Abigail Clutterbuck-James

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.

Alternatives to continuous positive airway pressure 2: mandibular advancement devices compared.

Purpose of review Although mandibular advancement devices (MADs) provide an alternative to continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea (OSA), their effectiveness and role remain unclear. Several recent studies and an updated meta-analysis have attempted to address these uncertainties. This review examines their contribution to the existing evidence and discusses the future priorities for MAD research. Recent findings Recent work has examined the impact of MAD design on clinical and cost-effectiveness in milder disease. A robust comparison of CPAP and MADs in more severe OSA has reported equivalent improvements in several important health outcomes. Other notable contributions have examined compliance, definitions of treatment success and longer term outcomes of MAD therapy. Summary There is now a growing body of evidence suggesting that MADs are a clinically and cost-effective treatment for OSA; and in some cases, patient preference may make them a better option than CPAP. Further work needs to continue to refine MAD therapy in order to optimize treatment response and compliance, whilst retaining a pragmatic and cost-effective approach that is relevant to clinical practice and sustainable in the longer term.

S27 Predictive performance of STOPBANG questionnaire for diagnosis of sleep apnoea in a cardiac surgical cohort

Introduction and objectives Questionnaires to assess the risk of obstructive sleep apnoea (OSA) prior to surgery could reduce the need for screening sleep studies. STOPBANG questionnaire is user friendly and was previously validated in a general surgical population. A high risk of OSA has been defined as a score of ≥3 and low risk as a score 0–2. We aimed to validate the STOPBANG against nocturnal oximetry in a population undergoing major cardiac surgery and assessed its prognostic value for postoperative outcomes. Methods Patients were screened for high risk of OSA with the STOPBANG questionnaire. The presence of sleep apnoea (SA), prior to surgery, was assessed with overnight oximetry. SA was defined as mild with a 4% oxygen desaturation index (ODI) of 5–14/hr, moderate with ODI of 15–29/hr and severe ODI ≥30/hr. Predictive performance of STOPBANG against nocturnal oximetry was assessed for diagnosis of mild and moderate SA by assessing the area under curve receiver operating characteristic (AUC-ROC) and sensitivity and specificity were calculated. A multiple-logistic regression model was used to assess association of STOPBANG and post-operative outcomes. Results The AUC-ROC for mild SA was low 0.57 (95% CI = 0.47–0.67). Good performance was observed for moderate SA with AUC-ROC 0.82 (95% CI = 0.69–0.95) (Figure 1) but specificity of STOPBANG at the conventional cut of value of ≥3 for moderate SA was very low at 5% whilst sensitivity was 100%. The best predictive STOPBANG cut-off value for moderate SA was ≥6 with sensitivity and specificity of 75% and 77% respectively. Assessing predictive value for severe SA was not possible due to the lack of severe SA cases in our cohort. STOPBANG was not found to be an independent predictor of worse post-operative outcomes.Abstract S27 Figure 1 ROC curves for STOPBANG to predict ODI ≥5 and ODI ≥15 Conclusion Predictive performance of STOPBANG in our patient cohort at the conventional cut off value was poor. The probable explanation is that the cardiac surgical population is preselected as male, older and most suffer with hypertension. Thus the majority will score as high risk for OSA. STOPBANG had no prognostic value on worse postoperative outcomes in our study, which again contrasts with the findings in general surgical cohorts.

S28 Effect of sleep apnoea on post-operative outcomes in cardiac surgery

Introduction and objectives Obstructive sleep apnoea (OSA) is common and can be associated with adverse health outcomes. There are conflicting data for the impact of undiagnosed OSA on the outcome of surgical procedures but at least some results suggest an association with worse outcomes. EuroSCORE risk model was developed to calculate the risk of mortality after cardiac surgery. We evaluated the prevalence and impact of undiagnosed sleep apnoea (SA) on postoperative outcomes in cardiac surgery. Methods Patients undergoing coronary artery bypass grafting with or without cardiac valve surgery were screened for the presence of SA, prior to surgery, with the STOPBANG questionnaire and overnight oximetry. SA was defined as a 4% oxygen desaturation index (ODI) of ≥5/hr. A Weibull model was used to analyse lengths of stay (LoS) in intensive care unit (ICU). Complications in ICU were dichotomised and analysed with binary logistic regressions. Parsimonious models were obtained using a combination of step-wise regression and manually removing predictors that did not reach the 5% significance level. Results 122 subjects were included in final analysis of which 57 (47%) had a new diagnosis of SA. Of those, 45 (79%) had mild SA and 12 (21%) had moderate/severe SA. There was no simple relationship between OSA as measured by ODI and LoS in ICU. The most significant predictor for ICU LoS was developing complications at ICU (p < 0.001). The independent predictors associated with increasing likelihood of developing major organ complications following cardiac surgery were EuroSCORE, ODI and intravenous opioid analgesia (IOA). When patients with mild and moderate SA received IOA, predicted probability of complications rose 2.4 and 1.4 times respectively (Figure 1).Abstract S28 Figure 1 Predicted probabilities and 95% CI of suffering a complication at ICU as ODI increases for individuals with average EuroSCORE (5) and with or without IOA Conclusion We found a high prevalence of undiagnosed sleep apnoea in our cohort. EuroSCORE, SA and the administration of intravenous morphine were found to be independent risk factors for developing post-operative complications. This risk has increased when patients with SA received intravenous morphine.

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.