Elsevier

Sleep Medicine Reviews

Volume 49, February 2020, 101229
Sleep Medicine Reviews

Clinical Review
Phenotypes of responders to mandibular advancement device therapy in obstructive sleep apnea patients: A systematic review and meta-analysis

https://doi.org/10.1016/j.smrv.2019.101229Get rights and content

Summary

Mandibular advancement device (MAD) therapy is the most commonly used non-continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA). Although OSA patients prefer MAD over CPAP, on average over one third have minimal or no major reduction in OSA severity with MAD therapy. Improved understanding of responder characteristics (or “phenotypes”) to MAD may facilitate more efficient use of limited medical resources and optimize treatment efficacy.

The aim of this review is to describe the baseline phenotypic characteristics of responders to MAD therapy in OSA patients. Pubmed, Web of Science, EMBASE, Scopus were searched for eligible studies published until Feb 2019. A total of 650 studies were identified. 41 studies were included in this review and meta-analysis. The quality of the studies was assessed using the risk of bias assessment tool for non-randomized studies (RoBANS). Based on meta-analysis, the responders to MAD therapy had certain clinical phenotypic characteristics: lower age (95% CI: −4.55 to −1.62, p < 0.00001), female (95% CI: 0.56 to 0.91, p = 0.006), lower body mass index (95% CI: −2.80 to −1.11, p < 0.00001), smaller neck circumference (95% CI: −1.57 to −0.52, p < 0.00001), lower apnea-hypopnea index (95% CI: −7.23 to −1.89, p < 0.00001), a retracted maxilla and mandible, a narrower airway and a shorter soft palate than non-responders. The above-mentioned phenotypic responder characteristics provides useful information for the clinician when considering prescribing MAD therapy for OSA patients.

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).

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