Clinical ReviewPhenotypes of responders to mandibular advancement device therapy in obstructive sleep apnea patients: A systematic review and meta-analysis
Introduction
Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by recurrent episodes of partial or complete upper-airway obstruction during sleep. It is associated with oxygen desaturations and arousals from sleep [1]. The World Health Organization estimates that 100 million individuals worldwide have OSA [2], and that up to 90% remain undiagnosed and untreated [3]. OSA has a range of deleterious long-term consequences including increased cardiovascular morbidity, neurocognitive impairment and overall mortality [4]. As untreated OSA is associated with serious long-term adverse consequences, efficient and effective treatment may be advantageous.
Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA. However, compliance with CPAP therapy is often very poor [5]. As an alternative, mandibular advancement device (MAD) therapy is the most commonly performed non-CPAP therapy for OSA [6]. MAD can prevent upper airway collapse by protruding the mandible to reduce upper airway collapsibility [7,8]. The most commonly used definitions of response are 1) treatment AHI < 5/h or complete resolution of OSA (definition 1), 2) treatment AHI < 10/h and ≥50% reduction in AHI from baseline (definition 2), and 3) ≥ 50% reduction in AHI from baseline (definition 3) [9,10]. Considering all the definitions, on average over one third have minimal or no major reduction in OSA severity with MAD therapy [9]. To avoid wasting medical resources and to optimize the treatment modality for OSA patients, especially for those who do not respond to MAD, it is essential to explore the underlying mechanism behind the difference in treatment response in OSA patients and identify (non)-responders to MAD before starting the treatment.
The pathophysiologic causes of OSA include anatomical factors, such as a smaller upper airway; and functional factors, such as a high passive critical closing pressure of the upper airway (Pcrit) [[11], [12], ∗[13], [14], [15]]. The above factors play an important role not only in the pathogenesis of OSA but also in the treatment response in OSA patients. Moreover, knowledge about the extent to which these factors play an important role in the treatment response in OSA continues to evolve [16]. Previous studies suggest that certain clinical, craniofacial, polysomnographic (PSG), and physiological characteristics of OSA patients are associated with treatment response to MAD therapy [9,[17], ∗[18], [19], [20]]. In clinical practice, however, it is still a challenge to identify responders to MAD, because the phenotypes of responders to MAD therapy are incompletely understood [[20], [21], ∗[22], [23]]. In the literature, due to the small sample size of various studies, there are contradictory findings [24]. For example, one study found that responders have a smaller inferior airway space (IAS) than non-responders [25], while another study found that the responders had a larger IAS [26]. In addition, there are only a few systematic reviews and/or meta-analyses on the phenotypes of responders to MAD treatment in OSA [27]. In a previous review done by Okuno et al., in 2016, the accuracy of the tests used to predict MAD treatment response in OSA was investigated. However, the authors did not include a synthesis of information on the phenotypes of responders to MAD [27].
Accordingly, the aim of this systematic review and meta-analysis is to gain insight into the phenotypes (clinical, craniofacial, PSG and physiological characteristics) at baseline of responders and non-responders to MAD to help guide the clinicians in OSA disease management.
Section snippets
Study design
To address the research objective, the investigators designed and implemented a systematic review according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) protocol [28]. No ethical approval was required for this systematic review. This review was registered at PROSPERO (registration number: CRD42019119513).
Eligibility criteria
This review includes studies that assess the clinical, craniofacial, PSG or physiological characteristics of responders and non-responders to MAD therapy
Study selection
Search results are shown in Fig. 1. In the first phase, 931 potentially relevant studies were obtained following the PICO search strategy. After removing the 281 duplicates, 650 unique studies were left for the first phase screening. Based on the inclusion and exclusion criteria, 586 studies were removed, and 64 studies moved into the second full-text phase. After the second phase, 41 studies were suitable for this systematic review. Of these, six of the studies assessed the clinical
Discussion
We conducted a systematic review and meta-analysis to quantify phenotypes of responders to MAD therapy in OSA patients. Responders to MAD had certain clinical, craniofacial, PSG, physiological characteristics. Based on meta-analysis findings, responders to MAD were lower age, female, had a lower BMI, smaller NC, lower AHI, a retracted maxilla and mandible, a narrower airway, and a shorter soft palate than non-responders.
Clinical characteristics
Responders to MAD therapy were found to be lower age, female, have a lower BMI or smaller NC. Additionally, the chance of treatment success decreases if the patient gains weight during MAD therapy [38,52]. Obesity is the most prominent risk factor both in the pathogenesis of OSA and treatment response to MAD therapy [65]. However, although the responders and non-responders showed a significant difference in BMI and NC, there is significant overlap between groups. Thus, there is no reliable BMI
Conclusions
Based on the results of this systematic review and meta-analysis, it may be possible to provide useful information for clinicians regarding the phenotypes of responders and non-responders to MAD therapy. However, the definition of treatment response in OSA research has not been standardized. A standardized definition which is not solely limited to AHI reduction criteria based on PSG recording, but that also includes changes in relevant OSA symptoms, and long-term compliance would be desirable.
