Dentistry, Faculty of
DSpace
UBCV
Hamoda, Mona Mohamed Fathy
Doctor of Philosophy - PhD
University of British Columbia
Background Obstructive Sleep Apnea (OSA) is a highly prevalent chronic condition that requires lifelong treatment with multidisciplinary management. Continuous-Positive-Airway-Pressure (CPAP) is the first-line treatment and Mandibular-Advancement-Splint (MAS) is a leading alternative. This thesis focuses on these two main treatment modalities for OSA and the overall aim of this work is to address some of the knowledge gaps pertaining to these two treatments in adults. The objectives were to characterize the long-term side-effects of MAS and to assess the comparative effectiveness of CPAP and MAS. Objectives also included an assessment of the two forms of CPAP-MAS combination therapy; both treatments used interchangeably or simultaneously. Additionally, this work aimed to compare these two forms of combination to CPAP and MAS monotherapies. Methods This thesis consists of a literature review (chapter 2) and three clinical trials. Trials include a retrospective trial (chapter 3) assessing long term side-effects of MAS, a cross-over randomized trial (chapter 4) comparing the effectiveness of CPAP, MAS and one form of combination (the interchangeable use of CPAP-MAS). Chapter 5 includes a prospective trial comparing CPAP, MAS and the two forms of combination therapy in a subgroup of participants from the randomized cross-over trial. Results CPAP showed higher efficacy, as indicated by the respiratory event index, compared to MAS (p<0.0001) with mean CPAP-MAS difference (95% confidence interval) of 10.4(7.8-13). MAS showed higher adherence with mean±SD of 7.0±1.2 hours/night of use compared to 5.9±1.6 hours/night of CPAP use (p<0.0001). Both showed comparable effects on blood pressure and patient centered outcomes. The two forms of CPAP-MAS combination showed improved adherence relative to CPAP monotherapy in both trials. Long-term dental side-effects of MAS included significant (p<0.001) maxillary incisor retroclination (mean of ≈6˚) and mandibular incisor proclination (mean of ≈8˚) over a mean follow-up period of 12.6 years. Conclusions While CPAP was superior to MAS in efficacy, MAS was superior in adherence however, it was associated with long-term dental side-effects. The combination of both therapies showed increased adherence relative to CPAP monotherapy and provided comparable long-term effectiveness. Combination therapy could be considered as a viable option for the long-term management of OSA.
MANDIBUAR ADVANCEMENT SPLINTS, CONTINUOUS POSITIVE AIRWAY PRESSURE AND A COMBINATION OF BOTH FOR THE MANAGEMENT OF OBSTRUCTIVE SLEEP APNEA by Mona Mohamed Fathy Hamoda BDS, Alexandria University, 2000 MSc, Alexandria University, 2007 MHSc, The University of British Columbia, 2013 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Craniofacial Science) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) May 2022 © Mona Mohamed Fathy Hamoda, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Mandibular Advancement Splints, Continuous Positive Airway Pressure and a Combination of Both for the Management of Obstructive Sleep Apnea submitted by Mona Mohamed Fathy Hamoda in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Craniofacial Science Examining Committee: Dr. Fernanda Almeida, Associate Professor, Department of Oral Health Sciences, UBC Supervisor Dr. Edwin Yen, Professor, Department of Oral Health Sciences, UBC Supervisory Committee Member Dr. Jeremy Road, Professor, Department of Medicine, UBC University Examiner Dr. Bingshuang Zou, Associate Professor, Department of Oral Health Sciences, UBC University Examiner Additional Supervisory Committee Members: Dr. Benjamin Pliska, Associate Professor, Department of Oral Health Sciences, UBC Supervisory Committee Member Dr. Najib Ayas, Associate Professor, Department of Medicine, UBC Supervisory Committee Member iii Abstract Background Obstructive Sleep Apnea (OSA) is a highly prevalent chronic condition that requires lifelong treatment with multidisciplinary management. Continuous-Positive-Airway-Pressure (CPAP) is the first-line treatment and Mandibular-Advancement-Splint (MAS) is a leading alternative. This thesis focuses on these two main treatment modalities for OSA and the overall aim of this work is to address some of the knowledge gaps pertaining to these two treatments in adults. The objectives were to characterize the long-term side-effects of MAS and to assess the comparative effectiveness of CPAP and MAS. Objectives also included an assessment of the two forms of CPAP-MAS combination therapy; both treatments used interchangeably or simultaneously. Additionally, this work aimed to compare these two forms of combination to CPAP and MAS monotherapies. Methods This thesis consists of a literature review (chapter 2) and three clinical trials. Trials include a retrospective trial (chapter 3) assessing long term side-effects of MAS, a cross-over randomized trial (chapter 4) comparing the effectiveness of CPAP, MAS and one form of combination (the interchangeable use of CPAP-MAS). Chapter 5 includes a prospective trial comparing CPAP, MAS and the two forms of combination therapy in a subgroup of participants from the randomized cross-over trial. Results CPAP showed higher efficacy, as indicated by the respiratory event index, compared to MAS (p<0.0001) with mean CPAP-MAS difference (95% confidence interval) of 10.4(7.8-13). MAS showed higher adherence with mean±SD of 7.0±1.2 hours/night of use compared to 5.9±1.6 hours/night of CPAP use iv (p<0.0001). Both showed comparable effects on blood pressure and patient centered outcomes. The two forms of CPAP-MAS combination showed improved adherence relative to CPAP monotherapy in both trials. Long-term dental side-effects of MAS included significant (p<0.001) maxillary incisor retroclination (mean of ≈6˚) and mandibular incisor proclination (mean of ≈8˚) over a mean follow-up period of 12.6 years. Conclusions While CPAP was superior to MAS in efficacy, MAS was superior in adherence however, it was associated with long-term dental side-effects. The combination of both therapies showed increased adherence relative to CPAP monotherapy and provided comparable long-term effectiveness. Combination therapy could be considered as a viable option for the long-term management of OSA. v Lay Summary Obstructive sleep apnea (OSA) is a chronic condition that is on the rise in Canada and worldwide due to the obesity pandemic. It is characterized by pauses in breathing during sleep and may affect the quality of life. It is also linked to multiple complications, some of which may be serious and life-threatening. Continuous positive airway pressure (CPAP) is considered to be the primary treatment for OSA, and mandibular advancement splint (MAS) is the leading alternative treatment. We conducted clinical trials to compare the effectiveness of CPAP and MAS. We also explored the alternating use of both CPAP and MAS and their simultaneous use (combination therapy) and compared these combinations to CPAP and MAS used alone, within the same patients. Additionally, we better characterized the long-term side-effects of MAS. This work is a step towards providing a personalized treatment approach and an improved overall management of OSA. vi Preface This thesis is the result of my research work in the investigation of Mandibular Advancement Splints, Continuous Positive Airway Pressure and the combination of both therapies for the management of Obstructive Sleep Apnea (OSA). All inferences, opinions and conclusions represent those of the authors and do not reflect the opinions of the providers of any of the devices used in the clinical trials conducted in this thesis. This dissertation is an original and independent work by the author, Mona M.F. Hamoda and was divided into six chapters as follows: Chapter 1– Introduction. A summary of the current literature and concepts in Obstructive Sleep Apnea (OSA) that are pertinent to this thesis. This chapter is original, unpublished and independent work by the thesis author. Chapter 2– Oral Appliances for the Management of OSA. An Updated Review of the Literature. A version of chapter 2 has been published. “Hamoda, M. Kohzuka, Y. and Almeida, F. (2018) Oral Appliances for the Management of OSA. An Updated Review of the Literature. CHEST; 153(2):544-553”. I was involved in all steps of this work and wrote the manuscript. The sections on ‘Titration’ (section 2.5) and ‘Predictors of treatment response’ (section 2.6) were originally drafted by Kohzuka, Y. Almeida, F. was the supervisory author on this manuscript and was involved throughout the project in manuscript edits in addition to reviewing the final manuscript. This review article was published in 2018 and was specifically focused on oral appliances, unlike chapter 1 which was intended to be a comprehensive review of the current OSA literature related to all aspects of this thesis. vii Chapter 3– Long-Term Side Effects of Sleep Apnea Treatment with Oral Appliances: Nature, Magnitude and Predictors of Long-Term Changes. A version of chapter 3 has been published. “Hamoda, M. Almeida, F. and Pliska, B. (2019) Long-term side effects of sleep apnea treatment with oral appliances: nature, magnitude and predictors of long-term changes. Sleep Medicine; 56: 184-191”. Ethics approval for the study was obtained from the UBC Clinical Research Ethics Board (H11-01661). I was involved in all aspects of this study excluding data collection (due to the retrospective nature of the study) and including preparation of ethics amendments, data entry, data interpretation and writing of the manuscript. Pliska B. and Almeida, F were responsible for conceptualization of the idea and provided the raw data. Pliska, B. applied for ethics approval and conducted all the cephalometric tracings. Pliska, B. and Almeida, F. reviewed the data and manuscript. Chapter 4– Continuous Positive Airway Pressure, Mandibular Advancement Splints or Both: A Randomized Controlled Trial (CHOICE study). This trial was registered prospectively (ClinicalTrials.gov Identifier: NCT02242617) and approved by the UBC Clinical Research Ethics Board (H14-01215), by the Université de Montréal Research Ethics Board (14-125-CERES-D(2)) and by the Université Laval Research Ethics Board (2015-2434). This chapter is original, unpublished work that is currently under preparation for publication. I was involved in all aspects of this work since 2014 (following grant approval for funding) except for the financial aspects. I was involved in protocol modifications, ethics amendments and renewals, created data collection forms and procedure manuals, contributed to the development of the data capturing system (REDCap), coordinated and communicated with other study sites in addition to data collection, management of day-to-day aspects of the study and data entry at the UBC site. I also contributed to the analysis, interpretated the results and wrote the manuscript. viii Chapter 5– Continuous Positive Airway Pressure and Mandibular Advancement Splint Monotherapies Versus Combination Therapy: A Clinical Trial (DOT study). This trial was prospectively registered (ClinicalTrials.gov Identifier: NCT03435731) and obtained ethics approval from the UBC Clinical Research Ethics Board (H18-00175). This chapter is original, unpublished work that is currently under preparation for publication. It is a continuation from the previous work done in chapter 4. I was involved in all aspects of this study including study design, obtaining ethics approval/renewals, preparation of study forms, development of the data capturing system (REDCap) for this trial, data collection, data entry, data analysis and interpretation and writing of the manuscript. Chapter 6– Discussion, Summary, Overall limitations and Strengths, Clinical Implications, Future Directions and Conclusions. This chapter is original, unpublished and independent work by the thesis author ix Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ................................................................................................................................. v Preface ........................................................................................................................................... vi Table of Contents .......................................................................................................................... ix List of Figures ............................................................................................................................ xxii List of Abbreviations ................................................................................................................ xxiv List of Symbols .......................................................................................................................... xxvi Acknowledgements .................................................................................................................. xxvii Dedication .................................................................................................................................. xxix Chapter 1: Introduction ................................................................................................................ 1 1.1 Normal Sleep Architecture .............................................................................................. 1 1.2 Obstructive Sleep Apnea ................................................................................................. 1 1.2.1 Definition and Diagnosis of OSA ............................................................................ 1 1.2.2 Epidemiology and Risk factors for OSA ................................................................. 2 1.2.3 Sleep Apnea Evaluation Studies .............................................................................. 4 1.2.4 Pathophysiology of OSA ......................................................................................... 5 1.2.4.1 Upper Airway Anatomy and Collapsibility ......................................................... 6 1.2.4.2 Dilator Muscle Activity and Responsiveness ...................................................... 6 1.2.4.3 Arousal Threshold ............................................................................................... 7 1.2.4.4 Ventilatory Control Stability ............................................................................... 7 1.2.5 Consequences of Untreated OSA ............................................................................ 8 x 1.2.6 OSA Endotypes, Phenotypes and Clusters .............................................................. 9 1.2.7 Quality of Life Measures ....................................................................................... 10 1.2.7.1 General Health Measures .................................................................................. 11 1.2.7.2 Functional Outcomes ......................................................................................... 12 1.2.7.3 Daytime Sleepiness and Sleep Quality .............................................................. 13 1.2.7.4 Fatigue ............................................................................................................... 14 1.3 Obstructive Sleep Apnea Management ......................................................................... 15 1.3.1 Unimodal Approaches to Therapy ......................................................................... 15 1.3.1.1 Positive Airway Pressure (PAP) ........................................................................ 15 1.3.1.1.1 Types of PAP ............................................................................................... 15 1.3.1.1.2 Effects of PAP Treatment ............................................................................ 16 1.3.1.1.3 PAP Adherence Monitoring, Predictors and Methods to Augment It ......... 18 1.3.1.2 Oral Appliances ................................................................................................. 22 1.3.1.2.1 Influence of Design ..................................................................................... 22 1.3.1.3 Other Treatment Modalities Including Weight Loss, Positional Therapy, Pharmacological Agents and Surgical Intervention .......................................................... 24 1.3.2 Randomized Controlled Trials Comparing CPAP and MAS ................................ 28 1.3.3 Multimodal Approach to Therapy (Combination Therapy) in Obstructive Sleep Apnea Management ............................................................................................................... 29 1.3.4 Patient Centered Care Approach and Shared Decision Making ............................ 32 1.4 Current Knowledge Gaps, Research Goals and Research Outline ................................ 35 1.4.1 Current Knowledge Gaps and Research Goals ..................................................... 35 1.4.2 Research Outline ................................................................................................... 37 xi Chapter 2: Oral Appliances for the Management of OSA; an updated review of the literature ....................................................................................................................................... 39 2.1 Introduction ................................................................................................................... 39 2.2 Classification of OAs .................................................................................................... 40 2.3 Pathophysiologic Traits of OSA and Mechanism of Action of OAs ............................ 41 2.4 Types of OA and Indications for Use ............................................................................ 42 2.5 Titration ......................................................................................................................... 44 2.6 Predictors of Treatment Response ................................................................................. 46 2.7 Definition of Treatment Success ................................................................................... 47 2.8 Treatment Efficacy vs Effectiveness ............................................................................. 47 2.9 Comparative Effectiveness of CPAP and OAms ........................................................... 48 2.10 OAm Adherence ............................................................................................................. 48 2.11 Mean Disease Alleviation and Sleep Adjusted Residual AHI ...................................... 49 2.12 Determinants of OAm Adherence .................................................................................. 50 2.13 Combination Therapy .................................................................................................... 51 2.14 Side Effects of OAms ..................................................................................................... 52 2.15 Future Direction: Patient-Centered Medicine ............................................................... 53 2.16 Conclusions ................................................................................................................... 54 Chapter 3: Long-Term Side Effects of Sleep Apnea Treatment with Oral Appliances: Nature, Magnitude and Predictors of Long-Term Changes ................................................... 55 3.1 Introduction ................................................................................................................... 56 3.2 Materials and methods ................................................................................................... 57 3.2.1 Design .................................................................................................................... 57 xii 3.2.2 Cephalometric Analysis ......................................................................................... 58 3.2.3 Statistical Analysis ................................................................................................ 59 3.2.4 Method Error ......................................................................................................... 59 3.3 Results ........................................................................................................................... 60 3.3.1 Direction and Magnitude of Change ..................................................................... 62 3.3.1.1 Dental Variables ................................................................................................ 62 3.3.1.2 Skeletal Variables .............................................................................................. 63 3.3.2 Rate of Change ...................................................................................................... 64 3.3.3 Predictors of Change ............................................................................................. 65 3.4 Discussion ...................................................................................................................... 67 3.5 Conclusion ..................................................................................................................... 73 Chapter 4: Continuous Positive Airway Pressure, Mandibular Advancement Splints or Both: A Randomized Controlled Trial (CHOICE study) ........................................................ 74 4.1 Introduction ................................................................................................................... 75 4.2 Methods ......................................................................................................................... 77 4.2.1 Trial Design ........................................................................................................... 77 4.2.2 Study Sites and Patient Population ........................................................................ 77 4.2.3 Eligibility Criteria .................................................................................................. 77 4.2.4 Sample Size Calculation ........................................................................................ 78 4.2.5 Intervention ............................................................................................................ 78 4.2.6 Randomization and Sequence Generation ............................................................. 79 4.2.7 Allocation Concealment ........................................................................................ 79 4.2.8 Blinding ................................................................................................................. 79 xiii 4.2.9 Study Design and Data Collection Methods ......................................................... 80 4.2.10 Objective Measures ............................................................................................... 81 4.2.10.1 Respiratory Parameters .................................................................................. 81 4.2.10.2 Objective Adherence Calculation .................................................................. 82 4.2.10.3 Classification of Adherence During the Observation Period ........................ 82 4.2.10.4 Blood Pressure (BP) ...................................................................................... 82 4.2.10.5 Body Mass Index (BMI) ................................................................................ 83 4.2.11 Self-reported Measures .......................................................................................... 83 4.2.11.1 Total Sleep Time ........................................................................................... 83 4.2.11.2 Snoring Loudness .......................................................................................... 84 4.2.11.3 Preference Assessment .................................................................................. 84 4.2.11.4 Willingness to Pay Out of Pocket for Treatment ........................................... 85 4.2.11.5 Side-effects .................................................................................................... 85 4.2.12 Measures of Treatment Effectiveness ................................................................... 86 4.2.13 Relationship between Hours of Treatment Usage and Normalization of Symptoms in Highly Symptomatic Participants ...................................................................................... 86 4.2.14 Statistical Analysis ................................................................................................ 86 4.3 Results ........................................................................................................................... 88 4.3.1 Participants ............................................................................................................ 88 4.3.2 Numbers Screened, Trial Completion Rate and Drop-outs ................................... 91 4.3.3 Treatment Efficacy: ............................................................................................... 91 4.3.4 Adherence During 1-month on MAS, 1-month on CPAP, 1-month on Observation and 6-months on Observation ................................................................................................ 92 xiv 4.3.5 Total Sleep Time and Time Off-treatment ............................................................ 96 4.3.6 Treatment Usage Pattern During the Observation Phase ...................................... 97 4.3.7 Treatment Usage Pattern During the Observation Phase and Changes in Symptoms .............................................................................................................................. 98 4.3.8 Correlation Between Frequency and Duration of Treatment Use ....................... 100 4.3.9 Blood Pressure: .................................................................................................... 100 4.3.9.1 Mean SBP (Total Study Population) ............................................................... 100 4.3.9.2 Mean DBP (Total Study Population) .............................................................. 100 4.3.9.3 BP Analysis (for the Subset of the Study Population with elevated BP at Baseline).. ........................................................................................................................ 101 4.3.10 BMI ...................................................................................................................... 102 4.3.11 QoL Questionnaires ............................................................................................. 102 4.3.11.1 ESS Scores (Total Study Population) .......................................................... 102 4.3.11.2 ESS Scores (for the Subset of the Study Population who were Highly Symptomatic at Baseline) ................................................................................................ 102 4.3.11.3 FOSQ-10, CFQ and MCS Scores of SF-36 ................................................. 103 4.3.11.4 PCS Scores of SF-36 ................................................................................... 103 4.3.11.5 Snoring Loudness ........................................................................................ 105 4.3.12 Percentage of Symptomatic Participants at the End of 1-month CPAP, 1-month MAS and 6-months Observation from the Total Study Population .................................... 105 4.3.13 Percentages of Highly Symptomatic Participants at Baseline Who Were Able to Achieve Normal Scores with Treatment ............................................................................. 105 4.3.14 Preference ............................................................................................................ 106 xv 4.3.15 Willingness to Pay Out of Pocket for Treatment ................................................. 106 4.3.16 Measures of Treatment Effectiveness ................................................................. 109 4.3.17 Relation Between Adherence to Treatment and Symptoms at Baseline ............. 109 4.3.18 Correlation Between Treatment Usage and Changes in Questionnaire Scores ... 110 4.3.19 Effect of Study Centre, Sequence of Treatment and Time on Treatment on the Efficacy, Adherence, Blood-pressure and Questionnaire Scores During the Cross-over Phase…… ............................................................................................................................ 