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

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

Sleep disorders in COPD: the forgotten dimension

Sleep in chronic obstructive pulmonary disease (COPD) is commonly associated with oxygen desaturation, which may exceed the degree of desaturation during maximum exercise, both subjectively and objectively impairing sleep quality. The mechanisms of desaturation include hypoventilation and ventilation to perfusion mismatching. The consequences of this desaturation include cardiac arrhythmias, pulmonary hypertension and nocturnal death, especially during acute exacerbations. Coexistence of COPD and obstructive sleep apnoea (OSA), referred to as overlap syndrome, has been estimated to occur in 1% of the general adult population. Overlap patients have worse sleep-related hypoxaemia and hypercapnia than patients with COPD or OSA alone. OSA has a similar prevalence in COPD as in a general population of similar age, but oxygen desaturation during sleep is more pronounced when the two conditions coexist. Management of sleep-related problems in COPD should particularly focus on minimising sleep disturbance via measures to limit cough and dyspnoea; nocturnal oxygen therapy is not generally indicated for isolated nocturnal hypoxaemia. Treatment with continuous positive airway pressure alleviates hypoxaemia, reduces hospitalisation and pulmonary hypertension, and improves survival

Vitamin D and obesity

Obesity is a significant health problem world-wide, particularly in developed nations. Vitamin D deficiency is pandemic, and has been implicated in a wide variety of disease states. This paper seeks to examine the consistently reported relationship between obesity and low vitamin D concentrations, with reference to the possible underlying mechanisms. The possibility that vitamin D may assist in preventing or treating obesity is also examined, and recommendations for future research are made. There is a clear need for adequately-powered, prospective interventions which include baseline measurement of 25D concentrations and involve adequate doses of supplemental vitamin D. Until such studies have been reported, the role of vitamin D supplementation in obesity prevention remains uncertain.Simon Vanlin

Managing fatigue in sarcoidosis – a systematic review of the evidence

Fatigue is a common manifestation of sarcoidosis, often persisting without evidence of disease activity. First-line therapies for sarcoidosis have limited effect on fatigue. This review aimed to assess the treatment options targeting sarcoidosis-associated fatigue. Medline and Web of Science were searched in November 2015; the bibliographies of these papers, and relevant review papers, were also searched. Studies were included if they reported on the efficacy of interventions (both pharmacological and non-pharmacological) on fatigue scores in sarcoidosis patients. Eight studies were identified that fulfilled the inclusion criteria. These studies evaluated six different interventions (infliximab, adalimumab, ARA 290, methylphenidate, armodafinil and exercise programmes). There is evidence to support a treatment effect of anti-tumour necrosis factor (TNF)-αtherapies (adalimumab and infliximab) and neurostimulants (methylphenidate and armodafinil), but within five of the studies, the risk of bias was high within most domains and the remaining three studies included only small numbers of participants and were short in duration. Trial evidence for treating fatigue as a manifestation of sarcoidosis is limited and requires further investigation. Anti-TNF-α therapies may be beneficial in patients with organ-threatening disease. Neurostimulants have some trial evidence supporting improvements in fatigue but further investigation is needed before they can be recommended

Sleep and cardiometabolic comorbidities in the obstructive sleep apnoea-COPD overlap syndrome: data from the European Sleep Apnoea Database

Aim The impact of obstructive sleep apnoea (OSA)-COPD overlap syndrome (OVS) on sleep quality and cardiovascular outcomes has not been fully explored. We aimed to compare clinical and polysomnographic characteristics of patients with OVS versus patients with OSA, and to explore pathophysiological links between OVS and comorbidities. Study design and methods This cross-sectional analysis initially included data from 5600 patients with OSA and lung function in the European Sleep Apnoea Database. Two subgroups of patients with OSA (n=1018) or OVS (n=509) were matched (2:1) based on sex, age, body mass index and apnoea-hypopnea index at baseline. Results After matching, patients with OVS had more severe hypoxia, lower sleep efficiency and presented with higher prevalences of arterial hypertension, ischaemic heart disease and heart failure compared with patients with OSA. OVS was associated with a significant decrease in sleep efficiency (mean difference (beta) -3.0%, 95% CI -4.7 to -1.3) and in nocturnal mean peripheral oxyhaemoglobin saturation (S-pO2) (beta -1.1%, 95% CI -1.5 to -0.7). Further analysis revealed that a decrease in forced expiratory volume in 1 s and arterial oxygen tension was related to a decrease in sleep efficiency and in mean nocturnal S-pO2. A COPD diagnosis increased the odds of having heart failure by 1.75 (95% CI 1.15-2.67) and systemic hypertension by 1.36 (95% CI 1.07-1.73). Nocturnal hypoxia was strongly associated with comorbidities; the mean nocturnal S-pO2 and T90 (increase in time below S-pO2 of 90%) were associated with increased odds of systemic hypertension, diabetes and heart failure but the oxygen desaturation index was only related to hypertension and diabetes. Conclusion Patients with OVS presented with more sleep-related hypoxia, a reduced sleep quality and a higher risk for heart failure and hypertension.The ESADA study group received unrestricted funding grants from the Respironics and Resmed Foundations, and an unrestricted collaboration grant from Bayer AG