Assessment of Clinical Worsening End Points as a Surrogate for Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

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 (R2trial, 0.35 [95% CI, 0.10-0.59]; P<0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical. 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.

Impact of continuous positive airway pressure mode on adherence to treatment in obstructive sleep apnea patients awaiting bariatric surgery.

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.

Novel insights on the pulmonary vascular consequences of COVID-19.

In the last few months, the number of cases of a new coronavirus-related disease (COVID-19) rose exponentially, reaching the status of a pandemic. Interestingly, early imaging studies documented that pulmonary vascular thickening was specifically associated with COVID-19 pneumonia, implying a potential tropism of the virus for the pulmonary vasculature. Moreover, SARS-CoV-2 infection is associated with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, DNA damage, and lung coagulopathy promoting endothelial dysfunction and microthrombosis. These features are strikingly similar to what is seen in pulmonary vascular diseases. Although the consequences of COVID-19 on the pulmonary circulation remain to be explored, several viruses have been previously thought to be involved in the development of pulmonary vascular diseases. Patients with preexisting pulmonary vascular diseases also appear at increased risk of morbidity and mortality. The present article reviews the molecular factors shared by coronavirus infection and pulmonary vasculature defects, and the clinical relevance of pulmonary vascular alterations in the context of COVID-19.

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension.

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<0.01) and capillary density (CD31(+) immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals. 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.

Adherence to continuous positive airway pressure for the treatment of obstructive sleep apnea in neurodegenerative diseases: A systematic review.

Obstructive sleep apnea (OSA) is prevalent in patients with neurodegenerative diseases and is associated with worse outcomes. Positive airway pressure therapy has the potential to benefit these patients but can be challenging in this population. Our primary aim was to describe positive pressure therapy adherence. Secondarily, we aimed at identifying identify predictors of adherence to treatment in adults with neurodegenerative diseases and OSA, and report the effect of PAP adherence on outcomes such as cognitive function, quality of life and patient/caregiver satisfaction. We performed a systematic review of the literature and identified seventeen studies, eight reporting on adults with obstructive sleep apnea and mild cognitive impairment (MCI) and/or Alzheimer's disease (AD), 6 with Parkinson's disease (PD), and 3 with multiple system atrophy (MSA). Meta-analyses were not performed due to lack of systematic and standardized reporting of the primary outcome. Study duration ranged from 6 weeks to an average of 3.3 years. PAP adherence definition was widely variable between studies. Attrition rates ranged from 12% to 75%. In MCI/AD, adherence rates ranged from 28% to 61% (study duration range: 3 weeks to 3.3 years). Younger age, race (white) and better CPAP confidence scores at 1 week were associated with more CPAP use while APOE4 positive and unmarried individuals were more likely to abandon CPAP. In most studies, adherent patients had improvement in excessive daytime sleepiness, depressive symptoms, sleep quality, ability to manage daily activities and certain aspects of cognition (composite score or global cognition, psychomotor speed, executive function), as well as less cognitive decline over time. Caregiver satisfaction was also better in PAP adherent patients in one study. In PD, 15-25% of individuals refused treatment with PAP upfront, and attrition ranged from 8 to 75%. Adherent patients used their device for an average of 3h27 to 5h12 per night (study duration range: 6 weeks to 12 months). Longer disease duration, worse motor symptoms or sleep quality and lower % of REM sleep were identified as predictors of lower PAP adherence in a preliminary study, while race (non-white) and sex (women) were linked to lower adherence in a large retrospective study. In the study reporting the highest attrition rate (75%), individuals had lower educational levels. PAP adherence improved daytime sleepiness, anxiety symptoms, sleep architecture and quality and global non-motor symptoms. However, in one short-term (3 weeks) study, there was no improvement in neuropsychological testing composite score. Three studies on MSA patients suffering from sleep-disordered breathing showed that most patients are accepting of PAP (69-72%) with an average nightly use of 4h42 to 6h18. Floppy epiglottis was more frequently seen in patients discontinuing PAP in one study. In one study, four adults with MSA and long-term PAP use reported better sleep and improved vigilance. Survival time was no different between treated and untreated individuals. In conclusion, PAP therapy is challenging in patients with OSA and NDD, as evidenced by the considerable attrition and low adherence rates reported in this systematic review. There is emerging evidence proposing OSA a treatable target to prevent clinical and functional deterioration in patients with neurodegenerative diseases and addressing potential barriers to PAP adherence is paramount to maximize adherence. Our systematic review outlines several of these potential barriers, underscoring the need for future studies to standardize the definition of and explore long-term adherence to PAP therapy and assess interventions that can optimize adherence in this patient population.

