Comparative Efficacy and Safety of Wakefulness-Promoting Agents for Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea

Background: Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. Purpose: To compare the effectiveness of drugs for EDS in OSA using network meta-analysis. Data Sources: MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022. Study Selection: Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention. Data Extraction: Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Data Synthesis: Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], −3.85 [95% CI, −5.24 to −2.50]; high certainty), and armodafinil–modafinil (MD, −2.25 [CI, −2.85 to −1.64]; moderate certainty) and pitolisant–H3-autoreceptor blockers (MD, −2.78 [CI, −4.03 to −1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil–modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant–H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil–modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events. Limitations: There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies. Conclusion: Solriamfetol, armodafinil–modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil–modafinil and may increase the risk for discontinuation with solriamfetol. Primary Funding Source: None.