Scholarly article on topic 'A custom-made mandibular repositioning device for obstructive sleep apnoea–hypopnoea syndrome: the ORCADES study'

A custom-made mandibular repositioning device for obstructive sleep apnoea–hypopnoea syndrome: the ORCADES study Academic research paper on "Clinical medicine"

CC BY-NC-ND
0
0
Share paper
Academic journal
Sleep Medicine
OECD Field of science
Keywords
{"Obstructive sleep apnoea" / "Mandibular repositioning device" / Compliance / Tolerance}

Abstract of research paper on Clinical medicine, author of scientific article — Marie-Françoise Vecchierini, Valérie Attali, Jean-Marc Collet, Marie-Pia d'Ortho, Pierre El Chater, et al.

Abstract Background Mandibular repositioning devices (MRDs) are usually recommended as the first therapy option in patients with mild-to-moderate obstructive sleep apnoea (OSA). However, data on the long-term efficacy of MRDs are limited, not only in OSA patients who are noncompliant with continuous positive airway pressure (CPAP) but also in those with more severe OSA. The ORCADES study aimed to prospectively determine the long-term efficacy and tolerability of two custom-made Narval™ MRDs for obstructive sleep apnoea–hypopnoea syndrome (OSAHS) patients. The interim 3- to 6-month data are reported. Methods Eligible patients had OSAHS and had refused or were noncompliant with prescribed CPAP. Outcome measurements after gradual mandibular advancement titration included: apnoea–hypopnoea index (AHI), oxygen saturation, sleepiness, symptoms, quality of life, side effects and compliance. Results A total of 369 patients were included. Overall, MRD treatment was successful (≥50% decrease in AHI) in 76.2% of the participants; complete response (AHI <10/h) was achieved in 63.5%. Severe OSAHS was effectively treated (AHI <15/h) in about 60% of the participants; 38% had complete symptom resolution. Mandibular repositioning devices significantly decreased subjective sleepiness, eliminated symptoms and improved quality of life. They were well tolerated and compliance was excellent. Only 8% of the participants stopped MRD treatment due to side effects. Conclusion Custom-made Narval™ MRDs are effective for mild to severe OSA in patients who refuse or are noncompliant with CPAP. They are well tolerated and have excellent compliance.

Academic research paper on topic "A custom-made mandibular repositioning device for obstructive sleep apnoea–hypopnoea syndrome: the ORCADES study"

ARTICLE IN PRESS

Sleep Medicine ■■ (2015) ■■-■■

ELSEVIER

Contents lists available at ScienceDirect

Sleep Medicine

journal homepage: www.elsevier.com/locate/sleep

sleepmedicine

Original Article

A custom-made mandibular repositioning device for obstructive sleep apnoea-hypopnoea syndrome: the ORCADES study

Marie-Françoise Vecchieriniab*, Valérie Attalic,d,e, Jean-Marc Colletf, Marie-Pia d'Orthog,h, Pierre El Chateri, Jean-Baptiste Kerbratfj, Damien Legera,b, Christelle Monacak, Pierre-Jean Monteyroll, Laurent Morin m, Eric Mullensn, Bernard Pigeariaso, Jean-Claude Meuricep for the ORCADES investigators

a Hôpital Hôtel Dieu, Centre du Sommeil et de la Vigilance, AP-HP, Paris, France

b Sorbonne Paris Cité, EA 7320 VIFASOM, Université Paris Descartes, Paris, France

c Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Pathologies du Sommeil, AP-HP, Paris, France

d UPMC Université Paris 06, Sorbonne Universités, UMR_S 1158, "Neurophysiologie Respiratoire Expérimentale et Clinique", Paris, France e ¡NSERM, UMR_S 1158, "Neurophysiologie Respiratoire Expérimentale et Clinique", Paris, France f Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Stomatologie et Chirurgie Maxillo-Faciale, AP-HP, Paris, France g DHU FIRE, Hôpital Bichat-Claude Bernard, Physiologie et Explorations Fonctionnelles, AP-HP, Paris, France h Université Denis Diderot Paris 7, UFR de Médecine, Paris, France 1 Chirurgie Oto-Rhino-Laryngologie, Hôpital André Grégoire, Montreuil, France j Stomatologie et Chirurgie Maxillo-Faciale, Hôpital Charles Nicolle, Rouen, France k Neurophysiologie Clinique, Hôpital Roger Salengro, Lille, France ' Oto-Rhino-Laryngologie, Polyclinique du Tondu, Bordeaux, France m ResMed Science Center, Saint Priest cedex, France n Laboratoire du Sommeil, Fondation Bon Sauveur, Albi, France o Laboratoire du Sommeil, Nice, France

p Pneumologie, Centre Hospitalier Universitaire, Poitiers, France

ABSTRACT

Background: Mandibular repositioning devices (MRDs) are usually recommended as the first therapy option in patients with mild-to-moderate obstructive sleep apnoea (OSA). However, data on the long-term efficacy of MRDs are limited, not only in OSA patients who are noncompliant with continuous positive airway pressure (CPAP) but also in those with more severe OSA. The ORCADES study aimed to prospectively determine the long-term efficacy and tolerability of two custom-made Narval™ MRDs for obstructive sleep apnoea-hypopnoea syndrome (OSAHS) patients. The interim 3- to 6-month data are reported. Methods: Eligible patients had OSAHS and had refused or were noncompliant with prescribed CPAP. Outcome measurements after gradual mandibular advancement titration included: apnoea-hypopnoea index (AHI), oxygen saturation, sleepiness, symptoms, quality of life, side effects and compliance. Results: A total of 369 patients were included. Overall, MRD treatment was successful (>50% decrease in AHI) in 76.2% of the participants; complete response (AHI <10/h) was achieved in 63.5%. Severe OSAHS was effectively treated (AHI <15/h) in about 60% of the participants; 38% had complete symptom resolution. Mandibular repositioning devices significantly decreased subjective sleepiness, eliminated symptoms and improved quality of life. They were well tolerated and compliance was excellent. Only 8% of the participants stopped MRD treatment due to side effects.

Conclusion: Custom-made Narval™ MRDs are effective for mild to severe OSA in patients who refuse or are noncompliant with CPAP. They are well tolerated and have excellent compliance.

© 2015 Elsevier B.V. All rights reserved.

ARTICLE INFO

Article history: Received 25 February 2015 Received in revised form 4 May 2015 Accepted 5 May 2015 Available online

Keywords:

Obstructive sleep apnoea Mandibular repositioning device Compliance Tolerance

* Corresponding author. Centre du Sommeil et de la Vigilance, AP-HP, Hôpital Hôtel Dieu, 1 Place du Parvis de Notre Dame, 75181 Paris cedex 4, France. Tel.: +33 (0)142348243; fax: +33 (0)142348227.