Use of Positive Airway Pressure in the Treatment of Hypoventilation.

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.

Diagnosis and management of sleep apnea by a clinical nurse: a noninferiority randomized clinical trial.

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 Spectrum of Sleep Disorders in Parkinson Disease: A Review.

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.

Feasibility of remote neurocognitive assessment: pandemic adaptations for a clinical trial, the Cognition and Obstructive Sleep Apnea in Parkinson's Disease, Effect of Positive Airway Pressure Therapy (COPE-PAP) study.

BACKGROUND: The COVID-19 pandemic poses challenges for timely outcome assessment in randomized clinical trials (RCT). Our aim was to describe our remote neurocognitive testing (NCT) protocol administered by telephone in patients with Parkinson's disease (PD) and obstructive sleep apnea (OSA). METHODS: We studied PD patients with OSA and Montreal Cognitive Assessment (MoCA) score ≤ 27 participating in a RCT assessing OSA treatment impact on cognition. Trial outcomes included change in MoCA and specific cognitive domains from baseline to 3 and 6 months. With COVID19 pandemic-related restrictions, 3-month visits were converted from in-person to telephone administration with materials mailed to participants for compatible tests and retrieved by courier the same day. In exploratory analyses, we compared baseline vs. 3-month results in the control arm, which were not expected to change significantly (test-re-test), using a paired t-test and assessed agreement with the intraclass correlation coefficient (ICC). RESULTS: Seven participants were approached and agreed to remote NCT at 3-month follow-up. Compared to the in-person NCT control arm group, they were younger (60.6 versus 70.6 years) and had a shorter disease course (3.9 versus 9.2 years). Remote NCT data were complete. The mean test-retest difference in MoCA was similar for in-person and remote NCT control-arm groups (between group difference - 0.69; 95%CI - 3.67, 2.29). Agreement was good for MOCA and varied for specific neurocognitive tests. CONCLUSION: Telephone administration of the MoCA and a modified neurocognitive battery is feasible in patients with PD and OSA. Further validation will require a larger sample size.

Obstructive Sleep Apnea in Neurodegenerative Disorders: Current Evidence in Support of Benefit from Sleep Apnea Treatment.

Obstructive sleep apnea (OSA) is a prevalent disorder characterized by recurrent upper airway obstruction during sleep resulting in intermittent hypoxemia and sleep fragmentation. Research has recently increasingly focused on the impact of OSA on the brain's structure and function, in particular as this relates to neurodegenerative diseases. This article reviews the links between OSA and neurodegenerative disease, focusing on Parkinson's disease, including proposed pathogenic mechanisms and current knowledge on the effects of treatment.

Interpreting risk reduction in clinical trials for pulmonary arterial hypertension.

Because of scepticism concerning study results when relying solely on relative effect estimates, the number needed to treat (NNT) has been used extensively to quantify the net clinical benefit of an intervention, and is reported increasingly in randomised trials and observational studies. This method is a simple measure representing the number of patients who would need to be treated to prevent one additional adverse event. However, like relative risk, the NNT is an inherently time-dependent measure. Thus, its calculation may lead to misleading interpretations, especially for studies involving varying follow-up times or recurrent outcomes. In addition to study duration and the efficacy of the therapy and the comparator, multiple other factors directly influence the NNT and should be taken into account in its interpretation as for comparative effectiveness of therapies. Its accurate estimation and interpretation, as well as its limitations, are therefore crucial to avoid erroneous clinical and public health decisions. We discuss the calculation and the interpretation of risk reduction and the NNT in the context of the changing landscape of clinical trials in pulmonary arterial hypertension.

Trial Duration and Risk Reduction in Combination Therapy Trials for Pulmonary Arterial Hypertension: A Systematic Review.

BACKGROUND: 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). METHODS: 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. RESULTS: There were 3,801 patients throughout 15 studies included. The RR for clinical worsening positively correlated with trial duration (R2 = 0.67, P = .0002), whereas the NNT did not (mean NNT, 7; R2 = 0.02; P = .65). Among long-term event-driven trials, the mean NNT progressively decreased until 52 weeks of follow-up, being stable thereafter. Conversely, the mean RR progressively increased from approximately 0.40 at week 16 to approximately 0.68 at week 104. CONCLUSIONS: Absolute 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.