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

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 mgld 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.Peer reviewe

Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP A Randomized Trial

BACKGROUND: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects. RESEARCH QUESTION: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS? STUDY DESIGN AND METHODS: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety. RESULTS: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS # 10 or change in ESS $ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported. INTERPRETATION: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity.Peer reviewe

Non-Dipping Blood Pressure Profile in Narcolepsy with Cataplexy

BACKGROUND: Patients with narcolepsy-cataplexy (NC) mostly exhibit undetectable hypocretin levels. Hypocretin system is one of the key players in the complex interaction between sleep and the cardiovascular system. We tested the hypothesis that hypocretin deficiency affects cardiovascular risk factors by measuring nighttime and daytime ambulatory blood pressure (BP) and the night-to-day BP ratio as well as endothelial dysfunction by the digital pulse amplitude response in drug-free patients with NC compared to controls. METHODOLOGY: Sleep, clinical and biological cardiovascular risk factors, fingertip peripheral arterial tonometry, and 24-hour ambulatory BP monitoring were recorded in 50 drug-free patients with NC and 42 healthy control subjects, except for BP monitoring available in all controls but in 36 patients with NC. PRINCIPAL FINDINGS: More patients than controls were smokers, obese and with dyslipidemia. One-third of patients with NC were "non-dippers" (defined as <10% drop in BP during sleep) compared to only 3% of controls. The diastolic non-dipper BP profile had up to 12-fold higher odds of being associated with NC. We noted negative correlations between mean diastolic BP fall during night, REM sleep percentage and number of sleep onset REM periods, and a positive correlation with mean sleep latency on the MSLT. The digital pulse amplitude response measured by fingertip was similar between NC and controls. CONCLUSION: We found a high percentage of non-dippers in patients with NC with association with REM sleep dysregulation. The blunted sleep-related BP dip in NC may be of clinical relevance, as it may indicate increased risk for cardiovascular events

Investigation and management of residual sleepiness in CPAP-treated patients with obstructive sleep apnoea: the European view

Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnoea (OSA), defined as the inability to stay awake during the day. Its clinical descriptors remain elusive, and the pathogenesis is complex, with disorders such as insufficient sleep and depression commonly associated. Subjective EDS can be evaluated using the Epworth Sleepiness Scale, in which the patient reports the probability of dozing in certain situations; however, its reliability has been challenged. Objective tests such as the multiple sleep latency test or the maintenance of wakefulness test are not commonly used in patients with OSA, since they require nocturnal polysomnography, daytime testing and are expensive. Drugs for EDS are available in the United States but were discontinued in Europe some time ago. For European respiratory physicians, treatment of EDS with medication is new and they may lack experience in pharmacological treatment of EDS, while novel wake-promoting drugs have been recently developed and approved for clinical use in OSA patients in the USA and Europe. This review will discuss 1) the potential prognostic significance of EDS in OSA patients at diagnosis, 2) the prevalence and predictors of residual EDS in treated OSA patients, and 3) the evolution of therapy for EDS specifically for Europe

Choroidal Blood Flow Regulation after Posture Change or Isometric Exercise in Men with Obstructive Sleep Apnea Syndrome

PURPOSE. Obstructive sleep apnea (OSA) syndrome generates hypertension, atherosclerosis, and endothelial and autonomic dysfunction, which may mutually interact with ocular vascular regulation. Exercise and posture changes can be used to manipulate blood pressure, ocular perfusion pressure (OPP), or both. It was hypothesized that choroidal vascular reactivity in response to isometric exercise and posture changes could be altered in OSA patients. METHODS. Healthy men were matched 1:1 for body mass index, sex, and age with patients with newly diagnosed OSA without cardiovascular comorbidities. All subjects underwent sleep studies and cardiovascular phenotyping (24-hour blood pressure monitoring, arterial stiffness measurements, and cardiac and carotid echography). Choroidal reactivity was assessed by laser Doppler flowmetry, which measured subfoveal choroidal blood flow. RESULTS. During exercise, blood pressure parameters increased significantly within the same range, with a similar profile over time in OSA patients and control subjects. A significant linear relationship (P ϭ 0.0003) was noted between choroidal vascular resistance and the OPP changes during exercise in OSA patients and control subjects. From the sitting to the supine position, a significant decrease in mean arterial pressure occurred in both groups (10.9%-13.4%; P Ͻ 0.001). In both populations, no significant change in choroidal blood flow or vascular resistance was found during the posture change. Choroidal blood flow responses to exercise and posture changes were unchanged after 6 to 9 months of continuous positive airway pressure treatment. CONCLUSIONS. This study strongly suggests that the regulation of choroidal blood flow, which depends on the orthosympathetic and parasympathetic systems, is unaltered in men with OSA who have no comorbidities. (ClinicalTrials.gov number, NCT00874913.) (Invest Ophthalmol Vis Sci. 2011; 52:9489 -9496

