Win ratio analysis of transvenous phrenic nerve stimulation to treat central sleep apnoea in heart failure.

AIMS: Central sleep apnoea (CSA) is present in 20-40% of heart failure (HF) patients and is associated with poor clinical outcomes and health status. Transvenous phrenic nerve stimulation (TPNS) is an available treatment for CSA in HF patients. The impact on HF outcomes is incompletely understood. The win ratio (WR) allows inclusion of multiple endpoint components, considers the relative severity of each component, and permits assessment of recurrent events in evaluation of clinical benefit. METHODS AND RESULTS: A WR hierarchy was pre-defined for analysis of the HF subgroup of the remede® System Pivotal Trial. The analysis used three hierarchical components to compare all treated to all control subjects: longest survival, lowest HF hospitalization rate, and ≥2-category difference in Patient Global Assessment at 6 months. Sensitivity analyses were performed substituting Epworth Sleepiness Scale and 4% oxygen desaturation index for the third component, and a 4-component WR hierarchy was also evaluated. Ninety-one HF subjects, 43 receiving TPNS and 48 in the control group, provided 2064 pairwise comparisons. More patients treated with TPNS experienced clinical benefit compared with control (WR 4.92, 95% confidence interval 2.27-10.63, P < 0.0001). There were 1111 (53.83%) winning pairwise comparisons for the treatment group and 226 (10.95%) for the control group. Similarly, large WRs were observed for all additional WR hierarchies. CONCLUSIONS: This WR analysis of the remede® System Pivotal Trial suggests that TPNS may be superior to untreated CSA in HF patients with CSA using a hierarchical clinical benefit endpoint composed of mortality, HF hospitalization, and health status.

Insights, recommendations, and research priorities for central sleep apnea: report from an expert panel.

Central sleep apnea (CSA) is commonly encountered among patients with sleep-disordered breathing, however its clinical consequences are less well-characterized. We therefore convened an expert panel to discuss the common presentations of CSA, as well as challenges and knowledge gaps in the diagnosis and management of CSA. The panel identified several key research priorities essential for advancing our understanding of the disorder. Within the diagnostic realm, panel members discussed the utility of multi-night assessments, and importance of the development and validation of novel metrics and automated assessments for differentiating central versus obstructive hypopneas, such that their impact on clinical outcomes and management may be better evaluated. The panel also discussed the current therapeutic landscape for the management of CSA and agreed that therapies should primarily aim to alleviate sleep-related symptoms, after optimizing treatment to address the underlying cause. Most importantly, the panel concluded that there is a need to further investigate the clinical consequences of CSA, as well as the implications of therapy on clinical outcomes, particularly among those who are asymptomatic. Future research should focus on endo-phenotyping central events for a better mechanistic understanding of the disease, validating novel diagnostic methods for implementation in routine clinical practice, as well as the use of combination therapy and comparative effectiveness trials in elucidating the most efficacious interventions for managing CSA.

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

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.

Effectiveness of remote monitoring in improving CPAP compliance and the impact of preexisting organisation of standard care: a randomised controlled trial.

PURPOSE   : Continuous positive airway pressure (CPAP) is often the treatment of choice for obstructive sleep apnea (OSA). Short-term adherence and early perceived benefits are the best predictors of long-term adherence. The aim of this study was to determine the effect of telemonitoring in the first period of treatment with CPAP (auto-titrating PAP) on compliance and the long-term outcome. METHODS: Patients aged between 18-75 years old with symptomatic severe OSA (apnea-hypopnea index (AHI) ≥ 30) requiring CPAP therapy were included in this single-blind, single-centre, randomised, controlled trial. They were divided into 2 groups (telemonitored standard clinical care versus standard clinical care without telemonitoring). RESULTS: A total of 230 patients (115 patients/group) were included (mean age 54 ± 16.6 years, BMI 32.6 ± 5.4 kg/m2, ESS 13.1 ± 6.2, AHI 47.5 ± 14.8/hr). At week 10 compliance was similar in both groups (telemonitoring vs control 6:27 and 6:35 h, respectively, p = 0.57), as were AHI (2.4; 2.4/hr, p = 0.89) and ESS (5.8; 4.9, p = 0.22). The number of contacts of a patient with a healthcare professional was significantly higher during the follow-up from week 3 until week 10 (0.25; 0.13, p = 0.03). The number of patients who could be evaluated after 1 year was equally distributed in both groups (104; 104, p = 1.00), as were compliance (6:43; 6:49 h, p = 0.59) and residual AHI (1.9; 2.2/hr, p = 0.41). CONCLUSIONS: In patients with severe OSA with standard intensive follow-up during the initial weeks of CPAP therapy and good compliance, telemonitoring did not improve CPAP compliance nor the clinical outcome in the short or long term. The practical consequences can be highly relevant for patients and healthcare professionals.

