Rebecca Chadwick

Meta-analysis of randomised controlled trials of oral mandibular advancement devices and continuous positive airway pressure for obstructive sleep apnoea-hypopnoea.

Summary Obstructive sleep apnoea-hypopnoea (OSAH) causes excessive daytime sleepiness, impairs quality-of-life, and increases cardiovascular disease and road traffic accident risks. Continuous positive airway pressure (CPAP) treatment and mandibular advancement devices (MAD) have been shown to be effective in individual trials but their effectiveness particularly relative to disease severity is unclear. A MEDLINE, Embase and Science Citation Index search updating two systematic reviews to August 2013 identified 77 RCTs in adult OSAH patients comparing: MAD with conservative management (CM); MAD with CPAP; or CPAP with CM. Overall MAD and CPAP significantly improved apnoea-hypopnoea index (AHI) (MAD −9.3/hr (p < 0.001), CPAP −25.4 (p < 0.001)). In direct comparisons mean AHI and Epworth sleepiness scale score were lower (7.0/hr (p < 0.001) and 0.67 (p = 0.093) respectively) for CPAP. There were no CPAP vs. MAD trials in mild OSAH but in comparisons with CM, MAD and CPAP reduced ESS similarly (MAD 2.01 (p < 0.001); CPAP 1.23 (p = 0.012). Both MAD and CPAP are clinically effective in the treatment of OSAH. Although CPAP has a greater treatment effect, MAD is an appropriate treatment for patients who are intolerant of CPAP and may be comparable to CPAP in mild disease.

A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO)

Rationale Mandibular advancement devices (MADs) are used to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS) but evidence is lacking regarding their clinical and cost-effectiveness in less severe disease. Objectives To compare clinical- and cost-effectiveness of a range of MADs against no treatment in mild to moderate OSAHS. Measurements and methods This open-label, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with Apnoea-Hypopnoea Index (AHI) 5–<30/h and Epworth Sleepiness Scale (ESS) score ≥9 underwent 6 weeks of treatment with three non-adjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment. Secondary outcomes included ESS, quality of life, resource use and cost. Main results 90 patients were randomised and 83 were analysed. All devices reduced AHI compared with no treatment by 26% (95% CI 11% to 38%, p=0.001) for SP1, 33% (95% CI 24% to 41%) for SP2 and 36% (95% CI 24% to 45%, p<0.001) for bMAD. ESS was 1.51 (95% CI 0.73 to 2.29, p<0.001, SP1) to 2.37 (95% CI 1.53 to 3.22, p<0.001, bMAD) lower than no treatment (p<0.001 for all). Compliance was lower for SP1, which was the least preferred treatment at trial exit. All devices were cost-effective compared with no treatment at a £20 000/quality-adjusted life year (QALY) threshold. SP2 was the most cost-effective up to £39 800/QALY. Conclusions Non-adjustable MADs achieve clinically important improvements in mild to moderate OSAHS and are cost-effective. Of those trialled, the semi-bespoke MAD is an appropriate first choice. Trial registration number ISRCTN02309506.

Clinical effectiveness and cost-effectiveness results from the randomised controlled Trial of Oral Mandibular Advancement Devices for Obstructive sleep apnoea–hypopnoea (TOMADO) and long-term economic analysis of oral devices and continuous positive airway pressure