E-mail address: marie-francoise.vecchierini@htd.aphp.fr (M.-F. Vecchierini).

http://dx.doi.org/10.1016Zj.sleep.2015.05.020 1389-9457/© 2015 Elsevier B.V. All rights reserved.

1. Introduction

The consensus definition of obstructive sleep apnoea-hypopnoea syndrome (OSAHS) states that it is characterised by repetitive episodes of complete or partial upper airway obstruction during sleep and is usually associated with snoring, intermittent hypoxaemia and sleep fragmentation [1]. Excessive daytime sleepiness is frequent and

ARTICLE IN PRESS

M.-F. Vecchierini et al./Sleep Medicine ■■ (2015) ■■ ■■

increases the risk for vehicle crashes and occupational accidents [2]. Obstructive sleep apnoea-hypopnoea syndrome is associated with significant comorbidities and impaired quality of life (QOL) [3-5], and is considered to be a major public health problem.

Treatment of behavioural consequences such as fatigue, sleepiness, and memory problems are important but not sufficient enough to cure OSA. Upper airway surgery is only indicated in a small subset of OSAHS patients who have a specific aetiology [6]. The most widely used disease-specific therapies for treating OSAHS symptoms are: continuous positive airway pressure (CPAP) and mandibular repositioning devices (MRDs). Continuous positive airway pressure has been shown to be a very effective treatment; it reduces sleepiness, road accidents, cardiovascular risk and mortality [7-9]. However, good adherence is needed to realise treatment benefits [10] and 20-50% of OSAHS patients are unable or unwilling to comply with CPAP [11].

Mandibular repositioning devices enlarge the upper airway during sleep by holding the mandible in a forward position. They are efficacious treatment alternatives for patients with mild-to-moderate [12] or supine-position-dependent [13] OSAHS, or in those who are noncompliant with CPAP. The effects of MRDs on sleep-disordered breathing are usually inferior to CPAP, especially for apnoea-hypopnoea index (AHI) reductions, but patient acceptability may be better [14], with similar QOL and symptom effects.

Guidelines recommend MRDs as first-line therapy for patients with mild-to-moderate obstructive sleep apnoea (OSA) [15,16]. However, few studies have specifically assessed the long-term efficacy of MRDs in OSA patients who are noncompliant with CPAP. Discontinuation rates for MRD therapy in the literature are 1463% after four to five years [17-19].

These uncertainties about the long-term clinical benefits of MRD therapy resulted in the French Health Technology Assessment agency (Haute Autorité de Santé) to request that each MRD manufacturer provide additional clinical data on both the efficacy and side effects of their MRD devices over five years of treatment. The prospective, multicentre, observational ORCADES study determined the efficacy of two custom-made Narval™ MRDs in real-life conditions over five years in a cohort of OSAHS patients who refused or were noncompliant with CPAP. This paper presents the interim 3- to 6-month follow-up results.

2. Methods

2.1. Subjects

Patients with newly diagnosed OSAHS were recruited from 28 sleep centres across France. Inclusion criteria were: age >18 years; OSAHS (AHI >30/h or AHI 5-30/h on polysomnography (PSG) or cardiorespiratory polygraphy [PG]); excessive daytime sleepiness assessed by the clinician and/or an Epworth Sleepiness Scale (ESS) score >10; and refusal of or noncompliance with CPAP (pressure or mask intolerance, compliance <3 hours/night). Patients were excluded if they had received previous MRD treatment or any of the following characteristics: central apnoea index >5/h; AHI <30/h with severe sleep comorbidities other than OSAHS; or coexisting psychiatric disease. Patients with contraindications for MDR that had been assessed by a dental specialist investigator were also excluded. All patients gave written informed consent to participate in the study, which had ethics committee approval and was conducted according to the Declaration of Helsinki principles (ClinicalTrials.gov identifier: NCT01326143).

2.2. Intervention

The Narval™ devices used in this study were bi-block MRDs that were made with semi-rigid plastic materials (biocompatible

Fig. 1. Examples of: (A) a non-computer-aided design/computer-aided manufacturing mandibular repositioning device and (B) a computer-aided design/computer-aided manufacturing mandibular repositioning device.

polymer) and customised using either a high-precision computer-aided design (CAD)/computer-aided manufacturing (CAM) (ResMed, Narval CC™) or non-CAD/CAM process (ResMed, Narval™) (Fig. 1). Devices manufactured using non-CAD/CAM processes are reserved for patients with tooth morphology that is unsuitable for CAD/CAM technology (eg, short teeth or removable appliance leading to inadequate retention with CAD/CAM device). The MRDs were gradually adjusted to provide mandibular advancement over a 15-mm range. Each MRD was fitted by a dental specialist with an initial advancement of 67 ± 18% of maximal jaw protrusion. During titration, mandibular advancement was adjusted at the discretion of the dental sleep specialist until the best benefit-risk ratio between symptom resolution and tolerability was achieved.

2.3. Endpoints

The primary endpoint used to assess the success of MRD therapy was the proportion of patients with a >50% decrease in AHI from baseline to follow-up (three to six months). This threshold is commonly used in clinical trials and was selected for this study because of the evaluation of MRD as a second-line treatment in the absence of another alternative therapy [16].

Secondary endpoints included: complete response to MRD treatment (using AHI cut-off values of <5/h or <10/h), mean AHI decrease, evolution of other respiratory criteria, OSAHS symptoms, QOL, compliance and tolerability. Additional pre-planned subgroup analyses were conducted in subgroups of patients according to AHI severity, previous CPAP therapy, diagnosis method (PG or PSG), and MRD type.

ARTICLE IN PRESS

M.-F. Vecchierini et al./Sleep Medicine ■■ (2015) ■■ ■■ 3

2.4. Assessments

Sleep and/or respiratory parameters were recorded during sleep at baseline and the 3-month follow-up visit using the same PG or PSG device used to diagnose OSAHS. If MRD therapy was suboptimal (AHI decrease of <50% and/or persistent symptoms), PSG/PG was performed again at a 6-month follow-up visit after additional mandibular advancement. The PSG/PG recordings were manually scored according to the American Academy of Sleep Medicine (AASM) guidelines [20]. Obstructive apnoea was defined as a >10-s cessation of airflow on the pressure nasal cannula, with or without association with an oro-nasal thermal sensor. Hypopnoea was defined as a >50% reduction in airflow, or a <50% airflow reduction on the nasal pressure cannula accompanied by a >3% decrease in arterial oxyhaemoglobin saturation (SpO2) recorded using finger pulse oximetry or an arousal. The oxygen desaturation index (ODI) describes the average number of desaturation episodes per hour, with desaturation defined as a >3% decrease in SpO2 from the average value. Other recorded parameters were: the lowest value of SpO2 (nadir SpO2) and the total time that SpO2 was <90% (SpO2 <90%). Objective data on snoring were obtained from PSG, including snoring duration (as a percentage of total sleep time (TST)) and the number of snoring events per hour of sleep.