Conflicts of interest
DJE is supported by a National Health and Medical Research Council of Australia Senior Research Fellowship (1116942), has a Cooperative Research Centre (CRC)-P grant: a collaborative grant between the Australian Government, Academia and Industry (Industry partner Oventus Medical), has been a collaborator on research projects in which SomnoMed and Zephyr have provided equipment, has research grants from Apnimed and Bayer and serves on the Scientific Advisory Board for Apnimed. The other authors
Funding acknowledgement
Supported by Canadian Institutes of Health Research (grant number: 325899) and Supported by Youth scientific research funds of School of Stomatology, Shandong University (grant number: 2018QNJJ02).
References∗ (80)
- et al.
Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study
Lancet (London, Engl)
(2005) - et al.
Treatment of snoring and obstructive sleep apnea with mandibular repositioning appliances
Sleep Med Rev
(2004) Phenotypic approaches to obstructive sleep apnoea - new pathways for targeted therapy
Sleep Med Rev
(2018)- et al.
Clinical co-morbidities in obstructive sleep apnea syndrome treated with mandibular repositioning appliance
Respir Med
(2006) - et al.
Cephalometric and physiologic predictors of the efficacy of an adjustable oral appliance for treating obstructive sleep apnea
Am J Orthod Dentofacial Orthop
(2001) - et al.
Prediction of oral appliance treatment outcomes in obstructive sleep apnea: a systematic review
Sleep Med Rev
(2016) - et al.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
Int J Surg
(2010) - et al.
Dental and skeletal changes associated with long-term oral appliance use for obstructive sleep apnea: a systematic review and meta-analysis
Sleep Med Rev
(2018) - et al.
Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity
J Clin Epidemiol
(2013) - et al.
A comparison of responders and nonresponders to oral appliance therapy for the treatment of obstructive sleep apnea
Am J Orthod Dentofacial Orthop
(2006)
Mandibular advancement device therapy for obstructive sleep apnea: a prospective study on predictors of treatment success
Sleep Med
Craniofacial morphologic predictors of oral appliance outcomes in patients with obstructive sleep apnea
J Am Dent Assoc
Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea
Chest
Treatment outcomes of mandibular advancement devices in positional and nonpositional OSA patients
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
Mandibular advancement devices in 630 men and women with obstructive sleep apnea and snoring
Chest
Oropharyngeal crowding and obesity as predictors of oral appliance treatment response to moderate obstructive sleep apnea
Chest
Impact of upper airway abnormalities on the success and adherence to mandibular advancement device treatment in patients with Obstructive Sleep Apnea Syndrome
Braz J Otorhinolaryngol
Predictors of long-term orthodontic side effects from mandibular advancement devices in patients with snoring and obstructive sleep apnea
Am J Orthod Dentofacial Orthop
Pathogenesis of obstructive sleep apnea
J Appl Physiol (1985)
Global alliance against chronic respiratory diseases
Allergy
Increased prevalence of sleep-disordered breathing in adults
Am J Epidemiol
Educational video to improve CPAP use in patients with obstructive sleep apnoea at risk for poor adherence: a randomised controlled trial
Thorax
An update on mandibular advancement devices for the treatment of obstructive sleep apnoea hypopnoea syndrome
J Thorac Dis
Dose-dependent effects of mandibular advancement on upper airway collapsibility and muscle function in obstructive sleep apnea
Sleep
Oral appliance treatment response and polysomnographic phenotypes of obstructive sleep apnea
J Clin Sleep Med
Optimal positive airway pressure predicts oral appliance response to sleep apnoea
Eur Respir J
Upper airway collapsibility in snorers and in patients with obstructive hypopnea and apnea
Am Rev Respir Dis
Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold
Clin Sci (Lond)
Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets
Am J Respir Crit Care Med
Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders
J Appl Physiol (1985)
Mechanisms used to restore ventilation after partial upper airway collapse during sleep in humans
Thorax
Qualitative assessment of awake nasopharyngoscopy for prediction of oral appliance treatment response in obstructive sleep apnoea
Sleep Breath
Risk factors for the efficacy of oral appliance for treating obstructive sleep apnea: a preliminary study
Cranio
Upper-airway collapsibility and loop gain predict the response to oral appliance therapy in patients with obstructive sleep apnea
Am J Respir Crit Care Med
Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea
J Physiol
Remotely controlled mandibular protrusion during sleep predicts therapeutic success with oral appliances in patients with obstructive sleep apnea
Sleep
Differences in three-dimensional craniofacial anatomy between responders and non-responders to mandibular advancement splint treatment in obstructive sleep apnoea patients
Eur J Orthod
Treatment success with titratable thermoplastic mandibular advancement devices for obstructive sleep apnea: a comparison of patient characteristics
Ear Nose Throat J
The mandibular advancement device and patient selection in the treatment of obstructive sleep apnea
Arch Otolaryngol Head Neck Surg
Use of flow-volume curves to predict oral appliance treatment outcome in obstructive sleep apnea: a prospective validation study
Sleep Breath
Cited by (0)
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The most important references are denoted by an asterisk.