111 4.3.20 Side-effects .......................................................................................................... 112 4.3.20.1 CPAP ........................................................................................................... 112 4.3.20.2 MAS ............................................................................................................ 112 4.4 Discussion .................................................................................................................... 112 4.4.1 Efficacy ................................................................................................................ 113 4.4.2 Adherence ............................................................................................................ 114 4.4.2.1 Adherence During the Different Trial Timepoints .......................................... 114 4.4.2.2 Correlation Between Frequency and Duration of Treatment Usage ............... 114 4.4.2.3 Treatment Usage Pattern During the Observation Phase ................................ 115 4.4.3 Effect of Treatment on Patient-Centered Outcomes ............................................ 117 4.4.3.1 Effect on the Magnitude of Symptoms ............................................................ 117 4.4.3.2 Percentages of Highly Symptomatic Participants at Baseline Who Were Able to Achieve Normal Scores with Treatment ......................................................................... 118 4.4.4 Treatment Usage Patterns in Participants Who Were Highly Symptomatic at Baseline……. ...................................................................................................................... 119 4.4.5 Correlation Between Treatment Usage and Changes in Questionnaire Scores ... 120 xvi 4.4.6 Symptom Improvement Based on Adherence During the Observation Period ... 120 4.4.7 Patient Preferences and the Decision Aid Tool ................................................... 121 4.4.8 Measures of Effectiveness ................................................................................... 122 4.4.9 Effect of Treatment on Blood Pressure ............................................................... 124 4.4.10 MAS and CPAP Side-effects ............................................................................... 125 4.4.11 Choices and Shared Decision Making ................................................................. 127 4.4.12 Disadvantages of Combination Therapy ............................................................. 129 4.4.13 Study Limitations and Strength ........................................................................... 129 4.5 Conclusions ................................................................................................................. 131 Chapter 5: Continuous Positive Airway Pressure and Mandibular Advancement Splint Monotherapies Versus Combination Therapy: A Clinical Trial (DOT study) .................... 133 5.1 Introduction ................................................................................................................. 134 5.2 Materials and Methods ................................................................................................ 135 5.2.1 Study Design and Setting .................................................................................... 135 5.2.2 Participants .......................................................................................................... 136 5.2.3 Eligibility Criteria ................................................................................................ 136 5.2.4 Interventions ........................................................................................................ 136 5.2.5 Procedures ........................................................................................................... 137 5.2.6 Objective Measures ............................................................................................. 138 5.2.6.1 CPAP Pressure Requirements ......................................................................... 138 5.2.6.2 Portable Monitoring and Body Mass Index (BMI) ......................................... 138 5.2.6.3 Adherence Calculation .................................................................................... 138 5.2.6.4 Blood Pressure (BP) ........................................................................................ 139 xvii 5.2.7 Self-reported Measures ........................................................................................ 139 5.2.8 Sample Size ......................................................................................................... 140 5.2.9 Randomization ..................................................................................................... 140 5.2.9.1 Sequence Generation ....................................................................................... 140 5.2.9.2 Allocation Concealment .................................................................................. 140 5.2.10 Blinding ............................................................................................................... 140 5.2.11 Statistical Analysis .............................................................................................. 141 5.3 Results ......................................................................................................................... 141 5.3.1 Participants .......................................................................................................... 141 5.3.2 Outcomes ............................................................................................................. 143 5.3.2.1 Objective Outcomes ........................................................................................ 143 5.3.2.1.1 Effect of Dual-Therapy on Therapeutic CPAP Pressure Requirements, Mask Air Leaks and Machine Estimated Apnea-Hypopnea Index ............................. 143 5.3.2.1.1 Oxygen Desaturation Index (ODI) 3% and BMI ...................................... 145 5.3.2.1.2 Adherence During 1-month on CPAP, MAS, Alternating Therapy and Dual Therapy…. ................................................................................................................... 147 5.3.2.1.3 Blood Pressure ........................................................................................... 149 5.3.2.2 Self-reported Outcomes ................................................................................... 149 5.3.2.2.1 ESS Scores ................................................................................................. 149 5.3.2.2.2 FOSQ-10 Scores ........................................................................................ 150 5.3.2.2.3 Participants’ Perceptions with MAS-monotherapy, CPAP-monotherapy and Dual Therapy ............................................................................................................... 151 5.3.2.2.4 Side-effects with Dual Therapy ................................................................. 153 xviii 5.3.2.2.5 Comparison Between Individuals Who Participated and Those Who Did Not Participate in Phase IV ......................................................................................... 153 5.4 Discussion .................................................................................................................... 153 5.5 Conclusions ................................................................................................................. 159 Chapter 6: Discussion, Summary, Overall limitations and Strengths, Clinical Implications, Future Directions and Conclusions .......................................................................................... 160 6.1 Discussion .................................................................................................................... 160 6.1.1 Beyond the AHI ................................................................................................... 160 6.1.2 Patient Centered Care Approach and Shared Decision-making .......................... 161 6.1.3 Comparison of CPAP and MAS: ......................................................................... 162 6.1.4 Comparison of CPAP Adherence Between Studies ............................................ 164 6.1.5 Combination Therapy .......................................................................................... 166 6.1.6 Burden of Treatment: Chronic Illness Comes with Chronic Patient Workload .. 170 6.1.7 Treatment side-effects ......................................................................................... 172 6.1.8 CPAP, MAS or a Combination of Both? ............................................................. 173 6.1.9 When is Monotherapy Sufficient? ....................................................................... 174 6.1.10 Who May Benefit from Combination Therapy? ................................................. 174 6.2 Summary of the Work Done and of the Main Findings .............................................. 178 6.3 Clinical implications of our findings ........................................................................... 181 6.4 Overall Limitations and Strengths ............................................................................... 182 6.4.1 Limitations ........................................................................................................... 182 6.4.2 Strengths .............................................................................................................. 184 6.5 Future Directions ......................................................................................................... 184 xix 6.6 Conclusions ................................................................................................................. 185 Bibliography ............................................................................................................................... 187 Appendix A ................................................................................................................................. 240 A.1 Supplemental Figure 4.1. A custom-made Mandibular Advancement Splint (SomnoDent®) with Dentitrac® adherence monitor, fabricated for one of the trial participants .......................................................................................................................... 240 A.2 Supplemental Figure 4.2. Study Protocol ................................................................ 241 A.3 Supplemental Figure 4.3. Disclosure Letter ............................................................ 242 A.4 Supplemental Figure 4.4. Snoring Scores at the Different Timepoints ................... 244 A.5 Supplemental Figure 4.5. A) Willingness to Pay Out of Pocket for CPAP and MAS B) Self-reported Total Yearly Household Income .............................................................. 245 A.6 Supplemental Table 4.1. Hours of Treatment Usage Per Night for Participants with Values Above or Below the Threshold Defining Normalcy at Baseline for ESS, FOSQ-10, CFQ and SF-36 (MCS) ........................................................................................................ 246 Appendix B ............................................................................................................................. 247 B.1 Supplemental Figure 5.1: Time Points for Assessment of Eligibility and For Data Collection ............................................................................................................................ 247 xx List of Tables Table 3.1 Baseline Patient Characteristics .................................................................................... 60 Table 3.2 Overall Cephalometric Changes During Treatment (n=62) .......................................... 62 Table 3.3 Rate of Change Per Year for Variables That Showed a Statistically Significant Change Between Final and Initial Measurements ...................................................................................... 65 Table 3.4 Adjusted Models for the Effect of BMI and ANB Angle on Upper and Lower Incisor Inclination. ..................................................................................................................................... 67 Table 4.1 Baseline Characteristics for the Study Population ........................................................ 89 Table 4.2 Efficacy of CPAP and MAS as Indicated by HSAT ..................................................... 92 Table 4.3 (A) Intention to Treat Analysis for Objectively Measured Adherence During the Cross-over Phase of the Trial (n=73). (B) Per Protocol Analysis for Objectively Measured Adherence at the Different Time Points .............................................................................................................. 95 Table 4.4 Treatment Adherence and Effectiveness Measures ....................................................... 96 Table 4.5 ESS, FOSQ, CFQ and SF-36 questionnaires for the Total Trial Population and for the Subset of Participants Who Were Highly Symptomatic at Baseline ........................................... 104 Table 4.6 Preferred Treatment at the End of The Trial and How It Compares to the Preferred Treatment at Baseline .................................................................................................................. 108 Table 4.7 Treatment Predominantly Used During the 6-months Observation Period and How It Compares to Pre-treatment Preference. ....................................................................................... 108 Table 5.1 Baseline Characteristics for The Thirteen Participants Included in The Trial (phase IV) ..................................................................................................................................................... 143 xxi Table 5.2 Treatment Outcomes Divided by The Trial Timepoints: CPAP-monotherapy, MAS-monotherapy, Alternating and Dual therapy ............................................................................... 146 Table 5.3 Characteristics of Participants Based on Their Willingness to Continue to Use Dual Therapy Long Term ..................................................................................................................... 152 xxii List of Figures Figure 2.1 Examples of Commercially Available Oral Appliances .............................................. 43 Figure 2.2 Flow Chart Showing Oral Appliance Decision-making and Management Process for OSA Patients ................................................................................................................................. 45 Figure 3.1 The Following Landmarks and Planes Were Identified on Lateral Cephalograms ..... 61 Figure 3.2 Individual Variations in the Mean Change of U1SN (A) and L1MP (B) .................... 63 Figure 3.3 Tracing of One of the Study Patient's Initial (T0) and Final (TF) Lateral Cephalograms Showing the Lower Incisor Proclination and Upper Incisor Retroclination. ........ 64 Figure 3.4 All Data Points for the Entire Study Population for U1SN (A) and L1MP (B) in Degrees, As A Function of Number of Years in Treatment. Data for Each Patient Are Connected by a Line ........................................................................................................................................ 66 Figure 4.1 Study Flow Chart ......................................................................................................... 90 Figure 4.2 Adherence Pattern at the Different Timepoints ........................................................... 94 Figure 4.3 All Participant’s individual Objective Adherence Data for 6-months Observation (Following the Cross-over Phase) ................................................................................................. 97 Figure 4.4 Change in Questionnaire Scores by Adherence Group During the 6-months Observation Period ........................................................................................................................ 99 Figure 4.5 Mean Blood Pressure at the Different Timepoints ..................................................... 101 Figure 4.6 Attributes of Treatment Considered by the Participants to be of Lesser Importance 107 Figure 4.7 Mean Disease Alleviation (MDA) and Sleep Adjusted Residual Apnea Index (SARAH Index) ........................................................................................................................... 109 xxiii Figure 4.8 Correlation Between Treatment Usage and Changes in Questionnaire Scores and Correlation Between Different Measures of Adherence ............................................................. 111 Figure 5.1 Study flow-chart of the four phases of the trial ......................................................... 142 Figure 5.2 CPAP Pressure Requirements For (A) Total Sample, (B) Pressure ≥ 10cmH2O with CPAP-monotherapy, (C) Pressure <10cmH2O with CPAP-monotherapy ................................. 144 Figure 5.3 Mean Objectively Measured Adherence: Number of Hours Per Night (When Used) During Each of The Trial Phases ................................................................................................. 148 Figure 5.4 ESS and FOSQ-10 Scores for The Total Sample (A and C Respectively) and for Participants Who Are Highly Symptomatic at Baseline, (B) Baseline ESS ≥10 and (D) Baseline FOSQ-10 <17.9 ........................................................................................................................... 150 Figure 6.1 A Simplistic Representation of the Decision-making Scheme .................................. 177 xxiv List of Abbreviations ANB A-point, Nasion, B-point APAP auto-adjusting PAP AHI apnea-hypopnea index BMI body mass index BPAP bilevel PAP CFQ Chalder Fatigue Questionnaire CPAP continuous positive airway pressure DBP diastolic blood pressure DOT Dual OSA Therapy ECG electrocardiogram EEG electroencephalogram EMG electromyogram EOG electrooculogram ESS Epworth Sleepiness Scale FOSQ-10 functional outcomes of sleep questionnaire h/night hours per night HSAT home sleep apnea testing IQR interquartile range ITT intention to treat MAS mandibular advancement splint MCID minimal clinically important difference MCS mental component summary MDA mean disease alleviation NM nasal mask NREM non-rapid eye movement OAm oral appliances that reposition the mandible forward Obs observation ODI 3% oxygen desaturation index with a 3 % drop in blood oxygen levels ONM oro-nasal mask OSA obstructive sleep apnea PAP positive airway pressure xxv PCS physical component summary PSG polysomnography PSQI Pittsburgh Sleep Quality Index PtDA patient Decision Aid QoL quality of life RCT randomized control trial REDCap Research Electronic Data Capture REI respiratory event index REM rapid eye movement RICCADSA randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnea RT respiratory therapist SAQLI sleep Apnea Quality of Life Index SARAH sleep adjusted residual AHI SAVE Sleep Apnea Cardiovascular Endpoints SBP systolic blood pressure SD standard deviation SF-36 Medical Outcomes Study Short-Form Health Survey SNA Sella, Nasion, point A SNB Sella, Nasion, point B TRT total recording time TSD Tongue Stabilizing Device TST total sleep time UBC University of British Columbia VAS visual analogue scale vs versus xxvi List of Symbols a alpha ≈ approximately ˚ degrees Δ difference xxvii Acknowledgements I would first and foremost like to thank my mother and father. Throughout my life they have gone above and beyond what any parents can do for their children and have supported me in every possible way during this journey. I owe all my successes to them. I am so grateful to have a kind, caring and understanding husband by my side. I would have not been able to do this without his continuous support. I owe a special thanks to my children for their patience, for bearing with me and for their endless sacrifices during this journey. I am privileged to have Dr. Fernanda Almeida as my supervisor, and I would like to thank her for giving me the opportunity to be part of this project. I am grateful to her for the continuous encouragement and guidance, she has been a great mentor to me. I would also like to sincerely thank my committee members, Dr. Edwin Yen, Dr. Benjamin Pliska and Dr. Najib Ayas for providing me with support and guidance throughout these years. I would like to thank Dr. Ismail Laher for being part of the comprehensive examination committee. I would also like to thank Sandy Harrison, Mary Wong, Dr. Nelly Huynh, Pierre Rompre and all collaborators and team members who made data collection possible at their study centers. The success of these projects was made possible due to the hard work of many people to whom I owe a special thanks. I would like to extend my gratitude to the Canadian Institution of Health Research for providing funding that made a big part of this work possible. The CHOICE trial was supported by a Canadian Institute of Health Research (CIHR) grant. MOP-136987, ISU-157533. xxviii I offer my gratitude to the faculty, staff, my fellow students at UBC and to the patients who were part of these studies. I would also like to thank my brother, sister-in-law, nephews, niece and my entire family for their love and support. xxix Dedication To my parents who instilled in me the love of learning and research, to my caring husband and to my beloved children, Omar, Yousef and Maryam, the blessing of my life. 1 Chapter 1: Introduction Sleep is a universal need for all humans, it is an essential part of human life and an average person spends a third of their lifetime sleeping. Furthermore, this one third of the life span directly affects the other two thirds. Sleep is considered to be a complex physiological process that is essential for many vital functions including cognition, performance, vigilance, psychological state, brain waste clearance, modulation of the immune responses and growth1. 1.1 Normal Sleep Architecture The duration of sleep in adults is usually 6 to 9 hours, with most sleeping 7.5 hours on average2. Sleep is a cyclic process that alternates between rapid eye movement (REM) and non-REM (NREM) phases. NREM consists of stages N1, N2 and N3 (with N3 being the deepest) and precedes REM at the onset of sleep and thereafter. REM sleep as a percentage of total sleep time is 20-25%. There are usually 4 to 6 cycles of NREM-REM per night with the duration of REM sleep increasing in each cycle as the night progresses and is longest in the last third of the sleep episode. The average length of the first NREM-REM sleep cycle is about 70 to 100 minutes and the average length of the second and later cycles is about 90 to 120 minutes3. 1.2 Obstructive Sleep Apnea 1.2.1 Definition and Diagnosis of OSA Sleep-related breathing disorders encompasses a range of disorders that fall under it and according to the third edition of the International Classification of Sleep Disorders (ICSD-3)4, obstructive sleep apnea (OSA) is one of four conditions within the sleep-related breathing disorders. In addition to OSA, sleep-related breathing disorders also includes central sleep apnea syndromes, sleep-related hypoventilation disorders and sleep-related hypoxemia disorder. OSA is a common type of sleep-related 2 breathing disorders and is characterized by recurrent episodes of partial (hypopneas) or complete (apneas) obstruction of the upper airway during sleep. Disease severity is classified according to the apnea-hypopnea index (AHI). An AHI > 5 and < 15 is considered mild OSA, 15 to 30 is moderate, and > 30 is severe OSA5. Polysomnography (PSG) is an essential tool for the diagnosis of a variety of sleep disorders and is the gold standard for the diagnosis of OSA6,7. The AHI is obtained from an overnight PSG and is the key measurement used to assess the presence and severity of OSA. The updated 2012 American Academy of Sleep Medicine (AASM) scoring criteria determined an apnea to be a drop in the peak flow signal excursion by ≥ 90% for ≥ 10 seconds from pre-event baseline. A hypopnea is determined to be a ≥ 30% drop in peak flow signal excursions for ≥ 10 seconds with either a ≥ 3% oxygen desaturation from pre-event baseline, or the event is associated with an arousal8. The International Classification of Sleep Disorders defines OSA as (1) ≥5 events/hour in addition to the presence of symptoms or certain comorbidities or (2) ≥15 events/hour in asymptomatic patients4. Symptoms of OSA include excessive daytime sleepiness, fatigue, morning headaches and snoring, witnessed apneas, choking, nocturnal enuresis and frequent awakenings during sleep9,10. 1.2.2 Epidemiology and Risk factors for OSA A recent global estimate of the prevalence of OSA suggests that close to 1 billion adults worldwide aged 30–69 years could have OSA and 425 million of them may have moderate to severe OSA11. Similarly, a large population-based study showed that the prevalence of moderate to severe OSA was 50% in males and 23% in females aged 40 to 85 years of European decent12. Prevalence has been found to be greater in certain patient populations such as the elderly, obese and hypertensive patients in addition to patients with coronary disease13. Obesity, male sex and increased age are the three main risk factors for OSA14. 3 Obesity: Obesity is considered to be one of the strongest risk factors for OSA15. Findings of Peppard et al16 indicate that prevalence rates have risen substantially in middle-aged adults in recent decades. This increasing prevalence has been linked to the increasing obesity rates. Young et al17 have demonstrated that a one standard deviation increase in body mass index (BMI) was associated with a fourfold increased risk of OSA. Multiple mechanisms have been hypothesized to explain the association between obesity and OSA. Local fat deposition could impair the neuromuscular control of upper airway patency and increase mechanical load which increase upper airway collapsibility and airflow obstruction. Excessive fat deposition can also contribute to breathing events via reduced lung volume, increased effort during breathing and greater whole-body metabolic demand15. Male Sex: OSA is more prevalent in males than in females and the male to female ratio is estimated to be approximately 2:118. Possible mechanisms underlying the differences in the pathogenesis of OSA in men and women include differences in upper airway dilator muscle activity, which appears to be increased in females, making upper airway closure less likely to occur during sleep19. Differences in soft tissue and fat distribution have also been hypothesized to contribute to the difference in prevalence. Men tend to have predominantly upper body fat whereas women have lower body fat, and upper airway soft tissue structures tend to be larger in men than in women19. A longer airway is more vulnerable to collapse, and pharyngeal airway length has been shown to be greater in men relative to in women20. It has also been hypothesized that differences in the chemical control of breathing between males and females (possibly mediated by sex hormones) may also play a role21. Prevalence is low in premenopausal women relative to in postmenopausal women. The difference in prevalence of OSA between men and women seems to diminish with older age, as it becomes closer to that of men12,16. Age: A linear relationship exists between age and the prevalence of OSA, with prevalence increasing with increasing age16. Different mechanisms have been proposed to explain the relationship between age and OSA including a reduction in muscle tone and deterioration in reflex with aging, in addition to 4 differential fat deposition surrounding the pharynx that is independent of systemic fat14. However, the effect of age has shown to plateau at the age of ≥ 6522. Other important predisposing risk factors for OSA include craniofacial morphology, genetics/family history of OSA, ethnicity, smoking and alcohol consumption22,23. 