in random order. Subsequently, 18 patients underwent an open-label TripleRx phase. Each phase lasted 3 days and concluded with polysomnography. The primary outcome was the placebo-adjusted change in apnea-hypopnea index during supine, non-rapid eye movement sleep (AHINREM,supine) from baseline to DualRx. Secondary outcomes included other OSA metrics, sleep parameters, and select clinical outcomes (blood pressure, symptoms, vigilance).

Results: Participants were on average middle-aged, overweight and relatively diverse (20% women, 60% non-white) with severe OSA (median [IQR] AHINREM,supine 32.8 [20-48.8] events/h). Compared with placebo, DualRx was well tolerated, improved the AHINREM,supine (-13.8 [-24.1 to -5.2] events/h or -45 [-77 to -14] %, PWilcoxon=0.003), AHIOverall, hypoxic burden and sleep architecture (P<0.05), but not the selected clinical outcomes. TripleRx did not provide a clear benefit relative to DualRx, although some measures of OSA-related hypoxemia improved more substantially. There were no serious side effects.

Discussion: Short-term use of dual-drug therapy with acetazolamide+eszopiclone substantially improved OSA severity. Adding venlafaxine did not generally improve OSA severity but may be beneficial for some patients. Longer term studies are needed to assess effects on clinically important outcomes. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT04639193.