title: 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.
abstract: 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.
  
  
  OBJECTIVE
  (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.
  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, Addenbrooke's 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.
  
  
  METHODS
  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)].
  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.
  
  
  BACKGROUND
  This trial is registered as ISRCTN02309506.
  
  
  BACKGROUND
  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.
authors.affiliation: University of Leeds Clinical Trials Research Unit, Leeds, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Sharples
authors.affiliation: Health Economics Research Unit, Brunel University, Uxbridge, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Glover
authors.affiliation: Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK.
authors.forename: Abigail
authors.initials: A
authors.lastname: Clutterbuck-James
authors.affiliation: Medical Research Council Biostatistics Unit, Cambridge, UK.
authors.forename: Maxine
authors.initials: M
authors.lastname: Bennett
authors.affiliation: Health Economics Research Unit, Brunel University, Uxbridge, UK.
authors.forename: Jake
authors.initials: J
authors.lastname: Jordan
authors.affiliation: Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chadwick
authors.affiliation: Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Pittman
authors.affiliation: Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: East
authors.affiliation: Maxillofacial Unit, Addenbrooke's NHS Foundation Trust, Cambridge, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Cameron
authors.affiliation: Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Davies
authors.affiliation: Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Oscroft
authors.affiliation: Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Morrell
authors.affiliation: Health Economics Research Unit, Brunel University, Uxbridge, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Fox-Rushby
authors.affiliation: Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Quinnell
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000191:economics / Q000209:etiology*; D015897:Comorbidity; D045422:Continuous Positive Airway Pressure / Q000191:economics / Q000295:instrumentation* / Q000379:methods; D003362:Cost-Benefit Analysis; D018592:Cross-Over Studies; D006970:Disorders of Excessive Somnolence / Q000209:etiology*; D004739:England; D005260:Female; D006801:Humans; D008297:Male; D019186:Mandibular Advancement / Q000191:economics / Q000295:instrumentation* / Q000379:methods; D008875:Middle Aged; D010349:Patient Compliance / Q000706:statistics & numerical data; D019057:Quality-Adjusted Life Years; D012044:Regression Analysis; D018570:Risk Assessment; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000191:economics / Q000628:therapy*; D013222:State Medicine / Q000191:economics