At follow-up, investigators recorded self-reported clinical symptoms, including: snoring (daily snoring/loud snoring/bothersome

snoring); nocturnal polyuria; libido disorders; and nocturnal mouth breathing. Sleep quality, state on waking and morning headache were recorded by the patient at baseline and follow-up on a visual analogue scale (VAS) from 0 to 10. Subjective sleepiness, assessed using the Epworth Sleepiness Scale (ESS score), QOL (Quebec Sleep Questionnaire [21]) and fatigue (Pichot scale [22]), was also determined at baseline and the 3- to 6-month follow-up visits. Office blood pressure (BP) was measured after 10 min of rest in the supine position at baseline and during follow-up.

During the clinical examination at each follow-up visit, the treating physician subjectively determined, by patient self-report, compliance with the MRD (number of hours used per night and number of nights used per week). Comprehensive data on MRD-related side effects were also collected at follow-up visits. The sleep and dental sleep physicians determined the severity of side effects and their impact on MRD treatment.

2.5. Statistical analysis

In this prospective study based on pre- and post-treatment evaluations of the same subjects, the sample size was determined by the accuracy required to estimate the primary endpoint with a confidence interval (CI) of 95%; a minimum sample size of n = 323 was determined. It was also estimated that about 10% of participants

Baseline sleep assessment (screening; n=515) Sleep physician

—» Declined or lost to follow-up, n=48

Baseline dental maxillofacial evaluation (inclusion; />=467) Dental sleep specialist

Not included, /7=98

• MRD contraindications, n=74

• Declined or lost to follow-up, n=22

• Other reason, n=2

Included and treated with custom-made Narval MRD: CAD/CAM (n=312) or non-CAD/CAM [n=57)

Fig. 2. Flow of participants through the study. CAD/CAM, computer-aided design/computer-aided manufacturing; MRD, mandibular repositioning device; PG, polygraphy; PSG, polysomnography.

ARTICLE IN PRESS

4 M.-F. Vecchierini et al./Sleep Medicine ■■ (2015) ■■ ■■

would be lost to follow-up, resulting in a target sample size of 360 patients.

Quantitative changes from baseline to the 3- to 6-month follow-up visits were presented as mean values, with standard deviation, minimum, maximum, median and quartile values, and compared using unpaired or paired Student's t-test or the Wilcoxon-Mann-Whitney nonparametric test according to normality of distribution and group comparison. Qualitative changes were described using frequency distribution and compared using Fisher's exact test or Chi-squared test. Comparisons between patient subgroups were assessed using the Student's t-test, ANOVA or Wilcoxon-Mann-Whitney test. Statistical analyses were performed using SAS version 9.

A logistic procedure with backward stepwise regression analysis was used to determine the independent factors associated with treatment success and complete response after selection of variables, with a p-value of <0.10 on univariate analysis. A p-value of <0.05 was considered statistically significant.

3. Results

3.1. Population

A total of 515 eligible patients were screened between May 2011 and September 2013. One hundred and forty six were not recruited into the study according to the following main reasons: 74 had maxillofacial contraindications to MRD therapy (temporoman-dibular joint disorders, craniofacial dimorphism, poor dental or periodontal status) and 72 declined to participate. Therefore, 369 eligible patients were included and treated with a CAD/CAM (n = 312) or non-CAD/CAM (n = 57) MRD (Fig. 2). Overall, 50% of the participants had previously received CPAP (median duration 11 months; median therapy pressure 11 cmH2O (Q1-Q3: 9-12 cmH2O)). Thirty MRD-treated participants withdrew from the study before the 3-month follow-up, mainly because of side effects (n = 16). The PG/ PSG follow-up data were available for 337 participants. Eleven participants without PG/PSG follow-up for either no valid reason (n = 7) or early study withdrawal for subjective lack of efficacy (n = 4) were classified as treatment failures. Therefore, the primary endpoint was assessed in 348 participants. Baseline participant demographic and clinical data are shown in Table 1.

3.2. MRD titration

In 84% of participants, at least one MRD titration visit was required (median 2, range 0-4); 25% required additional titration after the first PG/PSG control and were evaluated at the 6-month follow-up visit. Mean mandibular advancement after the last titration was 7.3 ± 2.1 mm (85 ± 26% of maximal, Q1-Q3: 73-100%) irrespective of the type of MRD.

3.3. Efficacy

3.3.1. Primary endpoint

Mandibular repositioning device treatment success was achieved in 76.2% of the participants (95% CI 71.4-80.3%).

3.3.2. Secondary endpoints

The complete response rates were 35.9% (AHI <5/h) and 63.5% (AHI <10/h). An AHI <15/h was achieved in 78% of participants during MRD therapy. Correction of AHI was greater in mild-to-moderate vs severe OSAHS (Fig. 3). However, more than half of all participants with severe OSAHS achieved an AHI of <15/h.

Treatment success was equivalent, irrespective of OSAHS severity at baseline (Fig. 3), previous CPAP therapy and diagnosis method. However, the treatment success rate was higher in those using a CAD/CAM vs non-CAD/CAM MRD (79.1% (95% CI 74.1-83.4%) vs 60.7%

Table 1

Participant demographic, respiratory and clinical data at baseline.

Total (n = 369)

Male, n (%) 273 (74.0)

Age, years 52.6 ± 11.3

Body mass index, kg/m2 27.2 ± 4.3

Overweight, n (%) 171 (46.7)

Obese, n (%) 80(21.9)

Waist circumference, cm 97.4 ± 12.4

Neck circumference, cm 39.7 ± 3.8

Systolic blood pressure, mmHg 127.2 ± 12.5

Diastolic blood pressure, mmHg 78.3 ± 10.3

AHI, /h 29.5 ± 15.2

Supine AHI, /h 37.0 ± 22.4

AI, /h 12.7 ± 12.9

HI, /h 16.8 ± 10.3

cAI, /h 0.5 ± 1.2

SpO2, % 93.7 ± 2.0

Minimum SpO2, % 81.7 ± 7.6

Median time SpO2 <90%, min 7

ODI, /h 21.7 ± 18.4

Dental status, n (%)

Good 301 (82.2)

Acceptable 65(17.8)

Periodontal status, n (%)

Good 294 (80.3)

Acceptable 72(19.7)

Dental mobility, n (%)

None 342 (93.4)

Low and limited 24 (6.6)

Angle malocclusion, n (%)

Type 1 236 (66.7)

Type 2 102(28.8)

Type 3 16(4.5)

Values are mean ± standard deviation or number of patients (%), unless otherwise stated.

