REVIEW URRENT C OPINION
Alternatives to continuous positive airway pressure 2: mandibular advancement devices compared Timothy G. Quinnell and Abigail L. Clutterbuck-James
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. Keywords continuous positive airway pressure, mandibular advancement device, obstructive sleep apnea
INTRODUCTION Mandibular advancement devices (MADs) provide an alternative to continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea (OSA). By protruding the mandible, they can improve upper airway dimensions and reduce collapsibility. Although some clinical guidelines recommend MADs as the first-line treatment in mild OSA and as an alternative to CPAP in more severe disease [1], their effectiveness and role remain unclear. This is partly because heterogeneity of trial methodology, device design and treatment implementation makes it difficult to evaluate published evidence. Three meta-analyses [2–4] have consistently found MADs to be better than placebo at reducing the frequency of obstructive events, but less efficacious than CPAP. Nonetheless, the two treatments seem equally effective at improving excessive daytime sleepiness (EDS). Most MAD trials have focussed on more severe OSA, whereas milder disease, device comparisons and cost-effectiveness
have been understudied. Recently, a large trial compared different MADs in patients with mild-to-moderate OSA and evaluated cost-effectiveness [5 ]. The results will be discussed in this review along with other studies from the last year that reflect the current research priorities. &
MANDIBULAR ADVANCEMENT DEVICES VERSUS CONTINUOUS POSITIVE AIRWAY PRESSURE CPAP is considered the gold-standard treatment for OSA. Pneumatic airway splinting greatly reduces Respiratory Support and Sleep Centre (RSSC), Papworth Hospital NHS Foundation Trust, Cambridge, UK Correspondence to Dr Timothy G. Quinnell, Respiratory Support and Sleep Centre, Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, CB23 3RE, UK. Tel: +44 1480 364174; fax: +44 1480 364568; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:595–600 DOI:10.1097/MCP.0000000000000096
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KEY POINTS Mandibular advancement devices (MADs) appear clinically and cost-effective for the treatment of mild-tomoderate obstructive sleep apnea (OSA). Good MAD compliance makes them a genuine alternative to continuous positive airway pressure (CPAP) in patients with more severe OSA. Recent research has investigated ways of improving MAD efficacy, tolerance and side-effects. Further work is needed to refine MAD therapy to optimize its clinical and cost-effectiveness.
obstructive events as measured by the apnea hypopnoea index (AHI) and can improve EDS, driving safety, quality of life (QoL) and blood pressure (BP), with possible additional cardiovascular benefits. However, CPAP intolerance remains a major obstacle, with treatment failure rates of 46–83% [6]. Numerous studies have compared MADs to CPAP and many have fed into meta-analyses [1–3]. An updated systematic review is currently in press [7]. It shows that the majority of CPAP trials remain focussed on moderate-to-severe OSA, although it is possible that AHI differences between CPAP and MADs would be less in milder disease. The results continue to demonstrate that MADs and CPAP significantly improve AHI, with CPAP having greater effects. The impact of both treatments on EDS is still positive and similar. The update also observes stronger treatment effects in trials of shorter duration, suggesting effectiveness may decrease over time. The review echoes its predecessors in calling for robust secondary QoL and cardiovascular outcomes; long-term follow-up data; and trials across the entire range of disease severity including milder OSA. In the last year, results from a large, well designed, crossover randomized controlled trial (RCT) were published [8 ]. One hundred and twenty-six patients with moderate-to-severe OSA used an adjustable, patient-titrated MAD and CPAP for 1 month each. The study was not only powered to measure BP effects, but also examined other health outcomes. Although CPAP reduced AHI more than MADs, this was offset by greater MAD compliance. Neither showed a BP effect, but both were associated with improvements in subjective EDS, driving simulator performance and QoL. The results support the hypothesis that similar reallife MAD and CPAP effectiveness may be due to greater MAD compliance achieving net equivalent &&
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AHI reduction [9,10]; and suggest MADs provide a genuine alternative to CPAP in more severe OSA. Although traditional MAD vs. CPAP trials remain relevant, novel approaches to using these two treatments are being explored. One small study recently evaluated the utility of MADs as a temporary CPAP substitute [11]. Adherent CPAP users with mostly moderate-to-severe OSA were transitioned to MADs, then left to use either treatment at their discretion for 3 months. MADs significantly reduced both AHI and sleepiness (measured by the Epworth Sleepiness Scale; ESS) compared with pretreatment baseline levels, and the majority of patients reported they would use MADs as an alternative short-term therapy to CPAP. Although from a select patient group, the results suggest a different more flexible approach to OSA treatment. Although potentially helpful for some patients, the resource implications of dual therapy are likely to prevent it becoming widely adopted outside specific scenarios, such as in the military [12].