1.2.3 Sleep Apnea Evaluation Studies Sleep studies have been categorized as Type I, Type II, Type III and Type IV24. Type I is an in hospital attended PSG while Types II to IV are unattended studies. Type I standard polysomnography measures a minimal of 7 parameters; electroencephalogram (EEG), electrooculogram (EOG), chin electromyogram (EMG), electrocardiogram (ECG), airflow, respiratory effort and oxygen saturation. Type II studies use the same sensors as Type I but are unattended and are performed outside of the sleep laboratory. Type III studies use devices that measure 4 or more parameters that include two respiratory variables (respiratory movement and airflow), oxygen saturation, and a cardiac variable (heart rate or ECG). They do not record EEG, EOG or chin electromyogram (EMG) and, therefore, do not allow for determination of wakefulness and the stages of sleep. Type IV studies measure only 1 or 2 parameters, and these are typically oxygen saturation and heart rate or airflow24,25. Portable monitoring devices or home sleep apnea testing (HSAT) has emerged as an alternative diagnostic tool in some situations as it is of high diagnostic accuracy in suspected OSA patients who have a moderate to high pre-test probability5,6,26. The limitations of HSAT include lack of sleep staging, of leg movements tracking and of body position tracking (in some devices)25. HSAT tend to underestimate the severity of OSA for 2 main reasons. Firstly, since HSAT does not record sleep, the respiratory event rate is calculated using a denominator of the total recording time and not the total sleep time, which could be equal to or less than the total recording time25,27. Secondly, HSAT do not detect hypopneas due to arousals from sleep, as there is no EEG25. However, level III studies are useful for 5 confirmation of treatment efficacy25. While AHI quantifies the OSA severity obtained from a PSG and represents the number of apneas and hypopneas per hour of total sleep time, the respiratory event index (REI) represents the number of apneas and hypopneas per hour of total recording time on portable monitoring devices25. For HSAT, manual scoring of home sleep test recordings has shown to be superior to the automated scoring, as it can decrease the misclassification of OSA severity based on REI28. The oxygen desaturation index (ODI) however was not different between manual and automated scoring28. Another important objective measure of OSA severity is the ODI. The ODI represents the average number of desaturation episodes per hour of sleep (or hour of recording) and is typically reported as ODI 3% or ODI 4%29. It is obtained from the pulse oximetry sensor present in all types of sleep studies (Levels I to IV) hence, it is available in both PSG and HSAT25. The ODI obtained from HSAT is underestimated relative to that obtained from PSG since total recording time and not total sleep time is used as the denominator27. ODI is also considered an important respiratory parameter and ODI 4% has shown to be superior to AHI in predicting prevalent hypertension30. A potential advantage of ODI over AHI is that it is highly reproducible29,30 if recorded and analyzed using the same device and software29. Furthermore, ODI has been shown to have a strong correlation with REI (R2 = 0.99) in HSAT31. 1.2.4 Pathophysiology of OSA OSA is considered to be a heterogeneous disorder both in terms of its pathophysiology (endotype) and clinical presentation (phenotype)32. The pathophysiological causes of OSA demonstrate individual variability nevertheless, there are four main mechanisms that contribute to the pathophysiology of OSA14,32,33. Currently, identification of these endotypes has been feasible only in highly specialized research labs and has not yet translated into clinical practice32. 6 1.2.4.1 Upper Airway Anatomy and Collapsibility Some degree of anatomical compromise leading to upper airway collapsibility is considered a prerequisite for OSA34 and the most common site for collapse within the upper airway has shown to be the velopharynx (between the hard and soft palate)35. A narrow airway is more susceptible to collapse14, the upper airway is surrounded by both soft tissues (pharyngeal muscles, tongue, soft palate, tonsils and parapharyngeal fat pads) and bony structures (maxilla, mandible and hyoid bone) with the mandible and hyoid bone being the main bony structures that determine the airway size35. The interaction between the volume of soft tissue and the size of the bony compartment determine the magnitude of the extraluminal tissue pressure. A soft tissue excess (as in the case of obesity) and/or a restriction in the size of the bony compartment (as in the case of retrognathia) can increase the extraluminal tissue pressure, which can decrease the caliber of the upper airway36. Edema surrounding the upper airway associated with rostral fluid shift will have a similar effect in terms of collapsibility of the upper airway37. 1.2.4.2 Dilator Muscle Activity and Responsiveness Approximately 69% of the patients have one or more nonanatomical pathophysiologic traits in addition to the anatomical traits. These nonanatomical traits play an important role in the pathogenesis of OSA particularly in non-obese patients33. The non-anatomical traits include: (1) pharyngeal dilator muscle responsiveness (2) respiratory arousal threshold and (3) stability of ventilatory control system33. In response to increased ventilatory drive, additional ventilation can be achieved by recruitment of the pharyngeal muscles which depends on the pharyngeal dilator muscle responsiveness. In OSA patients, this responsiveness is diminished during sleep14 and especially during REM sleep2. Eckert 7 et al33 have demonstrated that more than a third of the patients with OSA have minimal muscle responsiveness to negative airway pressure during sleep. 1.2.4.3 Arousal Threshold Arousal from sleep typically occurs at the termination of an apnea or hypopnea and takes place when the increasing negative intra-thoracic pressure reaches the arousal threshold34,38. A low arousal threshold indicates that very little stimuli is required to trigger an arousal. Nearly 30 to 50% of patients with OSA have these cortical arousals in response to small changes in intrathoracic pressure33. While initially a low arousal threshold was thought to be a protective mechanism14, more recent research has shown that some patients with OSA may be able to maintain a patent airway during sleep if they are able to remain asleep for a sufficient duration to recruit the upper airway muscles33. 1.2.4.4 Ventilatory Control Stability Loop gain is an engineering term used to describe sensitivity of the ventilatory control system (sensitivity of a negative feedback loop) and the term is used to quantify the ventilatory response/ventilatory disturbance ratio. A high loop gain represents an overreaction of the ventilatory response to a respiratory stimulus while a low loop gain represents a dampened ventilatory response to an equivalent respiratory stimulus. A high loop gain system is unstable in comparison to a low loop gain system and approximately 36% of patients with OSA are considered to have a high loop gain14,33,34. 8 1.2.5 Consequences of Untreated OSA The repetitive airflow obstruction in OSA leads to intermittent cyclic hypoxemia and hypercapnia, increased sympathetic activity and sleep fragmentation that affect daytime functioning and the quality of life. OSA is associated with increased daytime sleepiness, fatigue, cognitive decline, psychological and neurocognitive impairment, depression, reduced work productivity, occupational injury, increased risk of motor vehicle accidents, in addition to long-term metabolic and cardiovascular consequences and premature death22,39,40. Cognitive impairment is highly prevalent in patients with OSA and (moderate and severe) OSA is considered an independent risk factor for cognitive impairment. Patients with mild cognitive impairment are at a greater risk of progressing to dementia which in turn has many consequences on the patients, their caregivers and the healthcare system41. Evidence supports a causal relationship between OSA and systemic hypertension. Repetitive apneas and oxygen desaturations have been implicated in the development of elevated blood pressure21. Furthermore, OSA is considered an independent risk factor for cardiovascular disease (CVD) and a significant relationship has been found between the presence of OSA, its severity and CVD21. A number of mechanisms explaining the role of OSA in the development of CVD have been suggested including sustained activation of the sympathetic nervous system, systemic inflammation, insulin resistance, endothelial dysfunction and blood hypercoagulability42. All of the aforementioned consequences of untreated OSA lead to increased financial cost and utilization of the healthcare system39,43 and do not only affect the individual but rather, the effect extends to the family members and beyond. An American Academy of Sleep Medicine report considered the cost of diagnosing and treating OSA to be approximately 12.4 billion dollars in the United States in 2015. Furthermore, the estimated cost burden of undiagnosed OSA among U.S. adults was $149.6 9 billion during the same year and hence it was predicted that 100.1 billion dollars could have been saved if every patient with OSA were to be diagnosed and treated44. 1.2.6 OSA Endotypes, Phenotypes and Clusters Edwards et al32 have demonstrated some evidence linking endotype to phenotype. For example, those who have a low arousal threshold (endotype) have been shown to have hypertension (phenotype) less frequently than those with a normal arousal threshold. They also hypothesized that there may be a bidirectional relationship between endotype and phenotype with phenotype being the one driving the endotype32. As previously mentioned, OSA is a heterogenous condition both in terms of its pathophysiology (endotype), clinical presentation (phenotype), risk factors, comorbidities and treatment response32,45. The most commonly described phenotypes are the excessively sleepy, the minimally symptomatic and those with insomnia46. This heterogeneity has led researchers to recognize patterns and develop clusters that group together individuals who share similar phenotypic characteristics, creating more homogenous subtypes of the disorder47,48. The development of clusters has been done in an attempt to better understand the effect of treatment on the different subtypes, to better target specific therapies towards the correct subtypes and to further our understanding of the potential consequences and risks associated with certain subtypes45,47,49–51. The seminal work conducted on the Icelandic Sleep Apnea Cohort47 has identified 3 main clusters, the “Excessively sleepy” cluster (prevalence = 42%), the “Minimally symptomatic (prevalence =25%) and the “Disturbed sleep” cluster (prevalence= 33%). While Ye et al47 and others49 focused on symptoms and comorbidities to identify their clusters, other work has focused on polysomnographic characteristics such as association of events with hypoxemia versus arousals, metrics of degree of flow reduction and 10 sleep fragmentation in identifying clusters48,52. Furthermore, other groups evaluated multiple variables including symptoms, polysomnography, comorbidities and anthropometric data53. Zinchuk and Yaggi46 in 2020 reviewed the main work done on the clusters prior to that date and based on the collective findings of the reviewed studies they were able to identify 4 main subtypes with common themes: (1) Subtype A– includes younger, obese, predominantly male individuals with severe OSA and “classic” symptoms; (2) Subtype B– older, obese, predominantly male individuals with minimal to moderate symptoms, frequent comorbidities, and severe OSA with marked hypoxemic burden; (3) Subtype C– middle-aged, mildly obese, predominantly female individuals with symptoms of insomnia and; (4) Subtype D– younger nonobese, predominantly male individuals with primarily upper airway symptoms. Despite the development of these clusters, this has not yet translated to clinical or treatment changes46. 1.2.7 Quality of Life Measures Quality of life (QoL) in the medical literature is a term commonly used to imply health-related quality of life54. It describes the overall state of well-being that individuals experience, and is used to assess the effect of disease, trauma or treatment54,55. While there is no single definition of health related quality of life and no gold standard for its measurement, it is generally agreed upon to include physical, social, emotional or mental function, burden of symptoms and sense of well-being54,55. It has been shown that at least some QoL domains are almost always affected in patients experiencing chronic sleep disturbance55. Additionally, it has been shown that there is limited correlation between the impairment of quality of life and the severity of OSA, which reinforces the need for direct measurement of QoL status in OSA56,57. There are both generic and disease specific measures of QoL54,55. Generic measures are useful for cross-disease and cross-population comparisons and give a sense of the individual’s general well-being 11 however, they tend to lack sensitivity to the impact of a specific disease or treatment54,55. To overcome the lack of sensitivity, it has been suggested to use a generic QoL measure in addition to a disease specific one55 to be able to fully understand the impact of the disease and treatment on the individual patient. 1.2.7.1 General Health Measures The Medical Outcomes Study Short-Form Health survey (SF-36)58 is a self-administered general health survey that is the most widely used generic QoL measurement tool in a variety of health disciplines54,59. It is used to assess an individual’s general perception of his or her overall health and well-being, evaluates the burden of disease and the benefits of treatment. It consists of 36 questions divided into 8 domains that assess general physical, mental and emotional aspects. It provides two summary scales, the physical component summary (PCS) and the mental component summary (MCS)59,60. Scores range from 0 to 100, with higher scores indicating better quality of life. SF-36 has shown to be a valid and reliable tool with a Cronbach alpha of >0.85 for all dimensions except social functioning (Cronbach alpha= 0.73)60,61. An advantage of the SF-36 is that it is widely used in the OSA literature60 and some sub analyses can be done for cost-effectiveness studies. A change of 3 points on both the MCS and PCS scores has been considered as the clinically significant threshold in OSA25. This minimal clinically important difference (MCID) is a term used in the medical literature to represent the smallest change in an outcome variable that is necessary to provide a noticeable improvement or worsening in disease outcome62,63. Other generic QoL measures include SF-12 (a shortened form of SF-36)64, the Nottingham Health Profile65 , the World Health Organization Quality of Life measure66 and the Sickness Impact Profile67, the latter being the longest of the commonly used generic measures55. 12 1.2.7.2 Functional Outcomes Disease specific QoL measures have been developed for sleep disorders. There are 2 commonly used ones, the Functional Outcomes of Sleep Questionnaire and the Calgary Sleep Apnea Quality of Life Index. The Quebec Sleep Questionnaire being68 too long is infrequently used and hard to compare to other studies. Functional Outcomes of Sleep Questionnaire (FOSQ): FOSQ is a self-reported functional measure designed to detect the impact of disorders that involve excessive sleepiness on physical, mental and social functioning in everyday activities. It was originally developed as a 30-item questionnaire and a shorter version consisting of 10-items was latter developed (FOSQ-10). Scores for both the long and short versions range between 0 and 20 and higher scores indicate better outcomes69. The test-retest reliability of FOSQ-10 is alpha = 0.95 and scoring internal consistency is r = 0.9070. The internal consistency of the 10-item questionnaire was found to be similar to the long form with a Cronbach alpha= 0.87 (compared to 0.95 for the long version)70. With similar psychometric performance of the short form in comparison to the long form, similar conclusions can be drawn when using the short form as compared to the long form, yet it is easily administered and rapidly completed making it an ideal measure to assess functional status in the clinical setting70. A difference of 1 point in the FOSQ score is considered as the MCID in patients with OSA, as set by the task force of the American Academy of Sleep Medicine Clinical Practice Guideline25. One of the strengths of the FOSQ involves its inclusion of a response option to indicate if respondents do not engage in a particular activity for reasons other than their sleep disorder and the ability to exclude this item from the total score54,55. Another strength is its inclusion of a subscale that addresses intimacy/sexual activity that is unique to this questionnaire and a topic that is often neglected yet affected by sleep disorders54,55. A study comparing the general QoL measure SF-36 and 13 the disease specific QoL measure FOSQ showed weak positive correlation between FOSQ and both the SF-36 MCS (r=0.31, p < 0.001) and the SF-36 PCS (r=0.37, p< 0.001) scores59. This has been attributed to that each instrument measures different aspects, as SF-36 is a global scale while FOSQ is strictly a functional measure54. Calgary Sleep Apnea Quality of Life Index (SAQLI): SAQLI is a tool to measure QoL consisting of 35 items grouped into 4 domains encompassing daily functioning, social interactions, emotional functioning, and symptoms54,55. Originally developed as an interviewer administered instrument, the short (and more recently developed) form allows for self-completion54,55. Its unique feature is its inclusion of a fifth domain pertinent to treatment-related symptoms where respondents are asked to enter and rate ≤3 troubling symptoms they experienced with treatment54,55. Higher scores represent better quality of life and the internal consistency of this instrument has been reported as 0.92 (range 0.88 to 0.92)54,59. There has been a moderate correlation noted between the SAQLI and both the SF-36 MCS (r=0.52, p <0.001) and the SF-36 PCS (r=0.42, p <0.001) scores59. A comparison between the two disease-specific questionnaires (SAQLI and FOSQ) shows that the correlation was r=0.66, p <0.00159. Despite being a great tool, the SAQLI is too long and is therefore used less often in treatment assessment. 1.2.7.3 Daytime Sleepiness and Sleep Quality A symptom specific measure is a tool used to assess a particular symptom, such as sleepiness. Excessive daytime sleepiness is present in 52-58% of patients with moderate to severe OSA71. A widely used tool to assess daytime sleepiness is the Epworth Sleepiness Scale (ESS). It is a self-reported questionnaire that measures a patient’s proneness to doze off or fall asleep in eight specific situations: “sitting and reading,” “watching TV,” “sitting inactive in a public place,” “as a passenger in a car for an hour without a break,” “lying down to rest in the afternoon when circumstances 14 permit,” “sitting and talking to someone,” “sitting quietly after a lunch without alcohol,” “in a car, while stopped for a few minutes in traffic”72. Scores range between 0 and 24 with higher scores indicating more daytime sleepiness72. Scores ≥10 indicate excessive daytime sleepiness73,74. The MCID for ESS has been determined to be between 2 and 3 points23,57,69. The ESS has shown high validity and reliability in numerous studies, in addition to good internal consistency (Cronbach’s alpha= 0.74 to 0.88)71,72. Pittsburgh Sleep Quality Index (PSQI): The PSQI is a validated, self-reported questionnaire assessing sleep quality76. It consists of 19 questions assessing 7 aspects of sleep quality: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medicine, and daytime dysfunction76. Scores range between 0 and 21 with lower scores (≤5 points) indicating better sleep quality71. Internal consistency of PSQI is Cronbach alpha= 0.8376. One difference between the PSQI and other sleep questionnaires is that it specifies a particular time frame for the respondents to consider when answering the questions which is 1-month76. 1.2.7.4 Fatigue Fatigue is a common symptom that is not specific to sleep disorders and is among the most frequently reported symptoms by patients with chronic illnesses77. Fatigue has been described as lack of energy, weakness or tiredness, or even sustained exhaustion associated with a decreased capacity for physical and/or mental work77,78. Fatigue, tiredness, and lack of energy were reported to be a problem by 57%, 61%, and 62% of patients with OSA respectively10, indicating that it is a common symptom associated with OSA. Despite the small number of studies in OSA with a fatigue specific questionnaire, this aspect is becoming an important focus of recent trials79. Sleepiness and fatigue have shown to be not correlated in patients with OSA, indicating the importance of combining the ESS questionnaire with a more specific tool for assessing fatigue79. 15 Many questionnaires have been developed for the self-reporting of fatigue, including the Chalder Fatigue Questionnaire (CFQ)80. The CFQ is a self-administered, widely used questionnaire for measuring fatigue within different disciplines81,82. It is an 11-item questionnaire, and the global score spans two dimensions, both physical fatigue (measured by items 1–7) and mental fatigue (measured by items 8–11)80,82. The global score ranges between 0 and 33 with higher scores indicating greater fatigue severity81,82. Internal consistency of CFQ is alpha = 0.9080,81. The MCID has been shown to vary based on discipline, patient population and estimation method78. While no MCID has been determined for the CFQ in patients with OSA, it has been estimated to be 7.0 and 9.9 for patients with systemic lupus erythematosus and rheumatoid arthritis respectively62,78. 1.3 Obstructive Sleep Apnea Management 1.3.1 Unimodal Approaches to Therapy 1.3.1.1 Positive Airway Pressure (PAP) PAP is considered to be the first line therapy for OSA. Since it was introduced by Sullivan et al in 198183, it has been subject to continuous advancement. While it does not eliminate the underlying cause of OSA, this therapy involves the delivery of pressurized air to the upper airway during sleep via a mask interface and flexible tubing connected to a pump to keep the airway open83; The pressurized air acts to splint open the upper airway preventing it from collapsing during sleep. 1.3.1.1.1 Types of PAP Subsequent to the invention of the Continuous Positive Airway Pressure (CPAP), which applies a constant pressure throughout the respiratory cycle to splint open the airway other forms of PAP have been developed84. These include the bilevel PAP (BPAP) and the auto-adjusting PAP (APAP)85. The BPAP delivers a higher inspiratory positive airway pressure relative to the 16 expiratory pressure in an attempt to increase comfort, specifically during expiration85. APAP dynamically (in real-time on a breath by breath basis) increases the positive airway pressure when obstructive breathing events are detected and periodically reduces the delivered pressure (auto-adjusted) when no events are detected85,86. Titration describes the process by which the pressure of the CPAP is adjusted in order to provide the optimum pressure needed to splint the upper airway open. For the initiation of PAP therapy, PAP titration is traditionally done in the laboratory but could alternatively be performed with APAP at home85. At home APAP titration versus in-laboratory PAP titration for the initiation of PAP treatment demonstrated similar effects in terms of the reduction in OSA severity, adherence to treatment, effect on daytime sleepiness and effects on both sleep-related and general QoL85. Potential benefits of at home titration include a reduced time to initiation of therapy (of greater importance in areas where limited laboratory resources are available), at home sleep being more natural, reduced time away from home, lower overall cost, and greater access to care. However, difficulties in identifying and immediately addressing problems related to mask fit or leak may be a limitation of the in home APAP titration85. 1.3.1.1.2 Effects of PAP Treatment The efficacy of CPAP in reducing OSA severity is shown to be consistently high, with an estimated 86% mean reduction in AHI with treatment compared to pre-treatment85. Furthermore, CPAP is effective in reducing OSA severity across the spectrum of OSA severity85. Additionally, treatment of OSA with CPAP results in clinically significant improvements in both self-reported and objectively measured sleepiness85. It reduces the risk of motor vehicle accidents in patients with moderate to severe OSA85,87. It has been shown to improve sleep related QoL, but not overall QoL nor neurocognitive function85. PAP use also reduces blood pressure (BP) in adults with OSA, 17 particularly in those with moderate to severe OSA, it reduces nighttime and 24-hour BP in adults with predominantly moderate to severe OSA and resistant hypertension85. A mean BP reduction of approximately 2 mmHg in 24 hours has been reported. Albeit seemingly modest, a 2mmHg reduction in BP has been associated with a 3% reduction in all-cause mortality in the general population88. While the potential for positive effects regarding cardiovascular events and mortality cannot be ruled out with PAP therapy as indicted by observational studies. Randomized controlled trials namely the Sleep Apnea Cardiovascular Endpoints (SAVE) trial and the Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnea (RICCADSA) trial assessing the effects of CPAP on cardiovascular outcomes did not find cardiovascular benefits associated with treatment89,90. This was however attributed to the low adherence to therapy (mean adherence of < 4 hours/night) observed in these trials and there was some evidence that there was a reduced risk of adverse events for patients who were adherent to treatment. Other possible explanation for the lack of cardiovascular benefits could be that the follow up period was relatively short in these trials and insufficient to express the cardiovascular benefits of therapy91. Additionally, the benefits of PAP on cardiovascular event risk may be greater in more symptomatic and more severe disease (severe hypoxemia), which are the groups that were excluded from the randomized controlled trials85,89,90. It has been shown that CPAP and APAP have similar effects on the reduction of OSA severity, adherence to therapy, daytime sleepiness, sleep related and general QoL and on neurocognitive function85. Differences in side-effects between them were not clinically significant however, it has been suggested that the alternate modality may be tried when treatment intolerance due to side effects occurs85. On the long term, APAP has the potential benefit of minimizing the need for adjustments of the pressure settings over time in response to changes in OSA severity due to factors such as weight fluctuations, nighttime alcohol consumption, seasonal variations (such as upper 18 respiratory tract infections) and body position during sleep85. However, their effect on BP and cardiovascular risk may not be similar, while the results are not conclusive, some studies have suggested that CPAP may be superior to APAP in that regards92,93. Similar to APAP, BPAP has been shown to be comparable to CPAP in terms of OSA related outcomes however, a potential benefit of BPAP has been recognized in some patients who are intolerant to CPAP, specifically due to high pressure requirements85. Due to the lower pressure during exhalation with BPAP, it may have a benefit over CPAP in improving comfort which may then improve patient adherence85. 