AHI, apnoea-hypopnoea index; AI, apnoea index; cAI, central apnoea index; HI, hypopnoea index; MRD, mandibular repositioning device; ODI, oxygen desaturation index; SpO2, oxygen saturation.

(95% CI 47.6-72.4%); p = 0.0031). The complete response rate with AHI <10/h was also higher in the CAD/CAM subgroup (66.2% (60.571.5%) vs 49.1% (36.1-62.1%); p = 0.017).

3.3.2.1. Other respiratory criteria. Mandibular repositioning device therapy had significant beneficial effects on AHI, apnoea index (AI), hypopnoea index (HI), and ODI. Changes from baseline were significantly greater in participants with severe OSAHS at baseline vs those with mild or moderate disease (Table 2). Mandibular repositioning device therapy had no significant effect on mean SpO2, but nadir values significantly increased from baseline to follow-up, and time with SpO2 <90% significantly decreased during MRD therapy (Table 2). Based on PSG assessment, the number of snoring events decreased by 50% and the duration of snoring decreased by 75% compared with baseline during MRD therapy (Fig. 4A).

3.3.2.2. PSG data. Baseline and follow-up PSG data were available for 142 participants. There were no significant changes from baseline in total sleep time (TST) (417.1 ± 72.3 vs 411.9 ± 73.9 min), sleep latency (-2.7 ± 39.0 min) and sleep stage durations (stage 1-2 nonrapid eye movement (NREM): -2.8 ± 14.4% of TST; stage 3-4 NREM: +1.7 ± 11.9% of TST; REM: +1.2 ± 8.4% of TST) during MRD therapy. The number of arousals per hour decreased, irrespective of OSAHS severity, from 24.2 ± 17.5 at baseline to 16.1 ± 12.1 at follow-up (p < 0.0001). Although there was no overall change, participants with severe OSAHS showed a significant decrease in stage 1-2 NREM sleep (median 6% decrease; p = 0.014) in favour of an increase in REM sleep (median 3% increase; p = 0.023), without change in TST. Supine and non-supine AHI were significantly reduced from 37.0 ± 22.2 to 12.2 ± 16.0/h of TST (p < 0.001) and from 18.0 ± 17.5 to 6.3 ± 10.9 of

ARTICLE IN PRESS

M.-F. Vecchierini et al./Sleep Medicine ■■ (2015) I

p<0.0001

Mild AHI

■ Moderate AHI

■ Severe AHI

p<0.0001

Success rate

AHI <5/h

Outcomes

AHI <10/h

AHI <15/h

Fig. 3. Mandibular repositioning device efficacy by obstructive sleep apnoea-hypopnoea syndrome severity at 3- to 6-month foiiow-up. AHI, apnoea-hypopnoea index; Success rate, percentage of patients with a >50% decrease in AHI from baseline to follow-up.

TST (p < 0.001), respectively; TST in the supine (197.6 ± 109.5 vs 208.8 ± 115.4 min) or non-supine (226.0 ± 121.1 vs 212.9 ± 116.0 min) position was unchanged.

3.3.2.3. Daytime sleepiness. The ESS score decreased from 11.2 ± 4.8 at baseline to 7.8 ± 4.3 during MRD therapy; p < 0.0001). Overall, 62% of participants with excessive sleepiness at baseline had complete symptom resolution.

3.3.2.4. Clinical symptoms. Most clinical symptoms significantly improved during MRD therapy. Data on reductions in objective and subjective snoring are shown in Fig. 4A and B, respectively. Nocturnal polyuria and libido disorders resolved in 64% and 81% of participants affected by these problems at baseline and there was a significant reduction in the percentage of those with moderate or severe OSAHS who had nocturnal mouth breathing (p = 0.0001). Improvements in polyuria were seen across disease severity subgroups (p < 0.0001), but libido disorders only improved in those with severe OSAHS (p < 0.01). Visual analogue scale scores for sleep, state on waking, and morning headache significantly improved from baseline to follow-up (p < 0.0001).

3.3.2.5. Quality of life. Significant improvements from baseline (+24%) were documented in all five domains of the Quebec Sleep Questionnaire during MRD therapy (Fig. 5), irrespective of OSAHS severity. The Pichot score significantly decreased from 14.1 ± 7.8 at baseline to 9.0 ± 7.2 at follow-up (p < 0.0001).

3.3.2.6. Blood pressure and body weight. There were no changes in body weight, mean office systolic or diastolic BP, or heart rhythm from baseline to 3-month follow-up.

3.3.3. Tolerability

Fifty per cent of participants reported side effects during MRD therapy (Table 3). The most common events were temporoman-dibular joint or dental pain, and feelings of dental occlusion change. The majority of side effects were of mild severity and the investigators classified only 14% as severe. Pain was usually transitory and resolved within a median of 10 min of MRD removal in the morning. Twenty-eight participants (8%) prematurely discontinued MRD therapy because of side effects, which were similar across OSAHS severity subgroups, and there were no differences between the two types of MRD.

3.3.4. Compliance

Mean subjective compliance was 6.7 ± 1.3 hours/night, 6.7 ± 0.9 nights/week. The majority of participants (96.1%) used the MRD for >4 h/night, >4 days/week, and 86% used the device every night. Compliance results were similar regardless of OSAHS severity or MRD type.

3.3.5. Factors predictive of MRD efficacy

Univariate analysis identified a number of statistically significant factors at a threshold of 10% to predict a >50% decrease in AHI from baseline (Table 4). In an adjusted multivariate analysis, five factors remained as statistically significant predictors of a >50% decrease in AHI: use of a CAD/CAM MRD (odds ratio (OR) 3.02, 95%

ARTICLE IN PRESS

6 M.-F. Vecchierini et al./Sleep Medicine ■■ (2015) ■■ ■■

Changes in respiratory parameters from baseline to follow-up based on severity of obstructive sleep apnoea-hypopnoea syndrome in participants treated with a mandibular repositioning device.