MANDIBULAR ADVANCEMENT DEVICES COMPARED Despite the obvious need to understand the influence of device design on MAD effectiveness, there have been few studies comparing MADs with MADs that have been sufficiently robust to inform device selection in the clinical setting. One recent crossover RCT compared three nonadjustable (‘fixed’-‘f’)MADs of varying sophistication and cost in 90 patients with mild-tomoderate OSA [5 ]. The results of the Trial of Oral Mandibular Advancement Devices in Obstructive sleep apnea (TOMADO) showed all fMADs to improve objective and subjective health outcomes over no treatment, and to be cost-effective. Although there were no significant differences in sleep study or EDS effects between the three devices, a thermoplastic patient moulded device was arguably less effective. It was poorly retained, less popular with patients and often prematurely discontinued, suggesting limited longer term utility. Tolerance and retention were, however, similar for a ‘semi-bespoke’ fMAD, which required no specialist dental input, and a bespoke dentally produced device. The results suggest that a less expensive semi-bespoke nonadjustable device might be a reasonable first choice in most patients with mildto-moderate OSA, but that dental expertise will be required for patients who have difficulty producing the mould for a semi-bespoke device, or whose dentition or oral health is poor. There is a need for a similarly robust and pragmatic comparison of fMADs with adjustable &
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(‘a’)MADs. The ability to adjust protrusion according to efficacy and tolerance carries several advantages, and aMADs are increasingly recommended [13,14]. However, the cost range of this more sophisticated approach is probably greater than for nonadjustable alternatives and its real-life superiority remains unproven. There is contradictory evidence regarding the impact of greater protrusion in milder disease; and high compliance with nonadjustable MADs [5 ] may leave little room for improvement. Prospective comparisons are needed because research to date has not tackled this uncertainty. One study compared aMADs with fMADs. Both groups had a similar reduction in AHI from baseline up to 1 month [15]. The aMADs reduced AHI significantly more than fMADs for patients with moderate OSA, but this involved a minor, 3.8 per hour difference in only 12 patients. Furthermore, protrusion was fixed: at 85% of maximal jaw advancement for aMADs and at 75% for fMADs; so the study essentially compared protrusions rather than devices. A much larger retrospective review of MAD-treated mild-to-severe OSA patients reported slightly greater AHI effects for aMADs compared with fMADs [12]. However, differences were often not statistically significant and clinical significance was doubtful, particularly as ESS reductions were similar. The adjustability question is complicated by the ever-increasing range of titration techniques. Researchers have used complex sleep studies to determine optimal protrusion, with either singlenight titration [16] or serial reviews to guide adjustment [17]. This more intensive approach has not seemed to yield additional benefits. Outcomes have been comparable to earlier studies, with AHI reduction being less than for CPAP but EDS improvements similar [16,17]. One study used four nights to determine the most efficacious protrusion. This improved AHI similar to CPAP, but curiously ESS effects were no better than placebo for either treatment [18]. Serial complex sleep studies are unlikely to be acceptable in routine clinical practice, but singlenight titration might be if sufficiently beneficial. Recently, one group used a remotely controlled mandibular positioner during polysomnography (PSG) to predict therapeutic response and effective target protrusion for aMAD treatment [19 ]. Titration caused little sleep disturbance and showed higher predictive accuracy than earlier studies, attributed to better equipment and predetermined response criteria. If consistently validated, this technique could help identify MAD candidates, potentially justifying its role by reducing expenditure on &
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nonresponders. However, complex sleep study titration still considerably increases the cost of MAD therapy. TOMADO reported a desaturation index effect similar to that for AHI [5 ], so oximetry may provide a more accessible and affordable compromise. If aMADs are tested against fMADs in a robust comparative effectiveness study, then it would be worth exploring the role of oximetry titration. For any objective method, a significant advantage needs to be demonstrated over subjective titration, given the CPAP equivalent outcomes already reported using that alone [8 ,20]. Drug-induced sleep endoscopy continues to be evaluated for its utility in predicting MAD response. Improved upper airway patency in 135 anaesthetized patients whilst in maximal tolerated mandibular protrusion was associated with a positive response (defined by AHI reduction to 50% of baseline; P < 0.01) [21]. Although of research interest, real-life advantages of this more intrusive approach are unknown, and there may be other obstacles to its widespread clinical uptake. &
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COMPLIANCE AND PREDICTORS OF COMPLIANCE A key factor interacting with CPAP and MAD effectiveness is compliance. Recent work reflects the recognition that patient preference should be included in treatment considerations [22]. One group studying 82 patients reported that type D personality was associated with higher risk of discontinuing MAD treatment [23]. A discrete choice experiment in 121 newly diagnosed French patients calculated the demanding probabilities for CPAP and MAD to be 60.2 and 36.2%, respectively [24]. However, the previously described study of MAD substitution in the established CPAP users found that 75% were happy to continue using MADs as a short-term alternative [11]. That study also reflected the influence that bed partners may have, with 88% preferring MADs over CPAP. One clinical and research advantage that CPAP has held over MADs has been the facility to objectively monitor compliance. Significant progress has recently been made to bring MAD therapy up to speed, with the validation of affordable implantable thermoactive compliance chips [10]. Not only do they appear accurate, but also initial data suggest that, at least in the trial setting, subjective and objective compliance concord [25 ]. Whether these chips become standard MAD issue waits to be seen. They have obvious research value, particularly given the frequently cited superior MAD tolerance that is argued to underlie their CPAP equivalence. If MAD uptake increases, then objective monitoring may
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become more necessary clinically to identify poor compliers in need of early intervention and to inform ‘fitness to drive’ decisions.
DEFINING TREATMENT SUCCESS Another challenge faced by the researchers in their evaluation of MAD effectiveness is the definition of treatment success. This is particularly important when trying to compare MADs to the more efficacious CPAP. Response criteria have been developed, which are usually based on AHI reduction, for example, complete response ¼ AHI less than 5 per hour [5 ]; treatment efficacy ¼ AHI decrease at least 50% of baseline [11]. Although these represent useful efforts to standardize the assessment of MAD effectiveness, their use lacks consistency. The validity of different criteria is unproven and the success rates they give range widely [14]. It remains difficult to define OSA treatment success. It is likely to be a combination of objective respiratory event reduction, subjective improvement and compliance, but the vagaries of arbitrary success definitions must be kept in mind when comparing OSA treatments. &
MANDIBULAR ADVANCEMENT DEVICE THERAPY IN THE LONGER TERM – EFFECTIVENESS
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Although most complications of MAD therapy are mild and transient, they sometimes limit device tolerance and effectiveness, and efforts are being made to mitigate this. An orthodontic MAD has shown promise in increasing the overjet of patients at risk of developing negative bite changes [29], whereas mandibular exercises may allow patients with temporomandibular problems to continue to use MADs [30]. The incidence of more significant, longer term complications has been unclear and more information has been sought. One group found MAD usage of more than 5 years to be linked to mild skeletal and occlusal changes in 25 patients [31]. Another study reported small but significant dental changes in MAD users after 2 years, supporting the case for regular dental follow-up [32]. However, it seems increasingly accepted that dental side-effects may be a price worth paying for effective OSA treatment [33].
