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. 2024 Sep 19:76:102843.
doi: 10.1016/j.eclinm.2024.102843. eCollection 2024 Oct.

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

Jean-Louis Pépin  1   2 , Philippe Lehert  3   4 , Raoua Ben Messaoud  2 , Marie Joyeux-Faure  1   2 , Christian Caussé  5 , Jerryll Asin  6 , Ferran Barbé  7 , Maria R Bonsignore  8   9 , Winfried Randerath  10 , Johan Verbraecken  11   12 , Sonya Craig  13 , Yves Dauvilliers  14   15
Affiliations

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

Jean-Louis Pépin et al. EClinicalMedicine. .

Abstract

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.

Keywords: Network meta-analysis; Obstructive sleep apnoea; Systematic review.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Study selection.
Fig. 2
Fig. 2
Network diagram for efficacy outcomes. The thickness of lines (edges) joining two treatments is proportional to the inverse standard error of the comparison between these two treatments. The number in the middle of each edge is the number of studies used for estimating the effect between the two joined treatments. Each treatment is represented by a green circle with a radius that is proportional to the number of the patients having received this treatment. MDF2, modafinil 200 mg; MDF4, modafinil 400 mg; PITL, pitolisant; PLAC, placebo; SMFT, solriamfetol.
Fig. 3
Fig. 3
A. Forest plot for efficacy Z-score (ESS + OSLER/MWT). Random Effects Model, effect sizes (95% CI) relative to placebo are shown. MDF2, modafinil 200 mg; MDF4, modafinil 400 mg; PITL, pitolisant; SMFT, solriamfetol. B. Forest plot for overall safety (risk ratio). Random Effects Model, effect sizes (95% CI) relative to placebo are shown. Comparison of Risk Ratios of at least one Treatment-Emergent Adverse Event (TEAE) of any type. MDF2, modafinil 200 mg; MDF4, modafinil 400 mg; PITL, pitolisant; SMFT, solriamfetol. C. Forest plot for cardiovascular safety (risk ratio). Random Effects Model, effect sizes (95% CI) relative to placebo are shown. MDF2, modafinil 200 mg; MDF4, modafinil 400 mg; PITL, pitolisant; SMFT, solriamfetol. D. Forest plot for benefit/risk BR ratio. Random Effects Model, effect sizes (95% CI) relative to placebo are shown. MDF2, modafinil 200 mg; MDF4, modafinil 400 mg; PITL, pitolisant; SMFT, solriamfetol.
Fig. 4
Fig. 4
Principal components analysis (PCA) of each treatment relative to efficacy (EFFIC), safety, benefit-risk (BR) and quality of life (QOL) axes (green lines). This is a summarized graphical comparison of treatments on multiple possibly discordant criteria in showing the treatments and the characteristics (efficacy, safety, QoL benefit-risk) on the two main factors F1 (Explained Variance [EV] = 48%) and F2 (EV = 34%) of a principal components analysis (PCA). The figure allows various conclusions: (1) Each characteristic (Efficacy, Safety, Benefit-risk and Quality of life) is represented by a green directed axis. The angle between two variables visualizes their correlation, axes with opposed directions are inversely correlated: QoL and efficacy are correlated, whereas safety and efficacy are inversely correlated. (2) The projections of each treatment on an axis are an approximate measure of the treatment on this axis, and the axis origin is the average for all the measurements. For instance, looking at safety by decreasing value, the best treatment is placebo (P5 point) followed by pitolisant (P4), etc. until solriamfetol (P1) whereas, for efficacy, the projections are in reverse order. (3) The mutual position of the treatments (blue points) suggests a visual clustering: placebo alone with an obvious image of good safety combined with a lack of efficacy; the two treatments SMFT and MDF4 characterized by good efficacy but less satisfactory safety, MDF2 assimilable with this group. Finally, pitolisant constitutes a third cluster characterized by both satisfactory efficacy and safety resulting in an optimal benefit-risk value. QoL appears to be more correlated with efficacy, and SMFT, MDF4 and PITL are shown to be similar on this dimension. MDF2, modafinil 200 mg; MDF4, modafinil 400 mg; PITL, pitolisant; PLAC, placebo; SMFT, solriamfetol. Projections of each treatment on the safety axis are shown for placebo (P5), pitolisant (P4), modafinil 200 mg (P3), modafinil 400 mg (P2), and solriamfetol (P1).
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