Efficacy of Pharmacotherapy for Obstructive Sleep Apnea in Adults: A Systematic Review and Network Meta-Analysis

Background: Obstructive sleep apnea (OSA) is highly prevalent and has significant health implications but treatment options are limited. The purpose of this systematic review and network meta-analysis is to summarize evidence on the efficacy of pharmacotherapy in adults with OSA and delineate the underlying mechanisms. Methods: Seven Databases (Medline, EMBASE, Cochrane, Web of Science, PsycInfo, Clinicaltrials.gov, ICTRP-WHO) were systematically screened for randomized controlled trials (RCTs) from their inception to September 01 2018. The primary outcome was effect on the apnea-hypopnea-index (AHI) based on data extracted from published reports. According to a pre-registered study protocol (PROSPERO-ID-CRD42018086446) network meta-analysis was used to obtain intervention effects. Findings: We identified 58 RCTs (n=1,710 patients) investigating 46 different drugs or drug-combinations. Interventions were classified into seven pathomechanism-groups and summarized narratively. A meta-analysis of 17 trials for seven drugs versus placebo (acetazolamide, donepezil, mirtazapine, ondansetron, paroxetine, protriptyline, theophylline) indicated a small effect for acetazolamide (mean difference in AHI -9·6/h [-17·7, -1·4]). In the network meta-analysis (I2=50%) nine drugs (tramazoline, liraglutide, spironolactone/furosemide, acetazolamide, dronabinol, zonisamide, phentermine, spironolactone, and ondansetron/fluoxetine) significantly lowered the AHI compared to placebo. Interpretation. Although some studies indicate favorable outcomes, these results are only valid for distinctive OSA-phenotypes or were not clinically significant. The effect sizes were small, the majority of trials were not adequately powered. There is currently insufficient evidence to recommend any pharmacotherapy for OSA and no phase-III trials are available. Future studies need to account for the underlying mechanisms of the intervention, as current evidence suggests that pharmacotherapy may not be a stand-alone therapy in OSA. Funding: There was no funding source for this study. Declaration of Interest: TG and MK served as consultants for Bayer AG for the conduction of a phase-II trial (BAY2253651) in pharmacotherapy in OSA. All other authors declare no competing interests.