1.3.1.1.3 PAP Adherence Monitoring, Predictors and Methods to Augment It Adherence has been defined by the World Health Organization as “the extent to which a person’s behaviour- taking medications, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider” 94. Adherence in the field of health care in general has been found to be related to patient characteristics as well as disease and treatment aspects, and adherence in OSA has been no exception 94–96. While type D (distressed) personality has shown to have lower adherence to therapy97 and higher neighborhood socioeconomic status was associated with higher adherence, other patient characteristics such as sex, age and marital status did not show consistent association with CPAP adherence95,96. Similarly, OSA severity has not shown to be associated with adherence but rather increased sleepiness pre-treatment (ESS score >10) was associated with increased adherence96. CPAP adherence has also been associated with the patient’s perception of OSA symptoms in addition to the perceived benefits of therapy, yet very high and unrealistic treatment outcome expectations may be associated with worse adherence96. Additionally, patients who self-initiate their referral have been shown to have greater adherence to CPAP. Social support has also been 19 suggested to play a role in increasing adherence95,96. Adherence during the first days following the initiation of treatment, the reporting of problems during those initial days of CPAP use and the initial perception of treatment and its benefits have been shown to be a predictor of subsequent adherence98. Hence, they provide an important opportunity to intervene and improve adherence99. Self-reported adherence has been shown to overestimate adherence by close to 1 hour/night99 hence, objective adherence monitoring has been considered an important advancement in PAP technology96. Information from the PAP machine can be transmitted via modem or wireless transmission. Cloud-based platforms receive regular data updates from the PAP machines and allow for real-time monitoring of adherence by providers85,96. A patient is considered adherent to PAP if it is used for at least 4 hours per night during 70% of the nights. However, these threshold values tend to be arbitrary and were chosen based on average usage values observed in earlier PAP adherence studies99. Nevertheless, they have gained importance, as they represent the criteria by which third-party insurance companies determine PAP reimbursement in the US, despite not being correlated to optimal outcomes. Research findings indicate that more PAP use is likely to result in better outcomes with a dose-response relationship existing between PAP use and a range of outcomes86,95,100. Stradling and Davies100 showed a positive relation between improvement in outcomes and duration of use, with the best outcomes achieved with at least 5 hours/night of PAP use. Weaver et al73 demonstrated that 4 hours of nightly CPAP use was associated with improvement in the ESS score however, 7.5 hours of nightly use was required for improvement in both the Multiple Sleep Latency Test (an objective assessment of sleepiness) and FOSQ scores. Antic et al74 also identified a similar trend for subjective sleepiness among moderate to severe PAP treated OSA patients after three months of PAP use. Similarly, each 1-hour improvement in PAP adherence was associated with a reduction in mean BP of 1.4 mm Hg101. Despite the benefits of PAP therapy, 20–50% of OSA patients are 20 unable or unwilling to comply with PAP and using the criteria of < 4 of nightly use to indicate non-adherence, PAP non-adherence has been estimated to be between 29% and 83%, limiting its long-term effectiveness95. PAP adherence has shown to be similar between two major PAP providers, Phillips Respironics® and Resmed® indicating that the device itself is not a factor in adherence102. A great variety of mask interfaces are available that include nasal masks, nasal pillows, full face masks, and oral masks85,103. The variability in mask designs and the continuous attempts to evolve them has allowed for better individualization of the interface to a patient, in order to reduce leaks and improve comfort85. However, differences have been noted between nasal and oronasal masks with superior adherence associated with the use of nasal masks103. Nasal masks have been associated with less overall leaks, lower therapeutic pressure requirements, have shown to be more comfortable with lower risk of aerophagia and associated with higher adherence rates. Oronasal masks have been associated with better control of mouth leaks103. Due to the suboptimal adherence to PAP therapy, interventions to increase adherence have been introduced and these are divided into 3 main categories (1) educational interventions, which focus primarily on providing information at initiation of PAP therapy about OSA, its consequences, what does treatment involve, and the potential benefits of treatment85. This includes written material, watching a video or face-to-face didactic sessions; (2) behavioral interventions, these focus on behavioral changes regarding PAP therapy by utilizing strategies such as cognitive behavioral therapy or motivational enhancement; and (3) troubleshooting interventions, which focus on close communication with the patients to identify PAP related problems and to find potential solutions85,86,104. In reality, these interventions are interrelated as both behavioral and troubleshooting interventions involve some patient education to motivate a behavioral change or understand how to address problems85. 21 Telemedicine has also been utilized and in addition to the remote monitoring of PAP involves personalized feedback to patients, targeted troubleshooting and support based on individual patient data85,86. A meta-analysis that assessed the impact of the aforementioned interventions demonstrated a clinically significant improvement in PAP usage of 0.6 hours/night, 1.2 hours/night, 0.7 hours/night and 1.0 hour/night compared to usual care for educational, behavioural, troubleshooting and telemedicine interventions respectively85. The authors note that the follow-up assessments ranged from 1 month to 1 year in the studies assessing the impact of educational, behavioural and troubleshooting interventions, and ranged between 1 to 3 months in the studies assessing the impact of telemedicine85. PAP modifications to increase comfort and augment adherence include flexible pressure (often referred to as C-flex), heated humidification and pressure ramp96. Flexible pressure reduces pressure during the first part of exhalation then restoring it to a therapeutic level for the latter part of expiration and subsequent inhalation96,105. Adherence, treatment efficacy, subjective and objective sleepiness and psychomotor vigilance did not appear to be different when compared to CPAP in a meta-analysis105. Heated humidification may reduce symptoms of dry nose, mouth and throat96 however, a meta-analysis demonstrated no clinically significant difference in PAP usage, self-reported sleepiness or QoL with humidification as compared to no humidification85 thus this approach should be individualized95,96. The ramp feature starts the initial PAP pressure low and gradually increases the pressure over a set time period to the prescribed target96. Like the previous two, this modification also did not show improved adherence96. 22 1.3.1.2 Oral Appliances Oral appliances used for the treatment of OSA that advance the mandible forward have been given different names in the literature including mandibular advancement splints, mandibular advancement devices, mandibular repositioning appliances, oral appliances and oral appliances that advance the mandible forward (OAm). In this thesis, we refer to them as mandibular advancement splints (MAS), oral appliances and OAm. 1.3.1.2.1 Influence of Design There are many different types of MAS and they could be custom-made or non-custom (prefabricated), monobloc or bibloc (duobloc), titratable or non-titratable. The monobloc MAS consist of attached maxillary and mandibular parts that hold the mandible in a fixed position106. Duobloc MAS consist of two pieces with an intermaxillary adjustment mechanism to allow adjustment of the degree of protrusion, in order to reach the optimal therapeutic position (a process named titration)106.The use of custom-made, titratable MAS is the preferred option as indicated by the 2015 American Academy of Sleep Medicine and American Academy of Dental Sleep Medicine updated clinical practice guidelines107. This is based on research that shows better outcomes with the custom-made titratable appliances, as custom-made appliances were shown to have a 60% success rate while non-custom-made appliances have a 31% success rate108. Nevertheless, a recently published meta-analysis has shown that there is no difference in the dropout rate between patients who were using monobloc custom-made, dubloc custom-made or non-custom-made appliances106. This meta-analysis also demonstrated that the hours per night of adherence to duobloc MAS were significantly higher than the hours per night adherence of non-custom-made MAS106. 23 Venema et al109 showed that within the custom-made, titratable MAS, there are no differences in outcomes between the different appliance designs and types. With any MAS, it is important to ensure good retention to prevent the appliance from dislodging. Additionally, a reduced number of teeth may adversely affect retention of the MAS. Recently, the factors influencing adherence to MAS therapy have been systematically reviewed110 and the factors that have been found to be predictors of adherence include: the oral appliance being custom-made, were an increased adherence for custom-made appliances was shown in comparison to ready-made appliances. Similar to the findings pertinent to CPAP adherence, psychological and social factors such as perception of treatment benefits, type D personality and bed partner satisfaction have been shown to be determinants of MAS adherence110,111. Furthermore, in agreement with the findings regarding CPAP adherence, increased adverse effects were shown to be associated with the discontinuation of MAS treatment within 3 months110. Additionally, mood and decrease in socially disturbing snoring were also considered predictors of adherence110. Age, sex, obesity, anthropometric characteristics, polysomnographic parameters (AHI) and excessive daytime sleepiness were considered weak predictors of adherence110. In line with the findings regarding initial CPAP adherence and its importance in predicting long-term adherence, Sutherland et al112 objectively assessing adherence over the first 60 days of MAS therapy and found that adherence during the initial 20 days was able to predict longer term adherence (i.e. adherence at 60 days). They were also able to identify patterns of MAS use and classified the subtypes of MAS users into ‘Consistent users’, ‘Inconsistent users’ and ‘Patchy users’112. Chapter 2 of this thesis consists of a review on oral appliances113. Topics reviewed in chapter 2 include: classification of oral appliances, pathophysiologic traits of OSA and mechanism of action 24 of OAs, types of OA and indications for use, titration, predictors of treatment response, definition of treatment success, comparative effectiveness of CPAP and OAs, OA adherence, Mean Disease Alleviation and Sleep Adjusted Residual AHI, determinants of OA adherence, combination therapy, side-effects of OA and future directions. 1.3.1.3 Other Treatment Modalities Including Weight Loss, Positional Therapy, Pharmacological Agents and Surgical Intervention Weight Loss: Weight reduction is yet another treatment modality that targets the anatomical component of OSA. Weight reduction is a potential key treatment option not only for OSA but also for related comorbidities114. Weight changes correlate to changes in OSA severity, where an increase in weight leads to an increase in the incidence and severity of OSA while weight loss reduces the severity or can in some cases eliminate OSA114. Weight reduction can be ‘medical’ (in the form of a combination of lifestyle modification, reduced caloric intake and increased physical activity) or surgical (Bariatric surgery)34,114. Bariatric surgery however is reserved for those with BMI >35 kg/m2 who have failed nonsurgical weight loss interventions115. With medical weight reduction, a 3-18% weight loss can lead to a 3-62% decrease in AHI and with surgical weight reduction a 12-37% weight loss can lead to a 48-90% decrease in AHI114. Physical activity on its own has also been shown to reduce OSA116. Limitations of this treatment modality includes the difficulty and the time needed to achieve weight loss and the difficulty to maintain the lost weight34. A network meta-analysis116 comparing the effects of CPAP, MAS, exercise training and dietary weight loss showed that all interventions were able to significantly improve the AHI, with CPAP showing superior efficacy relative to the other treatment modalities. Additionally, supervised aerobic exercise training without weight loss has shown to be comparable to MAS in terms of efficacy and 25 reduction in daytime sleepiness116. It has been suggested that exercise training can be an adjunctive treatment to CPAP and MAS116. Positional Therapy: Positional therapy is a treatment option for a subset of the OSA population who are considered to have positional OSA. Techniques range from the traditional tennis ball sewed at the back of a shirt to technological devices that have evolved over time and are worn in order to reduce time sleeping in the supine position34,117. A meta-analysis117 shows that positional therapy devices were able to reduce the AHI by a mean difference of 11events/hour (54% reduction) and reduce the percentage total sleeping time in the supine position by 34% (84% reduction). Additionally, these devices showed high short term adherence117. Limitations include the lack of long term data on clinical efficacy, symptom improvement and adherence34. This treatment may also cause back pain in some patients as a side-effect34. Pharmacological Agents: The effect of sedatives as a potential therapy for patients with OSA and low arousal threshold has been studied. Trazodone and Zopiclone in standard prescribed doses (7.5 and 100mg respectively) were able to increase the respiratory arousal threshold without major impairment in dilator muscle activity or upper airway collapsibility118,119. Similarly, Eszopiclone (3mg) was able to demonstrate the same in addition to a 23% reduction in the AHI120. Limitations of these medications include the potential for worsening of hypoxemia in certain patients exists, especially with higher doses34. Additionally, only modest increases in the arousal threshold and reductions in AHI have been shown with the standard doses of these medications34. Similarly, the respiratory stimulant acetazolamide, a carbonic anhydrase inhibitor has been shown to reduce loop gain by 41% with minimal improvements on the remaining respiratory traits121. Supplemental oxygen effectively reduces loop gain and AHI (53% reduction) in patients with high loop gain122. Thus, it has been proposed as a potential therapy for patients with ventilatory control 26 instability122. Nevertheless, a meta-analysis comparing CPAP and supplemental oxygen therapy has shown significantly greater therapeutic effects with CPAP compared to supplemental oxygen in patients with OSA. Limitations of supplemental oxygen therapy include that its applicability may be limited as its delivery in the home setting is considered somewhat cumbersome34. Furthermore, research published so far on pharmacological agents as monotherapies shows that these pharmacological agents can improve but are rarely capable of completely resolving OSA123. Additionally, most pharmacological agents are still under investigation and have not yet been recommended for the long-term treatment of OSA. Surgeries That Target the Upper Airway Anatomy: A variety of surgical procedures can be performed as a treatment for OSA that target specific areas of the upper airway. Uvulopalatopharyngoplasty is the most well-known oropharyngeal surgical procedure and it aims to enlarge the oropharynx by resection of the uvula, margin of the soft palate, and redundant pharyngeal tissue124. Its success has been attributed to improvement of the retropalatal airway collapsibility124. Uvulopalatopharyngoplasty was successfully able to improve OSA in 73% of patients with an abnormally high collapsible airway exclusively at the retropalatal area and success rate of this procedure has been reported to be even lower (< 50%) without patient selection124. Other surgical procedures include volumetric tongue reduction and genioglossus advancement125. Genioglossus advancement is a procedure that involves the advancement of the genial tubercle/genioglossus muscle for the treatment of hypopharyngeal obstruction125. Hyoid suspension is yet another adjuvant surgical procedure performed during or following other surgical sleep procedures to anteriorly displace the hyoid bone resulting in increased patency of the hypopharyngeal airway and reduction in airway resistance125. Limitations of surgical procedures include their high cost, invasive nature and unpredictable efficacy34. 27 A recently published randomized controlled trial comparing multi-level surgery (modified uvulopalatopharyngoplasty and tongue volume reduction) to medical management in moderate and severe OSA patients showed greater reduction in AHI and ESS scores in the surgery group 6 months following the procedure relative to the medical management group126. Maxillomandibular advancement is an invasive yet effective surgical option for OSA that achieves enlargement of the upper airway, specifically the nasopharyngeal, retropalatal, and hypopharyngeal areas of the upper airway127. The surgical procedure involves a Le Fort I maxillary and sagittal split mandibular osteotomies to advance the maxilla and mandible respectively128. The pooled results from a meta-analysis demonstrated a mean decrease in the AHI from 57 to 10 events/hour with a surgical success rate of 86% and OSA cure rate of 39%127. A previously conducted meta-analysis showed comparable results with a success rate of 86% and cure rate of 43%128. Hypoglossal Nerve Stimulation is a relatively novel therapy for moderate to severe OSA in patients who are unable to tolerate CPAP therapy and ideally in whom the BMI is < 32 kg/m(2) 129. A hypoglossal nerve stimulator is a device that generates electrical impulses through a generator that is implanted underneath the skin on the upper right side of the chest129. The impulse is transmitted via a tunneled lead that ends with a cuff that surrounds the hypoglossal nerve. The purpose of hypoglossal nerve stimulation is to decrease airway collapsibility, secondary to tongue protrusion129. Since this treatment involves an invasive procedure, there are multiple associated risks and potential adverse effects129. The median AHI score at 12 months decreased significantly by 68%, from 29 events/hour to 9 events/hour130. Five-year follow up data show that the results can be considered sustainable131. At 5-years, 75% of participants met the criteria for surgical success, normalization of FOSQ and ESS scores occurred in 67% and 78% of the participants respectively131. 28 Due to the heterogenous nature of OSA and the large variability in risk factors, pathophysiology, clinical presentation, associated comorbidities and treatment response, a personalized treatment approach is recommended instead of the ‘one size fits all’ approach132,133 . 1.3.2 Randomized Controlled Trials Comparing CPAP and MAS Studies comparing the effectiveness of CPAP and MAS have been described in chapter 2. One of the largest randomized controlled trials comparing CPAP and MAS has shown that all metrics of OSA improved markedly with both treatments, with greater improvements shown by CPAP compared to MAS134. With regards to 24-hour blood pressure (BP), both treatments showed a comparable reduction in BP that was not statistically significant from baseline134. However, there was a 2-4mmHg reduction in BP in both groups that was statistically significant compared to baseline, in a subset of their study population who were initially hypertensive at baseline134. Additionally, both CPAP and MAS demonstrated comparable improvements in ESS and FOSQ scores and in a driving simulation assessment. MAS performed better than CPAP in improving four of eight SF-36 general QOL domains and the overall mental component score134. Finally, self-reported adherence was higher for MAS134. Despite it being a well-designed study that assessed multiple outcomes, it was relatively short term (< 6 months) and lacked an objective assessment of MAS adherence. The authors concluded that the greater efficacy of CPAP has been offset by its inferior adherence relative to MAS, resulting in a similar overall effectiveness134. More recently, other studies have been published comparing the two treatments. These include a randomized cross-over trial comparing CPAP and MAS using objectively measured adherence for both treatments135. Daytime sleepiness, nocturia, comfort and preference were assessed, in addition to endothelial function and effect on blood pressure. In this relatively short term study (< 6months follow-up) similar adherence and improvement in self-reported symptoms between the two treatments has been 29 found however, neither improved cardiovascular parameters, even in the highly adherent subgroup135. More patients preferred MAS over CPAP135. A 10-year follow up study136 comparing CPAP and MAS based on self-reported adherence found that both groups showed a significant improvement in AHI and in oxygen saturation relative to baseline. A slight increase in the AHI at the 10-year follow-up in both groups was observed when compared to the 1 and 2-year follow-up albeit, still being significantly different from baseline values136. Similar trends were observed with ESS and FOSQ questionnaires, as improvements were observed that were maintained at the 1, 2, and 10-year follow-ups however, slight deterioration in sleepiness between the 2 and 10-year follow-up, especially in the MAS group, was noted yet still significantly improved at the 10-year follow-up compared to baseline136. The three aforementioned studies134–136 have concluded that CPAP and MAS are comparable in terms of outcomes. However, there are no randomized controlled trials yet that compare the long term effectiveness of these two therapies on a wide range of outcomes and using an objective assessment of adherence to both therapies. 1.3.3 Multimodal Approach to Therapy (Combination Therapy) in Obstructive Sleep Apnea Management As mentioned earlier, there are multiple treatment modalities available for the treatment of OSA that vary in their degree of invasiveness, efficacy, effectiveness, patient acceptance and adherence. With patient adherence being crucial for all non-surgical therapies. Multimodal therapy describes combining two or more treatment modalities that target different aspects of a disease137. Multimodal therapy has been utilized in many health disciplines including cancer treatment, chronic pain, neurological 30 disorders, hypertension and diabetes in an attempt to maximize therapeutic effectiveness, minimize toxicity and improve patient acceptance138–140. Combination therapy is “frequently used to refer to two or more drugs or biologics used in combination—either to enhance delivery of a drug or target different aspects of a disease, or to improve outcomes toward the same aspect of a disease—and also sometimes used to refer to approaches involving multiple modalities”137. The combination of therapies in OSA involves those that target more than one physiologic trait (anatomical and non-anatomical or 2 non-anatomical traits) and those that target the same physiological trait, namely the anatomical trait, being the main contributor to the pathophysiology of OSA in the majority of OSA patients. One of the earliest attempts to assess combination therapy in OSA was a study, published in 1991, in which a tongue retaining device was used in conjunction with positional therapy, where the authors suggested an additive effect resulting from the combination141. A more recent study assessed the effects of combining MAS with positional therapy (mainly targeting the same physiological traits with both interventions)142 showed that the combination was found to further reduce the OSA severity compared to either positional therapy or MAS used as monotherapies. MAS has also been combined with other treatment modalities to increase efficacy. Oliven et al143 assessed the combined effect of mandibular advancement (targeting anatomy/collapsibility of the upper airway) with genioglossus muscle stimulation (targeting muscle responsiveness) and found that the combination had an additive effect and possibly a synergistic effect. However, changes in OSA severity were not assessed in this study. MAS combined with a serotonin type-3 receptor antagonist (ondansetron) and serotonin reuptake inhibitor (fluoxetine) was able to improve respiratory parameters compared to MAS monotherapy144. Similarly, combining MAS with uvulopalatopharyngoplasty surgery and MAS with expiratory positive airway pressure showed further reduction in AHI compared to MAS monotherapy145,146. 31 A study was conducted to assess the combination of two pharmacological agents123 that target more than one non-anatomical trait include the combination of oxygen and a hypnotic to lower the loop gain and to raise the arousal threshold. This combination was found to be effective in patients whose anatomy was not severely compromised and was able to resolve OSA only in select individuals123. Another study147 assessing the effect of the combination of atomoxetine, a noradrenergic, and oxybutynin, an antimuscarinic, showed that a combination of these drugs administered for 1 night improved the AHI by 63%, improved oxygen desaturation, and enhanced the genioglossus muscle activity. Interestingly, neither atomoxetine nor oxybutynin reduced the AHI when administered separately147. The attempts to combine CPAP with other treatment modalities have been limited. CPAP combined with a weight loss intervention148 provided an incremental reduction in insulin resistance and serum triglyceride levels as compared to CPAP alone. In addition to incremental reductions in blood pressure as compared to either intervention alone148. Some attempts have been made to combine CPAP and MAS, the target population for these trials were patients who were considered “CPAP intolerant”, a term used to describe patients who were unable to tolerate CPAP due to the high-pressure requirement and the associated discomfort subsequently leading them to be non-adherent to treatment. The combination of the two therapies was shown to decrease the CPAP pressure requirement by 29-48%149 and increase comfort, which was associated with increased adherence150. The reduction in CPAP pressure requirements with combination therapy has been attributed to a reduction in upper airway collapsibility from the MAS149. Another group of patients targeted by the combination of CPAP and MAS were patients who were incomplete responders to MAS150. The three studies that assessed respiratory parameters with the combination showed that the combination was able to significantly improve respiratory parameters relative to MAS monotherapy150–152. El-Solh et al150 and De Vries et al151 showed that the improvements were comparable to CPAP monotherapy while Liu et al152 showed that they were significantly greater than CPAP monotherapy. Furthermore, a trial assessing the effect of this 32 combination, and using a MAS with a built-in oral airway showed that pharyngeal pressure swings can be normalized with the combination149. Tanaka et al153 compared connected versus disconnected CPAP combined with MAS and showed no differences in terms of effects on respiratory parameters or therapeutic pressure between the two configurations. In a unique attempt to assess CPAP and MAS as alternating therapies in CPAP tolerant patients, Almeida et al154 showed that this method of combining the two therapies allows greater flexibility of treatment and opportunity to maintain adherence during circumstances in which CPAP cannot be used, such as when traveling. Relative to the body of literature published on the treatment of OSA over the past decades, the number of studies assessing combinations is considered very minimal. Furthermore, most of the studies assessing combinations of two or more treatment modalities were short term (ranging from 1 day to < 6 months) except for one study152 that included a 3-year follow-up, had small sample sizes, were conducted at a single study center, and were mainly only assessing efficacy. The effect of these combinations on patient centered outcomes, long term effectiveness and on side-effects has not been assessed. 1.3.4 Patient Centered Care Approach and Shared Decision Making Patient participation has been defined by the United States National Library of Medicine as “the involvement of the patient in the decision-making process regarding health issues”. The term patient participation has been used interchangeably with patient involvement, patient-centered care and patient empowerment155. The importance of the patient centered care approach has become increasingly recognized in the setting of OSA and involves many aspects such as the recognition of patient specific needs, values and preferences, patient engagement in the decision making process and in having access to their treatment progress and patient education and support156,157. 