Multi-night home assessment of sleep structure in OSA with and without insomnia.

OBJECTIVE: To explore sleep structure in participants with obstructive sleep apnea (OSA) and comorbid insomnia (COMISA) and participants with OSA without insomnia (OSA-only) using both single-night polysomnography and multi-night wrist-worn photoplethysmography/accelerometry. METHODS: Multi-night 4-class sleep-staging was performed with a validated algorithm based on actigraphy and heart rate variability, in 67 COMISA (23 women, median age: 51 years) and 50 OSA-only (15 women, median age: 51) participants. Sleep statistics were compared using linear regression models and mixed-effects models. Multi-night variability was explored using a clustering approach and between- and within-participant analysis. RESULTS: Polysomnographic parameters showed no significant group differences. Multi-night measurements, during 13.4 ± 5.2 nights per subject, demonstrated a longer sleep onset latency and lower sleep efficiency for the COMISA group. Detailed analysis of wake parameters revealed longer mean durations of awakenings in COMISA, as well as higher numbers of awakenings lasting 5 min and longer (WKN≥5min) and longer wake after sleep onset containing only awakenings of 5 min or longer. Within-participant variance was significantly larger in COMISA for sleep onset latency, sleep efficiency, mean duration of awakenings and WKN≥5min. Unsupervised clustering uncovered three clusters; participants with consistently high values for at least one of the wake parameters, participants with consistently low values, and participants displaying higher variability. CONCLUSION: Patients with COMISA more often showed extended, and more variable periods of wakefulness. These observations were not discernible using single night polysomnography, highlighting the relevance of multi-night measurements to assess characteristics indicative for insomnia.

Sleep structure in patients with COMISA compared to OSA and insomnia.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and insomnia frequently co-occur, making diagnosis and treatment challenging. We investigated differences in sleep structure between patients with OSA, insomnia, and comorbid insomnia and sleep apnea (COMISA) to identify characteristics that can be used to improve the diagnosis of COMISA. METHODS: We obtained polysomnography data of 326 patients from the Sleep and OSA Monitoring with Non-Invasive Applications database. The group included patients with OSA (n = 199), insomnia (n = 47), and COMISA (n = 80). We compared statistics related to sleep structure between the 3 patient groups. RESULTS: Wake after sleep onset was significantly shorter for the OSA group (median: 60.0 minutes) compared to the COMISA (median: 83.3 minutes, P < .01) and the insomnia (median: 83.5 minutes, P = .01) groups. No significant differences were found in the total number of awakenings and the number of short (up to and including 2 minutes) and medium-length awakenings (2.5 up to and including 4.5 minutes). However, the number of long awakenings (5 minutes or longer) and wake after sleep onset containing only long awakenings was significantly lower for patients with OSA (median: 2 awakenings and 25.5 minutes) compared to patients with COMISA (median: 3 awakenings, P < .01 and 43.3 minutes, P < .001) or with insomnia (median: 3 awakenings, P < .01 and 56.0 minutes, P < .001). Total sleep time was significantly longer and sleep efficiency was significantly higher for the OSA group (median: 418.5 minutes and 84.4%) compared to both the COMISA (median: 391.5 minutes, P < .001 and 77.3%, P < .001) and the insomnia (median: 381.5 minutes, P < .001 and 78.2%, P < .001) groups. The number of sleep-stage transitions during the night for patients with COMISA (median: 194.0) was lower compared to that for patients with OSA (median: 218.0, P < .01) and higher compared to that for patients with insomnia (median: 156.0, P < .001). Other sleep architectural parameters were not discriminative between the groups. CONCLUSIONS: Patients with COMISA show specific characteristics of insomnia, including prolonged awakenings. This variable is distinctive in comparison to patients with OSA. The combination of prolonged awakenings and the presence of sleep-disordered breathing leads to increased sleep disturbance compared to patients having only 1 of the sleep disorders. CITATION: Wulterkens BM, Hermans LWA, Fonseca P, et al. Sleep structure in patients with COMISA compared to OSA and insomnia. J Clin Sleep Med. 2023;19(6):1051-1059.

Psychomotor Vigilance Performance in Participants with Excessive Daytime Sleepiness in Obstructive Sleep Apnea or Narcolepsy Compared with SAFTE-FAST Model Predictions.

INTRODUCTION: Excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS associated with narcolepsy (75-150 mg/day) or OSA (37.5-150 mg/day). The analysis reported here explored the use of the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model (used in transport industries to model performance based on accumulated sleep and circadian variability) as a substitute for healthy controls using psychomotor vigilance task (PVT) data collected during clinical studies. METHODS: Data were analyzed from two phase 2 studies of solriamfetol in adults with OSA (NCT02806895, EudraCT 2015-003930-28) or narcolepsy (NCT02806908, EudraCT 2015-003931-36). Participants were randomly assigned 1:1 to solriamfetol 150 mg/day (3 days) followed by 300 mg/day (4 days), or placebo (7 days), then crossed over to the other treatment. Actual task effectiveness scores were calculated from average PVT inverse reaction time (pre-dose; 2 h post-dose; 6 h post-dose). Actigraphy-derived sleep intervals were used in SAFTE to determine modeled healthy control task effectiveness scores. RESULTS: In participants with OSA (N = 31) on placebo or solriamfetol, actual and modeled healthy control task effectiveness did not differ at any time point. In participants with narcolepsy (N = 20) on placebo, actual task effectiveness at 2 h post-dose was lower than modeled healthy control task effectiveness (nominal P = 0.03), a difference not present with solriamfetol. There was no main effect of solriamfetol on actual or modeled healthy control task effectiveness across time points. CONCLUSION: This study represents a novel application of the SAFTE biomathematical model to approximate healthy controls in sleep disorder research and provides valuable lessons that may optimize future research. Future studies should perform a priori power analyses for model-tested outcomes and use sleep measures that capture sleep fragmentation characteristic of sleep disorders for sleep input (e.g., total sleep time rather than time in bed). TRIAL REGISTRATION: NCT02806895, EudraCT 2015-003930-28: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Obstructive Sleep Apnea. NCT02806908, EudraCT 2015-003931-36: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Narcolepsy.

Effects of solriamfetol on on-the-road driving performance in participants with excessive daytime sleepiness associated with obstructive sleep apnoea.

OBJECTIVE: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with obstructive sleep apnoea (OSA). METHODS: Eligible participants were aged 21-75 years with OSA and EDS (Maintenance of Wakefulness Test mean sleep latency <30 minutes and Epworth Sleepiness Scale score ≥10). Participants were randomised 1:1 to solriamfetol (150 mg/day [3 days], then 300 mg/day [4 days]) or placebo for 7 days, before crossover to the other treatment paradigm. On Day 7 of each period, standardised on-road driving tests occurred (2 and 6 hours postdose). Standard deviation of lateral position (SDLP) was the primary endpoint. RESULTS: Solriamfetol significantly reduced SDLP at 2 (n = 34; least squares mean difference, -1.1 cm; 95% CI, -1.85, -0.32; p = 0.006) and 6 hours postdose (n = 32; least squares mean difference, -0.8 cm; 95% CI, -1.58, -0.03; p = 0.043). Two hours postdose, 4 placebo-treated and 1 solriamfetol-treated participants had incomplete driving tests; 6 hours postdose, 7 and 3 participants, respectively, had incomplete tests. Common treatment-emergent adverse events included headache, nausea, and insomnia. CONCLUSIONS: Solriamfetol 300 mg/day significantly improved on-the-road driving performance in participants with EDS associated with OSA.

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.

Maxillomandibular advancement in edentulous patients as a treatment option for obstructive sleep apnea: report of two cases and a proposed treatment protocol.

Obstructive sleep apnea (OSA) is a common disease that often causes debilitating symptoms. In its most severe form, OSA increases the risk of cardiovascular disease and mortality. OSA is characterized by repeated episodes of pharyngeal collapse leading to airway obstruction. The treatment options available in severe cases are limited to continuous positive airway pressure ventilation and maxillomandibular advancement (MMA). OSA is particularly difficult to treat successfully in edentulous patients. Two cases are presented here to illustrate use of MMA in edentulous patients with OSA. Our learning points based on these cases are shared, and a treatment and follow-up protocol is proposed for this specific patient group.

The Severe Respiratory Insufficiency Questionnaire scored best in the assessment of health-related quality of life in chronic obstructive pulmonary disease.

OBJECTIVE: There are limited data on health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure during an admission requiring ventilatory support. The aim was to assess and compare the reliability and validity of the Clinical COPD Questionnaire (CCQ), Chronic Respiratory Questionnaire (CRQ), Maugeri Respiratory Failure-28 (MRF-28) Questionnaire, and Severe Respiratory Insufficiency (SRI) Questionnaire in patients with very severe COPD. STUDY DESIGN AND SETTING: One hundred eighty hospitalized patients filled out the CCQ, CRQ, MRF-28, SRI, Groningen Activity Restriction Scale (GARS), Hospital Anxiety and Depression Scale (HADS), and the Medical Research Council Dyspnea Scale (MRC). Reliability was examined by assessing distribution of total scores, floor and ceiling effects, and internal consistency (using Cronbach α coefficient). Construct validity between questionnaires and also the other measurements were tested with Spearman ρ. RESULTS: All four questionnaires were feasible in this setting and had reasonable characteristics for distribution of total scores, floor and ceiling effects, internal consistency, and construct validity. On balance, the SRI scored best. Additionally, the SRI had a remarkable high explained variance by HADS, GARS, and MRC (73%). CONCLUSION: The SRI performed slightly better than the CCQ, CRQ, and MRF-28, which renders it the preferred questionnaire for scoring HRQL in patients with very severe COPD.

Markers of inflammation and oxidative stress in exacerbated chronic obstructive pulmonary disease patients.

COPD is characterised by damage to small airways due to an inflammatory process as well as an imbalance between oxidants and antioxidants. Several cytokines and cell adhesion molecules enhancing a mainly neutrophilic inflammation have been associated with COPD. The aim of the study was to investigate whether inflammation or oxidative markers gave an indication of the course of COPD during an exacerbation. Fourteen patients with moderate to severe COPD admitted to the St. Antonius Hospital because of an exacerbation have been monitored during treatment with prednisolone 50 mg intravenously during 24 h at admission, reduced to 25 mg at day 3 and tapered off with oral prednisolone at day 7. On three separate occasions, day 1, 3 and 7, H2O2 in exhaled air, IL-8 and the soluble cell adhesion molecule sICAM and sE-selectin in serum were measured. We compared the patients at day 1 with healthy controls (in both non-smokers and smokers). Furthermore, we examined the changes from the study group in time during therapy. At admission all the markers were raised in comparison with the control groups. During treatment H2O2 concentrations in breath condensate declined significantly (P<0.001) as well as IL-8 and sICAM in serum (P=0.002, respectively, P<0.001). There was no significant change in sE-selectin (P=0.132). No significant improvement has been found in spirometry. These data suggest that the markers H2O2 in exhaled air, IL-8 and sICAM in serum are suitable markers in monitoring exacerbated COPD.