BACKGROUND Obstructive sleep apnoea-hypopnoea (OSAH) causes excessive daytime sleepiness (EDS), impairs quality of life (QoL) and increases cardiovascular disease and road traffic accident risks. Continuous positive airway pressure (CPAP) treatment is clinically effective but undermined by intolerance, and its cost-effectiveness is borderline in milder cases. Mandibular advancement devices (MADs) are another option, but evidence is lacking regarding their clinical effectiveness and cost-effectiveness in milder disease. OBJECTIVES (1) Conduct a randomised controlled trial (RCT) examining the clinical effectiveness and cost-effectiveness of MADs against no treatment in mild to moderate OSAH. (2) Update systematic reviews and an existing health economic decision model with data from the Trial of Oral Mandibular Advancement Devices for Obstructive sleep apnoea-hypopnoea (TOMADO) and newly published results to better inform long-term clinical effectiveness and cost-effectiveness of MADs and CPAP in mild to moderate OSAH. TOMADO A crossover RCT comparing clinical effectiveness and cost-effectiveness of three MADs: self-moulded [SleepPro 1™ (SP1); Meditas Ltd, Winchester, UK]; semibespoke [SleepPro 2™ (SP2); Meditas Ltd, Winchester, UK]; and fully bespoke [bespoke MAD (bMAD); NHS Oral-Maxillofacial Laboratory, Addenbrookes Hospital, Cambridge, UK] against no treatment, in 90 adults with mild to moderate OSAH. All devices improved primary outcome [apnoea-hypopnoea index (AHI)] compared with no treatment: relative risk 0.74 [95% confidence interval (CI) 0.62 to 0.89] for SP1; relative risk 0.67 (95% CI 0.59 to 0.76) for SP2; and relative risk 0.64 (95% CI 0.55 to 0.76) for bMAD (p < 0.001). Differences between MADs were not significant. Sleepiness [as measured by the Epworth Sleepiness Scale (ESS)] was scored 1.51 [95% CI 0.73 to 2.29 (SP1)] to 2.37 [95% CI 1.53 to 3.22 (bMAD)] lower than no treatment (p < 0.001), with SP2 and bMAD significantly better than SP1. All MADs improved disease-specific QoL. Compliance was lower for SP1, which was unpopular at trial exit. At 4 weeks, all devices were cost-effective at £20,000/quality-adjusted life-year (QALY), with SP2 the best value below £39,800/QALY. META-ANALYSIS A MEDLINE, EMBASE and Science Citation Index search updating two existing systematic reviews (one from November 2006 and the other from June 2008) to August 2013 identified 77 RCTs in adult OSAH patients comparing MAD with conservative management (CM), MADs with CPAP or CPAP with CM. MADs and CPAP significantly improved AHI [MAD -9.3/hour (p < 0.001); CPAP -25.4/hour (p < 0.001)]. Effect difference between CPAP and MADs was 7.0/hour (p < 0.001), favouring CPAP. No trials compared CPAP with MADs in mild OSAH. MAD and CPAP reduced the ESS score similarly [MAD 1.6 (p < 0.001); CPAP 1.6 (p < 0.001)]. LONG-TERM COST-EFFECTIVENESS An existing model assessed lifetime cost-utility of MAD and CPAP in mild to moderate OSAH, using the revised meta-analysis to update input values. The TOMADO provided utility estimates, mapping ESS score to European Quality of Life-5 Dimensions three-level version for device cost-utility. Using SP2 as the standard device, MADs produced higher mean costs and mean QALYs than CM [incremental cost-effectiveness ratio (ICER) £6687/QALY]. From a willingness to pay (WTP) of £15,367/QALY, CPAP is cost-effective, although the likelihood of MADs (p = 0.48) and CPAP (p = 0.49) being cost-effective is very similar. Both were better than CM, but there was much uncertainty in the choice between CPAP and MAD (at a WTP £20,000/QALY, the probability of being the most cost-effective was 47% for MAD and 52% for CPAP). When SP2 lifespan increased to 18 months, the ICER for CPAP compared with MAD became £44,066. The ICER for SP1 compared with CM was £1552, and for bMAD compared with CM the ICER was £13,836. The ICER for CPAP compared with SP1 was £89,182, but CPAP produced lower mean costs and higher mean QALYs than bMAD. Differential compliance rates for CPAP reduces cost-effectiveness so MADs become less costly and more clinically effective with CPAP compliance 90% of SP2. CONCLUSIONS Mandibular advancement devices are clinically effective and cost-effective in mild to moderate OSAH. A semi-bespoke MAD is the appropriate first choice in most patients in the short term. Future work should explore whether or not adjustable MADs give additional clinical and cost benefits. Further data on longer-term cardiovascular risk and its risk factors would reduce uncertainty in the health economic model and improve precision of effectiveness estimates. TRIAL REGISTRATION This trial is registered as ISRCTN02309506. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 67. See the NIHR Journals Library website for further project information.

Weaning from prolonged invasive ventilation in motor neuron disease: analysis of outcomes and survival

Introduction Non-invasive ventilation (NIV) improves prognosis in patients with motor neuron disease (MND) in the absence of major bulbar involvement. However, some experience a rapid and unexpected decline in respiratory function and may undergo emergency tracheal intubation. Weaning from invasive ventilation can be difficult, and reported independence from invasive ventilation is uncommon with poor prognosis. The outcomes of patients with MND referred to a specialist weaning service following emergency tracheal intubation were examined and compared with MND patients electively initiating NIV. Methods A case note review was performed on all patients with MND invasively ventilated and referred to a specialist weaning service between 1992 and 2007. Outcomes were compared with those electively commenced on NIV during the same period. Results Thirty patients were referred for weaning from invasive ventilation which was started in 17 before MND was diagnosed. Fourteen patients (47%) were weaned from invasive ventilation but still required NIV, 13 failed to wean, and three died. Seventeen were discharged home from hospital. The median survival from tracheal intubation was 13.7 months (95% CI 0 to 30.8) for those previously diagnosed and 7.2 months (95% CI 5.1 to 9.4) for those not previously known to have MND. Comparison with patients initiated electively on NIV demonstrated similar survival estimates to that from emergency intubation (median 9.4 (95% CI 6.9 to 12.0) vs 7.8 (95% CI 2.6 to 12.9) months respectively). Conclusion The prognosis in MND following acute respiratory failure and intubation is not always complete ventilator dependence if patients are offered a comprehensive weaning programme.

The impact of changing people with sleep apnea using CPAP less than 4 h per night to a Bi-level device.