OSAHS severity at baseline

Mild (n = 61)

Moderate(n = 150)

Severe (n = 158)

p (between-group comparison)

AHI, /h Baseline Three months Difference AI, /h Baseline Three months Difference HI, /h Baseline Three months Difference Supine AHI, /h Baseline Three months Difference Mean SpO2, % Baseline Three months Difference cAI, /h Baseline Three months Difference Nadir SpO2,% Baseline Three months Difference

TSpO2 <90%, min (median (Q1, Q3)) Baseline Three months Difference ODI, /h Baseline Three months Difference

11.1 ± 2.8

4.0 ± 3.7* -7.0 ± 4.0

4.4 ± 3.5 1.0 ± 1.6*

-3.3 ± 3.5

6.8 ± 3.4

2.9 ± 2.8* -3.8 ± 3.6

20.2 ± 13.5

5.5 ± 5.7* -14.9 ± 12.5

94.6 ± 1.7 94.6 ± 1.5 -0.1 ± 1.6

0.2 ± 0.4 0.2 ± 0.3 -0.04 ± 0.36

84.6 ± 6.0 86.9 ± 8.0*

2.1 ± 10.4

2(0,7) 0(0,1)*** -1 (-22.8,1.5)

10.9 ± 8.3 4.4 ± 6.8* -5.9 ± 10.7

22.5 ± 4.4 7.1 ± 6.1* -15.1 ± 6.7

7.7 ± 6.4

2.0 ± 3.5* -5.6 ± 5.9

14.8 ± 6.5

5.1 ± 4.2* -9.6 ± 7.4

32.1 ± 17.5

9.7 ± 10.7* -20.9 ± 18.3

93.9 ± 1.8 94.0 ± 1.8

0.1 ± 1.5

0.4 ± 0.8 0.3 ± 1.1# -0.03 ± 1.05

82.3 ± 6.7 84.9 ± 9.1*

2.8 ± 10.0

6(1,17) 0.9 (0, 8)* -2 (-12, 0)

16.3 ± 13.1

8.2 ± 9.7* -8.6 ± 14.3

43.3 ± 12.3 17.9 ± 17.2*

-25.0 ± 16.4

20.7 ± 15.1 7.9 ± 13.3* -13.5 ± 15.4

22.5 ± 11.5 10.1 ± 8.9*

-11.4 ± 12.6

49.4 ± 23.1

20.6 ± 23.4* -26.9 ± 29.0

93.1 ± 2.1

93.5 ± 2.0 0.2 ± 2.1

0.8 ± 1.6 0.8 ± 2.6 0.04 ± 2.9

80.0 ± 8.6 83.5 ± 8.0** 3.5 ± 7.9

12.5(2, 42.5) 4.0 (0, 23)*** -1 (-4, 0)

30.9 ± 21.1

14.2 ± 16.1* -15.4 ± 23.2

<0.0001

<0.0001

<0.0001

Values are mean ± standard deviation, unless stated otherwise.

AHI, apnoea-hypopnoea index; AI, apnoea index; cAI, central apnoea index; HI, hypopnoea index; mild, AHI 5/h to <15/h; moderate, AHI >15/h to <30/h; NS, not significant; ODI, oxygen desaturation index; OSAHS, obstructive sleep apnoea-hypopnoea syndrome; severe, AHI >30/h; TSpO2 <90%, time with oxygen saturation <90%; SpO2, oxygen saturation; Success, > 50% decrease in AHI.

* p < 0.0001 vs baseline.

** p < 0.001 vs baseline.

*** p < 0.01 vs baseline.

# p < 0.05 vs baseline.

CI 1.44-6.33; p = 0.0035); waist circumference (OR0.97, 95% CI 0.940.99; p = 0.0072); dental overbite (OR 1.22, 95% CI 1.03-1.45; p = 0.022); maximal jaw protrusion (OR 1.18, 95% CI 1.03-1.35; p = 0.015); and baseline AI (OR 0.97, 95% CI 0.95-0.99; p = 0.016).

There were also a number of significant univariate predictors of complete response (AHI <10/h) during MRD therapy (Table 4). On adjusted multivariate regression analysis, four factors were significant independent predictors of complete response: use of CAD/ CAM MRD (OR 2.99, 95% CI 1.42-6.29; p = 0.0039); baseline AI (OR 0.89, 95% CI 0.87-0.92; p < 0.0001); maximal jaw protrusion (OR 1.21, 95% CI 1.07-1.37; p = 0.0018); and baseline HI (OR 0.93,95% CI 0.900.95; p < 0.0001). Age, body mass index, and supine AHI were not identified as predictive factors of MRD efficacy.

4. Discussion

This prospective observational study described the treatment of 369 patients with OSAHS and with an MRD. Although MRDs have a place in the management of OSAHS, it is believed that, to date, there are few comparative studies looking at the efficacy and tol-erability of different oral appliances [23]. Available data suggest that custom-made and adjustable devices are more effective than pre-

fabricated, fixed, thermoplastic appliances [24,25]. In the absence of direct comparative trials, multiple factors can make comparing data from different studies difficult, including: heterogeneity in OSAHS severity, variety in MRD type, and use of varying treatment success definitions [26].

This study had a number of strengths. These included its multicentre real-life design, the large sample (369 participants), objective titration with PSG/PG at the end of final titration, reevaluation of suboptimal efficacy after optimisation of mandibular advancement, and a multidisciplinary approach involving sleep physicians and sleep dental specialists. Primary and efficacy endpoints were assessed in more than 90% of participants and the proportion lost to follow-up was very low (<2%). In addition, the study identified some predictive factors of efficacy and showed that MRD therapy can be successful in some patients with severe OSAHS and/ or obesity.

Participants were carefully selected, based on oral conditions as recommended by current guidelines. However, the proportion of screened patients who were not selected by a dental specialist for MRD therapy (15%) was lower than expected. Other data show that MRD contraindications could be present in up to 34% of patients, mainly due to dental problems [27]. Furthermore, participants in

ARTICLE IN PRESS

M.-F. Vecchierini et al./Sleep Medicine ■■ (2015) I

Daily snoring Loud snoring Bothersome snoring

Fig. 4. Effects of mandibular repositioning device therapy on snoring: (A) based on polysomnology data or (B) patient self-report (*p < 0.0001 vs baseline).

this study were not excluded for criteria that were previously identified to influence MRD effectiveness (eg, AHI, BMI, sex, age) in other studies. The present results suggest that MRDs may be indicated for the majority of patients who are noncompliant with CPAP therapy. Moreover, 25% of participants received additional titration after the first 3-month PG/PSG control to achieve optimal efficacy, showing that objective measurement of AHI is essential for controlling MRD therapy and that proper individualised titration is probably as important as patient selection.

Improvements in snoring in this study were not only subjectively assessed but also objectively determined using PSG/PG, which confirmed that the MRD-related improvements reported by

patients and partners are consistent with existing data [28]. Reported reductions in daytime sleepiness and the incidence of excessive sleepiness were also of a similar magnitude to previously reported changes [28-31] and similar to those achieved with CPAP [29]. Furthermore, this study documented significantly improved QOL after MRD therapy using the Quebec Sleep Questionnaire. Not many previous studies have explored QOL after MRD treatment [30,32-34].

