Echocardiographic Changes with Positive Airway Pressure Therapy in Obesity Hypoventilation Syndrome. Long-Term Pickwick Randomized Controlled Clinical Trial.

Rationale: Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials assessing the impact of long-term noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) on cardiac structure and function assessed by echocardiography are lacking.Objectives: In a prespecified secondary analysis of the largest multicenter randomized controlled trial of OHS (Pickwick Project; N = 221 patients with OHS and coexistent severe obstructive sleep apnea), we compared the effectiveness of three years of NIV and CPAP on structural and functional echocardiographic changes.Methods: At baseline and annually during three sequential years, patients underwent transthoracic two-dimensional and Doppler echocardiography. Echocardiographers at each site were blinded to the treatment allocation. Statistical analysis was performed using a linear mixed-effects model with a treatment group and repeated measures interaction to determine the differential effect between CPAP and NIV.Measurements and Main Results: A total of 196 patients were analyzed: 102 were treated with CPAP and 94 were treated with NIV. Systolic pulmonary artery pressure decreased from 40.5 ± 1.47 mm Hg at baseline to 35.3 ± 1.33 mm Hg at three years with CPAP, and from 41.5 ± 1.56 mm Hg to 35.5 ± 1.42 with NIV (P < 0.0001 for longitudinal intragroup changes for both treatment arms). However, there were no significant differences between groups. NIV and CPAP therapies similarly improved left ventricular diastolic dysfunction and reduced left atrial diameter. Both NIV and CPAP improved respiratory function and dyspnea.Conclusions: In patients with OHS who have concomitant severe obstructive sleep apnea, long-term treatment with NIV and CPAP led to similar degrees of improvement in pulmonary hypertension and left ventricular diastolic dysfunction.Clinical trial registered with www.clinicaltrials.gov (NCT01405976).

Long-term clinical effectiveness of continuous positive airway pressure therapy versus non-invasive ventilation therapy in patients with obesity hypoventilation syndrome: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Obesity hypoventilation syndrome is commonly treated with continuous positive airway pressure or non-invasive ventilation during sleep. Non-invasive ventilation is more complex and costly than continuous positive airway pressure but might be advantageous because it provides ventilatory support. To date there have been no long-term trials comparing these treatment modalities. We therefore aimed to determine the long-term comparative effectiveness of both treatment modalities. METHODS: We did a multicentre, open-label, randomised controlled trial at 16 clinical sites in Spain. We included patients aged 15-80 years with untreated obesity hypoventilation syndrome and an apnoea-hypopnoea index of 30 or more events per h. We randomly assigned patients, using simple randomisation through an electronic database, to receive treatment with either non-invasive ventilation or continuous positive airway pressure. Both investigators and patients were aware of the treatment allocation. The research team was not involved in deciding hospital treatment, duration of treatment in the hospital, and adjustment of medications, as well as adjudicating cardiovascular events or cause of mortality. Treating clinicians from the routine care team were not aware of the treatment allocation. The primary outcome was the number of hospitalisation days per year. The analysis was done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT01405976. FINDINGS: From May 4, 2009, to March 25, 2013, 100 patients were randomly assigned to the non-invasive ventilation group and 115 to the continuous positive airway pressure group, of which 97 patients in the non-invasive ventilation group and 107 in the continuous positive airway pressure group were included in the analysis. The median follow-up was 5·44 years (IQR 4·45-6·37) for all patients, 5·37 years (4·36-6·32) in the continuous positive airway pressure group, and 5·55 years (4·53-6·50) in the non-invasive ventilation group. The mean hospitalisation days per patient-year were 1·63 (SD 3·74) in the continuous positive airway pressure group and 1·44 (3·07) in the non-invasive ventilation group (adjusted rate ratio 0·78, 95% CI 0·34-1·77; p=0·561). Adverse events were similar between both groups. INTERPRETATION: In stable patients with obesity hypoventilation syndrome and severe obstructive sleep apnoea, non-invasive ventilation and continuous positive airway pressure have similar long-term effectiveness. Given that continuous positive airway pressure has lower complexity and cost, continuous positive airway pressure might be the preferred first-line positive airway pressure treatment modality until more studies become available. FUNDING: Instituto de Salud Carlos III, Spanish Respiratory Foundation, and Air Liquide Spain.

