Acetazolamide for Obstructive and Central Sleep Apnea: A Comprehensive Systematic Review and Meta-Analysis

ABSTRACT Background Therapy options for obstructive (OSA) and central (CSA) sleep apnea are limited, thus many patients remain untreated. Clinically acetazolamide is sometimes used for central sleep apnea (CSA), but given overlapping pathophysiology of OSA and CSA, we hypothesized that acetazolamide is equally effective for both types. Prior reviews focused on specific subtypes of sleep apnea, study designs and languages, thus including few studies (typically ≤3) limiting insights. Research Question How efficacious is acetazolamide for sleep apnea, and is its effect modified by sleep apnea type or acetazolamide dose? Study Design and Methods We queried MEDLINE, EMBASE and ClinicalTrials.gov from inception until 3/11/2019. Any study in which adults with OSA/CSA received oral acetazolamide vs no acetazolamide (control) reporting sleep apnea-related outcomes was eligible, independent of study design or language. Two reviewers independently assessed eligibility and abstracted data. Primary outcomes were apnea-hypopnea index (AHI) and SpO2 nadir. Quality of evidence (QoE) was rated using GRADE-methodology. Results We included 28 studies (13 OSA/15 CSA; NSubjects,Acetazolamide=542, NSubjects,Control=553) enabling meta-analyses for 24 outcomes. Acetazolamide doses ranged from 36-1000mg/day and treatment duration from 1-90 days (median 6days). Overall, acetazolamide vs control lowered the AHI by -0.7 effect sizes (95%-CI -0.83 to -0.58; I2=0%; moderate QoE) corresponding to a reduction of 37.7% (95%-CI -44.7 to -31.3) or 13.8/h (95%-CI -16.3 to -11.4; AHIControl=36.5/h). The AHI reduction was similar in OSA vs CSA, but significantly greater with higher doses (at least up to 500mg/day). Furthermore, acetazolamide improved SpO2 nadir by +4.4% (95%-CI 2.3 to 6.5; I2=63%; no evidence of effect modification; very low QoE) and several secondary outcomes including sleep quality measures and blood pressure (mostly low QoE). Interpretation Short-term acetazolamide improved both OSA and CSA. Rigorous studies with long-term follow-up are warranted to assess acetazolamide’s value for the chronic management of sleep apnea patients.