Combination Drug Therapy with Acetazolamide, Eszopiclone ± Venlafaxine for Obstructive Sleep Apnea (RESCUE-Combo): A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

<b>Rationale:</b> Acetazolamide, eszopiclone, and venlafaxine may target different underlying mechanisms of obstructive sleep apnea (OSA) and individually may partially reduce OSA severity in select patients. We tested whether acetazolamide plus eszopiclone (DualRx) reduces OSA severity. We further explored whether the addition of venlafaxine (TripleRx) alleviates OSA in patients who do not fully respond to DualRx. <b>Methods:</b> In this double-blind crossover trial, 20 patients with OSA underwent 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 (AHI_NREM,supine) from baseline to DualRx. Secondary outcomes included other OSA metrics, sleep parameters, and select clinical outcomes (blood pressure, symptoms, and vigilance). <b>Results:</b> Participants were on average middle aged, overweight, and relatively diverse (20% women, 60% non-White), with severe OSA (median [interquartile range] AHI_NREM,supine, 32.8 [20 to 48.8] events/h). Compared with placebo, DualRx was well tolerated and improved AHI_NREM,supine (-13.8 [-24.1 to -5.2] events/h or -45% [-77% to -14%]; <i>P</i>_Wilcoxon = 0.003), overall AHI, hypoxic burden, and sleep architecture (<i>P</i> < 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. <b>Conclusions:</b> Short-term use of dual-drug therapy with DualRx substantially reduced OSA severity. Adding venlafaxine did not generally reduce OSA severity but may be beneficial for some patients. Longer term studies are needed to assess effects on clinically important outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT04639193).