First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

BACKGROUND: Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC. METHODS: We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. RESULTS: Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS: Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).

Primary Care Physicians Can Comprehensively Manage Patients with Sleep Apnea. A Noninferiority Randomized Controlled Trial.

Rationale: General practitioners play a passive role in obstructive sleep apnea (OSA) management. Simplification of the diagnosis and use of a semiautomatic algorithm for treatment can facilitate the integration of general practitioners, which has cost advantages.Objectives: To determine differences in effectiveness between primary health care area (PHA) and in-laboratory specialized management protocols during 6 months of follow-up.Methods: A multicenter, noninferiority, randomized, controlled trial with two open parallel arms and a cost-effectiveness analysis was performed in six tertiary hospitals in Spain. Sequentially screened patients with an intermediate to high OSA probability were randomized to PHA or in-laboratory management. The PHA arm involved a portable monitor with automatic scoring and semiautomatic therapeutic decision-making. The in-laboratory arm included polysomnography and specialized therapeutic decision-making. Patients in both arms received continuous positive airway pressure treatment or sleep hygiene and dietary treatment alone. The primary outcome measure was the Epworth Sleepiness Scale. Secondary outcomes were health-related quality of life, blood pressure, incidence of cardiovascular events, hospital resource utilization, continuous positive airway pressure adherence, and within-trial costs.Measurements and Main Results: In total, 307 patients were randomized and 303 were included in the intention-to-treat analysis. Based on the Epworth Sleepiness Scale, the PHA protocol was noninferior to the in-laboratory protocol. Secondary outcome variables were similar between the protocols. The cost-effectiveness relationship favored the PHA arm, with a cost difference of €537.8 per patient.Conclusions: PHA management may be an alternative to in-laboratory management for patients with an intermediate to high OSA probability. Given the clear economic advantage of outpatient management, this finding could change established clinical practice.Clinical trial registered with www.clinicaltrials.gov (NCT02141165).

Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.

BACKGROUND: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. METHODS: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. FINDINGS: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7-21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8-23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2-43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines. INTERPRETATION: In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted. FUNDING: AstraZeneca.

Echocardiographic changes with non-invasive ventilation and CPAP in obesity hypoventilation syndrome.

RATIONALE: Despite a significant association between obesity hypoventilation syndrome (OHS) and cardiac dysfunction, no randomised trials have assessed the impact of non-invasive ventilation (NIV) or CPAP on cardiac structure and function assessed by echocardiography. OBJECTIVES: We performed a secondary analysis of the data from the largest multicentre randomised controlled trial of OHS (Pickwick project, n=221) to determine the comparative efficacy of 2 months of NIV (n=71), CPAP (n=80) and lifestyle modification (control group, n=70) on structural and functional echocardiographic changes. METHODS: Conventional transthoracic two-dimensional and Doppler echocardiograms were obtained at baseline and after 2 months. Echocardiographers at each site were blinded to the treatment arms. Statistical analysis was performed using intention-to-treat analysis. RESULTS: At baseline, 55% of patients had pulmonary hypertension and 51% had evidence of left ventricular hypertrophy. Treatment with NIV, but not CPAP, lowered systolic pulmonary artery pressure (-3.4 mm Hg, 95% CI -5.3 to -1.5; adjusted P=0.025 vs control and P=0.033 vs CPAP). The degree of improvement in systolic pulmonary artery pressure was greater in patients treated with NIV who had pulmonary hypertension at baseline (-6.4 mm Hg, 95% CI -9 to -3.8). Only NIV therapy decreased left ventricular hypertrophy with a significant reduction in left ventricular mass index (-5.7 g/m2; 95% CI -11.0 to -4.4). After adjusted analysis, NIV was superior to control group in improving left ventricular mass index (P=0.015). Only treatment with NIV led to a significant improvement in 6 min walk distance (32 m; 95% CI 19 to 46). CONCLUSION: In patients with OHS, medium-term treatment with NIV is more effective than CPAP and lifestyle modification in improving pulmonary hypertension, left ventricular hypertrophy and functional outcomes. Long-term studies are needed to confirm these results. TRIAL REGISTRATION NUMBER: Pre-results, NCT01405976 (https://clinicaltrials.gov/).