Pressure intolerance is a reason for poor acceptance and subsequent compliance in some patients starting treatment with continuous positive airway pressure (CPAP). In unselected populations initiating CPAP; different types of pressure generating device have not been found to improve compliance. We hypothesized that using Bi-level PAP for patients who reported pressure related discomfort as a cause for poor compliance with CPAP might increase their hours of treatment use. Patients using CPAP <4 h/night with symptoms to suggest pressure intolerance were randomized to receive either a Bi-level PAP device or a new CPAP for 4 weeks. Following a washout period of 2 weeks, they were crossed over to the other device for 4 weeks. Twenty eight volunteers completed the protocol. Compared to the baseline (mean 1.49 h per night), improvement in compliance was noticed when changed to a new CPAP (2.23 h, p = 0.006) or Bi-level PAP (2.73 h, p < 0.001). The trend suggesting superior compliance with a Bi-level PAP device compared to new CPAP was not significant (p = 0.059) and there were no differences in subjective or objective measures of sleepiness. The results of this study suggest that routine intervention with Bi-level PAP in this group of sub-optimally compliant individuals was not very effective in improving PAP usage. There is however a subgroup of patients who complains of difficulty with exhalation; where favorable trends towards improved compliance were observed on Bi-level PAP.

S1 TOMADO: A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea

Introduction Obstructive sleep apnoea-hypopnoea (OSAH) causes excessive daytime sleepiness (EDS), impairs quality of life (Qol), and increases cardiovascular disease and road traffic accident risks. Continuous positive airway pressure therapy is effective but undermined by intolerance and cost effectiveness is borderline in milder cases. Mandibular Advancement Devices (MADs) are another treatment option but evidence is lacking regarding their effectiveness compared to no treatment in milder disease. This study compared clinical and cost effectiveness of a range of MADs and no treatment in these patients. Methods This 4-period, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with mild to moderate OSAH and EDS (Apnoea-Hypopnoea Index (AHI) 5-<30/hour; Epworth Sleepiness Scale score (ESS) > = 9) underwent 6 weeks of treatment with three non-adjustable MADs: self-moulded (SP1); semi-bespoke (SP2); fully-bespoke (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment and analysed by intention to treat. Secondary outcomes included ESS and QoL. Cost effectiveness was evaluated using validated tools, treatment costs and healthcare usage. Results Ninety patients were recruited. Sixteen withdrew before trial end. Seven did not complete any treatment and were excluded from analyses. All devices reduced AHI against no treatment, by 26% (95%CI 11%, 38%, p = 0.001) for SP1 to 36% (95%CI 24%, 45%, p < 0.001) for bMAD. ESS was 1.51 (SP1) to 2.37 (bMAD) lower versus no treatment (p < 0.001 for all). Compliance was lower for SP1 which was unpopular at trial exit. All devices were cost-effective compared with no treatment at a willingness to pay (WTP) of £20,000/quality-adjusted life year (QALY), based on mean costs and QALYs. SP2 was most cost-effective up to a WTP of £39,800/QALY after which, bMAD superseded it. Serious adverse events occurred in four patients (4%). Conclusions Mandibular Advancement Devices achieve clinically important improvements in mild to moderate OSAH syndrome and are cost effective. A semi-bespoke non-adjustable MAD would appear to be the appropriate first choice in most patients. Future work should explore whether adjustable MADs give additional clinical and cost benefits in this patient group. Funding NIHR Health Technology Assessment Programme, UK.

P228 Referral Patterns and Outcomes For Patients Treated in a National Centre Specialising in Weaning From Invasive Mechanical Ventilation

Introduction With increasing evidence for the use of non-invasive ventilation (NIV) for acute COPD1, a change in referral pattern to a national weaning unit was anticipated over time. We investigated the case mix and outcomes of patients referred to a unit specialising in weaning from invasive mechanical ventilation (IMV) over a 20 year period, comparing sequential 5-year cohorts. Methods We undertook a retrospective analysis of 453 patient records referred to a national centre for weaning from IMV between January 1992 and December 2011. They were divided into four 5-year cohorts. Age on admission, gender, diagnostic group, length of stay on the weaning unit, survival, number successfully weaned from IMV and those requiring long term NIV at discharge were examined and compared between cohorts. Results Figure 1. Kaplan Meier plot of post discharge survival, comparing the four 5-year cohorts. Abstract P228 Figure 1 A total of 453 patients were identified, 420 (93%) referred from other centres. Median age was 60.9 (IQR 49.6–70.2), 250 (55%) were male and median length of stay on the weaning unit was 27 days (IQR16–46). Thirty (7%) patients died before discharge. Of the survivors, 360 (79%) were weaned from IMV and 140 (31%) did not require any ventilatory support on discharge. No significant differences were found between the four cohorts in terms of age, gender, length of stay, proportions successfully weaned from IMV and requirement for NIV on discharge. There was no change in case mix, for example the proportions of patients with COPD were 18%, 23%, 26% and 22% across the four 5-year cohorts. Discussion We did not identify any change in the referral pattern to our weaning unit, despite widespread use of NIV. With rates of 79% successfully weaned from IMV and a median survival of 29.2 months (IQR 20.8–37.7) referral to our weaning centre remains highly relevant for those receiving prolonged IMV and good outcomes can be anticipated. References Ram FS, Picot J, Lightowler J, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of COPD. Cochrane database 2004; (3): CD004104.