Subjectively assessed MRD compliance in this study was excellent (95.8%). Previous reports of self-assessed compliance with MRD therapy have ranged from 76 to 95% [29]. Recent data suggest that there is good similarity between subjective and objective

ARTICLE IN PRESS

M.-F. Vecchierini et al./Sleep Medicine ■■ (20lS)

Sleepiness Diurnal symptoms Nocturnal symptoms

Quebec Sleep Questionnaire domain

Social interactions

Fig. 5. Effect of mandibular repositioning device on quality of life (Quebec Sleep Questionnaire) (*p < 0.0001 vs baseline).

long-term compliance rates with MRD therapy [35,36]. Thus, even though CPAP remains the treatment of choice in severe OSA, better long-term compliance with MRD therapy could minimise actual differences between the effectiveness of MRD and CPAP in clinical practice [16,35].

MRD therapy is currently recommended for the treatment of patients with mild or moderate OSAHS (level A recommendation) [15,16,29,37]. A large subgroup of participants (42.8%) in the current study had severe OSAHS (AHI >30/h) and MRD was able to significantly reduce AHI, despite high mean baseline AHI values (43 ± 12/ h). Thus, while an MRD might be less effective for resolving severe OSAHS compared with mild/moderate disease, a significant number of patients with severe OSAHS have been effectively treated with an MRD [16,38].

Table 3

Side effects reported during mandibular repositioning device therapy.

Side effects during MRD therapy, n (%)

Minor, Severe, Requiring

n(%) n(%) treatment withdrawal

TMJ pain 49(13.3) 13(3.5) 2 (0.5)

Dental pain 46(12.5) 8 (2.2) 8 (2.2)

Occlusion change 50(13.6) 1 (0.3) 2 (0.5)

Gingival bleeding 26(7.1) 3 (0.8) 3 (0.8)

Periodontal pain 23 (6.3) 6(1.6) 3 (0.8)

Dental mobility 19(5.1) 1 (0.3) 1 (0.3)

Mouth dryness 18 (4.9) 0 0

Hypersalivation 14(3.8) 1 (0.3) 1 (0.3)

Gingival pain 11 (3.0) 3 (0.8) 1 (0.3)

Jaw pain 10(2.8) 2 (0.5) 2 (0.5)

Teeth clenching 10(2.7) 0 1 (0.3)

TMJ disorders 7 (1.9) 3 (0.8) 0

Gingivitis 5(1.3) 5 (1.4) 2 (0.5)

Broken MRD 5(1.3) 4(1.1) 4(1.1)

Dental fracture 2 (0.5) 4(1.1) 0

Mild tooth migration 6 (1.6) 0 0

Jaw stiff 6 (1.6) 0 0

Local inflammatory reaction 1 (0.3) 1 (0.3) 1 (0.3)

Prosthesis loosening 2 (0.5) 0 0

MRD, mandibular repositioning device; TMJ, temporomandibular joint.

The results of this 'real-life' study show that a custom-made Narval™ MRD is effective and well tolerated in OSAHS patients who refuse or do not tolerate CPAP. Significant improvements were documented in AHI, SpO2, clinical symptoms and QOL in mild-to-moderate and severe OSAHS. The Narval™ MRD device is custom-made with flexible biocompatible polyamide; such soft acrylic materials have been shown to be better tolerated and to have better efficiency than thermoplastic monobloc or hard acrylic MRDs [23,29]. Moreover, the traction-based triangle and connector articulations enable mandibular advancement in parallel to the occlusion plane. This vector of advancement reduces stress on muscles and TMJ contact force [39], and may be a possible explanation for the good tolerance of MRD in the present cohort. MRD therapy was well tolerated in this study and most participants expressed a desire to continue using the MRD.

Treatment success (76%) and complete response (64%) rates with Narval™ MRD in this study were at the upper end of the range reported in previous studies of MRD devices in OSAHS. Data from randomised, controlled trials have shown mean decreases in the frequency of respiratory disturbances of 14-80% with MRD therapy [28,29] and complete response rates of 50-70% [28,32]. In parallel with AHI improvements, MRD therapy significantly increased minimal SpO2, significantly decreased time spent with SpO2 <90% and the ODI to a similar extent, as previously reported [29,40].

In the present study, use of a CAD/CAM MRD device was also a significant independent predictor of treatment success, suggesting that the type of MRD may have an important influence on the outcome of therapy. Waist circumference was found to be an independent predictor of MRD efficacy, and a much stronger predictor than BMI. Moreover, in univariate analysis, success rate and complete response in obese patients were 58.1% and 44.3%, respectively. Consistent with existing data, other results have suggested that MRD efficacy is not affected by supine-dependent OSAHS [41]. Greater overbite was a significant predictor of treatment success, which may predispose patients with mandibular retrognathia, especially those with class II division 2 malocclusions, to a high success rate, in accordance with previous data on MRDs. The associations that were found between MRD treatment outcome and both functional and morphological factors should be taken into account in therapeutic decision-making.

ARTICLE IN PRESS

M.-F. Vecchierini et al./Sleep Medicine ■■ (2015) I

Table 4

Univariate predictors of treatment success and complete response for mandibular repositioning device therapy.

No OR (95% CI) p

39.3 Reference

20.9 2.45(1.34-4.49) 0.0031

2б.4/1б.7 1.79 (0.9б-3.33) 0.063

40.8 ± 3.7 0.89 (0.82-0.9б) 0.0022

101.9 ± 12.7 0.9б (0.94-0.98) 0.0001

14.0 Reference

21.5 0.б0(0.31-1.1б) NS

41.9 0.23 (0.11-0.4б) <0.0001

25.2 Reference

14.б 1.98 (1.04-3.7б) 0.067

33.3 0.б8 (0.22-2.0б) NS

2.2 ± 1.9 1.27 (1.09-1.49) 0.0004

8.2 ± 2.1 1.20(1.07-1.34) 0.0019

2.3 ± 1.8 1.31 (l.ll-l.55) 0.0013

91.1 ± 2б.4 0.990 (0.980-0.999) 0.009

33.8 ± 18.3 0.98 (0.9б-0.99) 0.028

17.б ± 14.3 0.97 (0.95-0.99) 0.0001

41.9 ± 25.б 0.99(0.98-1.00) 0.098

2б.9/17.7 1.72 (0.95-3.09) 0.070

50.9 Reference

32.5 2.1б (1.20-3.91) 0.010

39.5/23.5 2.12 (1.21-3.73) 0.0078

40.9 ± 3.5 0.84(0.78-0.91) <0.0001

101.5 ± 11.3 0.95 (0.93-0.97) <0.0001

22.1 Reference

35.3 0.52(0.30-0.92) <0.0001

55.7 0.23(0.12-0.44) <0.0001

2.5 ± 2.0 1.1б (1.02-1.31) 0.0066

8.б ± 2.4 1.12(1.02-1.24) 0.028

2.5 ± 1.7 l.23(l.07-l.4l) 0.0047

88.3 ± 2б.4 0.99(0.98-1.00) 0.040

39.1 ± 15.8 0.92 (0.90-0.94) <0.0001

20.5 ± 15.7 0.92 (0.90-0.95) <0.0001

18.б ± 10.2 0.9б (0.94-0.98) 0.0012

4б.9 ± 25.2 0.97 (0.9б-0.98) <0.0001

41.7 Reference

31.0 1.59(0.99-2.55) 0.054

38.б/27.0 1.70 (i.01-2.86) 0.044

Variable

Treatment success (£50% decrease in AHI)