Biomarkers of carcinogenesis and tumour growth in patients with cutaneous melanoma and obstructive sleep apnoea.

The goal of this study was to assess the relationship between the severity of obstructive sleep apnoea (OSA) and the levels of carcinogenesis- and tumour growth-related biomarkers in patients with cutaneous melanoma.This multicentre observational study included patients who were newly diagnosed with melanoma. The patients were classified as non-OSA (apnoea-hypopnoea index (AHI) 0-5 events·h-1), mild OSA (AHI 5-15 events·h-1) and moderate-severe OSA (AHI >15 events·h-1). ELISAs were performed to analyse the serum levels of hypoxia- and tumour adhesion-related biomarkers (vascular endothelial growth factor (VEGF), interleukin (IL)-8, intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM)-1) and markers of tumour aggressiveness (S100 calcium-binding protein B (S100B) and melanoma inhibitory activity (MIA)). A logistic model adjusted for age, sex and body mass index was fitted to each biomarker, and the AHI served as the dependent variable.360 patients were included (52.2% male, median (interquartile range) age 55.5 (43.8-68.0) years and AHI 8.55 (2.8-19.5) events·h-1). The levels of VEGF, IL-8, ICAM-1, S100B and MIA were not related to the severity of OSA. The levels of VCAM-1 were higher in patients with OSA than those without OSA (mild OSA: odds ratio (OR) 2.07, p=0.021; moderate-severe OSA: OR 2.35, p=0.013).In patients with cutaneous melanoma, OSA was associated with elevated circulating levels of VCAM-1 that could indicate the contribution of OSA in tumorigenesis via integrin-based adhesion.

Sleep-disordered breathing, circulating exosomes, and insulin sensitivity in adipocytes.

BACKGROUND: Sleep-disordered-breathing (SDB), which is characterized by chronic intermittent hypoxia (IH) and sleep fragmentation (SF), is a prevalent condition that promotes metabolic dysfunction, particularly among patients suffering from obstructive hypoventilation syndrome (OHS). Exosomes are generated ubiquitously, are readily present in the circulation, and their cargo may exert substantial functional cellular alterations in both physiological and pathological conditions. However, the effects of plasma exosomes on adipocyte metabolism in patients with OHS or in mice subjected to IH or SF mimicking SDB are unclear. METHODS: Exosomes from fasting morning plasma samples from obese adults with polysomnographically-confirmed OSA before and after 3 months of adherent CPAP therapy were assayed. In addition, C57BL/6 mice were randomly assigned to (1) sleep control (SC), (2) sleep fragmentation (SF), and (3) intermittent hypoxia (HI) for 6 weeks, and plasma exosomes were isolated. Equivalent exosome amounts were added to differentiated adipocytes in culture, after which insulin sensitivity was assessed using 0 nM and 5 nM insulin-induced pAKT/AKT expression changes by western blotting. RESULTS: When plasma exosomes were co-cultured and internalized by human naive adipocytes, significant reductions emerged in Akt phosphorylation responses to insulin when compared to exosomes obtained after 24 months of adherent CPAP treatment (n = 24; p < 0.001), while no such changes occur in untreated patients (n = 8). In addition, OHS exosomes induced significant increases in adipocyte lipolysis that were attenuated after CPAP, but did not alter pre-adipocyte differentiation. Similarly, exosomes from SF- and IH-exposed mice induced attenuated p-AKT/total AKT responses to exogenous insulin and increased glycerol content in naive murine adipocytes, without altering pre-adipocyte differentiation. CONCLUSIONS: Using in vitro adipocyte-based functional reporter assays, alterations in plasma exosomal cargo occur in SDB, and appear to contribute to adipocyte metabolic dysfunction. Further exploration of exosomal miRNA signatures in either human subjects or animal models and their putative organ and cell targets appears warranted.

Conventional Polysomnography Is Not Necessary for the Management of Most Patients with Suspected Obstructive Sleep Apnea. Noninferiority, Randomized Controlled Trial.

RATIONALE: Home respiratory polygraphy may be a simpler alternative to in-laboratory polysomnography for the management of more symptomatic patients with obstructive sleep apnea, but its effectiveness has not been evaluated across a broad clinical spectrum. OBJECTIVES: To compare the long-term effectiveness (6 mo) of home respiratory polygraphy and polysomnography management protocols in patients with intermediate-to-high sleep apnea suspicion (most patients requiring a sleep study). METHODS: A multicentric, noninferiority, randomized controlled trial with two open parallel arms and a cost-effectiveness analysis was performed in 12 tertiary hospitals in Spain. Sequentially screened patients with sleep apnea suspicion were randomized to respiratory polygraphy or polysomnography protocols. Moreover, both arms received standardized therapeutic decision-making, continuous positive airway pressure (CPAP) treatment or a healthy habit assessment, auto-CPAP titration (for CPAP indication), health-related quality-of-life questionnaires, 24-hour blood pressure monitoring, and polysomnography at the end of follow-up. The main outcome was the Epworth Sleepiness Scale measurement. The noninferiority criterion was -2 points on the Epworth scale. MEASUREMENTS AND MAIN RESULTS: In total, 430 patients were randomized. The respiratory polygraphy protocol was noninferior to the polysomnography protocol based on the Epworth scale. Quality of life, blood pressure, and polysomnography were similar between protocols. Respiratory polygraphy was the most cost-effective protocol, with a lower per-patient cost of 416.7€. CONCLUSIONS: Home respiratory polygraphy management is similarly effective to polysomnography, with a substantially lower cost. Therefore, polysomnography is not necessary for most patients with suspected sleep apnea. This finding could change established clinical practice, with a clear economic benefit. Clinical trial registered with www.clinicaltrials.gov (NCT 01752556).

Non-invasive ventilation in obesity hypoventilation syndrome without severe obstructive sleep apnoea.

BACKGROUND: Non-invasive ventilation (NIV) is an effective form of treatment in patients with obesity hypoventilation syndrome (OHS) who have concomitant severe obstructive sleep apnoea (OSA). However, there is a paucity of evidence on the efficacy of NIV in patients with OHS without severe OSA. We performed a multicentre randomised clinical trial to determine the comparative efficacy of NIV versus lifestyle modification (control group) using daytime arterial carbon dioxide tension (PaCO2) as the main outcome measure. METHODS: Between May 2009 and December 2014 we sequentially screened patients with OHS without severe OSA. Participants were randomised to NIV versus lifestyle modification and were followed for 2 months. Arterial blood gas parameters, clinical symptoms, health-related quality of life assessments, polysomnography, spirometry, 6-min walk distance test, blood pressure measurements and healthcare resource utilisation were evaluated. Statistical analysis was performed using intention-to-treat analysis. RESULTS: A total of 365 patients were screened of whom 58 were excluded. Severe OSA was present in 221 and the remaining 86 patients without severe OSA were randomised. NIV led to a significantly larger improvement in PaCO2 of -6 (95% CI -7.7 to -4.2) mm Hg versus -2.8 (95% CI -4.3 to -1.3) mm Hg, (p<0.001) and serum bicarbonate of -3.4 (95% CI -4.5 to -2.3) versus -1 (95% CI -1.7 to -0.2 95% CI)  mmol/L (p<0.001). PaCO2 change adjusted for NIV compliance did not further improve the inter-group statistical significance. Sleepiness, some health-related quality of life assessments and polysomnographic parameters improved significantly more with NIV than with lifestyle modification. Additionally, there was a tendency towards lower healthcare resource utilisation in the NIV group. CONCLUSIONS: NIV is more effective than lifestyle modification in improving daytime PaCO2, sleepiness and polysomnographic parameters. Long-term prospective studies are necessary to determine whether NIV reduces healthcare resource utilisation, cardiovascular events and mortality. TRIAL REGISTRATION NUMBER: NCT01405976; results.

Efficacy of Different Treatment Alternatives for Obesity Hypoventilation Syndrome. Pickwick Study.

RATIONALE: The incidence of obesity hypoventilation syndrome (OHS) may be increasing in parallel with the present obesity epidemic. Despite extensive noninvasive ventilation (NIV) and continuous positive airway pressure (CPAP) use in patients with OHS, information regarding efficacy is limited. OBJECTIVES: We performed a large, multicenter randomized controlled study to determine the comparative efficacy of NIV, CPAP, and lifestyle modification (control group) using daytime PaCO2 as the main outcome measure. METHODS: Sequentially screened patients with OHS with severe sleep apnea were randomized into the above-mentioned groups for a 2-month follow up. Arterial blood gas parameters, clinical symptoms, health-related quality-of-life assessments, polysomnography, spirometry, 6-minute-walk distance, dropouts, compliance, and side effects were evaluated. Statistical analysis was performed using intention-to-treat analysis, although adjustments for CPAP and NIV compliance were also analyzed. MEASUREMENTS AND MAIN RESULTS: In total, 351 patients were selected, and 221 were randomized. NIV yielded the greatest improvement in PaCO2 and bicarbonate, with significant differences relative to the control group but not relative to the CPAP group. In the CPAP group, PaCO2 improvement was significantly different than in the control group only after CPAP compliance adjustment. Additionally, clinical symptoms and polysomnographic parameters improved similarly with NIV and CPAP relative to the control. However, some health-related quality-of-life assessments, the spirometry, and 6-minute-walk distance results improved more with NIV than with CPAP. Dropouts were similar between groups, and compliance and secondary effects were similar between NIV and CPAP. CONCLUSIONS: NIV and CPAP were more effective than lifestyle modification in improving clinical symptoms and polysomnographic parameters, although NIV yielded better respiratory functional improvements than did CPAP. Long-term studies must demonstrate whether this functional improvement has relevant implications. Clinical trial registered with www.clinicaltrials.gov (NCT01405976).

A Bayesian cost-effectiveness analysis of a telemedicine-based strategy for the management of sleep apnoea: a multicentre randomised controlled trial.

BACKGROUND: Compliance with continuous positive airway pressure (CPAP) therapy is essential in patients with obstructive sleep apnoea (OSA), but adequate control is not always possible. This is clinically important because CPAP can reverse the morbidity and mortality associated with OSA. Telemedicine, with support provided via a web platform and video conferences, could represent a cost-effective alternative to standard care management. AIM: To assess the telemedicine impact on treatment compliance, cost-effectiveness and improvement in quality of life (QoL) when compared with traditional face-to-face follow-up. METHODS: A randomised controlled trial was performed to compare a telemedicine-based CPAP follow-up strategy with standard face-to-face management. Consecutive OSA patients requiring CPAP treatment, with sufficient internet skills and who agreed to participate, were enrolled. They were followed-up at 1, 3 and 6 months and answered surveys about sleep, CPAP side effects and lifestyle. We compared CPAP compliance, cost-effectiveness and QoL between the beginning and the end of the study. A Bayesian cost-effectiveness analysis with non-informative priors was performed. RESULTS: We randomised 139 patients. At 6 months, we found similar levels of CPAP compliance, and improved daytime sleepiness, QoL, side effects and degree of satisfaction in both groups. Despite requiring more visits, the telemedicine group was more cost-effective: costs were lower and differences in effectiveness were not relevant. CONCLUSIONS: A telemedicine-based strategy for the follow-up of CPAP treatment in patients with OSA was as effective as standard hospital-based care in terms of CPAP compliance and symptom improvement, with comparable side effects and satisfaction rates. The telemedicine-based strategy had lower total costs due to savings on transport and less lost productivity (indirect costs). TRIAL REGISTER NUMBER: NCT01716676.

Effectiveness of sequential automatic-manual home respiratory polygraphy scoring.

Automatic home respiratory polygraphy (HRP) scoring functions can potentially confirm the diagnosis of sleep apnoea-hypopnoea syndrome (SAHS) (obviating technician scoring) in a substantial number of patients. The result would have important management and cost implications. The aim of this study was to determine the diagnostic cost-effectiveness of a sequential HRP scoring protocol (automatic and then manual for residual cases) compared with manual HRP scoring, and with in-hospital polysomnography. We included suspected SAHS patients in a multicentre study and assigned them to home and hospital protocols at random. We constructed receiver operating characteristic (ROC) curves for manual and automatic scoring. Diagnostic agreement for several cut-off points was explored and costs for two equally effective alternatives were calculated. Of 366 randomised patients, 348 completed the protocol. Manual scoring produced better ROC curves than automatic scoring. There was no sensitive automatic or subsequent manual HRP apnoea-hypopnoea index (AHI) cut-off point. The specific cut-off points for automatic and subsequent manual HRP scorings (AHI >25 and >20, respectively) had a specificity of 93% for automatic and 94% for manual scorings. The costs of manual protocol were 9% higher than sequential HRP protocol; these were 69% and 64%, respectively, of the cost of the polysomnography. A sequential HRP scoring protocol is a cost-effective alternative to polysomnography, although with limited cost savings compared to HRP manual scoring.

Therapeutic decision-making for sleep apnea and hypopnea syndrome using home respiratory polygraphy: a large multicentric study.

RATIONALE: Home respiratory polygraphy (HRP) is an alternative to polysomnography (PSG) for sleep apnea-hypopnea syndrome (SAHS) diagnosis. However, therapeutic decision-making is a different process than diagnosis. OBJECTIVES: This study aimed to determine the agreement between HRP and in-hospital PSG for therapeutic decision-making in a large sample. METHODS: Patients with an intermediate or high SAHS suspicion were included in a multicenter study (eight sleep centers) and assigned to home and hospital protocols in a random order. Therapeutic decisions (continuous positive airway pressure, no continuous positive airway pressure, or impossible decision) were made by an investigator in each center, based on using either HRP or PSG and a single set of auxiliary clinical variables. Patients and diagnostic methods (HRP and PSG) were assessed in random order using an electronic database. After a month the same therapeutic decision-making procedure was repeated with the same method. MEASUREMENTS AND MAIN RESULTS: Of 366 randomized patients, 348 completed the protocol. The "impossible decision" case was not observed with either PSG or HRP. Therapeutic decisions using HRP had a sensitivity of 73%, a specificity of 77%, and an agreement level (sum of true positives and negatives) of 76%. Patients with higher HRP apnea-hypopnea index (AHI) scores (≥ 30; 41% of the total sample) had a sensitivity of 94%, a specificity of 44%, and the agreement level was 91%. CONCLUSIONS: The HRP-based therapeutic decision was adequate when AHI was high, but deficient in the large population of patients with mild to moderate AHI. Therefore, both selecting patients with a high suspicion and severity of SAHS and future prospective cost-effectiveness studies are necessary.

Effectiveness of CPAP vs. Noninvasive Ventilation Based on Disease Severity in Obesity Hypoventilation Syndrome and Concomitant Severe Obstructive Sleep Apnea.

RATIONALE: Obesity hypoventilation syndrome (OHS) with concomitant severe obstructive sleep apnea (OSA) is treated with CPAP or noninvasive ventilation (NIV) during sleep. NIV is costlier, but may be advantageous because it provides ventilatory support. However, there are no long-term trials comparing these treatment modalities based on OHS severity. OBJECTIVE: To determine if CPAP have similar effectiveness when compared to NIV according to OHS severity subgroups. METHODS: Post hoc analysis of the Pickwick randomized clinical trial in which 215 ambulatory patients with untreated OHS and concomitant severe OSA, defined as apnoea-hypopnea index (AHI)≥30events/h, were allocated to NIV or CPAP. In the present analysis, the Pickwick cohort was divided in severity subgroups based on the degree of baseline daytime hypercapnia (PaCO2 of 45-49.9 or ≥50mmHg). Repeated measures of PaCO2 and PaO2 during the subsequent 3 years were compared between CPAP and NIV in the two severity subgroups. Statistical analysis was performed using linear mixed-effects model. RESULTS: 204 patients, 97 in the NIV group and 107 in the CPAP group were analyzed. The longitudinal improvements of PaCO2 and PaO2 were similar between CPAP and NIV based on the PaCO2 severity subgroups. CONCLUSION: In ambulatory patients with OHS and concomitant severe OSA who were treated with NIV or CPAP, long-term NIV therapy was similar to CPAP in improving awake hypercapnia, regardless of the severity of baseline hypercapnia. Therefore, in this patient population, the decision to prescribe CPAP or NIV cannot be solely based on the presenting level of PaCO2.

Risk factors associated with pulmonary hypertension in obesity hypoventilation syndrome.

STUDY OBJECTIVES: Pulmonary hypertension (PH) is prevalent in obesity hypoventilation syndrome (OHS). However, there is a paucity of data assessing pathogenic factors associated with PH. Our objective is to assess risk factors that may be involved in the pathogenesis of PH in untreated OHS. METHODS: In a post hoc analysis of the Pickwick trial, we performed a bivariate analysis of baseline characteristics between patients with and without PH. Variables with a P value ≤ .10 were defined as potential risk factors and were grouped by theoretical pathogenic mechanisms in several adjusted models. Similar analysis was carried out for the 2 OHS phenotypes, with and without severe concomitant obstructive sleep apnea. RESULTS: Of 246 patients with OHS, 122 (50%) had echocardiographic evidence of PH defined as systolic pulmonary artery pressure ≥ 40 mm Hg. Lower levels of awake PaO2 and higher body mass index were independent risk factors in the multivariate model, with a negative and positive adjusted linear association, respectively (adjusted odds ratio 0.96; 95% confidence interval 0.93 to 0.98; P = .003 for PaO2, and 1.07; 95% confidence interval 1.03 to 1.12; P = .001 for body mass index). In separate analyses, body mass index and PaO2 were independent risk factors in the severe obstructive sleep apnea phenotype, whereas body mass index and peak in-flow velocity in early/late diastole ratio were independent risk factors in the nonsevere obstructive sleep apnea phenotype. CONCLUSIONS: This study identifies obesity per se as a major independent risk factor for PH, regardless of OHS phenotype. Therapeutic interventions targeting weight loss may play a critical role in improving PH in this patient population. CLINICAL TRIAL REGISTRATION: Registry: Clinicaltrial.gov; Name: Alternative of Treatment in Obesity Hypoventilation Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT01405976; Identifier: NCT01405976. CITATION: Masa JF, Benítez ID, Javaheri S, et al. Risk factors associated with pulmonary hypertension in obesity hypoventilation syndrome. J Clin Sleep Med. 2022;18(4):983-992.

Effectiveness of home respiratory polygraphy for the diagnosis of sleep apnoea and hypopnoea syndrome.

INTRODUCTION: Home respiratory polygraphy (HRP) may be a cost-effective alternative to polysomnography for the diagnosis of sleep apnoea-hypopnoea syndrome (SAHS), but stronger evidence is needed. Normally, patients transport HRP equipment from the hospital to home and back, which may create difficulties for some patients. OBJECTIVES: To determine both the diagnostic efficacy and cost of HRP (with and without a transportation service moving the device and telematic transmission of data) in a large sample compared with in-hospital polysomnography. METHODS: Patients suspected of having SAHS were included in a multicentre study (eight hospitals). They were assigned to home and hospital protocols in random order. Receiver operating characteristic curves were constructed for manual respiratory polygraphy scoring protocol and different polysomnographic cut-off points. Diagnostic efficacies for several polysomnographic cut-off points were explored and costs for two equally effective alternatives were calculated. RESULTS: Of 366 randomised patients, 348 completed the protocol. The best receiver operating characteristic curve was obtained with a polysomnographic cut-off of the apnoea-hypopnoea index (AHI)≥5. The sensitive HRP AHI cut-off point (<5) had a sensitivity of 96%, a specificity of 57% and a negative likelihood ratio (LR) of 0.07; the specific cut-off (>10) had a sensitivity of 87%, a specificity of 86% and a positive LR of 6.25. The cost of HRP was half that of polysomnography. Telematic transmission costs were similar if the patients' costs were taken in to account. CONCLUSION: HRP is an alternative to polysomnography in patients with suspected SAHS. Telematic procedures may help patients with limited mobility and those who live a long way from the sleep centre.

Is the Next Generation Sequencing the Essential Tool for the Early Diagnostic Approach in Congenital Muscular Dystrophy? New Mutation in the Gen LMNA Associated with Serious Phenotype.

BACKGROUND: Laminopathies are a group of diseases caused by mutations in the LMNA gene. Congenital dystrophy of the LMN is a rare disease, with less than 100 cases described in the literature. OBJECTIVES AND MATERIALS AND METHODS: We present the clinical case of a patient with congenital muscular dystrophy associated with an undescribed mutation in the LMNA gene. RESULTS: The patient presented progressive motor delay from 10 months with a physical examination consisting of global hypotonia, bilateral winged scapula, areflexia, hip and knee flexion posture, and positive Gowers. The patient developed progressive weakness with neck tone loss, functional impairment, and loss of gait at 5 years. CONCLUSIONS: To date, more than 20 mutations associated with congenital LMNA muscular dystrophy have been identified, most due to a single amino acid change (aa), few due to the gain or loss of several aa as in our patient.

Validity and Cost-Effectiveness of Pediatric Home Respiratory Polygraphy for the Diagnosis of Obstructive Sleep Apnea in Children: Rationale, Study Design, and Methodology.

Obstructive sleep apnea (OSA) in children is a prevalent, albeit largely undiagnosed disease associated with a large spectrum of morbidities. Overnight in-lab polysomnography remains the gold standard diagnostic approach, but is time-consuming, inconvenient, and expensive, and not readily available in many places. Simplified Home Respiratory Polygraphy (HRP) approaches have been proposed to reduce costs and facilitate the diagnostic process. However, evidence supporting the validity of HRP is still scarce, hampering its implementation in routine clinical use. The objectives were: Primary; to establish the diagnostic and therapeutic decision validity of a simplified HRP approach compared to PSG among children at risk of OSA. Secondary: (a) Analyze the cost-effectiveness of the HRP versus in-lab PSG in evaluation and treatment of pediatric OSA; (b) Evaluate the impact of therapeutic interventions based on HRP versus PSG findings six months after treatment using sleep and health parameters and quality of life instruments; (c) Discovery and validity of the urine biomarkers to establish the diagnosis of OSA and changes after treatment.