33 Traditionally, the approach to treatment decision making in many health disciplines has been the ‘paternalistic approach’158. This approach is based on the fact that the health care provider knows what is best for the patient based on the health care provider’s training, skills and experience. The role of health care provider depicted in this model is that of a guardian of the patient's best interest158. The patient is a passive recipient of care under this approach and his or her preferences are not considered, and the patient is expected to comply with the recommendations of the health care provider155,158. While this model continues to be acceptable in emergency care situations, decision making in chronic disease management has taken different approaches158. In reaction to the paternalistic model, a model arose on the other end of the continuum which is the ‘informed decision-making model’158. In this model, the health care provider shares all the information necessary for the patient to make a decision and consequently the patient is no longer in an information deficit and now possess both the information and his or her own preferences to make an informed decision158. In this model, the decision-making control is given to the patient and the health care provider is not imposing their will on the patient158. While the paternalistic model leaves the patient out of the decision-making process, the informed decision-making model leaves the health care provider out of the decision-making process and limits their role to information sharing158. Both models have proven to be non-ideal and a model with intermediate characteristics was developed namely, the ‘shared decision-making model’158–160. There is increasing body of research confirming the importance of communication in health care and the impact that a patient centered approach has on increasing patient satisfaction, reducing emotional burden, increasing adherence, and improving some outcomes161. Shared decision making (SDM) is an interactive process between at least two parties (patient and health care provider) and has been recognized as an important component of patient-centered care158. Information and opinions are shared, patient preferences and the responsibilities of both parties are discussed and an agreement on a course of 34 action is reached158,161. Hence, both power and responsibility are shared161. Over the years, patients have increasingly reported a desire to be actively involved in the decision-making process, and SDM is being increasingly considered as an important tool to promote patient autonomy and satisfaction159,160.While evidence of a direct effect of SDM on health outcomes is still inconclusive160, its role in improving patient satisfaction may lead to trust in the health care provider, followed by adherence to the provider’s recommendations and ultimately improved health160,162. There are also multiple perspectives on which SDM have been recommended, these include an ethical mandate to protect patient autonomy and self-determination, it promotes trust between the patient and the health care provider, and there is an educational gain to the patient as their knowledge about treatment options, benefits, and harms increases through the SDM process158. Interventions that aid in the shared decision-making process include the treatment decision aid tools158. These tools provide patients with information regarding their condition and relevant treatment options158. Furthermore, they structure the decision-making process and break it down into a number of specific and sequential steps that focus on key issues. A primary goal of these decision aid tools is to help elicit patients’ treatment preferences158. Decision aid tools have been used by oncologists since the early 1990s and have been more recently introduced in the field of OSA163–165. Pelletier-Fleury et al163, developed an electronic decision board that they described based on their findings as being a valid, reliable and acceptable tool to elicit patient preferences regarding CPAP and MAS. Trenaman et al164 developed a web-based patient decision aid tool, also focused on CPAP and MAS as the treatment options and includes ‘no treatment’ as a third option. Ninety-six percent out of eighty participants who completed the survey thought that the decision aid tool was useful in decision making and would recommend it to others164. In an attempt to elucidate patient perspectives and preferences in the treatment of OSA, Braun et al166 have acknowledged that the patients’ perspectives are underrepresented 35 in the field of respiratory sleep medicine and that perspectives differ among subgroups of patients which calls for individualized treatment. 1.4 Current Knowledge Gaps, Research Goals and Research Outline 1.4.1 Current Knowledge Gaps and Research Goals OSA is a chronic condition that is becoming increasingly prevalent in Canada and worldwide due to the obesity pandemic. CPAP is the first-line treatment and MAS is considered the leading alternative, in this thesis we focus on these two main treatment modalities for OSA and the overall aim of this work is to address some of the knowledge gaps pertaining to these two treatment modalities. MAS has been used for many years in patients with mild to moderate OSA and in patients who have severe OSA who are unwilling to use or could not tolerate CPAP. A limitation commonly reported in the existing literature on MAS side effects is the relatively short observation period, leaving the nature of the progression of skeletal and dental changes inadequately characterized, considering the life-long need for treatment. It has also been previously speculated that the occlusal changes observed may be a combination of both tooth movement and mandibular posturing. The aim of this work was to determine the nature of the changes associated with long-term MAS treatment (whether dental and/or skeletal), to evaluate the magnitude and progression of these changes, and to determine if initial patient and dental characteristics are possible predictors of the observed long-term side effects of treatment. This accurate characterization of the long term side effects could lead to the development of strategies to mitigate them. Despite CPAP’s high efficacy, the overall improvement in health outcomes is suboptimal. This has been explained by the lower effectiveness, which takes into account not only the efficacy but also the adherence. On the other hand, it has been hypothesized that the sub-optimal efficacy of MAS is 36 counterbalanced by its superior adherence relative to CPAP, resulting in a similar overall effectiveness for both treatments. Previous studies that have conducted a comprehensive comparison between CPAP and MAS lacked an objective adherence assessment of MAS and the more recent studies that have objectively compared adherence between CPAP and MAS lacked a comprehensive assessment of outcomes. Hence, the existing literature lacks information regarding the comparative effectiveness of CPAP and MAS based on an objective assessment of adherence. As such, the aim of this work is to assess the comparative effectiveness of CPAP and MAS that encompasses objective adherence, efficacy, measures of effectiveness, blood pressure and patient-centered outcomes, in addition to an assessment of their side-effects. CPAP is routinely prescribed with the clinical expectation that patients will use it for the entire duration of their sleep, daily for the rest of their life. This expectation lacks practicality, and the majority of patients are unable to do so, as evident by 40 years of data on CPAP adherence. Therefore, there is a need to improve this suboptimal CPAP adherence which proves to be a major barrier to maximizing the effectiveness of therapy. There is increasing realization that combination therapies could be a tool to personalize medicine, yet few studies focus on the role of combination therapy in OSA and even fewer focus specifically on the role of the combination of CPAP and MAS. The aims of this work is to fill this knowledge gap and provide a detailed assessment of the role of the combination of CPAP and MAS in the management of OSA. More specifically, the aim of the current work is to provide an assessment of the effectiveness of both CPAP and MAS and to compare it to two forms of CPAP-MAS combination therapy; the long-term use of both treatments used interchangeably, and the short term use of both treatments used simultaneously. 37 1.4.2 Research Outline Chapter 2 provides an overview on the current knowledge on MAS and its comparative effectiveness to CPAP. It aims to highlight some of the knowledge gaps in the literature available on MAS. In chapter 3 the long-term side-effects of MAS therapy are characterized, and the magnitude and progression of these side-effects are described, in addition to an analysis of possible predictors of these side-effects. In order to assess the comparative effectiveness of CPAP and MAS that focuses on patient-centered outcomes, a key goal of chapter 4 is to produce strong research evidence, by means of conducting a randomized controlled cross-over trial, to evaluate their comparative effectiveness. This includes an assessment of objective adherence, efficacy, patient-centered outcomes, blood pressure and effectiveness. This chapter also aims to provide a better understanding of the role of multimodality treatment, named in this thesis as combination therapy, in the management of OSA and to identify treatment usage patterns when patients have access to both therapies. Additionally, this chapter aims to understand patient preferences, describe the side-effects and demonstrate the importance of offering patients with OSA choices with regards to treatment modalities. By means of an objective assessment of both CPAP and MAS adherence, chapter 5 aims to evaluate a second form of combination therapy namely, the simultaneous use of CPAP and MAS (referred to as dual therapy). The work presented in this chapter aims to characterize the effects of this form of therapy on CPAP pressure, adherence to treatment, efficacy, daytime sleepiness, disease specific quality of life and blood pressure. The work presented in this chapter also aims to compare this form of therapy to the interchangeable use of CPAP and MAS and to the use of CPAP and MAS as monotherapies, in the same patients. 38 Chapter 6 of this thesis provides an overall discussion and summary of the findings, how these findings can translate into clinical practice, the clinical implications of the findings, the overall limitations and strengths of the work done in this doctoral thesis, future directions and conclusions of this thesis. 39 Chapter 2: Oral Appliances for the Management of OSA; an updated review of the literature A version of the original review can be found in the journal CHEST as “Mona M. Hamoda, BDS, MSc, MHSc; Yuuya Kohzuka, DDS; and Fernanda R. Almeida, DDS, PhD, Oral Appliances for the Management of OSA. An Updated Review of the Literature. CHEST 2018; 153(2):544-553”. Summary Oral appliances (OAs) are becoming increasingly recognized not only as an alternative to but also possibly as an adjunct treatment modality for OSA. Compared with continuous positive airway pressure (CPAP), the gold standard therapy, OAs are less efficacious but are more accepted and tolerated by patients, which, in turn, may lead to a comparable level of therapeutic effectiveness. Different OA designs currently exist, and more are constantly emerging. Additionally, state-of-the-art technologies are being used in the fabrication of many; however, all the currently available OAs employ the same mechanism of action by targeting the anatomical component involved in the pathogenesis of the disease. Furthermore, the scope of use of OAs is expanding to include patients who are edentulous. For patients with OAs, the dentist is a member of an interdisciplinary team managing OSA, and constant communication and follow-up with the sleep physician and other team members is necessary for disease management. 2.1 Introduction OSA is an increasingly prevalent sleep disorder characterized by recurrent episodes of partial and/or complete obstruction of the upper airway (hypopneas and apneas, respectively). Untreated OSA is associated with multiple adverse health outcomes, including stroke, hypertension, coronary artery disease, atrial fibrillation, decreased quality of life, and increased mortality167. Disease severity is classified according to the apnea-hypopnea index (AHI). An AHI > 5 and < 15 is considered mild OSA, 15 to 30 is moderate, and > 30 is severe OSA6. 40 Management of OSA can be classified into four categories: (1) lifestyle modification, (2) upper airway surgery, (3) CPAP, and (4) oral appliance (OA) therapy168. Hypoglossal nerve stimulation is also a promising treatment modality in some patient populations130. The aim of this review is to provide a summary of the current aspects and concerns in the field of OAs as a treatment for OSA. 2.2 Classification of OAs OAs are classified into those that protrude the tongue and those that protrude the mandible. The former are termed “tongue-retaining devices” or “tongue-stabilizing devices” (TSDs) and occasionally are prescribed for patients with mild to moderate OSA or those who fail to use CPAP169. OAs that reposition the mandible forward (OAm) are the most commonly used type of OAs and different terms refer to this category of appliances, including “mandibular advancement devices”, “mandibular advancement splints” and “mandibular repositioning appliances.” Following the publication of the initial position statement by the American Academy of Sleep Medicine in 1995170, the clinical use of and research on OAms increased in quality and quantity. With the compilation of evidence supporting the use of OAms, the 1995 guidelines were revised and published in 2005169 and again in 2015171. Similar to previous guidelines, the latest guidelines recommend the use of OAms for primary snoring and as an alternative to CPAP for patients who prefer OAs or those who refuse to use or are unable to tolerate CPAP. The 2015 guidelines do not specify a particular disease severity for OAm use, which opens up the use of this therapy for severe OSA cases beyond what has been suggested in the previous guidelines. This change could be attributed to the growing body of high-quality evidence demonstrating the efficacy of OAs, their improvement in outcomes so that they are comparable with those of CPAP at various disease severities, and their suggested higher adherence rates172. 41 2.3 Pathophysiologic Traits of OSA and Mechanism of Action of OAs Various structural and functional factors can contribute to the narrowing and collapse of the airway and there is increasing evidence demonstrating the multifactorial nature of OSA. Besides the well-known anatomical factors, neuromuscular control, an oversensitive ventilatory control system (high loop gain), and low respiratory arousal threshold are some of the other key factors identified39,172. This emerging evidence has led to the belief that more than one phenotype of OSA exists173. Anatomically, there are both soft tissues and bony structures surrounding the upper airway. If the anatomical balance is disrupted obesity (increase in surrounding soft tissue), a smaller maxilla or mandible, or an imbalance between soft and hard tissues, then upper airway collapsibility increases174. Available treatment options that target the anatomical imbalance can be classified into causal and symptomatic treatments. Causal treatment includes lifestyle modification, such as weight loss for patients who are obese, and surgeries, such as maxillomandibular advancement, that advance the maxilla and mandible in an attempt to ameliorate anatomical discrepancies. Symptomatic treatment includes CPAP and OAms, the latter being the focus of this review. To date, studies have shown that OAms mainly target the anatomical component in the pathogenesis of the disease by increasing the upper airway size, particularly the velopharyngeal cross-sectional area. This reduces pharyngeal collapsibility and disease severity175,176. Eckert et al173 demonstrated that there are different phenotypic traits for patients with OSA and that 69% of the patients have one or more non-anatomical pathophysiologic traits; therefore, because OAms mainly target the anatomical imbalance175,177, it is reasonable to expect that OAms might not be effective in all patients with OSA. Accordingly, OAm therapy is completely effective in only 36% to 70% of OSA cases178. 42 Even though both OAms and TSDs increase upper airway dimension, a greater increase in velopharyngeal and oropharyngeal cross-sectional area has been demonstrated with tongue protrusion than with mandibular protrusion. This finding could be attributed to the greater anterior displacement of the tongue produced by TSDs in comparison with that produced by OAms176. Both treatments are effective in reducing apneas, though OAms are slightly superior to TSDs, which supports the notion that a decrease in AHI may not be proportional to the increase in upper airway size. To date, there are only a few studies assessing TSDs, and their use in clinical practice is limited. 2.4 Types of OA and Indications for Use An OAm can be custom made (made by qualified dentist) or prefabricated (ie, boil and bite), one piece (monobloc, one piece with no mouth opening) or two piece (duobloc, separate maxillary and mandibular plates), fixed or titratable (with various types of adjustable mechanisms), and can be fabricated from a hard or soft material171,179,180. There are more than 100 different appliance designs currently on the market. Similarly, TSDs can be custom made or prefabricated, and, despite both OAms and TSDs having similar efficacy in terms of AHI reduction, TSDs are less comfortable than OAms are. Nonetheless, TSDs are a viable option for patients who are completely or partially edentulous181. Custom-made, titratable, duobloc oral appliances are superior to monobloc and non-titratable appliances (Figure 2.1)6,179,181. Within the custom-made duobloc category of appliances, different designs seem to have comparable efficacy183,184. For OSA patients with bruxism, metal reinforcement of the occlusal surface of the OAm will help increase the longevity of the appliance. For the edentulous OSA patient, treatment options are limited. Tooth loss seems to increase upper airway obstruction during sleep185. Although some studies found that the use of dentures during sleep reduces OSA, Almeida et al186 reported that the use of dentures instead of OAs during sleep for patients with mild OSA increased the AHI, especially in the supine position. Alternative options for edentulous patients include implant-retained 43 OAms and surgical treatment187. Hoekema et al188 reported the use of implant-retained OAms in six edentulous patients, and the findings of de Carlos et al189 indicate that the use of orthoimplants, a type of dental implant used for orthodontic anchorage, improved AHI in patients with mild OSA who were edentulous. Studies on edentulous patients are mostly case reports, so future focus on this population is necessary. For OAms, a healthy dentition and periodontal tissues are necessary without active dental caries or periodontal disease. Additionally, a minimum of eight to 10 healthy teeth need to be present in the mandibular arch (the maxillary arch can be edentulous) to retain most types of OAms, and a protrusion range of ³ 5mm169 is a prerequisite. The presence of temporomandibular disorders is not a contraindication for OAm use. Figure 2.1 Examples of Commercially Available Oral Appliances A, SomnoDent Flex, a custom-made oral appliance that moves the mandible forward (OAm) for the dentate patient. B, SomnoDent Edentulous, a custom-made OAm for patients with an edentulous maxilla. C, Narval, a custom-made OAms for the dentate patient. D, AveoTSD, a prefabricated Tongue Stabilizing Device (TSD). 44 2.5 Titration Managing OSA by using OAm therapy requires an interdisciplinary team approach that starts with an assessment by a physician, followed by a consultation and oral examination by a qualified dentist. Impressions of the patient’s teeth and bite registration are obtained by the dentist to create a custom OAm. Appliance titration is attained by means of progressive mandibular advancement that incrementally moves the mandible forward190. Different advancement mechanisms exist depending on the appliance design. Kato et al191 examined dose-dependent effects of mandibular advancement and showed that each 2-mm advancement was associated with a 20% improvement in the oxygen desaturation index. Most studies have reported that patients require advancement > 50% of maximum protrusion to achieve the desired effects192–194. Nevertheless, a recent systematic review and meta-analysis showed that advancements > 50% may not necessarily improve the success rate; a limitation, however, was that confounding variables that may affect success were not controlled for in the included studies195. After approximately 1 month of OAm use, the dentist checks for side effects such as tooth, tissue, and joint pain and assesses the perceived efficacy as reported by the patient or sleep partner. The dentist adjusts the OAm to eliminate any pain or discomfort. The titration phase normally involves several visits over a 3- to 5-month period. Following titration, the dentist confirms efficacy by referring the patient back to the sleep physician for an objective assessment via a sleep test. Additionally, the use of portable sleep monitoring during titration or conducting a titration polysomnography could also facilitate ideal titration196–198. The American Academy of Dental Sleep Medicine recommends that patients be seen by the dentist a minimum of once every 6 months for the first year and at least once annually thereafter (Figure 2.2). The dentist must evaluate carefully the occlusion, appliance wear, and possible adverse effects. The average life of an OAm is approximately 3 years; cracks, discoloration, and lack of retention indicate a need for replacement6,168,198,199. 45 Figure 2.2 Flow Chart Showing Oral Appliance Decision-making and Management Process for OSA Patients Abbreviations: OA, oral appliance; OAm, OA that repositions the mandible forward; PSG, polysomnography; TSD, tongue-stabilizing device. 46 2.6 Predictors of Treatment Response OAm treatment response may be influenced by a number of factors that include: device features, patient characteristics and pathophysiologic traits, in addition to the clinical expertise of the provider178. Predictors of treatment response to TSDs have not been studied yet. The most effective OAms are described as the custom-made, two-piece (duobloc) OAms that have minimal vertical opening and that are titratable appliances (incorporate an adjustable mechanism that permits mandibular advancement over a range of at least 5 mm and allows for the reversal of the advancements)6,179,181. Patient characteristics include anthropomorphic factors, with positive predictors including younger age, female sex, lower BMI, smaller neck circumference, smaller oropharynx, and smaller overjet. Cephalometric positive predictors are a shorter soft palate, longer maxilla, shorter distance between the mandibular plane and hyoid bone, bigger ANB angle (A point-nasion-B point) and smaller SNB angle (sella-nasion-B point). Polysomnographic positive predictors are less severe OSA and supine-dependent OSA201. The American Academy of Dental Sleep Medicine guidelines recommend that treatment of OSA with an OA should be provided by a qualified dentist who has the technical skills and acquired knowledge and judgment regarding the outcomes and risks of this treatment modality171. This skill set is important to be able to choose a good appliance, to understand and address transient side-effects, to adjust and titrate mandibular protrusion optimally, and to follow up patients properly. Nasal endoscopy, CT scanning, MRI, drug-induced sleep endoscopy, and overnight titration studies help predict treatment response. Nonetheless, their routine use in the clinical setting is limited because they are still costly or are inconvenient to use. Despite major efforts, prediction of OAm efficacy has a sensitivity of no greater than 70% or has inconclusive results in 20% to 30% of cases201,202. On the basis of these numbers, OAm success is hard to predict, and contraindications to OAm use today are limited to an 47 edentulous mandibular arch and a BMI > 35 kg/m2. Although there are limited studies in the obese population, an increase in weight may be correlated with a decrease in OA efficacy203. 2.7 Definition of Treatment Success Even though there seems to be a consensus on the definition of treatment success with OAms as being a treated AHI of < 5/h, a consensus is lacking on the definition of partial treatment success. Partial treatment success frequently is defined as > 50% reduction in baseline AHI with or without a treated AHI below a prespecified level such as 10/h or 20/h. The definition of partial treatment success also may include symptomatic improvement182. Reported success rates greatly depend on the definition of treatment success used204, making it more challenging to compare the results of different studies. 2.8 Treatment Efficacy vs Effectiveness In OSA management, efficacy reflects the ability of treatment, when used, to minimize or prevent the occurrence of obstructive breathing events205. Both CPAP and OAms reduce upper airway collapse during sleep, with CPAP having superior efficacy in moderate to severe OSA206. Although treatment efficacy refers to how well an intervention works under ideal, well-controlled circumstances, effectiveness indicates how well an intervention performs under circumstances that more closely approximate the real world, employing less standardized and less controlled conditions205. Therefore, treatment effectiveness is particularly important in the management of chronic disease. Adherence is an important determinant of effectiveness and has been defined by the World Health Organization as “the extent to which a person’s behavior—taking medications, following a diet, and/or executing lifestyle changes—corresponds with agreed recommendations from a healthcare provider”207. Furthermore, the World Health Organization report on adherence to long-term therapies indicates that health outcomes cannot be assessed accurately if they are measured predominantly by the efficacy of interventions because outcomes predicted by treatment efficacy data cannot be achieved unless adherence rates are considered. Hence, it is imperative to assess adherence objectively to evaluate treatment outcomes. 48 2.9 Comparative Effectiveness of CPAP and OAms CPAP is superior to OAms in terms of reducing OSA parameters on polysomnography, such as eliminating obstructive breathing events and improving nocturnal oxygen saturation and arousals172,208,209. Although CPAP consistently demonstrates normalization of AHI, this is not necessarily the case with OAms208. However, this greater efficacy of CPAP does not necessarily translate into better health outcomes. Randomized controlled trials comparing CPAP with OAms and varying in baseline OSA severity from mild to severe have shown similar results in improving symptoms such as sleepiness116,208, quality of life209, and simulated driving performance134. In terms of cardiovascular outcomes, there were no differences between the two treatments with respect to short-term effects on blood pressure210 and reducing the risk of mortality in patients with severe OSA211. This comparable effectiveness has been attributed, in theory, to differences in adherence rates. However, to our knowledge, no trial has objectively compared adherence to both treatments and the effect of this adherence on long-term effectiveness. 