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Background: Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients. Methods: We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed. Results: We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55–0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47–0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38–0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48–0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742–0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality ( R 2 trial , 0.35 [95% CI, 0.10–0.59]; P Conclusions: PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable. Registration: URL: https://www.crd.york.ac.uk/PROSPERO ; Unique identifier: CRD42020178949.

The blood neutrophil-to-lymphocyte ratio (NLR) has recently emerged as a powerful predictor of adverse outcomes in some cardiovascular and lung diseases. Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with increased inflammation. Although PAH exhibits a higher prevalence among women, men have a poorer prognosis. We investigated the NLR as an independent predictor of transplant-free survival in PAH.We performed a retrospective analysis of 78 PAH patients from the Quebec PAHBiobank (71% female). We used univariate and multivariate (adjusted for age, sex, renal function, and disease severity) Cox regression analyses to assess the relationship between the NLR and transplant-free survival, in the whole sample, and according to sex. The NLR was categorized as high (≥ 4.8) or low ( 4.8) using receiver operating characteristic analysis. Unadjusted Kaplan-Meier analysis estimated survival per NLR category.The NLR was higher in patients who died, compared to that in patients who had transplant-free survival (The NLR is an independent predictor of transplant-free survival in PAH. We report a potential sexual dimorphism in the ability of the NLR to predict mortality in PAH, emphasizing the importance of considering sex-related differences in the development of biomarkers in PAH.Le rapport neutrophiles/lymphocytes (RNL) s’est récemment imposé comme un puissant facteur prédictif de l’issue défavorable de certaines maladies cardiovasculaires et pulmonaires. L’hypertension artérielle pulmonaire (HTAP) est une vasculopathie mortelle associée à une inflammation accrue. Bien que sa prévalence soit plus élevée chez les femmes, son pronostic est plus défavorable chez les hommes. Nous avons étudié le RNL en tant que prédicteur indépendant de la survie sans greffe chez des sujets atteints d’HTAP.Nous avons effectué une analyse rétrospective du matériel sur l’HTAP de la Biobanque du Québec se rapportant à 78 patients (71 % de femmes). Des analyses de régression de Cox univariées et multivariées (ajustées en fonction de l’âge, du sexe, de la fonction rénale et de la gravité de la maladie) nous ont permis d’évaluer la relation entre le RNL et la survie sans greffe dans l’ensemble de l’échantillon et selon le sexe. Le RNL a été classé comme élevé (≥ 4,8) ou faible (4,8) au terme d’une analyse des caractéristiques de fonctionnement du récepteur. Une analyse non ajustée effectuée selon la méthode de Kaplan-Meier a servi à estimer la survie par catégorie de RNL.Le RNL était plus élevé chez les patients décédés que chez les patients ayant survécu sans greffe (Le RNL est un facteur prédictif indépendant de la survie sans greffe chez les sujets atteints d’HTAP. Selon nos observations, un dimorphisme sexuel potentiel le caractérise en tant que prédicteur de la mortalité chez les sujets atteints d’HTAP. Il importe donc de tenir compte des différences liées au sexe dans le développement des biomarqueurs de l’HTAP.

STUDY OBJECTIVES: References for the evaluation of obstructive sleep apnea often exceed the sleep clinic’s capacity. We aimed to assess the noninferiority of a nurse-communicated model compared with a traditional physician-led model for the initial management of uncomplicated obstructive sleep apnea in the sleep clinic. METHODS: In this noninferiority, open-label randomized controlled trial, patients referred for the evaluation of uncomplicated obstructive sleep apnea (home sleep apnea test with respiratory event index ≥ 20 events/h) were randomized to a nurse-communicated or a physician-led management. The primary endpoint was noninferiority in the mean change from baseline of the Epworth Sleepiness Scale score at 3 and 6 months, assuming a noninferiority margin of −2.0 points. Secondary outcomes included quality of life (Quebec Sleep Questionnaire) and positive airway pressure adherence. RESULTS: Two hundred participants were randomized to a nurse-communicated (n = 101) or physician-led management (n = 99). Overall, 48 participants were lost at follow-up (27.7% and 20.4% in the nurse-communicated and physician-led groups, respectively). Most participants were treated with positive airway pressure (78.2% and 80.6% in the nurse-communicated and physician-led management groups, respectively). There was substantial missing data for the Epworth Sleepiness Scale (33% and 58% at 3 and 6 months in the nurse-communicated group and 29% and 55% in the physician-led group) and Quebec Sleep Questionnaire (86% and 91% at 3 and 6 months and 79.6% and 85.7% in the physician-led group). The difference in mean change between groups for the Epworth Sleepiness Scale was −0.71 (95% confidence interval −2.25 to 0.83) at 3 months and −0.21 (95% confidence interval −1.85 to 1.45) at 6 months. For each domain of the Quebec Sleep Questionnaire at 3 and 6 months, the lower bound of the 95% confidence interval was greater than the prespecified noninferiority margin. Positive airway pressure adherence was similar between groups. CONCLUSIONS: Among patients with uncomplicated obstructive sleep apnea, nurse-communicated management was noninferior to physician-led management in terms of sleepiness, quality of life, and positive airway pressure adherence at 6 months. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Management of Sleep Apnea Patients by a Clinical Nurse (Supernurse), URL: https://clinicaltrials.gov/ct2/show/NCT03455920; Identifier: NCT03455920. CITATION: Lajoie AC, Privé A, Roy-Hallé A, Pagé D, Simard S, Séries F. Diagnosis and management of sleep apnea by a clinical nurse: a noninferiority randomized clinical trial. J Clin Sleep Med. 2022;18(1):89–97.