Type of device, % participants Non-CAD/CAM CAD/CAM Sex: M/F, % participants Neck circumference, cm Waist circumference, cm BMI, % participants Normal Overweight Obese

Malocclusion dental class, % participants

Dental overbite, mm Maximum jaw protrusion, mm Dental overjet, mm Mandibular advancement, % Baseline AHI, /h Baseline AI, /h Supine AHI, /h

Mouth breathing: yes/no, % participants Complete response (AHI <10/h)

Type of device, % participants Non-CAD/CAM CAD/CAM Sex: M/F, % participants Neck circumference, cm Waist circumference, cm BMI, % participants Normal Overweight Obese Dental overbite, mm Maximum jaw protrusion, mm Dental overjet, mm Mandibular advancement, % Baseline AHI, /h Baseline AI, /h Baseline HI, /h Supine AHI, /h ESS score, % participants <10 >10

Mouth breathing: yes/no, % participants

73.б/83.3

39.2 ± 3.б

95.7 ± 11.9

78.5 58.1

74.8 85.4 бб.7

3.0 ± 2.0

9.1 ± 2.5 3.1 ± 1.8

85.6 ± 2б.0

28.3 ± 13.9 11.б ± 12.3 35.б ± 21.2 73.1/82.3

49.1 б7.5

б0.5/7б.5 38.9 ± 3.б 94.5 ± 12.1

77.9 б4.7 44.3

3.0 ± 2.0 9.2 ± 2.4

3.1 ± 1.8 83.0 ± 25.4 23.7 ± 11.4

8.9 ± 9.4 14.9 ± 8.9 31.5 ± 18.3

58.3 б9.0

б1.4/73.0

AHI, apnoea-hypopnoea index; BMI, body mass index; CAD, computer-aided design; CAM, computer-aided manufacturing; CI, confidence interval; ESS, Epworth Sleepiness Scale; NS, not significant; OR, odds ratio.

As mentioned briefly above, outcomes in the present study appeared to be better for participants treated with a CAD/CAM MRD. In most studies, greater protrusion was associated with better improvement in AHI, nocturnal oxygen desaturations, and pharyngeal collapsibility [23,32,42,43]. The same gradual titration procedures were followed with the two MRD devices, but results with the non-CAD/CAM device were comparable to recent published data from a study with no systematic MRD titration [26]. The present results suggest that the better efficacy of the CAD/CAM device may be due to its specific design and/or different manufacturing process compared with the non-CAD/CAM device. There are several potential explanations for this, including: differences in material plasticity, shape and thickness of splints, and the degree of vertical dimension of occlusion provided. It has been shown that vertical opening may have a significant effect on pharyngeal collapse in some patients [44] and may, therefore, reduce MRD efficacy. The manufacturing process for the CAD/CAM Narval™ device allows accurate adjustment of the vertical opening compared to the non-CAD/CAM device. This may be one mechanism that contributed to the higher efficacy seen with CAD/CAM device in this study. What is important is that use of a titratable and adjustable MRD device

is essential, and that effective and individualised mandibular titration plays a key role in therapy success [16,30,45].

Although MRD therapy had no significant effects on blood pressure in the overall study population, there was an indication that greater reductions in blood pressure from baseline were observed in those with pre-existing hypertension. This is something that warrants further investigation in future clinical trials.

The present study had some limitations. There was no control group, but the primary aim was to assess long-term MRD efficacy and tolerability in a large real-life cohort of severe and/or symptomatic OSAHS patients who were noncompliant with CPAP and required mandatory treatment. Compliance data were based on subjective reports, but because previous data have shown good concordance between subjective and objective compliance assessments [34], this is unlikely to have influenced the findings.

The results of this study, which show good efficacy, tolerability and adherence with MRD therapy, support the use of this intervention in OSAHS patients who refuse or do not tolerate CPAP, including those with severe disease. Long-term follow-up is continuing and further assessments, including PSG/PG, will be performed after two and five years, which will allow additional data

ARTICLE IN PRESS

10 M.-F. Vecchierini et al./Sleep Medicine ■■ (201S) I

analysis and more precise determination of factors predicting the success of therapy.

Funding sources

The ORCADES study and the preparation of this article are funded by ResMed (France). The Executive Steering Committee defined the study design and is responsible for the clinical and scientific conduct of the study and publication of the results. C.R.O. Clinact (France) mandated by ResMed performed the collection, quality control, management and analysis of the data. The Executive Steering Committee had full access to all of the data and takes responsibility for the integrity and accuracy of the data analysis.

Executive Steering Committee

Marie-Françoise Vecchierini (France) Principal Investigator, JeanClaude Meurice (France) Scientific Advisor, Marie-Pia d'Ortho (France), Pierre El Chater (France), Jean-Baptiste Kerbrat (France), Damien Leger (France), Christelle Monaca (France), Pierre-Jean Monteyrol (France), Eric Muller (France), Bernard Pigearias (France).

Conflict of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2015.05.020.

Acknowledgements

Medical writing support was provided by Nicola Ryan, independent medical writer, on behalf of ResMed.

References

[1] American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.

[2] Tregear S, Reston J, Schoelles K, et al. Obstructive sleep apnea and risk of motor vehicle crash: systematic review and meta-analysis. J Clin Sleep Med 2009;5:573-81.

[3] Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352-60.

[4] Jennum P, Kjellberg J. Health, social and economical consequences of sleep-disordered breathing: a controlled national study. Thorax 2011;66:560-6.

[5] Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-8.

[6] Aurora RN, Casey KR, Kristo D, et al. Practice parameters for the surgical modifications of the upper airway for obstructive sleep apnea in adults. Sleep 2010;33:1408-13.

[7] Antic NA, Catcheside P, Buchan C, et al. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep 2011;34:111-19.

