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Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial.

ABSTRACT: Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome.Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment.Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire.Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns.Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

SUBMITTER: Dauvilliers Y

PROVIDER: S-EPMC7193861 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Excessive daytime sleepiness (EDS) is a symptom of obstructive sleep apnea (OSA) that resolves under treatment with continuous positive airway pressure (CPAP). In some patients, sleepiness persists despite CPAP treatment. We retrospectively analyzed data on subjective residual EDS, assessed as an Epworth Sleepiness Scale score (ESS) >10, in patients from the European Sleep Apnea Database (n = 4,853, mean age ± SD 54.8 ± 11.8 years, 26.1% females), at baseline and at the first visit (median follow-up: 5 months, interquartile range 3-13). An ESS > 10 occurred in 56% of patients at baseline and in 28.2% of patients at follow-up. Residual EDS was analyzed in 2,190 patients (age: 55.1 ± 12.0 years, 26.1% females) with sleep monitoring data (median follow-up: 3 months, interquartile range 1-15). Sleep studies during CPAP use were obtained in 58% of these patients; EDS was reported by 47.2% of patients at baseline and by 30.3% at follow-up. Residual OSA, defined as an apnea-hypopnea index >10/h, and insufficient CPAP adherence, defined as nightly use <4 h, occurred with similar frequency in patients with and without EDS at follow-up. Prevalence of residual EDS was highest (40%) in patients with a first follow-up visit at 0-3 months, then it was 13-19% in patients with a first follow-up visit after 4 months to 2 years. The change in ESS (n = 2,190) was weakly correlated with CPAP use (R2 = 0.023, p < 0.0001). Logistic regression showed that an ESS score >10 at the first follow-up visit was associated directly with ESS at baseline and inversely with duration of follow-up, and CPAP use (R2 of the model: 0.417). EDS showed heterogeneity in different European countries both at baseline and at the first follow-up visit, suggesting modulation by cultural and lifestyle factors. In conclusion, residual EDS in CPAP-treated OSA occurred in approximately one in four patients at follow-up; its prevalence was highest (40%) in the first 3 months of treatment and subsequently decreased. The finding of residual EDS in a significant percentage of optimally treated OSA patients suggests that wake-promoting agents may be useful, but their indication should be evaluated after at least 3 months of treatment.

Project description:IntroductionWe performed a meta-analysis on whether heated humidification during positive airway pressure (PAP) could improve compliance and subjective daytime sleepiness in obstructive sleep apnea syndrome (OSAS) patients.Materials and methodsWe searched PubMed, EMBASE, Medline, Cochrane Library, Clinical Trials, Web of Science and Scopus from inception to Oct 29, 2017. We made meta-analysis on the all available randomized controlled trials (RCTs) which assessed effects of heated humidification intervention on PAP compliance and subjective daytime sleepiness, by subgroups of automatic adjusting positive airway pressure/ continuous positive airway pressure (APAP/CPAP) usage and patients with/without upper airway symptoms prior to PAP therapy.ResultsA total of nine RCTs were evaluated finally in this meta-analysis. When all the studies were pooled, heated humidification did not improve PAP usage time [weighted mean difference(WMD) = 13.28, 95% confidence interval(CI): -5.85 to 32.41, P = 0.17] or Epworth sleepiness scale (ESS) score (WMD = -0.63, 95% CI: -1.32 to 0.07, P = 0.08). In terms of PAP usage time, heated humidification failed to enhance compliance in both APAP (WMD = 22.34, 95%CI: -21.08 to 65.77, P = 0.31) or CPAP subgroup (WMD = 11.09, 95%CI: -10.21 to 32.40, P = 0.31) and it was also ineffective among patients with upper airway symptoms prior to PAP therapy (WMD = 22.74, 95% CI: -7.77 to 53.24, P = 0.14) or without (WMD = 13.22, 95%CI: -35.84 to 62.29, P = 0.60). In terms of ESS score, heated humidification did not reduce ESS scores in both APAP (WMD = -1.59, 95% CI: -3.81 to 0.64, P = 0.16) or CPAP subgroup (WMD = -0.39, 95% CI: -1.16 to 0.37, P = 0.32) and it was also helpless among patients with upper airway symptoms prior to PAP therapy (WMD = -1.17, 95% CI: -3.10 to 0.75, P = 0.23) or without (WMD = -0.30, 95%CI: -2.25 to 1.66, P = 0.76).ConclusionHeated humidification during PAP therapy improves neither the compliance nor ESS scores in OSAS patients, no matter what types of PAP or whether the patients had upper airway symptoms prior to PAP therapy. But to the population with upper airway symptoms and the APAP users, the conclusions were limited because of small sample size and possible selection bias. More attentions should be paid to these potentially possible benefited subgroups.

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Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial.

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