Comparative efficacy, safety and benefit/risk of alerting agents for excessive daytime sleepiness in patients with obstructive sleep apnoea: a network meta-analysis.

Background: Obstructive sleep apnoea (OSA) is a common chronic respiratory disease associated with a high burden of disabilities related to sleepiness and reduced quality of life. Despite first-line treatment with continuous positive airway pressure (CPAP) therapy, many patients experience residual excessive daytime sleepiness (EDS). The aim of this study is to compare the relative efficacy and safety of medications authorised for this indication in Europe and/or the United States (modafinil/armodafinil, solriamfetol, and pitolisant) for OSA.
Methods: In this systematic review and network meta-analysis, randomised controlled trials (RCTs) that compared the efficacy and safety of authorised medications for adult patients with OSA were identified by literature searches of PubMed, Embase and ClinicalTrials.gov databases (up to 12 June 2024). The primary efficacy endpoint was combined Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance (OSLER)/Maintenance of Wakefulness Test (MWT) Z-scores. Quality of life (QoL), overall and specific cardiovascular safety, and benefit-risk ratios were calculated. The study was registered with PROSPERO: CRD42023434640.
Findings: Of 4017 studies identified, a total of 20 RCTs involving 4015 patients were included. Analysis of combined subjective (ESS) and objective (OSLER/MWT) efficacy outcome Z-scores showed that solriamfetol (150 mg; effect size [ES] = 0.66 [95% CI: 0.36, 0.96]), pitolisant (20 mg; ES = 0.66 [95% CI: 0.44, 0.88]), and modafinil (200 mg; ES = 0.54: [95% CI: 0.33, 0.74]); 400 mg; ES = 0.54 [95% CI: 0.42, 0.65]) had a clinically meaningful improvement in efficacy. P-scores ranked placebo, then pitolisant, modafinil 200 mg, modafinil 400 mg and solriamfetol for overall safety; and pitolisant, then solriamfetol, modafinil 400 mg and modafinil 200 mg for benefit-risk ratio.
Interpretation: Pitolisant, solriamfetol and modafinil had comparable efficacy for maintaining wakefulness in patients with OSA. Pitolisant had a better safety profile and benefit-risk ratio compared with solriamfetol and modafinil. The overall and cardiovascular safety risk ratios suggest that pitolisant might be the best candidate for patients with OSA with multiple cardiovascular comorbidities.
Funding: Bioprojet.
Competing Interests: This analysis has been sponsored by Bioprojet Pharma. Jean-Louis Pépin has received grants or contracts from the National Research Agency, and lecture fees and travel grants from RESMED, SEFAM and Bioprojet. Jerryll Asin received support from Bioprojet for attending meetings and/or travel; received grants or contracts (paid to his institute) from Philips, Somnomed and Zoll Respicardia; consulting fees (paid to his institute) from Zoll Respicardia; participation on a Data Safety Monitoring Board or Advisory Board (paid to his institute) from Zoll Respicardia; member of the Dutch Association of Sleep Medicine (no payment). Ferran Barbé received support from Bioprojet for attending meetings and/or travel; received grants or contracts for sleep research from Instituto de Salud Carlos III. Maria Bonsignore received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bioprojet and Takeda; support for attending meetings and/or travel from Bioprojet; participation on a Data Safety Monitoring Board or Advisory Board for Bioprojet. Winfried Randerath received study funding from Bioprojet; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Heinen & Löwenstein, Habel Medizintechnik, Jazz Pharmaceuticals, Inspire, Philips Respironics and Bioprojet; support for attending meetings and/or travel from Heinen & Löwenstein, Habel Medizintechnik, Jazz Pharmaceuticals, Philips Respironics and Bioprojet; personal fees for participation on a Data Safety Monitoring Board or Advisory Board for Bioprojet, Jazz Pharmaceuticals and Procter & Gamble; unpaid roles with the European Respiratory Society Head Assembly 4, Sleep Disordered Breathing (until September 2023), Guidelines Director elect 2024 and the German Respiratory Society, Secretary General (until March 2024), authorised member since March 2024. Johan Verbraecken received study funding from Bioprojet; support for teaching courses (paid to his institute) from Air Liquide, Bioprojet, Inspire Medical Systems, Löwenstein Medical, Medidis, Mediq Tefa, Micromed OSG, Philips, ProSomnus, ResMed, Sefam, SomnoMed, SOS Oxygène, Tilman, Total Care, Vivisol, and Zoll Itamar outside the submitted work; royalties or licenses (paid to his institute) from Epilog; consulting fees (paid to his institute) from Desitin and Epilog; payment of honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (paid to his institute) from Atos Medical, Idorsia, Inspire Medical Systems; support for attending meetings and/or travel from Bioprojet; past-President (since 2020) of the Belgian Association for Sleep Research and Sleep Medicine. Yves Dauvilliers received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educationa events from Jass Pharmaceuticals, Bioprojet, Takeda, UCB, Orexia, Idorsia and Avadel; support for attending meetings and/or travel from Jazz Pharmaceuticals, Bioprojet and Avadel; participation on a Data Safety Monitoring Board or Advisory Board for Idorsia. Raoua Ben Messaoud, Marie Joyeux-Faure and Sonya Craig have no declaration of interest.
(© 2024 The Authors.)