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

      research-article
      1 , 2 , , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 13 , 14 , 12 , 12 , 12
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      American Journal of Respiratory and Critical Care Medicine
      American Thoracic Society
      excessive daytime sleepiness, obstructive sleep apnea, continuous positive airway pressure, pitolisant

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          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).

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          Most cited references26

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          Obstructive sleep apnoea syndrome.

          Obstructive sleep apnoea syndrome (OSAS) is a common clinical condition in which the throat narrows or collapses repeatedly during sleep, causing obstructive sleep apnoea events. The syndrome is particularly prevalent in middle-aged and older adults. The mechanism by which the upper airway collapses is not fully understood but is multifactorial and includes obesity, craniofacial changes, alteration in upper airway muscle function, pharyngeal neuropathy and fluid shift towards the neck. The direct consequences of the collapse are intermittent hypoxia and hypercapnia, recurrent arousals and increase in respiratory efforts, leading to secondary sympathetic activation, oxidative stress and systemic inflammation. Excessive daytime sleepiness is a burden for the majority of patients. OSAS is also associated with cardiovascular co-morbidities, including hypertension, arrhythmias, stroke, coronary heart disease, atherosclerosis and overall increased cardiovascular mortality, as well as metabolic dysfunction. Whether treating sleep apnoea can fully reverse its chronic consequences remains to be established in adequately designed studies. Continuous positive airway pressure (CPAP) is the primary treatment modality in patients with severe OSAS, whereas oral appliances are also widely used in mild to moderate forms. Finally, combining different treatment modalities such as CPAP and weight control is beneficial, but need to be evaluated in randomized controlled trials. For an illustrated summary of this Primer, visit: http://go.nature.com/Lwc6te.
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            Trends in CPAP adherence over twenty years of data collection: a flattened curve

            Background Obstructive sleep apnea (OSA) is a common disorder, and continuous airway positive pressure (CPAP) is considered to be the gold standard of therapy. CPAP however is known to have problems with adherence, with many patients eventually abandoning the device. The purpose of this paper is to assess secular trends in CPAP adherence over the long term to see if there have been meaningful improvements in adherence in light of the multiple interventions proposed to do so. Methods A comprehensive systematic literature review was conducted using the Medline-Ovid, Embase, and Pubmed databases, searching for data regarding CPAP adherence over a twenty year timeframe (1994–2015). Data was assessed for quality and then extracted. The main outcome measure was reported CPAP non-adherence. Secondary outcomes included changes in CPAP non-adherence when comparing short versus long-term, and changes in terms of behavioral counseling. Results Eighty-two papers met study inclusion/exclusion criteria. The overall CPAP non-adherence rate based on a 7-h/night sleep time that was reported in studies conducted over the twenty year time frame was 34.1 %. There was no significant improvement over the time frame. Behavioral intervention improved adherence rates by ~1 h per night on average. Conclusions The rate of CPAP adherence remains persistently low over twenty years worth of reported data. No clinically significant improvement in CPAP adherence was seen even in recent years despite efforts toward behavioral intervention and patient coaching. This low rate of adherence is problematic, and calls into question the concept of CPAP as gold-standard of therapy for OSA.
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              Sleep apnoea and the brain: a complex relationship.

              Intermittent hypoxia, reoxygenation, and hypercapnia or hypocapnia occur in both adults and children during untreated apnoea and hypopnoea, along with changes in cerebral blood flow and sleep fragmentation. These effects can result in cognitive deficits with functional effects on work and school efficiency. The assessment of how obstructive sleep apnoea affects cognition depends on the specificity and sensitivity of the tests, which are rarely developed specifically for obstructive sleep apnoea. In this Review, we discuss both the neural adaptive and maladaptive processes in response to hypoxaemia. The net result on cognitive and emotional performance depends on the stage of this dynamic process, effects on other body systems, cognitive reserve, and idiosyncratic susceptibility. We also explore the contribution of fragmented sleep, and the disruption of sleep structure, with focus on the effect at different times in the development of disease. This Review will address the gap in the underlying pathophysiology of new clinical and translational findings, and argue their contribution to the inherent complexity of the association between obstructive sleep apnoea and the brain.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                1 May 2020
                1 May 2020
                1 May 2020
                1 May 2020
                : 201
                : 9
                : 1135-1145
                Affiliations
                [ 1 ]National Reference Center for Narcolepsy, Sleep and Wake Unit, Department of Neurology, Gui-de-Chauliac Hospital, Montpellier University Hospital, Montpellier, France
                [ 2 ]INSERM U1061, Montpellier University, Montpellier, France
                [ 3 ]Multidisciplinary Sleep Disorders Center, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
                [ 4 ]University of Antwerp, Antwerp, Belgium
                [ 5 ]Helsinki Sleep Clinic, Vitalmed Research Center, Helsinki, Finland
                [ 6 ]Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland
                [ 7 ]Sleep and Vigilance Laboratory, Department of Internal Medicine, University of Göteborg, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
                [ 8 ]Sleep Research Center, Department of Pulmonary Diseases and Clinical Allergology, University of Turku, Turku, Finland
                [ 9 ]Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland
                [ 10 ]Pulmonology Unit, Department of Internal Medicine, Alexandrovska Hospital Medical University, Sofia, Bulgaria
                [ 11 ]Department of Internal Diseases, Sveti Ivan Rilski Multiprofile Hospital for Active Treatment, Kozloduy, Bulgaria
                [ 12 ]Bioprojet, 30 rue Francs Bourgois, Paris, France
                [ 13 ]Hypoxia-Physiopathology (HP2) Laboratory, INSERM U1042, University Grenoble Alpes, Grenoble, France; and
                [ 14 ]Cardio-Respiratory Functional Exploration Laboratory (EFCR), Grenoble Alpes University Hospital, Grenoble, France
                Author notes
                Correspondence and requests for reprints should be addressed to Yves Dauvilliers, M.D., Ph.D., National Reference Center for Narcolepsy, Sleep and Wake Disorders Center, Department of Neurology, INSERM U1061, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295 Montpellier cedex 5, France. E-mail: ydauvilliers@ 123456yahoo.fr .

                A complete list of HAROSA II Study Group members may be found before the beginning of the R eferences.

                Author information
                http://orcid.org/0000-0003-0683-6506
                Article
                201907-1284OC
                10.1164/rccm.201907-1284OC
                7193861
                31917607
                f0c9d582-14ef-4f0b-b072-c310e6441bb0
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

                History
                : 01 July 2019
                : 08 January 2020
                Page count
                Figures: 3, Tables: 4, Pages: 11
                Categories
                Original Articles
                Sleep and Control of Ventilation

                excessive daytime sleepiness,obstructive sleep apnea,continuous positive airway pressure,pitolisant

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