CARDIOVASCULAR OUTCOMES The effect of CPAP treatment on cardiovascular outcomes remains uncertain, although the Sleep Apnea cardioVascular Endpoints (SAVE) study of CPAP effects on new cardiovascular events in high-risk patients with moderate-to-severe OSA may provide insight [34]. There are no conclusive answers from MAD trials [5 ,8 ,35]. Phillips et al. reported no effect of CPAP or MADs on BP in moderate-to-severe OSA, and TOMADO showed no BP effect in milder OSA [5 ,8 ]. Dal-Fabbro et al. [35] showed no differences in BP parameters between CPAP, MAD and placebo MAD in moderate-tosevere OSA, except for more frequent diastolic BP dipping in the MAD group. An observational study recently reported that both MAD and CPAP treated patients with severe OSA had lower cardiovascular death rates than untreated patients, with no intertreatment differences despite residual AHI being greater in the MAD group [36]. However, these results may represent confounder bias, as the extension of non-compliance to other cardiovascular riskmodifying treatment is difficult to control for. Although the cardiovascular effects of OSA and its treatments remain uncertain, it is appropriate, given the similarity of many MAD and CPAP outcomes, to continue studying the impacts of MAD therapy. In the meantime, the existing evidence suggests that cardiovascular concerns need not exclude MADs as treatment option, particularly if driven by patient preference. Despite the recognized need for more research into MAD therapy, cost and lack of standardization between studies remain the limiting factors. &
However defined, the evidence for MAD effectiveness in the short term is increasingly compelling, but whether benefits are sustained is less clear. Until recently, there has been a lack of longer term information, but researchers have begun to address this knowledge gap. Follow-up data from a CPAP versus MAD study in mild-to-moderate OSA showed AHI effects to be maintained at 1 year, although CPAP continued to achieve better results, and improvements in ESS remained equivalent [26]. Dropouts were minimal during follow-up. Similar results were reported after 2 years in another RCT cohort, although dropouts were considerable for both treatment groups [27 ]. Extended follow-up of a 2009 crossover RCT of two MADs showed that they remained effective in improving sleep parameters, ESS, cardiovascular parameters and QoL up to 4.5 years after the original trial [28]. However, there was again significant attrition of the sample size, with many dropouts likely due to treatment failure. Nonetheless, these collective data suggest that when MADs are effective, benefits can be sustained. Given the frequently incurable nature of OSA, even longer term followup data regarding efficacy, compliance, device durability and side-effects are needed. 598
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Therefore, a collaborative international network [ORal Appliance Network on Global Effectiveness (ORANGE)] has recently been set up by academic researchers with the primary aim of evaluating longterm effectiveness and cardiovascular outcomes of MAD therapy in OSA patients [37]. This multinational, observational cohort study will collate standardized data through an online database, and will enable a thorough evaluation of the effectiveness and cardiovascular outcomes of MAD therapy in large numbers of OSA patients.
CONCLUSION There is increasing evidence for the effectiveness of MAD therapy across the range of OSA severity. Although traditionally seen as a poorer alternative to CPAP in more severe disease, MADs may actually be the better choice in patients who have particular difficulty tolerating CPAP. In milder disease, there is now evidence for MAD being beneficial and costeffective. Results from the recent pragmatic studies suggest that a straightforward approach to MAD treatment is effective but, as with CPAP, the added benefits of sophisticated innovations remain unclear. Several studies show promise and more work is needed to elucidate their clinical role, with parallel evaluation of cost-effectiveness. Acknowledgements The authors have received no funding for the production of this article. The authors have received a grant from National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 08/110/03) for a trial of mandibular advancement devices (TOMADO) which will be published in full in the Journal of Health Technology Assessment. Conflicts of interest There are no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. National Institute for Health and Care Excellence (NICE). Continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome. TA 139. 2008. Available at http://www.nice.org.uk/nicemedia/live/ 11944/40085/40085.pdf. [Accessed 15 April 2014] 2. McDaid C, Griffin S, Weatherly H, et al. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis. Health Technol Assess 2009; 13:; iii–iv, xi–xiv, 1–119, 143–274. 3. Lim J, Lasserson TJ, Fleetham J, et al. Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 2006; CD004435.