2.10 OAm Adherence Although a patient is considered adherent to CPAP if the patient uses it for > 4 h per night during 70% of nights, these cutoff values were chosen based on average usage values observed in earlier CPAP adherence studies99 and are not necessarily values that result in optimal outcomes. More recent studies have shown a positive correlation between improvement in outcomes and usage duration100,104. In 2016, the Sleep Apnea Cardiovascular Endpoints trial89 failed to show cardiovascular improvements with CPAP, likely because of low adherence (average of 3.5 h per night). Furthermore, 20% to 50% of patients with OSA are unable or unwilling to comply with CPAP, limiting its long-term effectiveness104. Objective monitoring of CPAP usage has been possible for many years212, but OAm monitoring, until more recently, predominantly relied on self-reporting169. Studies comparing subjective reporting of CPAP adherence with objective data revealed that patients generally overestimate their CPAP usage by 49 approximately 1 hour213,214. Subjective reporting, therefore, is not the most reliable method of evaluating patient adherence, and the studies that have objectively evaluated OAm adherence are still limited. Dieltjens et al215 reported an objective adherence of 6.7 ± 1.3 hour per night over a 3-month period216, which was maintained at > 6 h per night at 1 year. Adherence has been claimed to be higher with OAms than with CPAP172. A thermosensitive microsensor embedded in the OAm can be used to record OAm wear time and, hence, provides the means to assess adherence objectively. The three microsensors that are currently commercially available have shown high accuracy and reliability217. 2.11 Mean Disease Alleviation and Sleep Adjusted Residual AHI OSA is a chronic disease, and the treatments available are not curative; therefore, they are considered lifelong treatments, so adherence to OSA treatment is imperative. Disease alleviation of a treatment that is fully effective results in an AHI < 5 and could be 100% if always used, 0% if never used, and partially effective when sometimes used218. The absolute number of hours a treatment is being used does not seem to be as important as the number of hours of treatment use relative to the total sleeping time. If the patient is using treatment for one-half of the total sleep time, the true AHI is poorly represented by AHI on treatment. Therefore, it has been proposed that treatment comparisons should be made after adjusting for hours of usage over total sleep time205,213. Investigators in previous studies, who found similar health outcomes for CPAP and OAms despite the presence of residual apnea in patients using OAms, hypothesized that the suboptimal efficacy of OAm therapy is counterbalanced by the superior adherence relative to that for CPAP134,219,220. To explain this hypothesis, long-term effectiveness (efficacy and adherence) has been described as the mean disease alleviation221. The mean disease alleviation, expressed as a percentage, is calculated as follows: (adjusted objective adherence x therapeutic efficacy)/100205,215,216. Mean OSA alleviation by means of CPAP has been described as being 52%221, whereas the mean OSA alleviation by means of OAm use was 51%216. 50 Additionally, a Sleep Adjusted Residual AHI (SARAH Index) has been proposed as a more accurate assessment of treatment effectiveness and possibly a better indicator of long-term health benefits. It takes into account the time on and time off treatment relative to the total sleeping time205. Merely using the AHI on treatment to demonstrate therapeutic effectiveness is an oversimplistic approach because it fails to take into consideration the hours per night that the treatment is physically used. It also fails to take into consideration whether the treatment is being used during the time of night with concentrated rapid eye movement sleep and sometimes more severe OSA (rapid eye movement sleep tends to take place more toward the early morning hours, which is the time that most patients typically discontinue using their treatment). It also fails to take into consideration the long-term adherence rate, which is known to decline progressively with all therapies. 2.12 Determinants of OAm Adherence Although adherence to therapy is crucial to achieving long-term effectiveness, predictors of OAm adherence have not been a subject of extensive research, and previous studies were limited to self-reported use and lacked an objective adherence measurement. In a study using mailed questionnaires, the most frequent reasons for discontinuation of OAm use were that it was uncomfortable or had little or no effect222. Only more recently has an objective adherence monitor become available, and the only assessment of the treatment parameters that correlate with objectively measured adherence showed that absence of adverse effects, a decrease in visual analogue scale score for snoring, and a lower baseline AHI were predictors of higher objective mean wearing time at 3-month follow-up223. Being able to predict which patients will adhere to treatment and the treatment that they are most likely to adhere to is a step toward achieving “precision medicine,” a term that refers to “the tailoring of medical treatment to the individual characteristics of each patient”224. 51 Research has shown that medical treatment plans involving and valuing patient participation usually produce the most positive patient outcomes. Studies have shown that patient participation in chronic disease management leads to improved treatment adherence and a higher quality of life225. Efficacy alone is not sufficient for decision making in OSA management. Furthermore, it is neither respectful of patient autonomy nor beneficial for patients to impose a particular option on them, regardless of the clinical evidence for its efficacy. Based on a review that compared patient preference for CPAP with that for OAms226, four of six cross-over trials asking for patient treatment preference at the end of the trial found a higher preference for OAm treatment. One study showed slightly more preference for CPAP, and another study showed an equal preference for both226. Using a discrete choice experiment, Krucien et al227 and Trenaman et al164 highlighted the importance of communicating with the patient prior to the implementation of OSA treatment. Almeida et al228 conducted a qualitative study to understand participants’ perspectives and preferences regarding CPAP and OAms. Results suggested that matching treatment with participant preference could achieve greater therapy adherence and, thus, better health outcomes. 2.13 Combination Therapy It is reasonable to expect that using more than one therapy would lead to additive or synergistic effects, yet studies using a combination of OAms with other therapies are relatively scarce. To our knowledge, only one study investigated the applicability of alternating treatment between CPAP and OAms on a regular basis154. It demonstrated that an enhancement in the reduction of symptoms could be achieved with the availability of both treatments for the patient to use interchangeably. It could be hypothesized that, because patients were less likely to occasionally drop treatment, the long-term effects on alleviating daytime sleepiness were further consolidated. Therefore, a combination of treatments would likely permit greater flexibility and improve treatment outcomes. 52 Dieltjens et al229 evaluated the effect of combining positional therapy in patients with supine-dependent OSA with OAms and found that the combination led to a higher therapeutic efficacy compared with that of each treatment alone. Dort and Remmers230 assessed the combination of an OAm with a tongue-retention bulb and found that the combination could reduce respiratory events compared with results with an OAm without a tongue-retention bulb. A study examining the combination of an OAm with surgery demonstrated that the use of an OAm following uvulopalatopharyngoplasty could keep the cross-sectional area of the stenosis site bigger than could treatment with uvulopalatopharyngoplasty alone146. Attempts to use both OAms and CPAP concomitantly have shown that the combination helps reduce the required CPAP pressure, which increases patient comfort150,151. With only a few trials conducted on OAm combination therapies, there is a paucity of research in this area in which specific patient needs may be addressed. 2.14 Side Effects of OAms Although OAms are well tolerated, there are short-term and long-term side effects associated with therapy. The most common short-term side effects are increased salivation or dryness, pain or discomfort in the teeth or gums, perception of an abnormal occlusion in the morning, muscle tenderness, and jaw stiffness. These side effects being mostly mild and transient178. Long-term side effects are predominantly dental and occlusal changes in the form of retroclination of the maxillary incisors and proclination of the mandibular incisors with subsequent decrease in overjet and overbite, mesial tipping of the mandibular molars, and distal tipping of the maxillary molars231–236. Additionally, increased mandibular arch length and downward rotation of the mandible have been reported by some researchers231,232,236. These long-term changes are usually irreversible. To our knowledge, in the longest follow-up study published to date that assessed side effects (11.1 ± 2.8 years of follow-up), the investigators showed that the mean reductions in overbite and overjet were 1.9 53 and 2.3 mm, respectively233. Studies have shown that the magnitude of the changes is not related to appliance design or to baseline characteristics (such as baseline AHI, BMI) but rather to the duration of therapy and the amount of forward protrusion of the mandible233,234. To our knowledge, all studies published to date assessing OA side effects have relied on self-reporting of appliance usage duration. Although these side effects may seem substantial, they are outweighed by the benefits gained from using an OAm, especially considering the potentially life-threatening nature of OSA. Therefore, patients should not discontinue OAm therapy unless they are willing to adhere to another treatment modality. It is also imperative that the patients are informed of the possible long-term side effects prior to therapy initiation. 2.15 Future Direction: Patient-Centered Medicine Currently, there is an emerging trend towards a shift to P4 medicine, which is medicine that is predictive, preventive, personalized, and participatory where the ultimate objective is to maximize wellness for each individual rather than simply to treat disease237. Although research has been well under way for many decades on OSA management and OAm therapy, still more needs to be known to be able to select a treatment that is targeted to the individual on the basis of the individual’s phenotypic traits instead of using a one-for all approach. Having the ability to readily identify the pathophysiologic traits of OSA at the level of the individual (phenotyping238) will bring us a step closer to being able to prescribe personalized treatment. Furthermore, there is a need to develop validated methods to predict OAm treatment response prior to the initiation of treatment. Being able to choose the ideal treatment on an individual basis prior to treatment initiation will lead to more efficient use of time and resources, as well as avoiding patient frustration and loss of cooperation. To serve the same purpose, predictors of adherence and methods to enhance adherence warrant further investigation. Additionally, developing methods to minimize side effects and mitigate the deleterious 54 effects of treatment, if they occur, are important factors that require greater in-depth study. More rigorous studies are needed to assess whether combination therapies have any added benefits. 2.16 Conclusions Even though many different treatment modalities are available for managing OSA, CPAP and OAms are the most commonly used disease-specific therapies. CPAP has the advantage of greater efficacy, yet OAms remain a viable and promising treatment option that seems to have better patient adherence and acceptance. There is currently no single variable that can reliably predict treatment outcome with OAms, and there is no sole determinant of treatment success, but a constellation of features exist that if present or absent can possibly give an indication of treatment response. Similarly, there is no single ideal OAm design; an ideal appliance is custom made, protrudes the mandible, keeps the vertical opening to a minimum, and can be adjusted to achieve the optimum efficacy while being comfortable and well tolerated by the patient. 55 Chapter 3: Long-Term Side Effects of Sleep Apnea Treatment with Oral Appliances: Nature, Magnitude and Predictors of Long-Term Changes A version of the original paper can be found in the Journal of Sleep Medicine: “Mona M. Hamoda, Fernanda R. Almeida, Benjamin T. Pliska. Long-term side effects of sleep apnea treatment with oral appliances: nature, magnitude and predictors of long-term changes. Sleep Medicine 56 (2019) 184-191”. Summary Oral appliances for the treatment of obstructive sleep apnea (OSA) reduce upper airway collapse by advancing the mandible (OAm) and associated soft tissues. OAm are well tolerated but have side effects, mainly dental movement. It is not yet clear whether there are irreversible skeletal changes associated with treatment. As oral appliance treatment for OSA is a life-long therapy, careful and extended follow-up of patients is required. The objectives of this study were to evaluate the magnitude and progression of the dental and skeletal changes associated with long-term treatment, in addition to determining the predictors of the changes. Lateral cephalograms of adults treated for primary snoring or mild to severe OSA with a custom-made titratable OAm for a minimum of 8 years were retrospectively studied. The magnitude and rate of progression of the changes over time was determined and initial patient and dental characteristics were investigated as possible predictors of the observed side effects. Records of 62 patients with an average treatment time of 12.6 years (range:8-21 years) were included. Cephalometric analysis revealed significant (p<0.001) maxillary incisor retroclination (mean of 6˚) and mandibular incisor proclination (mean of 8˚) over the observation period. Maxillary incisors demonstrated a constant rate of retroclination -0.5˚/year, the rate of mandibular incisors proclination was variable. The number of treatment years was significantly associated with these variables (p<0.001). A greater BMI and 56 ANB were associated with more maxillary and mandibular incisor proclination, respectively. Although statistically significant (p<0.001) skeletal changes were noted, the difference in the SNB and mandibular plane angles were approximately 1° and were deemed not clinically significant. This study represents the longest observation period to date examining OAm side effects with up to 21 years of follow up for some patients. It confirms that there are significant and progressive dental changes with prolonged OAm use. Conversely, over the same time period skeletal or postural changes were negligible. Additionally, treatment duration was the predictor consistently associated with the magnitude of the observed side effects. 3.1 Introduction Obstructive sleep apnea (OSA) is a chronic condition in adults which, at present, has no permanent cure and all currently available treatment options require life-long adherence. An increasingly common treatment option are oral appliances, which protrude the mandible (OAm), improves the upper airway patency and decrease its collapsibility175. The short-term side-effects of OAm treatment have been shown to be mild and transient203,239. Tooth movement leading to changes in occlusion is a common side effect of long-term OAm use. Dental cast analysis and cephalometric analysis have been used to assess the dentoalveolar changes and studies have shown decreased overbite and overjet222,231,233,234,236,240–243, maxillary incisor retroclination and mandibular incisor proclination236,241,244,245, mesialization of the mandibular molars and distalization of the maxillary molars232,241,246 as well as changes in dental arch crowding232,233. These dental changes develop as a result of the forces exerted on the upper and lower dental arches by the oral appliance as it holds the protrusion, resisting the counteracting forces trying to return the mandible to its resting position232. 57 Unlike the data on the dentoalveolar changes that seem to be mostly consistent between studies, data on the skeletal side effects are conflicting with some studies showing skeletal changes244,247 and others showing no such alterations234,239. Furthermore, previous studies have shown contradictory results in terms of the skeletal characteristics that demonstrate changes in addition to contradictory results in relation to the direction of the changes. For example, some have shown changes to be in the position of the maxilla as indicated by the Sella, Nasion, Supramentale point A (SNA) angle but not in the position of the mandible (SNB angle)236 and vice versa241. Similarly, an increase in the vertical dimension of the mandibular plane angle and lower face height has been inconsistently reported234,242. Regarding the direction of change, some have shown a statistically significant decrease in the SNA angle236, an increase in the SNA angle244 or no statistically significant changes in SNA angle232,241,248 . A recent systematic review and meta-analysis has concluded that there are no significant changes in the skeletal variables, however, the duration of follow-up in the included studies that assessed skeletal changes was short243. A common limitation reported in the existing literature on OAm side effects are the relatively short observation periods, leaving the nature of the progression of skeletal and dental changes inadequately characterized considering the life-long need for treatment. It has also been previously speculated that the occlusal changes observed may be a combination of tooth movement and mandibular posturing. The aim of this study is to determine the nature of the occlusal changes associated with long-term oral appliance treatment (i.e., dental and/or skeletal), to evaluate the magnitude and progression of these changes, and to determine if initial patient and dental characteristics are possible predictors of the observed long-term side effects of treatment. 3.2 Materials and methods 3.2.1 Design This observational study evaluated the demographic and radiographic data obtained from adults treated for snoring or mild to severe OSA using an OAm. Patients were referred to the Sleep Apnea Dental 58 Clinic at the University of British Columbia or to an affiliated private practice for their OAm treatment. The OAm used by patients were either Klearway (Space Maintainers Laboratories Canada Ltd., Calgary, Canada) or SomnoDent (SomnoMed, Ontario, Canada). These appliances are custom made and titratable, constructed of a semi-rigid thermoplastic material covering the occlusal surfaces of all teeth. The amount of initial advancement set at two-thirds of maximum protrusion, and then further advancements were prescribed by 0.25-mm increments until self-reported resolution of snoring and daytime sleepiness symptoms, or until uncomfortable for the patient. Optimal titration was then verified by a follow-up polysomnography for the OSA patients. The vertical opening was kept to a minimum to avoid downward rotation of the mandible during use. In the aforementioned clinics, it is standard protocol to obtain lateral cephalometric radiographs prior to the initiation of treatment and with each OAm replacement if the replacements are ³ 1 year apart. Approval for the study was obtained from the UBC Clinical Research Ethics Board H11-01661. Charts and lateral cephalometric radiographs were retrieved for patients who were treated for a minimum of 8 years exclusively with OAm, between 1992 and 2016. Patients were excluded if the pre-treatment radiograph was of a poor quality due to image degradation as determined by a single investigator. The number of lateral cephalograms analyzed for each patient ranged between 2 to 9 and the duration of OAm treatment was calculated as the interval between the date of the initial and most recent cephalogram. 3.2.2 Cephalometric Analysis Pre-treatment and follow-up lateral cephalometric radiographs were obtained with the patients standing upright with their head oriented so that the Frankfurt Horizontal plane is parallel to the floor and the teeth in centric occlusion. 59 A custom-made analysis was developed in the cephalometric analysis software Dolphin (Dolphin® Imaging 11.7, Chatsworth, CA) to include the pre-selected variables of interest. All tracings were conducted by a single investigator (BTP). The main data collected pertained to the sagittal position of the maxilla and mandible, vertical dimension, intermaxillary relation, in addition to maxillary and mandibular dentoalveolar position. Figure 3.1 shows the cephalometric landmarks and reference planes used. 3.2.3 Statistical Analysis The data are presented as the mean values and standard deviations. The magnitude of change in each of the variables was determined to be the difference between the pre-treatment baseline (T0) value and the last follow-up (TF) value. Dental and skeletal characteristics at baseline (T0) and at the last follow-up (TF) were compared using the Student paired t-test in the SPSS statistical package version 21 (SPSS Inc., Chicago, Illinois, USA). A p value < 0.05 was considered statistically significant. The rate of change in the variables that showed statistically significant changes between T0 and TF and the effect of baseline characteristics on dental and skeletal variables were assessed using a mixed-effect polynomial regression analysis. Baseline characteristics of interest included baseline Apnea-Hypopnea Index (AHI), body mass index (BMI), age at the start of treatment, initial Maxillo-Mandibular skeletal relation (ANB), initial mandibular plane angle and number of treatment years as possible predictors of change. The correlation between the dental changes and the number of teeth present at baseline was assessed using the Pearson correlation coefficient. 3.2.4 Method Error To evaluate systematic measurement errors, 22 randomly selected lateral cephalograms were retraced by the same investigator (BTP) 6 month following the initial tracing. The reassessment included all the previously assessed cephalometric measurements and used the same software. Test–retest reliability was 60 calculated using the intraclass correlation coefficient (ICC) in SPSS (version 21). A two-way mixed effects model was used249. 3.3 Results A total of 62 patients (average age at start of treatment: 49 ± 8.6 years) were included in this study and average treatment length was 12.6 years (range: 8-21 years). The baseline characteristics of the study population are shown in Table 3.1. All the cephalometric variables assessed were angular measurements measured in degrees (Figure 3.1). Continuous variables are presented as mean ± standard deviation. Intra-examiner reliability for the measurements showed a high agreement with ICC values ranging from 0.90 to 0.98. Values greater than 0.90 indicating excellent reliability249. Standard deviation of the repeated measures for SNB angle, Mandibular plane Frankfort Horizontal (MPFH) and Sella-Naison line, Gonion, Gnathion (SNGOGn) were 0.8˚, 1.3˚ and 1.3˚, respectively. Table 3.1 Baseline Patient Characteristics N 62 Males/Females 52/10 Angle Classification (CI‡, CII‡‡, CIII‡‡‡) 31/26/4 Age (y) 49.0 ± 8.6 (29-65) BMI (kg/m2) 29.1 ± 6.9 (18.7-63.6) AHI (events/hour) (N=56) 30.0 ± 14.6 (7.4-66.2) Treatment duration (y) 12.6 ± 3.9 (8.0-21.4) Values presented as mean ± standard deviation (range). ‡(ANB 0-5˚), ‡‡(ANB >5˚), ‡‡‡(ANB <0˚) 61 Figure 3.1 The Following Landmarks and Planes Were Identified on Lateral Cephalograms Landmarks: S (sella), center of the sella turcica; N (nasion), deepest point in the concavity of the frontonasal suture; Po (Porion), midpoint of the upper contour of the external auditory canal (Anatomic Porion); Or (Orbitale), a point midway between the lowest point on the inferior margin of the two orbits ANS (anterior nasal spine), tip of the median, sharp bony process of the maxilla; PNS (Posterior Nasal Spine), tip of the posterior nasal spine of the palatine bone, at the junction of the soft and hard palate, A (Point A) deepest point in the concavity of the anterior maxilla; B (Point B), deepest point in the concavity of the anterior mandible; Me (menton), intersection of the bony inferior symphysis with the inferior margin of the mandibular body; Go (gonion), constructed point at the intersection of the ramus plane and the tangent to the lower border of the body of the mandible; Gn (Gnathion), most anteroinferior point on the bony chin. Planes: SN (sella-nasion line), line through the Sella and Nasion; FH (Frankfort Horizontal), a line connecting Porion to Orbitale; PP (palatal plane), a line through ANS and PNS; NA, a line through Nasion and A point; NB, a line through Nasion and B point; U1 (upper incisor line), line through the upper incisor root apex and the upper incisor incisal edge of the most prominent upper incisor; L1 (lower incisor line), line through the lower incisor root apex and the lower incisor incisal edge of the most prominent lower incisor; MP (mandibular plane), a plane from constructed gonion to menton; GoGn, a line through Gonion and Gnathion. 62 3.3.1 Direction and Magnitude of Change 3.3.1.1 Dental Variables Over the total treatment interval evaluated there was significant (p < 0.001) maxillary incisor retroclination (posterior tipping). Upper incisor inclination was assessed relative to multiple reference planes and a reduction of close to six degrees was consistently found (U1SN: -6.1˚ ± 5.9˚, U1FH: -6.3˚ ± 6.2˚, U1PP: -6.3˚ ± 6.0˚, U1NA: -5.9˚ ± 5.6˚) with a large amount of individual variation (Table 3.2 and Figure 3.2). Significant (p < 0.001) mandibular incisor proclination (anterior tipping) was also noted; lower incisor inclination was assessed relative to the MP and the NB plane and the magnitude of change was 7.9˚ ± 6.2˚ and 8.2˚ ± 6.2˚ respectively (Table 3.2 and Figure 3.2). Only one patient had an anterior crossbite indicated by negative overjet pre-treatment, however the number of patients with a negative overjet at their last follow-up was 27 out of the 62 patients (≈44%; see figure 3.3). Table 3.2 Overall Cephalometric Changes During Treatment (n=62) 63 3.3.1.2 Skeletal Variables A significant change in the position of the maxilla, as indicated by the SNA angle was not observed. The average total change in the SNB angle, a measure of the anterior-posterior position of the mandible was a reduction of 0.7˚ ± 1.3˚ (p < 0.001), which coincided with an increase in the ANB angle of 0.43˚ ± 1.1˚ (p=0.005). The SNGoGn and the MPFH angles, measures of the vertical position of the mandible, demonstrated statistically significant changes of 0.9˚ ± 2.1˚ and 1.1˚ ± 2.7˚, respectively, over the total observation period (Table 3.2). Figure 3.2 Individual Variations in the Mean Change of U1SN (A) and L1MP (B) 64 Figure 3.3 Tracing of One of the Study Patient's Initial (T0) and Final (TF) Lateral Cephalograms Showing the Lower Incisor Proclination and Upper Incisor Retroclination. 3.3.2 Rate of Change The rate of change of the upper incisor inclination was constant over the years and was -0.47 ˚, -0.49˚ and -0.49˚/year for U1SN, U1FH and U1PP, respectively (Table 3.3). The rate of change of L1MP and L1NB was variable over the years. While the mandibular incisors on average continued to procline with time, the rate at which this anterior tipping occurred decreased from year to year, as indicated by the declining rate of change. At approximately 19 years of follow up, change in the lower incisor inclination appeared to stop (Figure 3.4). The rate of change of the SNB angle was constant and minimal, -0.05°/year. The rate of change of SNGoGn was inconsistent, however, the amount of change declined over time. 65 Table 3.3 Rate of Change Per Year for Variables That Showed a Statistically Significant Change Between Final and Initial Measurements Variable (in degrees) Rate of change per year Dental U1SN -0.47° U1FH -0.49° U1PP -0.49° U1NA Inconsistent rate of change L1MP Inconsistent rate of change L1NB Declining rate of change that is variable each year Skeletal SNB -0.05° SNGoGn Declining rate of change that is variable each year A negative value indicates a decrease in the angle over time 3.3.3 Predictors of Change Baseline OSA severity, age and number of teeth present at the start of treatment were not associated with the magnitude of changes observed. Contrary to this, the number of treatment years was most significantly associated (p<0.001) with all of the measured cephalometric variables where changes did occur. Baseline patient BMI had a significant effect (p=0.02) on U1SN and on U1PP (p=0.03), where a coefficient of 0.39 indicates that patients with 1unit-higher BMI tend to have on average 0.39˚ less posterior tipping of the maxillary incisors over the years controlling for other variables. Similarly, the initial ANB angle had a significant effect (p<0.001 and p<0.01) on L1MP and L1NB, respectively. A higher ANB angle was associated with more anterior tipping relative to a lower ANB angle, controlling for other variables (Table 3.4). 