The treatment of chronic hypoventilation usually requires noninvasive ventilation. However, upper airway obstruction can lead to hypoventilation in conditions such as obesity-hypoventilation syndrome, or chronic obstructive lung diseases (overlap syndrome). In these situations, continuous positive airway pressure can be an effective therapeutic option. This article reviews the pathophysiology of sleep-related hypoventilation, discusses situations where treatment with continuous positive airway pressure is feasible and briefly outlines noninvasive ventilation modes and settings for the treatment of common sleep-related hypoventilation disorders.

There is increasing interest in the effects of sleep and sleep disturbances on the brain, particularly in relation to aging and neurodegenerative processes. Parkinson disease (PD) is the second most common neurodegenerative disorder, with growing prevalence worldwide. Sleep disorders, including sleep-disordered breathing (SDB), are among the most frequent non-motor manifestations of PD. They can substantially impair quality of life and possibly affect the course of the disease. This article reviews the etiology, implications, and management of sleep disturbances in PD, such as excessive daytime sleepiness, insomnia, restless legs syndrome, rapid eye movement sleep behavior disorder, and SDB. Also briefly explored is the potential role of sleep disorders, including SDB, in the progression of neurodegeneration.

Obstructive sleep apnea is prevalent in the bariatric population, and is associated with various complications. Despite increasing popularity, automatic positive airway pressure has not yet been studied in this population. The objective was to compare treatment adherence between automatic positive airway pressure and fixed positive airway pressure (continuous positive airway pressure) in obstructive sleep apnea patients awaiting bariatric surgery. This randomized controlled trial involved obese patients newly diagnosed with severe obstructive sleep apnea and awaiting bariatric surgery. The primary outcome was the difference in adherence between automatic positive airway pressure and continuous positive airway pressure pre-operatively. Secondary outcomes included positive airway pressure efficacy, adherence at 1 month, adverse effects, quality of life and peri-operative complications. Analyses were conducted using a modified intention-to-treat methodology. Fifty patients were randomized. Baseline characteristics and duration of positive airway pressure therapy were comparable between groups. At the time of surgery, the percentage of overall nights positive airway pressure used was 96.9% [95% confidence interval: 93.5-100] and 86.0% [95% confidence interval: 66.9-100] in the automatic positive airway pressure and continuous positive airway pressure groups, respectively (p = .047). Average use was 6.3 hr per night [95% confidence interval: 5.1-7.2] and 5.9 hr per night [95% confidence interval: 3.0-8.8], with a difference of 0.4 hr favouring automatic positive airway pressure (p = .75). Nightly use ≥ 4 hr per night was 86.4% and 74.0% in the automatic positive airway pressure and fixed continuous positive airway pressure groups, respectively (p = .22). There were no statistically significant differences regarding adherence at 1 month, efficacy parameters, adverse effects, quality of life and peri-operative complications. With no difference on the safety profile and efficiency parameters, treatment adherence is not improved with automatic positive airway pressure compared with fixed continuous positive airway pressure in obstructive sleep apnea patients awaiting bariatric surgery.