[8] Antonopoulos CN, Sergentanis TN, Daskalopoulou SS, et al. Nasal continuous positive airway pressure (nCPAP) treatment for obstructive sleep apnea, road traffic accidents and driving simulator performance: a meta-analysis. Sleep Med Rev 2011;15:301-10.

[9] Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012;307:2161-8.

[10] Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc 2008;5:173-8.

[11] Sawyer AM, Gooneratne NS, Marcus CL, et al. A systematic review of CPAP adherence across age groups: clinical and empiric insights for developing CPAP adherence interventions. Sleep Med Rev 2011;15:343-56.

[12] Li W, Xiao L, Hu J. The comparison of CPAP and oral appliances in treatment of patients with OSA: a systematic review and meta-analysis. Respir Care 2013;58:1184-95.

[13] Marklund M, Stenlund H, Franklin KA. Mandibular advancement devices in 630 men and women with obstructive sleep apnea and snoring: tolerability and predictors of treatment success. Chest 2004;125:1270-8.

[14] 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;17:659-66.

[15] Kushida CA, Morgenthaler TI, Littner MR, etal. Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: an update for 2005. Sleep 2006;29:240-3.

[16] Sutherland K, Vanderveken OM, Tsuda H, et al. Oral appliance treatment for obstructive sleep apnea: an update. J Clin Sleep Med 2014;10:215-27.

[17] Marklund M, Franklin KA. Long-term effects of mandibular repositioning appliances on symptoms of sleep apnoea. J Sleep Res 2007;16:414-20.

[18] Martinez-Gomis J, Willaert E, Nogues L, et al. Five years of sleep apnea treatment with a mandibular advancement device. Side effects and technicalcomplications. Angle Orthod 2010;80:30-6.

[19] Walker-Engstrom ML, Tegelberg A, Wilhelmsson B, et al. 4-year follow-up of treatment with dental appliance or uvulopalatopharyngoplasty in patients with obstructive sleep apnea: a randomized study. Chest 2002;121:739-46.

[20] American Academy of Sleep Medicine. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22:667-89.

[21] Lacasse Y, Bureau MP, Series F. A new standardised and self-administered quality of life questionnaire specific to obstructive sleep apnoea. Thorax 2004;59:494-9.

[22] Gardenas J. Echelles et outils d'évaluation en Médecine Générale, Le Généraliste, 2002; 2187.

[23] Chen H, Lowe AA. Updates in oral appliance therapy for snoring and obstructive sleep apnea. Sleep Breath 2013;17:473-86.

[24] Friedman M, Pulver T, Wilson MN, et al. Otolaryngology office-based treatment of obstructive sleep apnea-hypopnea syndrome with titratable and nontitratable thermoplastic mandibular advancement devices. Otolaryngol Head Neck Surg 2010;143:78-84.

[25] Vanderveken OM, Devolder A, Marklund M, et al. Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea. Am J Respir Crit Care Med 2008;178:197-202.

[26] Ahrens A, McGrath C, Hagg U. A systematic review of the efficacy of oral appliance design in the management of obstructive sleep apnoea. Eur J Orthod 2011;33:318-24.

[27] Petit FX, Pépin J-L, Bettega G, et al. Mandibular advancement devices rate of contraindications in 100 consecutive obstructive sleep apnea patients. Am J Respir Crit Care Med 2002;166:274-8.

[28] Hoffstein V. Review of oral appliances for treatment of sleep-disordered breathing. Sleep Breath 2007;11:1-22.

[29] Marklund M, Verbraecken J, Randerath W. Non-CPAP therapies in obstructive sleep apnoea: mandibular advancement device therapy. Eur Respir J 2012;39:1241-7.

[30] Petri N, Svanholt P, Solow B, et al. Mandibular advancement appliance for obstructive sleep apnoea: results of a randomised placebo controlled trial using parallel group design. J Sleep Res 2008;17:221-9.

[31] Verbruggen Ae, Dieltjens M, Wouters K, et al. Prevalence of residual excessive sleepiness during effective oral appliance therapy for sleep-disordered breathing. Sleep Med 2014;15:269-72.

[32] Gagnadoux F, Fleury B, Vielle B, et al. Titrated mandibular advancement versus positive airway pressure for sleep apnoea. Eur Respir J 2009;34:914-20.

[33] Vecchierini mF, Leger D, Laaban jP, et al. Efficacy and compliance of mandibular repositioning device in obstructive sleep apnea syndrome under a patient-driven protocol of care. Sleep Med 2008;9:762-9.

[34] Blanco J, Zamarron C, Abeleira Pazos MT, et al. Prospective evaluation of an oral appliance in the treatment of obstructive sleep apnea syndrome. Sleep Breath 2005;9:20-5.

[35] Dieltjens M, Braem MJ, Vroegop AV, et al. Objectively measured vs self-reported compliance during oral appliance therapy for sleep-disordered breathing. Chest 2013;144:1495-502.

[36] Vanderveken OM, Dieltjens M, Wouters K, et al. Objective measurement of compliance during oral appliance therapy for sleep-disordered breathing. Thorax 2013;68:91-6.

[37] Lim J, LassersonTJ, Fleetham J, et al. Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 2006;(1):CD004435.

[38] Phillips CL, Grunstein RR, Darendeliler MA, et al. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med 2013;187:879-87.

[39] Cheze L, Navailles B. Impact on temporomandibular joint of two oral appliances for sleep apnoea treatment. ITBM-RBM 2006;27:233-7.

[40] Mehta A, Qian J, Petocz P, et al. A randomized, controlled study of a mandibular advancement splint for obstructive sleep apnea. Am J Respir Crit Care Med 2001;163:1457-61.

[41] Dieltjens M, Braem MJ, Van de Heyning PH, et al. Prevalence and clinical significance ofsupine-dependent obstructive sleep apnea in patients using oral appliance therapy. J Clin Sleep Med 2014;10:959-64.

[42] Gindre L, Gagnadoux F, Meslier N, et al. Mandibular advancement for obstructive sleep apnea: dose effect on apnea, long-term use and tolerance. Respiration 2008;76:386-92.

[43] Kato J, Isono S, Tanaka A, et al. Dose-dependent effects of mandibular advancement on pharyngeal mechanics and nocturnal oxygenation in patients with sleep-disordered breathing. Chest 2000;117:1065-72.

[44] Vroegop AV, Vanderveken OM, Van de Heyning PH, et al. Effects of vertical opening on pharyngeal dimensions in patients with obstructive sleep apnoea. Sleep Med 2012;13:314-6.

[45] Pliska BT, Almeida F. Effectiveness and outcome of oral appliance therapy. Dent Clin North Am 2012;56(2):433-44.