66 Figure 3.4 All Data Points for the Entire Study Population for U1SN (A) and L1MP (B) in Degrees, As A Function of Number of Years in Treatment. Data for Each Patient Are Connected by a Line 67 Table 3.4 Adjusted Models for the Effect of BMI and ANB Angle on Upper and Lower Incisor Inclination. Variable Predictor Unit change in variable with 1-unit change in predictor (in degrees) P-value U1SN BMI 0.39 0.02 U1PP BMI 0.40 0.02 L1NB ANB CII 10.91 < 0.01 L1MP ANB CI 12.89 0.02 ANB CII 20.19 < 0.001 3.4 Discussion The present study confirms that there is significant dental movement associated with long-term OAm treatment but no clinically relevant skeletal changes. The principal effects noted were a mean of 6˚ of maxillary incisor retroclination and a mean of 8˚ of mandibular incisor proclination. Combined, these changes in incisor inclination resulted in 44% of the study population having a negative overjet at the end of their latest follow-up visit, which on average corresponded to more than 12 years of treatment. Additionally, the observed changes were not reversible over the duration of the study and in fact were progressive in nature with a constant rate of retroclination for upper incisors of −0.5°/year. The rate of change of the lower incisors proclination was not constant; the proclination overall increased with time, but at a declining rate of change year after year. Maxillary incisor retroclination and mandibular incisor proclination have been previously documented in the literature236,244,250 however, our findings indicate that these changes continue to progress over time. The rate of progression of maxillary incisor retroclination was constant for nearly up to 2 decades of treatment. Proclination of the mandibular incisors was also progressive, however, the rate of proclination seemed to decline with prolonged follow up and appeared to stop after approximately 19 68 years of treatment. This decline followed by cessation of proclination may be attributed to the force exerted by the lower lip on the proclined lower incisors which might be counteracting the force created by the OAm. When the opposing forces from the OAm (exerted during OAm use) and from the lower lip (exerted during awake time) are balanced, a state of equilibrium may be reached leading to no net change in the position of the lower incisors. Alternatively, the decline in proclination may be attributed to the inclination of the tooth and the vector of the horizontal force from the OAm acting upon it. A tooth that is already severely proclined may not be as susceptible to further proclination compared to a tooth that is relatively upright. In line with our findings regarding the rate of change in the maxillary and mandibular incisor inclination, it has been previously demonstrated that the maxillary incisors might retrocline an average of 1.9° and the mandibular incisors might procline an average of 2.8°232,248,251 after approximately 2 years of treatment. However, this study is the first to characterize the yearly rate of progression of the dental changes. More recently a systematic review252 reported on data assembled from 18 studies investigating dental and skeletal changes with OAm therapy ranging from a period of 2-11 years. The corresponding meta-regression analysis found that dental side effects are progressive in nature and strongly correlated to the duration of therapy; the longer the treatment time, the greater the magnitude of changes recorded. Also similar to the present study, this systematic review deemed the skeletal changes caused by long-term treatment to be clinically insignificant. Differences between the findings of the various studies in terms of the magnitude of dental changes has been previously observed and could be attributed to several factors including appliance design or material253,254, the amount of mandibular advancement and the adherence to treatment253. Discrepancies in the results of the various studies can also be attributed to the varying observation periods and different sample sizes233. 69 In this study, there was a wide range of individual response to treatment side effects, as indicated by the standard deviations. While 85% of the patients showed maxillary incisor retroclination and 92% of the patients showed mandibular incisor proclination, a few patients showed an opposite response. Notably, two individuals (both Class II at baseline and treated with the Klearway OAm) showed both maxillary incisor proclination and mandibular incisor retroclination. Additionally, the patients who showed change in the opposite direction were mostly the patients with a low AHI. The low AHI may have resulted in reduced appliance advancement or less frequent use of the OAm compared to patients with a higher AHI, hence their teeth were less prone to movement. The number of teeth present at the start of treatment may be a reasonable additional factor determining the distribution of forces exerted on the dentition and consequently, impacting the amount of tooth movement. Our findings do not indicate a correlation between the number of teeth retained at the beginning of treatment and the magnitude of the observed dental changes. Minagi et al have noted a weak negative correlation between the total number of teeth and overjet reduction250. The difference between the findings of the 2 studies could be attributed to the difference in the variables assessed. While Minagi et al assessed the changes in overjet, the present study assessed tooth inclination relative to cephalometric planes. The variability in the findings could also be attributed to the difference in follow up duration between the 2 studies. While there may be a weak correlation observed during a short duration of follow-up, this correlation is not evident with a prolonged follow-up period. The potential influence of appliance material (rigid versus flexible) and design on the magnitude and nature of the occlusal changes is not clear and warrants further investigation. Norrhem et al254 have shown that a flexible type of OAm without incisor coverage increased the irregularity of the lower anterior teeth compared to a more rigid OAm with incisor coverage. However, the overbite and overjet changes were similar between the flexible and rigid type of appliances. Ringqvist et al247 used an OAm with no incisor coverage and reported no significant changes to overjet and overbite over a period of 4 years. This could be attributed to the lack of incisor coverage or to limiting the mandibular protrusion to 70 50% of maximum protrusion which also has been suggested to influence the magnitude of the occlusal changes234. Changes in cephalometric variables were found to be similar between the traction and compression types of appliances255. The findings of this study confirm the findings of Marklund253 and Minagi et al250 who also reported that side effects increase with treatment duration. Our results also show that a higher BMI may have a protective effect against upper incisor retroclination, which may be attributed to the fact that individuals with increased BMI tend to have larger tongues256. During awake time, a large tongue will apply a force onto the lingual surface of the upper incisors and minimize their retroclination, relative to an individual with a smaller tongue. Previous findings by Pliska et al233 indicated no effect of BMI on occlusal changes in their study of dental models, while baseline AHI was positively associated with a reduction in overjet. Our findings also show that a higher ANB angle is associated with greater lower incisor proclination relative to a lower ANB angle. This may be attributed to the amount of OAm advancement, as skeletal Class II patients are often retrognathic and therefore might need greater amounts of advancement and hence greater forces are applied on the teeth leading to more labial tipping. However, the specific relationship between initial ANB angle (degree of retrognathia) and amount of therapeutic protrusion warrants further investigation. Alternatively, the lower incisors in retrognathic patients typically can be tipped labially to a greater extent before they meet an equilibrium with opposing pressure from the lips. In contrast to the present study, baseline AHI has been previously reported to correlate with the amount of overjet reduction. This discrepancy may be due to differences in the nature of the specific measurements (overjet vs. inclination of teeth), and in the length of the observation periods between studies. Similar to previous findings, this study demonstrated a reduction in the SNB angle241,248,257 and an increase in the SNGoGn236,242 and the mandibular plane angle242,247. However, the skeletal changes 71 observed in this study were approximately 1˚ in magnitude and although statistically significant, they are deemed clinically irrelevant, especially considering the standard deviation of the repeated measures of these variables. With prolonged follow up periods extending for over a decade, natural physiologic changes need to be considered. We attribute the skeletal changes recorded in this study, although clinically insignificant, to the physiologic changes that occur during mid to late adulthood. It has been shown that there are significant changes in total face height with aging, mainly due to an increase in the lower anterior facial height258–260. Sarnäs and Solow261 reported a significant increase in total face height of 1.5 mm in 5 years, which was mostly attributed to the increase in lower anterior face height. Bondevik262 reported a significant decrease in the SNB angle in women, while men showed no significant changes. The lack of skeletal contribution to the occlusal changes observed aligns with what is found in the orthodontic literature, where the use of functional appliances for the correction of Class II malocclusion in adults occurs predominantly due to dental movement and not due to skeletal or postural changes. Bock and Ruf263 used a Herbst appliance in adults average age 25.6 years, where the objective was to move the lower jaw and dentition forward. Patients wore the Herbst appliance which was bonded in place and therefore held the mandible forward 24 hours a day for an average treatment time of 9 months. It was found that at long term follow up, the malocclusion was corrected as a result of dentoalveolar tooth movement, rather than the mandible being moved or postured forward. There are some limitations to this study. First, selection bias might be a factor as severe long-term side effects might have caused some patients to discontinue OAm therapy early on and this study attempted to assess patients who could continue OAm treatment long-term. Nevertheless, often occlusal changes go unnoticed by the patients and two previous studies have shown that only 4 to 14%240,264 of patients notice the occlusal changes. Our observations concur with the study of Fritsch et al241 who demonstrated that the benefits experienced from OAm therapy typically outweigh the inconveniences experienced by the patients with therapy and do not lead to discontinuation of treatment in the majority of the cases. 72 Additionally, this study did not objectively assess patient adherence to treatment which may be an important factor when considering the rate of development of side-effects. Even though adherence to OAm treatment was self-reported in routine follow up questions for this study population. In the province where the study was conducted, patients pay out of pocket for oral appliance therapy. Therefore, it is highly unlikely that they would continue to purchase oral appliances if they are not being used continuously. The amount of mandibular advancement has also been suggested as a factor affecting the progression of side-effects250 and although the amount of mandibular advancement was not documented in this study, all patients were optimally titrated, as confirmed by a follow-up polysomnography. This study along with previous investigations, has not assessed the effect of the periodontal condition of the teeth on the magnitude of the tooth movement observed, although these factors may be related and warrant further investigation. Despite the absence of a control group, as there is no justification to obtain routine lateral cephalograms for an untreated population, there is an abundancy of literature describing the progression of dental and skeletal changes in untreated populations. Most studies have shown no physiologic changes to occur in overjet during adult life, indicating that there are no changes in the inclination of the incisors265–267 and confirming that the changes observed in maxillary and mandibular incisor inclination in this study are due to OAm treatment. The strengths of this study include the prolonged follow-up period which averaged 12.6 years and up to 21 years of follow-up for some patients. Unlike most previous studies, a wide range of baseline OSA severities were included in this study with a mean AHI of 30 events/hour, which increases the generalizability of the results. Additionally, this study utilized multiple lateral cephalograms for each patient. Besides the high accuracy and reproducibility of lateral cephalographic measurements, the availability of multiple lateral cephalograms obtained at different time points for each patient allowed 73 for a clear characterization of the progression of the changes and an analysis of the rate at which these changes occurred. Oral appliances are well-tolerated and both objective and subjective assessments of adherence have shown a high adherence rate to treatment215. Long-term side effects are an important aspect of treatment that require further research to mitigate their deleterious effects. However, even major occlusal changes should not deter patients from continuing on OAm therapy if they are not willing to adhere to any other OSA treatment. We continue to believe that effective treatment of a serious and potentially life-threatening condition such as OSA supersedes the maintenance of a stable baseline occlusion233,257. Nevertheless, it is of utmost importance to inform the patient about the long-term side-effects prior to the initiation of treatment and careful and extended follow up of oral appliance patients by a specialized dentist is imperative. Interestingly, dental changes have also been reported with prolonged Continuous Positive Airway Pressure (CPAP) use246,268,269 although the severity of the changes may be different. Due to the inevitable dental movements associated with OAm therapy, we recommend that if a patient is using an OAm for snoring only, the patient should be advised to not use the appliance every night, which will likely decrease the amount of changes in the long term. For OSA patients, a balance between therapeutic effectiveness and side-effects must be reached. 3.5 Conclusion This study represents the longest observation period to date examining OAm side effects, with up to 21 years of follow up for some patients. It confirms that dental changes are inevitable with long-term OAm treatment. Both clinically and statistically significant and progressive dental changes were observed with prolonged OAm use, and over the same time period, skeletal or postural changes of the mandible appear to be negligible. Treatment duration is the factor most strongly associated with the magnitude of the reported dental side effects. 74 Chapter 4: Continuous Positive Airway Pressure, Mandibular Advancement Splints or Both: A Randomized Controlled Trial (CHOICE study) This work will lead to multiple publications in preparation. Summary Obstructive sleep apnea (OSA) management requires life-long adherence to therapy. Continuous Positive Airway Pressure (CPAP) and Mandibular Advancement Splints (MAS) are the two main disease-specific therapies for OSA. The aims of this trial were to assess objective adherence to CPAP and MAS and to evaluate their comparative effectiveness. This trial also aimed to conduct an in-depth analysis on the effects of combining these two therapies as a relatively new and emerging therapeutic option. A multi-center, double-randomized, three-phase (titration/cross-over/observation) trial comparing CPAP and MAS during the cross-over phase and comparing them to the combination of both therapies (alternating use) during the observational phase was conducted. Outcomes were assessed at four main time-points; the end of each one-month on CPAP and MAS and following 1-month and 6-months observation. Outcomes included: objectively measured adherence, efficacy, quality of life measures (QoL), blood pressure, side-effects and preferences. Eighty patients were assessed at baseline, mean pre-treatment REI= 21 events/hour, mean age= 52 (range:24-74) years and 73% were males. Mean percentage efficacy of CPAP and MAS were 90% and 42% respectively. Mean and median hours of adherence (when used) were higher for MAS relative to CPAP (p<0.0001), with similar mean and higher median hours of use (p=0.003) during the observation phase relative to CPAP. Median percentage of nights treatment was used was >90% of nights for all timepoints. During the observation phase 60% of participants used both therapies interchangeably. There was a significant improvement in all QoL measures between pre-treatment and all timepoints, but not 75 between the treatment timepoints. Improvements were more profound for patients who were highly symptomatic pre-treatment. During the cross-over phase and the observation phase of this trial, overall adherence to treatment was high with a greater number of hours of use of MAS compared to CPAP during the cross-over phase. During the observation phase, the majority of the trial participants were using both CPAP and MAS. The availability of both CPAP and MAS helped maintain the high level of adherence observed during the cross-over phase into the observation phase. The high adherence has likely contributed to the clinically significant improvement in the patient-centered outcomes and blood pressure. 4.1 Introduction Obstructive Sleep Apnea (OSA) is a prevalent sleep disorder characterized by recurrent episodes of partial and/or complete obstruction of the upper airway, resulting in sleep fragmentation and oxygen desaturation. Hence, it is associated with a range of neurocognitive270 and cardiovascular consequences271–273. Excessive daytime sleepiness is a common symptom of OSA, which increases the risk of vehicle crashes and occupational accidents40. Additionally, OSA adversely affects the quality of life (QOL)56 and is considered a public health problem274. OSA management requires life-long adherence to therapy and the most widely used disease-specific therapies for OSA are Continuous Positive Airway Pressure (CPAP) and Mandibular-Advancement-Splints (MAS). CPAP involves delivery of pressurized air to the upper airway during sleep83; this splints open the airway preventing it from collapsing. Mandibular Advancement Splints (MAS) are oral appliances that increase upper airway patency by anterior displacement of the mandible and the tongue275,276. The efficacy of both treatments has been widely studied and comparisons between the two treatments consistently show that CPAP has higher efficacy277–280. Despite CPAP’s high efficacy, the mean 76 improvement in health outcomes has been suboptimal205. This has been explained by CPAP’s lower effectiveness, which takes into account not only the efficacy but adherence as well134,205. Previous studies have hypothesized that the sub-optimal efficacy of MAS is counterbalanced by the superior adherence relative to CPAP, resulting in a similar effectiveness for both treatments205. It has been estimated that MAS use is on average 1.1 hour/night longer than CPAP use, based on self-reported adherence281. Smart chips that objectively measure adherence are a relatively recent innovation for MAS that could enable a new and more complete comparison of effectiveness between MAS and CPAP. Understanding patient objective adherence together with treatment efficacy and personal preferences would provide vital information to clinicians that will assist them in choosing the right treatment for their patients. If overall adherence is better understood and consequently improved, the long-term health benefits will be greater. Furthermore, promising results have been previously described with the short-term alternating use of CPAP and MAS that warrant further in depth and longer-term investigation154. The aims of the current trial were to measure and compare objective adherence to treatment for CPAP, MAS and the combination of the two therapies and to evaluate their comparative effectiveness for patients with mild to severe OSA. The aims also included assessing patient preferences before and after treatment. The effects of combining these two therapies as a relatively new and emerging therapeutic option was evaluated in depth. 77 4.2 Methods 4.2.1 Trial Design This multi-center, double-randomized, open-label, two-treatment, three-phase clinical trial consists of a titration/adaptation phase, a cross-over phase and an observational phase. 4.2.2 Study Sites and Patient Population This study was conducted at 3 centers in Canada; the University of British Columbia (UBC), Université de Montréal, and Université Laval. Participants were recruited from hospital-based sleep clinics at each of these centers. Before consenting to the initial trial, participants were told that they will be provided with both CPAP and MAS at no cost. The trial was registered prospectively (ClinicalTrials.gov Identifier: NCT02242617) and approved by the institutional ethics board at UBC (H14-01215), Université de Montréal (14-125-CERES-D(2)) and Université Laval (2015-2434). 4.2.3 Eligibility Criteria Patients were screened by the referring sleep physician for 3 eligibility criteria: (1) treatment naïve (never used CPAP or MAS, nor had surgery for sleep apnea), (2) Apnea Hypopnea Index (AHI) within the range 10 ≤ AHI ≤ 50 with an objective diagnosis of OSA performed ≤ 2 years before recruitment and (3) age 19-75 years old. Inclusion criteria also included (4) Body Mass Index (BMI) of ≤ 35 and (5) presence of ≥ 8 teeth per arch intra-orally. Exclusion criteria included (1) extensive periodontal disease with significant tooth mobility; (2) inability to protrude the jaw; (3) insufficient vertical opening to accommodate treatment with MAS; (4) uncontrolled congestive heart failure that makes it unsafe in the opinion of the investigators for the subject to participate in the trial; (5) coronary artery disease unless stable for at least 6 months and considered by the investigators to have a stable disease; (6) any history of angina, myocardial infarction or stroke; (7) any history of major depressive disorder along with 78 current moderate-severe disease; (8) active cancer management (unless in remission for more than 1 year); (9) known renal failure (with need for dialysis); (10) pregnancy (if a subject becomes pregnant during the trial, the subject will be withdrawn from the trial); (11) history of a near miss or prior automobile accident due to sleepiness within the past 12 months; and/or (12) at nighttime, 30% of the night at ≤ 90% oxygen saturation levels. 4.2.4 Sample Size Calculation The sample size calculation was based on detecting an average difference of 1 hour of adherence between the two treatments as adherence was the primary outcome in this trial. To detect an average difference of 1 hour of adherence between the two treatments required 36 participants to complete both portions of the cross-over study. This calculation assumes a Type 1 error of 0.05 (2-sided), power of 85%, and a within-person standard deviation of 2.0212. One hour is the minimum clinically important difference for an impact on ESS and quality of life282. We anticipated a 10–15% dropout rate during the cross-over study134 thus we needed to recruit 42 participants for the cross-over study. Assuming 25% of the participants were not going to proceed to the trial after the titration phase, we anticipated recruiting 54 to 60 participants to the trial. 4.2.5 Intervention Control intervention was CPAP therapy (DreamStation AutoCPAP, Koninklijke Philips N.V. Netherlands) with built-in adherence monitoring. A nasal mask was the first choice of mask for the participants103 however, either a nasal mask, nasal pillows or oronasal mask was used based on the needs and preferences of the individual participants. CPAP is the first line treatment for OSA, the “experimental” intervention was MAS. The MAS was a custom-made and titratable bibloc (SomnoDent Flex G2, SomnoMed Ltd., Australia) that was initially set at 75% of the participant’s maximum advancement203,283 with an embedded adherence monitoring smartchip (DentiTrac®, Braebon Medical 79 Corporation, Ontario, Canada) as shown in Supplemental Figure 4.1. This temperature-sensitive adherence smart-chip was 10.5 × 8.5 × 4mm in dimension, embedded in the acrylic on the lower right side of the appliance. The Smart-chip sampling rate was 1 measurement every 5 minutes and can store data for up to 180 days, it has shown to be highly accurate and reliable in objectively measuring adherence217,284. 4.2.6 Randomization and Sequence Generation Computer generated randomization lists were prepared by the trial statistician. Participants were randomized twice, first to the order of treatment adaptation/titration and second to the order of treatment during the cross-over phase. Randomization was stratified285 by disease severity (mild/moderate versus severe) and by centre for the first randomization and was stratified by disease severity, centre and treatment adaptation/titration order for the second randomization. Permuted blocks285 of varying sizes have been employed and the unit of randomization was the individual patient. 4.2.7 Allocation Concealment The randomization list was concealed in the data capturing system (REDCap). The order of titration generated by the initial randomization was not revealed to the clinician nor the participant by the research coordinator (who was not directly involved in patient care) until all baseline information was collected. Likewise, the treatment sequence generated from the second randomization was revealed by the research coordinator to the clinician and participant only after the titration phase was complete. 4.2.8 Blinding Blinding of participants and clinicians was not possible due to the obvious differences in interventions. However, the investigator (technologist) assessing the respiratory parameters was blinded to treatment allocation and study timeline. 