There is increasing interest in the effects of sleep and sleep disturbances on the brain, particularly in relation to aging and neurodegenerative processes. Parkinson disease (PD) is the second most common neurodegenerative disorder, with growing prevalence worldwide. Sleep disorders, including sleep-disordered breathing (SDB), are among the most frequent non-motor manifestations of PD. They can substantially impair quality of life and possibly affect the course of the disease. This article reviews the etiology, implications, and management of sleep disturbances in PD, such as excessive daytime sleepiness, insomnia, restless legs syndrome, rapid eye movement sleep behavior disorder, and SDB. Also briefly explored is the potential role of sleep disorders, including SDB, in the progression of neurodegeneration.

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease and is associated with cognitive dysfunction. Obstructive sleep apnea (OSA) has been linked with cognitive dysfunction in the general population and in PD. Treatment with positive airway pressure (PAP), can improve cognition in the general population and in patients with other neurodegenerative diseases. However, the effect of PAP therapy on cognitive function has not been well studied in PD.Methods: This randomized controlled trial will assess the effect of 6 months of PAP therapy versus placebo on global cognitive function in PD patients with OSA and reduced baseline cognition. Secondary outcomes will include quality of life and other non-motor symptoms of PD. Exploratory outcomes will be specific domains of neurocognitive function and symptoms of REM sleep behaviour disorder.Conclusions: PD-related cognitive dysfunction often evolves towards dementia and has substantial personal, social and healthcare costs. Few interventions have been shown to improve cognition in PD to date. If positive, results from our study could prove OSA to be a new therapeutic target relevant to cognition and would support more systematic screening for OSA in PD patients with cognitive decline.Trial Registration: Trial registration number is NCT02209363.

Relative risk (RR) and number needed-to-treat (NNT) are frequently time-dependant measures. We performed a systematic review and meta-analysis to assess whether trial duration influenced the relative and absolute risk of worsening in randomized controlled trials (RCTs) comparing combination therapy (CT) of pulmonary arterial hypertension (PAH)-specific therapies vs monotherapy (MT).We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to September 2016) for RCTs assessing CT compared with MT in PAH. The primary outcome was the risk of clinical worsening. We assessed whether trial duration correlated with RR and NNT using weighted meta-regression with mixed effects. Changes in NNT overtime were also assessed using data from long-term event-driven trials.There were 3,801 patients throughout 15 studies included. The RR for clinical worsening positively correlated with trial duration (RAbsolute risk reduction of clinical worsening was relatively constant beyond 6 to 12 months of treatment in clinical trials comparing CT with MT in PAH. These results question the need for CT trials of very long duration in PAH.

Summary Background Several randomised controlled studies and a previous meta-analysis have reported conflicting results regarding the effect of combined targeted therapy compared with monotherapy for pulmonary arterial hypertension (PAH). We did a systematic review and meta-analysis to assess the effects of a combination of PAH-specific therapies compared with monotherapy on predefined clinical worsening in PAH. Methods We searched MEDLINE, Embase, and the Cochrane Library for reports published from Jan 1, 1990, to May 31, 2015, of prospective randomised controlled trials of at least 12 weeks that assessed a combination of PAH-specific therapies (upfront and sequential add-on) compared with background PAH-specific monotherapy in patients older than 12 years. We extracted data from the reports, and assessed the primary outcome of risk of clinical worsening, as defined a priori in each trial, using the Mantel-Haenszel method based on a fixed-effects model. Findings Of 2017 studies that we identified from our search, we included 17 (4095 patients) in our analysis. 15 studies assessed clinical worsening and were included in the primary analysis. Combined therapy was associated with significant risk reduction for clinical worsening compared with monotherapy (combined therapy 17% [332 of 1940 patients] vs monotherapy 28% [517 of 1862 patients], risk ratio [RR] 0·65 [95% CI 0·58–0·72], p I 2 =18%, p homogeneity =0·25). A publication bias was suggested by the results of an Egger test ( t =–2·3982, p=0·031), but when we excluded the four studies with the highest SEs, the RR for clinical worsening was identical (0·65 [95% CI 0·58–0·73], p Interpretation In our analysis, combined therapy for PAH was associated with a significant reduction in clinical worsening compared with monotherapy. However, our study was limited by the variable definition of clinical worsening among the trials and possible publication bias. Because many patients still had clinical worsening with combination therapy, identification of innovative therapeutic targets for PAH is thus urgently needed. Funding None.

Background— Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH. Methods and Results— We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription–polymerase chain reaction; P + immunofluorescence; P Conclusions— RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH.