Daniel J. Bratton

Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial

Background Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious. Methods This multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status. Results Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS −2.0 (95% CI −2.6 to −1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components. Conclusions In patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.

CPAP vs Mandibular Advancement Devices and Blood Pressure in Patients With Obstructive Sleep Apnea: A Systematic Review and Meta-analysis

IMPORTANCE Obstructive sleep apnea is associated with higher levels of blood pressure (BP), which can lead to increased cardiovascular risk. OBJECTIVE To compare the association of continuous positive airway pressure (CPAP), mandibular advancement devices (MADs), and inactive control groups (placebo or no treatment) with changes in systolic BP (SBP) and diastolic BP (DBP) in patients with obstructive sleep apnea. DATA SOURCES The databases of MEDLINE, EMBASE, and the Cochrane Library were searched up to the end of August 2015 and study bibliographies were reviewed. STUDY SELECTION Randomized clinical trials comparing the effect of CPAP or MADs (vs each other or an inactive control) on BP in patients with obstructive sleep apnea were selected by consensus. Of 872 studies initially identified, 51 were selected for analysis. DATA EXTRACTION AND SYNTHESIS Data were extracted by one reviewer and checked by another reviewer. A network meta-analysis using multivariate random-effects meta-regression was used to estimate pooled differences between each intervention. Meta-regression was used to assess the association between trial characteristics and the reported effects of CPAP vs inactive control. MAIN OUTCOMES AND MEASURES Absolute change in SBP and DBP from baseline to follow-up. RESULTS Of the 51 studies included in the analysis (4888 patients), 44 compared CPAP with an inactive control, 3 compared MADs with an inactive control, 1 compared CPAP with an MAD, and 3 compared CPAP, MADs, and an inactive control. Compared with an inactive control, CPAP was associated with a reduction in SBP of 2.5 mm Hg (95% CI, 1.5 to 3.5 mm Hg; P < .001) and in DBP of 2.0 mm Hg (95% CI, 1.3 to 2.7 mm Hg; P < .001). A 1-hour-per-night increase in mean CPAP use was associated with an additional reduction in SBP of 1.5 mm Hg (95% CI, 0.8 to 2.3 mm Hg; P < .001) and an additional reduction in DBP of 0.9 mm Hg (95% CI, 0.3 to 1.4 mm Hg; P = .001). Compared with an inactive control, MADs were associated with a reduction in SBP of 2.1 mm Hg (95% CI, 0.8 to 3.4 mm Hg; P = .002) and in DBP of 1.9 mm Hg (95% CI, 0.5 to 3.2 mm Hg; P = .008). There was no significant difference between CPAP and MADs in their association with change in SBP (-0.5 mm Hg [95% CI, -2.0 to 1.0 mm Hg]; P = .55) or in DBP (-0.2 mm Hg [95% CI, -1.6 to 1.3 mm Hg]; P = .82). CONCLUSIONS AND RELEVANCE Among patients with obstructive sleep apnea, both CPAP and MADs were associated with reductions in BP. Network meta-analysis did not identify a statistically significant difference between the BP outcomes associated with these therapies.

Effect of CPAP on blood pressure in patients with minimally symptomatic obstructive sleep apnoea: a meta-analysis using individual patient data from four randomised controlled trials

Background CPAP reduces blood pressure (BP) in patients with symptomatic obstructive sleep apnoea (OSA). Whether the same benefit is present in patients with minimally symptomatic OSA is unclear, thus a meta-analysis of existing trial data is required. Methods The electronic databases Medline, Embase and trial registries were searched. Trials were eligible if they included patients with minimally symptomatic OSA, had randomised them to receive CPAP or either sham-CPAP or no CPAP, and recorded BP at baseline and follow-up. Individual participant data were obtained. Primary outcomes were absolute change in systolic and diastolic BP. Findings Five eligible trials were found (1219 patients) from which data from four studies (1206 patients) were obtained. Mean (SD) baseline systolic and diastolic BP across all four studies was 131.2 (15.8) mm Hg and 80.9 (10.4) mm Hg, respectively. There was a slight increase in systolic BP of 1.1 mm Hg (95% CI −0.2 to 2.3, p=0.086) and a slight reduction in diastolic BP of 0.8 mm Hg (95% CI −1.6 to 0.1, p=0.083), although the results were not statistically significant. There was some evidence of an increase in systolic BP in patients using CPAP <4 h/night (1.5 mm Hg, 95% CI −0.0 to 3.1, p=0.052) and reduction in diastolic BP in patients using CPAP >4 h/night (−1.4 mm Hg, 95% CI −2.5 to −0.4, p=0.008). CPAP treatment reduced both subjective sleepiness (p<0.001) and OSA severity (p<0.001). Interpretation Although CPAP treatment reduces OSA severity and sleepiness, it seems not to have a beneficial effect on BP in patients with minimally symptomatic OSA, except in patients who used CPAP for >4 h/night.

Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial

BACKGROUND The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap. METHODS This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927. FINDINGS Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p<0·0001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2·0 points (-2·8 to -1·2; p<0·0001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0·01 (95% CI -0·03 to 0·04; p=0·787) and health-care costs were marginally reduced with CPAP (-£35, -390 to 321; p=0·847). CPAP improved objective sleepiness (p=0·024), mobility (p=0·029), total cholesterol (p=0·048), and LDL cholesterol (p=0·042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use. INTERPRETATION In older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome. FUNDING National Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

CPAP Improves Endothelial Function in Patients With Minimally Symptomatic OSA : Results From a Subset Study of the MOSAIC Trial

BACKGROUND Minimally symptomatic OSA is a highly prevalent disorder, and the effects of CPAP on vascular function in these patients are unknown. This trial aimed to investigate whether CPAP improves vascular function in minimally symptomatic OSA. METHODS In two centers taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial, 253 patients with minimally symptomatic OSA were randomized to 6 months of CPAP or standard care. Two hundred eight patients attended their follow-up visit within the predefined time window and had complete measurements of arterial stiffness (augmentation index [AIx]), and 64 patients had endothelial function measurements by brachial artery flow-mediated dilatation (FMD). Multivariable analyses adjusting for baseline measurements and minimization factors were performed to assess the effect of CPAP treatment on FMD (% dilatation) and AIx (% augmentation) compared with standard care. RESULTS The mean ± SD baseline oxygen desaturation index and Epworth Sleepiness Score (ESS) of the 208 patients (age 58 ± 7.3 years, 31 women) were 13.7 ± 12.8 events/h and 8.3 ± 4.2, respectively. There was no CPAP treatment effect on arterial stiffness (AIx, -1.4%; 95% CI, -3.6 to +0.9%; P = .23), but CPAP improved endothelial function (FMD, +2.1%; 95% CI, +1.0 to +3.2%; P < .0001). CPAP reduced daytime sleepiness (ESS, -2.2; 95% CI, -3.0 to -1.5; P < .0001) compared with standard care. There was a larger improvement in FMD in patients using CPAP for > 4 h/night than those who used it less (P = .013). CONCLUSIONS CPAP improves endothelial function, but not arterial stiffness, in minimally symptomatic OSA. Thus, minimally symptomatic OSA may be a cardiovascular risk factor. TRIAL REGISTRY ISRCTN Register; No.: ISRCTN 34164388; URL: http://isrctn.org.

Original ResearchSleep DisordersCPAP Improves Endothelial Function in Patients With Minimally Symptomatic OSA: Results From a Subset Study of the MOSAIC Trial

BACKGROUND Minimally symptomatic OSA is a highly prevalent disorder, and the effects of CPAP on vascular function in these patients are unknown. This trial aimed to investigate whether CPAP improves vascular function in minimally symptomatic OSA. METHODS In two centers taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial, 253 patients with minimally symptomatic OSA were randomized to 6 months of CPAP or standard care. Two hundred eight patients attended their follow-up visit within the predefined time window and had complete measurements of arterial stiffness (augmentation index [AIx]), and 64 patients had endothelial function measurements by brachial artery flow-mediated dilatation (FMD). Multivariable analyses adjusting for baseline measurements and minimization factors were performed to assess the effect of CPAP treatment on FMD (% dilatation) and AIx (% augmentation) compared with standard care. RESULTS The mean ± SD baseline oxygen desaturation index and Epworth Sleepiness Score (ESS) of the 208 patients (age 58 ± 7.3 years, 31 women) were 13.7 ± 12.8 events/h and 8.3 ± 4.2, respectively. There was no CPAP treatment effect on arterial stiffness (AIx, -1.4%; 95% CI, -3.6 to +0.9%; P = .23), but CPAP improved endothelial function (FMD, +2.1%; 95% CI, +1.0 to +3.2%; P < .0001). CPAP reduced daytime sleepiness (ESS, -2.2; 95% CI, -3.0 to -1.5; P < .0001) compared with standard care. There was a larger improvement in FMD in patients using CPAP for > 4 h/night than those who used it less (P = .013). CONCLUSIONS CPAP improves endothelial function, but not arterial stiffness, in minimally symptomatic OSA. Thus, minimally symptomatic OSA may be a cardiovascular risk factor. TRIAL REGISTRY ISRCTN Register; No.: ISRCTN 34164388; URL: http://isrctn.org.

Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial

BACKGROUND Mepolizumab, an anti-interleukin-5 monoclonal antibody approved as add-on therapy to standard of care for patients with severe eosinophilic asthma, has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo. We aimed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life (HRQOL). METHODS We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial (MUSCA) in 146 hospitals or research centres in 19 countries worldwide. Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines. Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years. We randomly assigned participants (1:1) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo, plus standard of care, every 4 weeks for 24 weeks (the final dose was given at week 20). We did the randomisation using an interactive voice response system and a centralised, computer-generated, permuted-block design of block size six. The two treatments were identical in appearance and administered in a masked manner; patients, investigators, other site staff and the entire study team including those assessing outcomes data were also masked to group assignment. The primary endpoint was the mean change from baseline in the St Georges Respiratory Questionnaire (SGRQ) total score at week 24 in the modified intention-to-treat (modified ITT) population (analysed according to their randomly assigned treatment). Safety was assessed in all patients who received at least one dose of trial medication (analysed according to the actual treatment received). This trial is registered with ClinicalTrials.gov, number NCT02281318. FINDINGS We recruited patients between Dec 11, 2014, and Nov 20, 2015, and the study was undertaken between Dec 11, 2014, and June 10, 2016. The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo. Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score (least squares mean [SE] change from baseline -15·6 (1·0) vs -7·9 (1·0), a treatment difference of -7·7 (95% CI -10·5 to -4·9; p<0·0001). No deaths occurred during the study. 192 (70%) of 273 patients who received mepolizumab and 207 (74%) of 278 who received placebo reported at least one on-treatment adverse event, the most common of which were headache (in 45 [16%] given mepolizumab vs 59 [21%] given placebo) and nasopharyngitis (in 31 [11%] given mepolizumab vs 46 [17%] given placebo). 15 (5%) and 22 (8%) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups, respectively; the most common was asthma in both groups (in three [1%] given mepolizumab vs nine [3%] given placebo). INTERPRETATION Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma, and had a safety profile similar to that of placebo. These results add to and support the use of mepolizumab as a favourable add-on treatment option to standard of care in patients with severe eosinophilic asthma. FUNDING GlaxoSmithKline.

Reducing bias in open-label trials where blinded outcome assessment is not feasible: strategies from two randomised trials.

BackgroundBlinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios.MethodsWe describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias.ResultsTRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination).TAPPS was an open-label trial whose primary outcome was whether the patient was referred for a pleural drainage procedure. Allowing a blinded assessor to decide whether to refer the patient for a procedure was not feasible as many clinicians may be reluctant to enrol patients into the trial if they cannot be involved in their care during follow-up. Assessment by an adjudication committee was not possible, as the outcome either occurred or did not. Therefore, the decision pathway for procedure referral was modified. If a chest x-ray indicated that more than a third of the pleural space filled with fluid, the patient could be referred for a procedure; otherwise, the unblinded clinician was required to reach a consensus on referral with a blinded assessor. This process allowed the unblinded clinician to be involved in the patient’s care, while reducing the potential for bias.ConclusionsWhen blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias.Trial registrationTRIGGER: ISRCTN85757829. Registered 26 July 2012.TAPPS: ISRCTN47845793. Registered 28 May 2012.

Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis

BACKGROUND Excessive daytime sleepiness is the most important symptom of obstructive sleep apnoea and can affect work productivity, quality of life, and the risk of road traffic accidents. We aimed to quantify the effects of the two main treatments for obstructive sleep apnoea (continuous positive airway pressure and mandibular advancement devices) on daytime sleepiness and to establish predictors of response to continuous positive airway pressure. METHODS We searched MEDLINE and the Cochrane Library from inception to May 31, 2015, to identify randomised controlled trials comparing the effects of continuous positive airway pressure, mandibular advancement devices or an inactive control (eg, placebo or no treatment) on the Epworth Sleepiness Scale (ESS, range 0-24 points) in patients with obstructive sleep apnoea. We did a network meta-analysis using multivariate random-effects meta-regression to assess the effect of each treatment on ESS. We used meta-regression to assess the association of the reported effects of continuous positive airway pressure versus inactive controls with the characteristics of trials and their risk of bias. FINDINGS We included 67 studies comprising 6873 patients in the meta-analysis. Compared with an inactive control, continuous positive airway pressure was associated with a reduction in ESS score of 2·5 points (95% CI 2·0-2·9) and mandibular advancement devices of 1·7 points (1·1-2·3). We estimated that, on average, continuous positive airway pressure reduced the ESS score by a further 0·8 points compared with mandibular advancement devices (95% CI 0·1-1·4; p=0·015). However, there was a possibility of publication bias in favour of continuous positive airway pressure that might have resulted in this difference. We noted no evidence that studies reporting higher continuous positive airway pressure adherence also reported larger treatment effects (p=0·70). INTERPRETATION Continuous positive airway pressure and mandibular advancement devices are effective treatments for reducing daytime sleepiness in patients with obstructive sleep apnoea. Continuous positive airway pressure seemed to be a more effective treatment than mandibular advancement devices, and had an increasingly larger effect in more severe or sleepier obstructive sleep apnoea patients when compared with inactive controls. However, mandibular advancement devices are an effective alternative treatment should continuous positive airway pressure not be tolerated. FUNDING Swiss National Science Foundation and the University of Zurich Clinical Research Priority Program Sleep and Health.

Markers of inflammation: data from the MOSAIC randomised trial of CPAP for minimally symptomatic OSA

ABSTRACT The Multi-centre Obstructive Sleep Apnoea Interventional Cardiovascular (MOSAIC) trial compared 6 months of CPAP therapy, versus no CPAP, in 391 patients with minimally symptomatic obstructive sleep apnoea (OSA). We now report some exploratory outcomes, markers of systemic inflammation (interleukin 6 (IL-6), IL-10, C reactive protein, tumour necrosis factor). We found no consistent changes (all p values >0.13). Trial registration number: ISRCTN 34164388.