4. Giles TL, Lasserson TJ, Smith BJ, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006; CD001106. 5. Quinnell TG, Bennett M, Jordan J, et al. A crossover randomised controlled & trial of oral mandibular advancement devices for obstructive sleep apnoea– hypopnoea (TOMADO). Thorax 2014; doi: 10.1136/thoraxjnl-2014-205464. [Epub ahead of print] This is the first large crossover RCT of three fixed MADs of varying cost and complexity to assess the pragmatic clinical effectiveness along with cost-effectiveness. 6. Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc 2008; 5:173–178. 7. Sharples LD, Glover MJ, Clutterbuck-James AL, et al. Clinical and costeffectiveness results from the TOMADO randomised controlled Trial of Oral Mandibular Advancement Devices for Obstructive sleep apnoea–hypopnoea and long-term economic analysis of oral devices and continuous positive airway pressure. Health Technol Assess 2014. (in press). 8. Phillips CL, Grunstein RR, Darendeliler MA, et al. Health outcomes of && continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea. Am J Respir Crit Care Med 2013; 187:879–887. This superb, large RCT pragmatically assesses the compliance, cardiovascular outcomes, symptom control, quality of life and the issues of titration for CPAP and MADs. 9. De Almeida FR. Complexity and efficacy of mandibular advancement splints: understanding their mode of action. J Clin Sleep Med 2011; 7:447–448. 10. Vanderveken OM, Dieltjens M, Wouters K, et al. Objective measurement of compliance during oral appliance therapy for sleep-disordered breathing. Thorax 2013; 68:91–96. 11. Almeida FR, Mulgrew A, Ayas N, et al. Mandibular advancement splint as short-term alternative treatment in patients with obstructive sleep apnea already effectively treated with continuous positive airway pressure. J Clin Sleep Med 2013; 9:319–324. 12. Lettieri CJ, Paolino N, Eliasson AH, et al. Comparison of adjustable and fixed oral appliances for the treatment of obstructive sleep apnea. J Clin Sleep Med 2011; 7:439–445. 13. Schmidt-Nowara W. Recent developments in oral appliance therapy of sleep disordered breathing. Sleep Breath 1999; 3:103–106. 14. De Almeida FR, Bittencourt LR, de Almeida CI, et al. Effects of mandibular posture on obstructive sleep apnea severity and the temporomandibular joint in patients fitted with an oral appliance. Sleep 2002; 25:507–513. 15. Sari E, Menillo S. Comparison of titratable oral appliance and mandibular advancement splint in the treatment of patients with obstructive sleep apnea. ISRN Dentistry 2011; 2011:581692. 16. Gagnadoux F, Fleury B, Vielle B, et al. Titrated mandibular advancement versus positive airway pressure for sleep apnoea. Eur Respir J 2009; 34:914–920. 17. Hoekema A, Stegenga B, Wijkstra PJ, et al. Obstructive sleep apnea therapy. J Dent Res 2008; 87:882–887. 18. Aarab G, Lobbezoo F, Hamburger HL, et al. Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea: a randomized, placebo-controlled trial. Respiration 2011; 81:411–419. 19. Remmers J, Charkhandeh S, Grosse J, et al. Remotely controlled mandibular & protrusion during sleep predicts therapeutic success with oral appliances in patients with obstructive sleep apnea. Sleep 2013; 36:1517–1525; 1525A. A well designed, prospective blinded study using a remotely controlled mandibular positioner to predict the treatment outcome with a MAD and determine an effective target protrusion. 20. Bishop B, Verrett R, Girvan T. A randomized crossover study comparing two mandibular repositioning appliances for treatment of obstructive sleep apnea. Sleep Breath 2014; 18:125–131. 21. Vroegop AV, Vanderveken OM, Dieltjens M, et al. Sleep endoscopy with simulation bite for prediction of oral appliance treatment outcome. J Sleep Res 2013; 22:348–355. 22. Almeida FR, Henrich N, Marra C, et al. Patient preferences and experiences of CPAP and oral appliances for the treatment of obstructive sleep apnea: a qualitative analysis. Sleep Breath 2013; 17:659–666. 23. Dieltjens M, Vanderveken OM, Van den Bosch D, et al. Impact of type D personality on adherence to oral appliance therapy for sleep-disordered breathing. Sleep Breath 2013; 17:985–991. 24. Krucien N, Gafni A, Fleury B, Pelletier-Fleury N. Patients’ with obstructive sleep apnoea syndrome (OSAS) preferences and demand for treatment: a discrete choice experiment. Thorax 2013; 68:487–488. 25. Dieltjens M, Braem MJ, Vroegop AV, et al. Objectively measured vs self& reported compliance during oral appliance therapy for sleep-disordered breathing. Chest 2013; 144:1495–1502. The first study to compare the objective and subjective measures of MAD compliance over 1 year. 26. Aarab G, Lobbezoo F, Heymans MW, et al. Long-term follow-up of a randomized controlled trial of oral appliance therapy in obstructive sleep apnea. Respiration 2011; 82:162–168. 27. Doff MH, Hoekema A, Wijkstra PJ, et al. Oral appliance versus continuous & positive airway pressure in obstructive sleep apnea syndrome: a 2-year followup. Sleep 2013; 36:1289–1296. An excellent follow-up study looking at both CPAP and MAD in the long term over 2 years.
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Sleep and respiratory neurobiology 28. Gauthier L, Laberge L, Beaudry M, et al. Mandibular advancement appliances remain effective in lowering respiratory disturbance index for 2.5–4.5 years. Sleep Med 2011; 12:844–849. 29. Marklund M, Legrell PE. An orthodontic oral appliance. Angle Orthod 2010; 80:1116–1121. 30. Cunali PA, Almeida FR, Santos CD, et al. Mandibular exercises improve mandibular advancement device therapy for obstructive sleep apnea. Sleep Breath 2011; 15:717–727. 31. Gong X, Zhang J, Zhao Y, et al. Long-term therapeutic efficacy of oral appliances in treatment of obstructive sleep apnea–hypopnea syndrome. Angle Orthod 2013; 83:653–658. 32. Doff MH, Finnema KJ, Hoekema A, et al. Long-term oral appliance therapy in obstructive sleep apnea syndrome: a controlled study on dental side effects. Clin Oral Investig 2013; 17:475–482.
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33. Almeida F. Long term side effects of MAS – does it matter? Sleep Biol Rhythms 2013; 11:6. 34. McEvoy RD, Anderson CS, Antic NA, et al. The Sleep Apnea Cardiovascular Endpoints (SAVE) trial: rationale and start-up phase. J Thorac Dis 2010; 2:138–143. 35. Dal-Fabbro C, Garbuio S, D’Almeida V, et al. Mandibular advancement device and CPAP upon cardiovascular parameters in OSA. Sleep Breath 2014; doi: 10.1007/s11325-014-0937-5. [Epub ahead of print] 36. Anandam A, Patil M, Akinnusi M, et al. Cardiovascular mortality in obstructive sleep apnoea treated with continuous positive airway pressure or oral appliance: an observational study. Respirology 2013; 18:1184–1190. 37. Almeida FR, Vanderveken OM, Cistulli PA, et al. ORal Appliance Network on Global Effectiveness (ORANGE): start-up and design description. J Dent Sleep Med 2014; 1:17–20.
Volume 20 Number 6 November 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Alternatives to continuous positive airway pressure 2: mandibular advancement devices compared Timothy G. Quinnell and Abigail L. Clutterbuck-James
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. Keywords continuous positive airway pressure, mandibular advancement device, obstructive sleep apnea
INTRODUCTION Mandibular advancement devices (MADs) provide an alternative to continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea (OSA). By protruding the mandible, they can improve upper airway dimensions and reduce collapsibility. Although some clinical guidelines recommend MADs as the first-line treatment in mild OSA and as an alternative to CPAP in more severe disease [1], their effectiveness and role remain unclear. This is partly because heterogeneity of trial methodology, device design and treatment implementation makes it difficult to evaluate published evidence. Three meta-analyses [2–4] have consistently found MADs to be better than placebo at reducing the frequency of obstructive events, but less efficacious than CPAP. Nonetheless, the two treatments seem equally effective at improving excessive daytime sleepiness (EDS). Most MAD trials have focussed on more severe OSA, whereas milder disease, device comparisons and cost-effectiveness
have been understudied. Recently, a large trial compared different MADs in patients with mild-to-moderate OSA and evaluated cost-effectiveness [5 ]. The results will be discussed in this review along with other studies from the last year that reflect the current research priorities. &
MANDIBULAR ADVANCEMENT DEVICES VERSUS CONTINUOUS POSITIVE AIRWAY PRESSURE CPAP is considered the gold-standard treatment for OSA. Pneumatic airway splinting greatly reduces Respiratory Support and Sleep Centre (RSSC), Papworth Hospital NHS Foundation Trust, Cambridge, UK Correspondence to Dr Timothy G. Quinnell, Respiratory Support and Sleep Centre, Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, CB23 3RE, UK. Tel: +44 1480 364174; fax: +44 1480 364568; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:595–600 DOI:10.1097/MCP.0000000000000096
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Sleep and respiratory neurobiology
KEY POINTS Mandibular advancement devices (MADs) appear clinically and cost-effective for the treatment of mild-tomoderate obstructive sleep apnea (OSA). Good MAD compliance makes them a genuine alternative to continuous positive airway pressure (CPAP) in patients with more severe OSA. Recent research has investigated ways of improving MAD efficacy, tolerance and side-effects. Further work is needed to refine MAD therapy to optimize its clinical and cost-effectiveness.
obstructive events as measured by the apnea hypopnoea index (AHI) and can improve EDS, driving safety, quality of life (QoL) and blood pressure (BP), with possible additional cardiovascular benefits. However, CPAP intolerance remains a major obstacle, with treatment failure rates of 46–83% [6]. Numerous studies have compared MADs to CPAP and many have fed into meta-analyses [1–3]. An updated systematic review is currently in press [7]. It shows that the majority of CPAP trials remain focussed on moderate-to-severe OSA, although it is possible that AHI differences between CPAP and MADs would be less in milder disease. The results continue to demonstrate that MADs and CPAP significantly improve AHI, with CPAP having greater effects. The impact of both treatments on EDS is still positive and similar. The update also observes stronger treatment effects in trials of shorter duration, suggesting effectiveness may decrease over time. The review echoes its predecessors in calling for robust secondary QoL and cardiovascular outcomes; long-term follow-up data; and trials across the entire range of disease severity including milder OSA. In the last year, results from a large, well designed, crossover randomized controlled trial (RCT) were published [8 ]. One hundred and twenty-six patients with moderate-to-severe OSA used an adjustable, patient-titrated MAD and CPAP for 1 month each. The study was not only powered to measure BP effects, but also examined other health outcomes. Although CPAP reduced AHI more than MADs, this was offset by greater MAD compliance. Neither showed a BP effect, but both were associated with improvements in subjective EDS, driving simulator performance and QoL. The results support the hypothesis that similar reallife MAD and CPAP effectiveness may be due to greater MAD compliance achieving net equivalent &&
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AHI reduction [9,10]; and suggest MADs provide a genuine alternative to CPAP in more severe OSA. Although traditional MAD vs. CPAP trials remain relevant, novel approaches to using these two treatments are being explored. One small study recently evaluated the utility of MADs as a temporary CPAP substitute [11]. Adherent CPAP users with mostly moderate-to-severe OSA were transitioned to MADs, then left to use either treatment at their discretion for 3 months. MADs significantly reduced both AHI and sleepiness (measured by the Epworth Sleepiness Scale; ESS) compared with pretreatment baseline levels, and the majority of patients reported they would use MADs as an alternative short-term therapy to CPAP. Although from a select patient group, the results suggest a different more flexible approach to OSA treatment. Although potentially helpful for some patients, the resource implications of dual therapy are likely to prevent it becoming widely adopted outside specific scenarios, such as in the military [12].
MANDIBULAR ADVANCEMENT DEVICES COMPARED Despite the obvious need to understand the influence of device design on MAD effectiveness, there have been few studies comparing MADs with MADs that have been sufficiently robust to inform device selection in the clinical setting. One recent crossover RCT compared three nonadjustable (‘fixed’-‘f’)MADs of varying sophistication and cost in 90 patients with mild-tomoderate OSA [5 ]. The results of the Trial of Oral Mandibular Advancement Devices in Obstructive sleep apnea (TOMADO) showed all fMADs to improve objective and subjective health outcomes over no treatment, and to be cost-effective. Although there were no significant differences in sleep study or EDS effects between the three devices, a thermoplastic patient moulded device was arguably less effective. It was poorly retained, less popular with patients and often prematurely discontinued, suggesting limited longer term utility. Tolerance and retention were, however, similar for a ‘semi-bespoke’ fMAD, which required no specialist dental input, and a bespoke dentally produced device. The results suggest that a less expensive semi-bespoke nonadjustable device might be a reasonable first choice in most patients with mildto-moderate OSA, but that dental expertise will be required for patients who have difficulty producing the mould for a semi-bespoke device, or whose dentition or oral health is poor. There is a need for a similarly robust and pragmatic comparison of fMADs with adjustable &
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(‘a’)MADs. The ability to adjust protrusion according to efficacy and tolerance carries several advantages, and aMADs are increasingly recommended [13,14]. However, the cost range of this more sophisticated approach is probably greater than for nonadjustable alternatives and its real-life superiority remains unproven. There is contradictory evidence regarding the impact of greater protrusion in milder disease; and high compliance with nonadjustable MADs [5 ] may leave little room for improvement. Prospective comparisons are needed because research to date has not tackled this uncertainty. One study compared aMADs with fMADs. Both groups had a similar reduction in AHI from baseline up to 1 month [15]. The aMADs reduced AHI significantly more than fMADs for patients with moderate OSA, but this involved a minor, 3.8 per hour difference in only 12 patients. Furthermore, protrusion was fixed: at 85% of maximal jaw advancement for aMADs and at 75% for fMADs; so the study essentially compared protrusions rather than devices. A much larger retrospective review of MAD-treated mild-to-severe OSA patients reported slightly greater AHI effects for aMADs compared with fMADs [12]. However, differences were often not statistically significant and clinical significance was doubtful, particularly as ESS reductions were similar. The adjustability question is complicated by the ever-increasing range of titration techniques. Researchers have used complex sleep studies to determine optimal protrusion, with either singlenight titration [16] or serial reviews to guide adjustment [17]. This more intensive approach has not seemed to yield additional benefits. Outcomes have been comparable to earlier studies, with AHI reduction being less than for CPAP but EDS improvements similar [16,17]. One study used four nights to determine the most efficacious protrusion. This improved AHI similar to CPAP, but curiously ESS effects were no better than placebo for either treatment [18]. Serial complex sleep studies are unlikely to be acceptable in routine clinical practice, but singlenight titration might be if sufficiently beneficial. Recently, one group used a remotely controlled mandibular positioner during polysomnography (PSG) to predict therapeutic response and effective target protrusion for aMAD treatment [19 ]. Titration caused little sleep disturbance and showed higher predictive accuracy than earlier studies, attributed to better equipment and predetermined response criteria. If consistently validated, this technique could help identify MAD candidates, potentially justifying its role by reducing expenditure on &
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nonresponders. However, complex sleep study titration still considerably increases the cost of MAD therapy. TOMADO reported a desaturation index effect similar to that for AHI [5 ], so oximetry may provide a more accessible and affordable compromise. If aMADs are tested against fMADs in a robust comparative effectiveness study, then it would be worth exploring the role of oximetry titration. For any objective method, a significant advantage needs to be demonstrated over subjective titration, given the CPAP equivalent outcomes already reported using that alone [8 ,20]. Drug-induced sleep endoscopy continues to be evaluated for its utility in predicting MAD response. Improved upper airway patency in 135 anaesthetized patients whilst in maximal tolerated mandibular protrusion was associated with a positive response (defined by AHI reduction to 50% of baseline; P < 0.01) [21]. Although of research interest, real-life advantages of this more intrusive approach are unknown, and there may be other obstacles to its widespread clinical uptake. &
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COMPLIANCE AND PREDICTORS OF COMPLIANCE A key factor interacting with CPAP and MAD effectiveness is compliance. Recent work reflects the recognition that patient preference should be included in treatment considerations [22]. One group studying 82 patients reported that type D personality was associated with higher risk of discontinuing MAD treatment [23]. A discrete choice experiment in 121 newly diagnosed French patients calculated the demanding probabilities for CPAP and MAD to be 60.2 and 36.2%, respectively [24]. However, the previously described study of MAD substitution in the established CPAP users found that 75% were happy to continue using MADs as a short-term alternative [11]. That study also reflected the influence that bed partners may have, with 88% preferring MADs over CPAP. One clinical and research advantage that CPAP has held over MADs has been the facility to objectively monitor compliance. Significant progress has recently been made to bring MAD therapy up to speed, with the validation of affordable implantable thermoactive compliance chips [10]. Not only do they appear accurate, but also initial data suggest that, at least in the trial setting, subjective and objective compliance concord [25 ]. Whether these chips become standard MAD issue waits to be seen. They have obvious research value, particularly given the frequently cited superior MAD tolerance that is argued to underlie their CPAP equivalence. If MAD uptake increases, then objective monitoring may
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become more necessary clinically to identify poor compliers in need of early intervention and to inform ‘fitness to drive’ decisions.
DEFINING TREATMENT SUCCESS Another challenge faced by the researchers in their evaluation of MAD effectiveness is the definition of treatment success. This is particularly important when trying to compare MADs to the more efficacious CPAP. Response criteria have been developed, which are usually based on AHI reduction, for example, complete response ¼ AHI less than 5 per hour [5 ]; treatment efficacy ¼ AHI decrease at least 50% of baseline [11]. Although these represent useful efforts to standardize the assessment of MAD effectiveness, their use lacks consistency. The validity of different criteria is unproven and the success rates they give range widely [14]. It remains difficult to define OSA treatment success. It is likely to be a combination of objective respiratory event reduction, subjective improvement and compliance, but the vagaries of arbitrary success definitions must be kept in mind when comparing OSA treatments. &
MANDIBULAR ADVANCEMENT DEVICE THERAPY IN THE LONGER TERM – EFFECTIVENESS
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Although most complications of MAD therapy are mild and transient, they sometimes limit device tolerance and effectiveness, and efforts are being made to mitigate this. An orthodontic MAD has shown promise in increasing the overjet of patients at risk of developing negative bite changes [29], whereas mandibular exercises may allow patients with temporomandibular problems to continue to use MADs [30]. The incidence of more significant, longer term complications has been unclear and more information has been sought. One group found MAD usage of more than 5 years to be linked to mild skeletal and occlusal changes in 25 patients [31]. Another study reported small but significant dental changes in MAD users after 2 years, supporting the case for regular dental follow-up [32]. However, it seems increasingly accepted that dental side-effects may be a price worth paying for effective OSA treatment [33].
CARDIOVASCULAR OUTCOMES The effect of CPAP treatment on cardiovascular outcomes remains uncertain, although the Sleep Apnea cardioVascular Endpoints (SAVE) study of CPAP effects on new cardiovascular events in high-risk patients with moderate-to-severe OSA may provide insight [34]. There are no conclusive answers from MAD trials [5 ,8 ,35]. Phillips et al. reported no effect of CPAP or MADs on BP in moderate-to-severe OSA, and TOMADO showed no BP effect in milder OSA [5 ,8 ]. Dal-Fabbro et al. [35] showed no differences in BP parameters between CPAP, MAD and placebo MAD in moderate-tosevere OSA, except for more frequent diastolic BP dipping in the MAD group. An observational study recently reported that both MAD and CPAP treated patients with severe OSA had lower cardiovascular death rates than untreated patients, with no intertreatment differences despite residual AHI being greater in the MAD group [36]. However, these results may represent confounder bias, as the extension of non-compliance to other cardiovascular riskmodifying treatment is difficult to control for. Although the cardiovascular effects of OSA and its treatments remain uncertain, it is appropriate, given the similarity of many MAD and CPAP outcomes, to continue studying the impacts of MAD therapy. In the meantime, the existing evidence suggests that cardiovascular concerns need not exclude MADs as treatment option, particularly if driven by patient preference. Despite the recognized need for more research into MAD therapy, cost and lack of standardization between studies remain the limiting factors. &
However defined, the evidence for MAD effectiveness in the short term is increasingly compelling, but whether benefits are sustained is less clear. Until recently, there has been a lack of longer term information, but researchers have begun to address this knowledge gap. Follow-up data from a CPAP versus MAD study in mild-to-moderate OSA showed AHI effects to be maintained at 1 year, although CPAP continued to achieve better results, and improvements in ESS remained equivalent [26]. Dropouts were minimal during follow-up. Similar results were reported after 2 years in another RCT cohort, although dropouts were considerable for both treatment groups [27 ]. Extended follow-up of a 2009 crossover RCT of two MADs showed that they remained effective in improving sleep parameters, ESS, cardiovascular parameters and QoL up to 4.5 years after the original trial [28]. However, there was again significant attrition of the sample size, with many dropouts likely due to treatment failure. Nonetheless, these collective data suggest that when MADs are effective, benefits can be sustained. Given the frequently incurable nature of OSA, even longer term followup data regarding efficacy, compliance, device durability and side-effects are needed. 598
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Therefore, a collaborative international network [ORal Appliance Network on Global Effectiveness (ORANGE)] has recently been set up by academic researchers with the primary aim of evaluating longterm effectiveness and cardiovascular outcomes of MAD therapy in OSA patients [37]. This multinational, observational cohort study will collate standardized data through an online database, and will enable a thorough evaluation of the effectiveness and cardiovascular outcomes of MAD therapy in large numbers of OSA patients.
CONCLUSION There is increasing evidence for the effectiveness of MAD therapy across the range of OSA severity. Although traditionally seen as a poorer alternative to CPAP in more severe disease, MADs may actually be the better choice in patients who have particular difficulty tolerating CPAP. In milder disease, there is now evidence for MAD being beneficial and costeffective. Results from the recent pragmatic studies suggest that a straightforward approach to MAD treatment is effective but, as with CPAP, the added benefits of sophisticated innovations remain unclear. Several studies show promise and more work is needed to elucidate their clinical role, with parallel evaluation of cost-effectiveness. Acknowledgements The authors have received no funding for the production of this article. The authors have received a grant from National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 08/110/03) for a trial of mandibular advancement devices (TOMADO) which will be published in full in the Journal of Health Technology Assessment. Conflicts of interest There are no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. National Institute for Health and Care Excellence (NICE). Continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome. TA 139. 2008. Available at http://www.nice.org.uk/nicemedia/live/ 11944/40085/40085.pdf. [Accessed 15 April 2014] 2. McDaid C, Griffin S, Weatherly H, et al. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis. Health Technol Assess 2009; 13:; iii–iv, xi–xiv, 1–119, 143–274. 3. Lim J, Lasserson TJ, Fleetham J, et al. Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 2006; CD004435.
4. Giles TL, Lasserson TJ, Smith BJ, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006; CD001106. 5. Quinnell TG, Bennett M, Jordan J, et al. A crossover randomised controlled & trial of oral mandibular advancement devices for obstructive sleep apnoea– hypopnoea (TOMADO). Thorax 2014; doi: 10.1136/thoraxjnl-2014-205464. [Epub ahead of print] This is the first large crossover RCT of three fixed MADs of varying cost and complexity to assess the pragmatic clinical effectiveness along with cost-effectiveness. 6. Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc 2008; 5:173–178. 7. Sharples LD, Glover MJ, Clutterbuck-James AL, et al. Clinical and costeffectiveness results from the TOMADO randomised controlled Trial of Oral Mandibular Advancement Devices for Obstructive sleep apnoea–hypopnoea and long-term economic analysis of oral devices and continuous positive airway pressure. Health Technol Assess 2014. (in press). 8. Phillips CL, Grunstein RR, Darendeliler MA, et al. Health outcomes of && continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea. Am J Respir Crit Care Med 2013; 187:879–887. This superb, large RCT pragmatically assesses the compliance, cardiovascular outcomes, symptom control, quality of life and the issues of titration for CPAP and MADs. 9. De Almeida FR. Complexity and efficacy of mandibular advancement splints: understanding their mode of action. J Clin Sleep Med 2011; 7:447–448. 10. Vanderveken OM, Dieltjens M, Wouters K, et al. Objective measurement of compliance during oral appliance therapy for sleep-disordered breathing. Thorax 2013; 68:91–96. 11. Almeida FR, Mulgrew A, Ayas N, et al. Mandibular advancement splint as short-term alternative treatment in patients with obstructive sleep apnea already effectively treated with continuous positive airway pressure. J Clin Sleep Med 2013; 9:319–324. 12. Lettieri CJ, Paolino N, Eliasson AH, et al. Comparison of adjustable and fixed oral appliances for the treatment of obstructive sleep apnea. J Clin Sleep Med 2011; 7:439–445. 13. Schmidt-Nowara W. Recent developments in oral appliance therapy of sleep disordered breathing. Sleep Breath 1999; 3:103–106. 14. De Almeida FR, Bittencourt LR, de Almeida CI, et al. Effects of mandibular posture on obstructive sleep apnea severity and the temporomandibular joint in patients fitted with an oral appliance. Sleep 2002; 25:507–513. 15. Sari E, Menillo S. Comparison of titratable oral appliance and mandibular advancement splint in the treatment of patients with obstructive sleep apnea. ISRN Dentistry 2011; 2011:581692. 16. Gagnadoux F, Fleury B, Vielle B, et al. Titrated mandibular advancement versus positive airway pressure for sleep apnoea. Eur Respir J 2009; 34:914–920. 17. Hoekema A, Stegenga B, Wijkstra PJ, et al. Obstructive sleep apnea therapy. J Dent Res 2008; 87:882–887. 18. Aarab G, Lobbezoo F, Hamburger HL, et al. Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea: a randomized, placebo-controlled trial. Respiration 2011; 81:411–419. 19. Remmers J, Charkhandeh S, Grosse J, et al. Remotely controlled mandibular & protrusion during sleep predicts therapeutic success with oral appliances in patients with obstructive sleep apnea. Sleep 2013; 36:1517–1525; 1525A. A well designed, prospective blinded study using a remotely controlled mandibular positioner to predict the treatment outcome with a MAD and determine an effective target protrusion. 20. Bishop B, Verrett R, Girvan T. A randomized crossover study comparing two mandibular repositioning appliances for treatment of obstructive sleep apnea. Sleep Breath 2014; 18:125–131. 21. Vroegop AV, Vanderveken OM, Dieltjens M, et al. Sleep endoscopy with simulation bite for prediction of oral appliance treatment outcome. J Sleep Res 2013; 22:348–355. 22. Almeida FR, Henrich N, Marra C, et al. Patient preferences and experiences of CPAP and oral appliances for the treatment of obstructive sleep apnea: a qualitative analysis. Sleep Breath 2013; 17:659–666. 23. Dieltjens M, Vanderveken OM, Van den Bosch D, et al. Impact of type D personality on adherence to oral appliance therapy for sleep-disordered breathing. Sleep Breath 2013; 17:985–991. 24. Krucien N, Gafni A, Fleury B, Pelletier-Fleury N. Patients’ with obstructive sleep apnoea syndrome (OSAS) preferences and demand for treatment: a discrete choice experiment. Thorax 2013; 68:487–488. 25. Dieltjens M, Braem MJ, Vroegop AV, et al. Objectively measured vs self& reported compliance during oral appliance therapy for sleep-disordered breathing. Chest 2013; 144:1495–1502. The first study to compare the objective and subjective measures of MAD compliance over 1 year. 26. Aarab G, Lobbezoo F, Heymans MW, et al. Long-term follow-up of a randomized controlled trial of oral appliance therapy in obstructive sleep apnea. Respiration 2011; 82:162–168. 27. Doff MH, Hoekema A, Wijkstra PJ, et al. Oral appliance versus continuous & positive airway pressure in obstructive sleep apnea syndrome: a 2-year followup. Sleep 2013; 36:1289–1296. An excellent follow-up study looking at both CPAP and MAD in the long term over 2 years.
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Sleep and respiratory neurobiology 28. Gauthier L, Laberge L, Beaudry M, et al. Mandibular advancement appliances remain effective in lowering respiratory disturbance index for 2.5–4.5 years. Sleep Med 2011; 12:844–849. 29. Marklund M, Legrell PE. An orthodontic oral appliance. Angle Orthod 2010; 80:1116–1121. 30. Cunali PA, Almeida FR, Santos CD, et al. Mandibular exercises improve mandibular advancement device therapy for obstructive sleep apnea. Sleep Breath 2011; 15:717–727. 31. Gong X, Zhang J, Zhao Y, et al. Long-term therapeutic efficacy of oral appliances in treatment of obstructive sleep apnea–hypopnea syndrome. Angle Orthod 2013; 83:653–658. 32. Doff MH, Finnema KJ, Hoekema A, et al. Long-term oral appliance therapy in obstructive sleep apnea syndrome: a controlled study on dental side effects. Clin Oral Investig 2013; 17:475–482.
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33. Almeida F. Long term side effects of MAS – does it matter? Sleep Biol Rhythms 2013; 11:6. 34. McEvoy RD, Anderson CS, Antic NA, et al. The Sleep Apnea Cardiovascular Endpoints (SAVE) trial: rationale and start-up phase. J Thorac Dis 2010; 2:138–143. 35. Dal-Fabbro C, Garbuio S, D’Almeida V, et al. Mandibular advancement device and CPAP upon cardiovascular parameters in OSA. Sleep Breath 2014; doi: 10.1007/s11325-014-0937-5. [Epub ahead of print] 36. Anandam A, Patil M, Akinnusi M, et al. Cardiovascular mortality in obstructive sleep apnoea treated with continuous positive airway pressure or oral appliance: an observational study. Respirology 2013; 18:1184–1190. 37. Almeida FR, Vanderveken OM, Cistulli PA, et al. ORal Appliance Network on Global Effectiveness (ORANGE): start-up and design description. J Dent Sleep Med 2014; 1:17–20.
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