Digital transformation of health and care to sustain Planetary Health : The MASK proof-of-concept for airway diseases-POLLAR symposium under the auspices of Finland's Presidency of the EU, 2019 and MACVIA-France, Global Alliance against Chronic Respiratory Diseases (GARD, WH0) demonstration project, Reference Site Collaborative Network of the European Innovation Partnership on Active and Healthy Ageing

In December 2019, a conference entitled "Europe That Protects: Safeguarding Our Planet, Safeguarding Our Health" was held in Helsinki. It was co-organized by the Finnish Institute for Health and Welfare, the Finnish Environment Institute and the European Commission, under the auspices of Finland's Presidency of the EU. As a side event, a symposium organized as the final POLLAR (Impact of air POLLution on Asthma and Rhinitis) meeting explored the digital transformation of health and care to sustain planetary health in airway diseases. The Finnish Allergy Programme collaborates with MASK (Mobile Airways Sentinel NetworK) and can be considered as a proof-of-concept to impact Planetary Health. The Good Practice of DG Sante (The Directorate-General for Health and Food Safety) on digitally-enabled, patient-centred care pathways is in line with the objectives of the Finnish Allergy Programme. The ARIACARE-Digital network has been deployed in 25 countries. It represents an example of the digital cross-border exchange of real-world data and experience with the aim to improve patient care. The integration of information technology tools for climate, weather, air pollution and aerobiology in mobile Health applications will enable the development of an alert system. Citizens will thus be informed about personal environmental threats, which may also be linked to indicators of Planetary Health and sustainability. The digital transformation of the public health policy was also proposed, following the experience of the Agency for Health Quality and Assessment of Catalonia (AQuAS).Peer reviewe

Obstructive sleep apnea and its malajemente in patients with atrial fibrillation: An International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT) global survey of practicing cardiologists

Background: Among international cardiologists it is unclear whether equipoise exists regarding the benefit of diagnosing and managing obstructive sleep apnea (OSA) to improve atrial fibrillation (AF) outcomes and whether clinical practice and equipoise are linked. Methods: Between January 2019 and June 2020 we distributed a web-based 12-question survey regarding OSA and AF management to practicing cardiologists in 16 countries. Results: The United States, Japan, Sweden, and Turkey accounted for two-thirds of responses. 863 cardiologists responded; half were general cardiologists, a quarter electrophysiologists. Responses regarding treating OSA with CPAP to improve AF endpoints were mixed. 33% of respondents referred AF patients for OSA screening. OSA was diagnosed in 48% of referred patients and continuous positive airway pressure (CPAP) was prescribed for 59% of them. Nearly 70% of respondents believed randomized controlled trials (RCTs) of OSA treatment in AF patients were necessary and indicated willingness to contribute to such trials. Conclusions: There was no clinical equipoise among surveyed cardiologists; a majority expressed certainty that combined OSA and AF treatment is superior to AF treatment alone for improving AF outcomes. However, a minority of surveyed cardiologists referred AF patients for OSA testing, and while half of screened AF patients had OSA, CPAP was prescribed in little more than half of them, reflecting the view that better clinical trial evidence is needed to support this practice. Our results underscore the need for larger, multi-national prospective studies of OSA treatment and AF outcomes to inform more uniform society guideline recommendations

Endothelial Dysfunction and Specific Inflammation in Obesity Hypoventilation Syndrome

BACKGROUND: Obesity hypoventilation syndrome (OHS) is associated with increased cardiovascular morbidity. What moderate chronic hypoventilation adds to obesity on systemic inflammation and endothelial dysfunction remains unknown. QUESTION: To compare inflammatory status and endothelial function in OHS versus eucapnic obese patients. METHODOLOGY: 14 OHS and 39 eucapnic obese patients matched for BMI and age were compared. Diurnal blood gazes, overnight polysomnography and endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), were assessed. Inflammatory (Leptin, RANTES, MCP-1, IL-6, IL-8, TNFalpha, Resistin) and anti-inflammatory (adiponectin, IL-1Ra) cytokines were measured by multiplex beads immunoassays. PRINCIPAL FINDINGS: OHS exhibited a higher PaCO(2), a lower forced vital capacity (FVC) and tended to have a lower PaO(2) than eucapnic obese patients. (HS)-CRP, RANTES levels and glycated haemoglobin (HbA1c) were significantly increased in OHS (respectively 11.1+/-10.9 vs. 5.7+/-5.5 mg x l(-1) for (HS)-CRP, 55.9+/-55.3 vs 23.3+/-15.8 ng/ml for RANTES and 7.3+/-4.3 vs 6.1+/-1.7 for HbA1c). Serum adiponectin was reduced in OHS (7606+/-2977 vs 13,660+/-7854 ng/ml). Endothelial function was significantly more impaired in OHS (RH-PAT index: 0.22+/-0.06 vs 0.51+/-0.11). CONCLUSIONS: Compared to eucapnic obesity, OHS is associated with a specific increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin and impaired endothelial function. These three conditions are known to be strongly associated with an increased cardiovascular risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT00603096