80 4.2.9 Study Design and Data Collection Methods Baseline: baseline data including medical history, socio-demographic, and completed the following questionnaires: Epworth Sleepiness Scale (ESS); Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10); Chalder Fatigue Questionnaire (CFQ); General Health SF-36 and snoring. Preference was assessed using a decision aid tool. Participants did the baseline at home sleep recording on the night of the baseline visit. Adjustment/titration phase—The order of treatment titration was randomized (first randomization). Titration/adaptation duration for each therapy was 2 to 4 months each, based on the time needed for each participant to achieve optimal titration hence, the total titration/adaptation phase varied between 4 and 8 months. The custom-made MAS was inserted and followed up by a trained and standardized dentist. During the first week on MAS, advancement was maintained at 75% of the maximum advancement in order for the participants to get accustomed to the new appliance. Daily advancements were initiated following the first week of MAS titration and continued until the maximum comfortable mandibular advancement was achieved134. CPAP was given to the participants by a standardized respiratory therapist (RT) and the mask adjusted. Automatic pressure changes were set from 6 to 16cmH2O during the first week of titration. After 1-week, the RT assessed the pressure data and set a fixed pressure at the 95th percentile pressure86. Adequate titration on either treatment was defined as an oxygen desaturation index (ODI) <5 events/hour. Cross-over trial—Following the adaptation/titration phase, participants underwent a 1-week washout period and were re-randomized (second randomization) at the beginning of the cross-over phase to the order of treatment during cross-over. The first treatment was given to the participants for 1 month which was followed by a complete assessment of outcomes at the end of the 1-month period and subsequently the first treatment was returned to the research team. Then participants underwent a 1-week washout 81 period, after which they switched to the second treatment for a 1-month period and all outcomes were assessed. The second treatment was also returned to the research team at the end of this 1-month. Observational trial—Following a 1-week washout, a written report was given to the participants (disclosure of the results) indicating their REI, ODI, ESS and FOSQ-10 scores at baseline, on 1-month CPAP and on 1-month MAS in addition to adherence values during each of the 1-month on CPAP and MAS. Participants then took both treatments home and were free to use on a nightly basis the treatment of their choice, according to their personal preference. All outcomes were assessed after 1-month of observation (at the end of the first month during the observation period) and at the end of the 6-months of observation (total observation period). Additionally, an End of Study questionnaire was completed at the 6-months observation visit. Supplemental Figure 4.2 outlines the study design and Supplemental Figure 4.3 shows the trial’s disclosure letter. 4.2.10 Objective Measures 4.2.10.1 Respiratory Parameters Level 3 home sleep apnea testing (HSAT) was conducted at baseline and the end of each of the 1-month on CPAP and on MAS (Alice NightOne, Respironics Inc., IL, USA). Participants were instructed to undergo a single night of testing at all previously mentioned timepoints. Recordings were considered acceptable if they were a minimum of 4 hours/night25. Participants were asked to indicate their sleep and wake up time for the night of testing using a sleep diary. All sleep studies in all the trial centers were manually scored according to the 2017 American Academy of Sleep Medicine scoring guidelines286 and by the same sleep technologist, who was blinded to the patients’ treatment allocation and trial timeline. Efficacy was indicated by the respiratory event index (REI) and the oxygen desaturation index (ODI 3%). Percentage efficacy was calculated as the (REI at baseline-REI on treatment) x 100/ REI at baseline287. 82 4.2.10.2 Objective Adherence Calculation MAS adherence readouts were obtained at the end of the 1-month on MAS, 1-month observation and 6-months observation. The following variables were calculated for CPAP and/or MAS for each of the 1-month periods and the observation period (6 months): (1) mean adherence (h/night) calculated over the nights the device was used (> 0 hours); (2) mean adherence (h/night) calculated over all nights (total duration); (3) median adherence (h/night) calculated over the nights the device was used; (4) percentage of nights used from the total duration; (5) percentage of nights with usage >4hours (when used) and; (6) percentage of nights with usage >4hours (over the total duration). Patients were then classified into (7) compliant users if the mean treatment usage rate was ≥4 hours/night99,215,223 and into (8) regular users if there were ≥70% of nights with at least 4 hours/night of use288 (9) frequent users if there were ≥70% of nights with at least 4 hours/night during the total duration288 and (10) non-adherent if usage was less than 1 h/night over duration of treatment289. 4.2.10.3 Classification of Adherence During the Observation Period Adherence during the 6-months observation period was divided into 5 groups: (1) participants who were adherent to using both treatments interchangeably (used treatment in total for ≥70% of nights with at least 4 hours/night); (2) adherent to CPAP-only (used CPAP for ≥70% of nights for ≥ 4 hours/night); (3) adherent to MAS-only (used MAS for ≥70% of nights for ≥ 4 hours/night); (4) partially adherent to the interchangeable use of both treatments (used treatment for <4 hours/night or <70% of nights and for >1 hour/night of use and; (5) non-adherent (used treatment for ≤ 1hour/night). 4.2.10.4 Blood Pressure (BP) At baseline and at the end of the 1-month on CPAP, 1-month on MAS, 1-month observation and 6-months observation, office BP readings were recorded on the dental chair using an automated Omron 83 BP monitor HEM-780 (OMRON Healthcare, Kyoto, Japan). Participants were in the seated position for at least 10 minutes prior to the first BP reading, and reporting was on the average of two measurements of the left arm taken five minutes apart, following the guidelines of the American Heart Association290. Participants were classified as Stage 1 or 2 hypertensive based on the American Heart Association’s 2017 guidelines291. 4.2.10.5 Body Mass Index (BMI) Height was recorded at the baseline visit and weight was recorded at baseline and at the end of the 1-month on CPAP, 1-month on MAS, 1-month observation and 6-months observation using the same weight scale with shoes and jackets off. 4.2.11 Self-reported Measures 4.2.11.1 Total Sleep Time A sleep diary was given to participants at the beginning of the 1-month on MAS and CPAP, and first month of observation. Participants were instructed to complete the diary every morning, indicating their daily hours of sleep during each of these 1-month periods. Diaries were returned to the research team at the end of each of the 1-month periods. The following validated questionnaires were administered at the following timepoints- baseline and at the end of the 1-month on CPAP, 1-month on MAS, 1-month observation and 6-months observation: (1) Epworth Sleepiness Scale (ESS): Daytime sleepiness was assessed using the ESS, a widely used questionnaire with good internal consistency (Cronbach’s alpha statistic = 0.74 to 0.88). Scores range between 0 and 24, lower scores indicate less daytime sleepiness72 and scores >10 indicate excessive daytime sleepiness73. 84 (2) Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10): FOSQ-10, the short version of the original 30-item FOSQ questionnaire69, was used to assess the impact of OSA on everyday activities and the effectiveness of interventions. Internal consistency of FOSQ-10 is alpha = 0.87 and scores range between 0 and 20, higher scores indicate better outcomes70. Scores <17.9 indicate sleep-related disease specific functional impairment69. (3) Chalder Fatigue Questionnaire (CFQ): This 11-item scale was used to assess fatigue. Items 1 to 7 measure physical fatigue and items 8 to 11 measure mental fatigue. The global score ranges between 0 and 33. Higher scores indicate worse outcomes. Internal consistency of CFQ is alpha = 0.9080,81. A cut off score >17 donates clinically significant fatigue82. (4) General Health SF-36: The short form of the general health survey (SF-36) is a widely used generic quality-of-life measurement tool. It is divided into a mental health component (MCS) and a physical health component (PCS)58. Scores range between 0 and 100, the higher the score the less disability and scores below 36 indicate more disability292. 4.2.11.2 Snoring Loudness Snoring was assessed using a horizontal visual analogue scale223,293 at baseline and at the end of the 1-month on CPAP, 1-month on MAS, 1-month observation and 6-months observation. 4.2.11.3 Preference Assessment A previously developed patient Decision Aid (PtDA) tool164 was administered to the recently diagnosed, treatment-naïve OSA patients at the baseline visit (prior to the first randomization). This web-based PtDA is an interactive application that describes the characteristics of two first-line treatment options: CPAP and MAS. The PtDA provides background information on OSA, value 85 clarification exercises that help patients consider which attributes of treatment matter most to them, an opportunity to indicate their treatment preference, a quiz to test knowledge, and ends with a summary screen that can be shared with their care provider. Seven attributes were included in the PtDA and patients were asked to rate the relative importance of each. These attributes were: (1) reduction in cardiovascular disease risk; (2) degree of side-effects; (3) reduction in daytime sleepiness and fatigue; (4) number of apneas; (5) snoring and noise; (6) convenience/transport; and (7) cost. Preference at the end of the trial was assessed using via a questionnaire using a Likert scale293 that asked patients if they prefer CPAP, MAS both equally or if they prefer no treatment. 4.2.11.4 Willingness to Pay Out of Pocket for Treatment At the end of the trial, participants were asked to indicate their willingness to pay out of pocket for CPAP and MAS (during an approximately 3-year period) with values ranging between $0 to $4000 or more, with $500 intervals. They were also asked to indicate their total yearly household income with options ranging from less than $20,000 per year to greater than $150,000 per year. 4.2.11.5 Side-effects Side effects were assessed at the following time-points: at the end of CPAP and MAS adaptation/titration, at the end of the 1-month on CPAP and MAS and at the end of the 1-month and 6-months observation. The validated side-effects to CPAP treatment inventory (SECI) questionnaire (internal consistency Cronbach’s alpha= 0.74-0.86) was used to assess CPAP side-effects294. A standardized UBC side-effects questionnaire was used to assess MAS side-effects295,296. Participants were asked to complete the side-effects questionnaires during the observation period only for the treatment that they had used during that period, if they had used only one. 86 4.2.12 Measures of Treatment Effectiveness Mean Disease Alleviation (MDA)216,221 and the Sleep Adjusted Residual AHI (SARAH Index)205,297 were calculated as measures of treatment effectiveness for participants who were responsive in terms of efficacy for the 1-month on CPAP, 1-month on MAS, 1-month and 6-months observation. For both MDA and SARAH index, total sleep period was obtained from the sleep diaries205 of the corresponding time periods (1-month on CPAP, 1-month on MAS and 1-month observation). The MDA was calculated as the product of the percentage efficacy and the adjusted objective adherence216,221. The SARAH Index calculation was the product of REI on treatment and the time (in hours) on treatment added to the product of the REI off treatment and the time (in hours) off treatment, divided by the total sleep time205. Both the MDA and SARAH Index calculations were done for each study participant for each of the aforementioned time periods. 4.2.13 Relationship between Hours of Treatment Usage and Normalization of Symptoms in Highly Symptomatic Participants Cut off scores for ESS, FOSQ, CFQ and SF-36 to be considered highly symptomatic at baseline have been described earlier. Adherence for this analysis was calculated only as the mean hours of daily treatment use over the entire follow-up period (including nights with zero hours of use)73. 4.2.14 Statistical Analysis Data is reported as means ± SD, numbers and frequencies have been reported for baseline characteristics and treatment preferences. Continuous variables were tested for normal distribution. For normally distributed variables, mixed models for repeated measures within subject, with sequence, treatment, center and visit as fixed-effects terms and participant as a random-effects term were used298. Likewise, 87 the corresponding non-parametric mixed models for repeated measures within subject, with sequence, treatment, center and visit as fixed-effects terms and participant as a random-effects term were used for non-normally distributed data298. All statistical analyses were corrected for multiple comparisons. Pearson Correlation was used to assess correlations between parametric continuous variables. Significance level was set at p < 0.05, and all tests were 2-tailed. An intention to treat analysis was performed for the primary outcome, adherence and for the respiratory parameters. Multiple imputation in SPSS Markov chain Monte Carlo method using linear regression was used for prediction of the missing values299. Missing data were assumed to be missing at random and five sets of missing were produced and aggregated300. Data was analyzed using SAS® software (SAS version 9.4, SAS Institute, Inc) or SPSS software (SPSS version 28, Statistical Package for Social Sciences, SPSS Inc., Chicago, Illinois, USA). 88 4.3 Results 4.3.1 Participants Eighty-one participants were randomized in the first randomization; one did not fulfill the trial’s selection criteria and hence did not proceed with the trial and was excluded from the baseline analysis. For the 80 eligible participants, mean REI at baseline was 21 events/hour, mean age was 52 (range: 24-74) years and 73% were males (as shown in Table 4.1). Sixty-one were Caucasian, 7 Asian, 4 Middle Eastern, 4 Hispanic and 4 Black. Twenty-eight were recruited at the University of British Columbia (UBC) center, 26 at Université Laval and 27 at Université de Montréal for the initial randomization. Seven dropped out during the adaptation/titration phase and one was withdrawn due to failure to meet the inclusion/exclusion criteria. Seventy-three were randomized in the second randomization (Figure 4.1). Therefore, 73 participants were assessed using an intention to treat (ITT) analysis for adherence and efficacy. All participants adhered to their randomization groups throughout the trial and participant enrollment took place between November 2015 and September 2017. 89 Table 4.1 Baseline Characteristics for the Study Population Parameter Mean (SD) or Frequency Range Age, years 52.3 (10.7) 30-74 Sex, M/F 58/22 -- Diagnostic OSA Severity* Type I sleep study (N= 43) AHI, events/hour 32.4 (15.2) 11-71 Type III sleep study (N= 34) REI, events/hour 32.9 (13.7) 11-59 Type IV sleep study (N= 1) ODI, events/hour 32.8 -- Baseline OSA Severity** REI, events/hour (N=78) 21.1 (14.5) 1-61 ODI, events/hour (N=78) 20.2 (13.7) 1-56 BMI, kg/m2 28.4 (3.8) 18.6-34.8 BMI (normal/overweight/obese) 14/36/29 -- Neck circumference, cm 39.5 (12.3) 30-47.5 Mean Office Systolic BP mmHg 128.5 (21.1) 100-183 Mean Office Diastolic BP mmHg 83.8 (13.9) 62-117 ESS, score 10 (5.6) 0-22 High ESS score (N=34) 15 (3.6) 11-22 FOSQ, score 15.4 (2.9) 9.7-20 Low FOSQ score (N=65) 14.5 (2.5) 9.7-17.7 CFQ, score 16.8 (5.8) 1-32 High CFQ score (N=35) 22.2 (3.8) 18-32 SF-36 MCS score 45.2 (10.7) 19.8-62.9 Low MCS score (N=19) 30 (4.5) 19.8-35.8 PCS score 50.1 (6.7) 25.6-61.5 Bed partner (Y/N) 48/32 -- Snorer (Y/N) n=77 73/4 -- Educational level (high school/higher education) 11/69 -- Occupational status (employed/retired/sick leave/other) 61/11/4/4 -- *Diagnostic OSA severity is based on the initial method of diagnosis- Type I, III or IV sleep study and the number of participants diagnosed by each method ** Baseline OSA severity is the severity based on the Type III sleep study done at baseline N=80 unless indicated otherwise Abbreviations: SD, Standard Deviation; OSA, Obstructive Sleep Apnea; AHI, Apnea-hypopnea Index; REI, Respiratory Event Index; ODI, Oxygen Desaturation Index; BMI, Body Mass Index; M, Male; F, Female; Y, Yes; N, No; BP, blood pressure; ESS, Epworth Sleepiness Scale; FOSQ, Functional Outcomes of Sleep Questionnaire; CFQ, Chalder Fatigue Questionnaire; SF-36, Short Form of Health Survey; MCS, Mental Component Summary; PCS, Physical Component Summary; N, Number of Participants. 90 Figure 4.1 Study Flow Chart 91 4.3.2 Numbers Screened, Trial Completion Rate and Drop-outs Screening data was available from two of the trial centres, UBC and Université de Montréal. Fifty-four patients were screened at UBC and 26 of them did not participate of which 17 did not meet the inclusion/exclusion criteria and 9 declined. At the Université de Montréal 40 patients were screened and 13 of them did not participate, of which 6 of them did not meet the inclusion/exclusion criteria and 7 declined. Overall trial completion rate was 78% based on the initial number randomized. The lowest completion rate was at the Université de Montréal where it was 50%. The majority of the dropouts were attributed to inability to adhere to the study timeline due to the length of the trial and frequency of follow up visits. Logistic issues at the Université de Montréal regarding participants’ follow ups and recalls have resulted in a higher inability to adhere to the trial protocol relative to other trial centers. 4.3.3 Treatment Efficacy: Mean (SD) percentage efficacy of CPAP and MAS were 90 ± 12.6% and 42 ± 48.5% respectively based on the ITT analysis. For MAS, percentage efficacy was highest for the most severe OSA group at baseline, 51 ± 37% followed by the moderate OSA group, 36 ± 48 % and the mild OSA group, 34 ± 41%. The percentage of participants who were in the mild, moderate and severe OSA groups at baseline as indicated by the HSAT was 39%, 31% and 30% respectively. ITT analysis was done for REI and ODI 3%. Both CPAP and MAS were able to reduce REI and ODI significantly relative to baseline (p<0.0001). CPAP was more effective at doing so (p<0.0001). Mean CPAP-MAS difference (95% confidence interval) for REI and ODI were 10.4 (7.8-13) and 9.8 (7.3-12.2) respectively (Table 4.3). There was no effect of sequence (MAS-CPAP or CPAP-MAS) or study center on REI or ODI. 92 Table 4.2 Efficacy of CPAP and MAS as Indicated by HSAT Baseline CPAP MAS ΔCPAP-Baseline Difference (95% CI) ΔMAS-Baseline Difference (95% CI) ΔCPAP-ΔMAS Difference (95% CI) ITT analysis REI (events/hour) 21.8 ± 14.4 2.2 ± 2.2 12.6 ± 11.3 19.6 (16.4-22.8)* 9.2 (6.5-11.9)* 10.4 (7.8-13.0)* ODI 3% (events/hour) 20.9 ± 13.6 2.2 ± 2.2 11.9 ± 10.9 18.8 (15.8-21.8)* 9.0 (6.5-11.5) 9.8 (7.3-12.2)* Per protocol analysis REI (events/hour) 22.1± 14.7 2.2 ± 2.3 12.7 ± 11.7 19.8 (15.7-24.0)* 9.4 (5.8-12.9)* 10.5 (7.7-13.3)* ODI 3% (events/hour) 21.3 ± 13.9 2.2 ± 2.3 12.1 ± 11.2 19.1 (15.2-23.0)* 9.2 (5.9-12.5)* 9.8 (7.2-12.5)* REI Supine (events/hour) 33.1 ± 23.1 3.3 ± 4.7 17.1 ± 16.3 29.6 (23.4-35.8)* 16.3 (11.1-21.4)* 13.7 (10.0-17.4)* REI non-supine (events/hour) 14.7 ± 17.3 2.7 ± 5.6 10.2 ± 13.3 12.0 (6.9-17.2)* 4.5 (0.2-8.9)* 7.5 (4.6-10.4)* All measurements are described as mean ± SD. *Statistically significant at P <0.0001 N= 73 for ITT analysis and N=68 for Per Protocol Analysis. Abbreviations: HSAT, Home Sleep Apnea Testing; CPAP, Continuous Positive Airway Pressure; MAS, Mandibular advancement Splint; ITT, Intention to Treat; CI, Confidence Interval; REI, Respiratory Event Index ODI, Oxygen Desaturation Index; SD, Standard Deviation; Δ, Difference 4.3.4 Adherence During 1-month on MAS, 1-month on CPAP, 1-month on Observation and 6-months on Observation Adherence during the 1-month on CPAP and 1-month on MAS was compared using the ITT analysis. As shown in Table 4.3A, the mean and median number of hours of adherence were significantly greater for MAS (p<0.01) compared to CPAP with 1.1 hours/night higher mean number of hours of adherence for MAS (when used). Percentage of nights of use was significantly greater for CPAP (p<0.01) with a 5.8% difference. The percentage of nights with >4 hours of use (when used) was greater for MAS (p<0.01). 93 Mean ± SD objectively measured number of hours of adherence to therapy (when used) in the per-protocol analysis were 5.9±1.6, 7.0±1.2, 6.2 ± 2.1 and 6.3±1.6 (h/night) for each of the 1-month on CPAP, MAS, observation and the 6-months observation respectively (Figure 4.2A and Table 4.3B). There was a statistically significant difference (p<0.0001) between mean therapy usage (when used) for the 1-month on MAS as compared to all the other timepoints (1-month CPAP, 1-month and 6-months observation) with higher usage during the 1-month on MAS and a difference of 1.1 hours/night between MAS and CPAP treatment usage. There was also a significant difference in mean usage between the 1-month on CPAP and 1-month observation (p=0.0003) with more hours of treatment usage during the observation period. Mean ± SD objectively measured number of nights/week with treatment usage were 6.1±1.4, 5.8±1.6, 5.9 ± 1.8 and 5.5±2.0 and the percentage of nights of treatment usage was 87.2 ± 20.6%, 83.2 ± 23.6%, 83.7 ± 26.2% and 78.8 ± 27.6% for each of the 1-month on CPAP, MAS, observation and the 6-months on observation respectively (Figure 4.2B and Table 4.3B). There was a statistically significant difference (p<0.0001) between the number and percentage of nights CPAP was used as compared to the 6-months observation with 8% more usage during the 1-month on CPAP. The reminder of adherence variables are described in tables 4.3A for the ITT analysis and 4.3B for the per protocol analysis. For all adherence variables, adherence during the 6-month observation period also included adherence during the 1-month observation. As shown in Table 4.4, the percentage of ‘compliant users’ was highest for 1-month MAS (95%) followed by the 6-months observation (93.7%) and the 1-month CPAP (86.6%). Similarly, the percentage of ‘regular users’ was highest for 1-month MAS (90%) followed by the 6-months observation (85.7%) and the 1-month CPAP (80.6%). The percentage of ‘frequent users’ was highest for the 1-month MAS (76.7%), followed by the 1-month CPAP (71.6%) and the 6-month observation (66.7%). 94 Figure 4.2 Adherence Pattern at the Different Timepoints A) Mean number of hours treatment was used (when used) during the 1-month CPAP, 1-month MAS, 1-month observation and 6-months observation. B) Percentage of nights treatment was used during the 1-month CPAP, 1-month MAS, 1-month observation and 6-months observation. Abbreviations: CPAP, Continuous Positive Airway Pressure MAS, Mandibular Advancement Splint; Obs, Observation Period; %, Percentage 95 Table 4.3 (A) Intention to Treat Analysis for Objectively Measured Adherence During the Cross-over Phase of the Trial (n=73). (B) Per Protocol Analysis for Objectively Measured Adherence at the Different Time Points A) Parameter CPAP MAS p-value Number of hours Mean number of hours used (when used) 5.9 ± 1.6 7.0 ± 1.1 <.0001 Median number of hours used (when used) 6.0 ± 1.6 7.0 ± 1.2 <.0001 Mean number of hours of use (total duration) 5.3 ± 2.0 6.0 ± 2.0 0.0002 Number of nights Percentage of nights/week with treatment usage 86.7 ± 19.9 80.9 ± 22.2 0.0056 Percentage of nights and number of hours Percentage of nights with usage >4 hours (when used) 81.8 ± 25.4 89.0 ± 17.8 0.0062 Percentage of nights with usage >4 hours (total duration) 73.4 ± 30.0 77.0 ± 25.6 0.71 B) Parameter CPAP MAS 1-month observation 6-months observation p-values a,b,c,d,e Number of hours Mean number of hours used (when used) 5.9 ± 1.6 7.0 ± 1.2 6.2 ± 2.1 6.3 ± 1.6 <.0001, 0.0003, 0.02, 0.002, <.0001 Median number of hours used (when used) 6.0 ± 1.7 7.0 ± 1.3 6.4 ± 2.0 6.5 ± 1.7 <.0001, <.0001, 0.003, 0.03, 0.003 Mean number of hours of use (total duration) 5.3 ± 2.1 6.0 ± 2.1 5.7 ± 2.4 5.3 ± 2.3 0.0008, 0.006, 0.90, 0.27, 0.001 Number of nights Mean number of nights/week with treatment usage 6.1 ± 1.4 5.8 ± 1.6 5.9 ± 1.8 5.5 ± 2.0 0.07, 0.21, <.0001, 0.39, 0.03 Percentage of nights/week with treatment usage 87.2 ± 20.6 83.2 ± 23.6 83.7 ± 26.2 78.8 ± 27.6 0.06, 0.23, <.0001, 0.36, 0.02 Percentage of nights and number of hours Percentage of nights with usage >4 hours (when used) 81.9 ± 26.3 92.0 ± 17.9 83.4 ± 27.9 84.8 ± 20.9 0.0001, 0.11, 0.29, 0.03, <.0001 Percentage of nights with usage >4 hours (total duration) 74.2 ± 31.0 78.8 ± 27.7 74.7 ± 32.0 70.5 ± 30.4 0.45, 0.62, 0.05, 0.76, 0.003 Data are presented as mean ± SD. Statistically significant p-values following correction for multiple comparisons are in bold. 96 Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; SD, Standard Deviation a, CPAP vs MAS; b, CPAP vs 1-month observation; c, CPAP vs 6-months observation; d, MAS vs 1-month observation; e, MAS vs 6-months observation. A non-parametric ANOVA statistic was for repeated measures within subject, with sequence, treatment and visit as fixed-effects terms and participant as a random-effects term. Table 4.4 Treatment Adherence and Effectiveness Measures CPAP MAS 1-month observation 6-months observation Percentage of regular users (mean use rate of ≥ 4hrs/night on ≥ 70% (when used)) 80.6 90.0 82.5 85.7 Percentage with 50% reduction in REI 69.7 42.0 66.7 61.8 Percentage with SARAH Index <10 78.8 52.0 70.0 65.5 Percentage with SARAH Index <10 and 50% reduction from baseline REI 65.2 32.0 58.3 49.1 Mean ± SD number of hours treatment was not used/night 1.2±1.7 0.5±1.2 1.1±2.1 1.0±1.6 Percentage of compliant users (mean ≥ 4hrs/night) 86.6 95.0 82.5 93.7 Percentage of frequent users (mean use rate of ≥ 4hrs/night on ≥ 70% (All days)) 71.6 76.7 73.0 66.7 Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; SD, Standard Deviation; SARAH Index, Sleep Adjusted Residual AHI; REI, Respiratory Event Index. 4.3.5 Total Sleep Time and Time Off-treatment Mean ± SD total sleep time for 1-month CPAP, MAS and observation were 7.1±1.9, 7.5±1.0 and 7.3±2.2 h/night. Mean total time off treatment per sleep time was highest for the 1-month CPAP, mean ± SD for the 1-month CPAP, MAS and observation and 6-months observation were 1.2±1.7, 0.5±1.2, 1.1±2.1 and 1.0±1.6 h/night respectively (Table 4.4). 97 4.3.6 Treatment Usage Pattern During the Observation Phase During the 6-months observation period, there were different treatment usage patterns (Figure 4.3): 21.5% of the participants who completed the trial were adherent to CPAP-only. Similarly, 9.2% were adherent to MAS-only and 7.7% were considered non-adherent and the majority of participants (60%) chose to use both treatments. Having both treatments to use at home, and the freedom to choose on a nightly basis the treatment to use has allowed 59% of the group who used both treatments to reach or exceed the ≥ 4hrs/night on ≥ 70% of nights. Twenty percent of participants were alternating between the therapies within the same nights and the remaining participants who used both alternated between the nights. For those who alternated between nights, a few of them tended to follow a constant pattern and the majority did not follow a specific pattern. Figure 4.3 All Participant’s individual Objective Adherence Data for 6-months Observation (Following the Cross-over Phase) Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint. 98 4.3.7 Treatment Usage Pattern During the Observation Phase and Changes in Symptoms Symptom improvement was assessed during the observation period based on the 5 adherence groups during observation: (1) participants who were adherent to using both treatments used interchangeably; (2) adherent to CPAP-only; (3) adherent to MAS-only; (4) partially adherent to the interchangeable use of both treatments and the (5) non-adherent. Groups 1, 2 and 3 were the highly adherent groups, using therapy for ≥ 4hrs/night on ≥ 70% of nights. Upon comparing the change in questionnaire scores (ESS, FOSQ-10, CFQ, MCS and PCS of SF-36) between baseline and the end of the observation period, there were no statistically significant differences between the groups based on adherence. As shown in Figure 4.4, not only did the non-adherent group fail to show an improvement in the FOSQ-10, the CFQ, and PCS questionnaire scores, the mean change indicated a worsening in the outcome of these questionnaires based on the change in score for this group. The partially adherent group showed some improvement in the outcomes of the questionnaires (except for the PCS component of SF-36 which also showed worsening) and the 3 highly adherent groups showed similar mean improvements in questionnaire scores. 99 Figure 4.4 Change in Questionnaire Scores by Adherence Group During the 6-months Observation Period Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; Δ, Difference; ESS, Epworth Sleepiness Scale; FOSQ-10, Functional Outcomes of Sleep Questionnaire; CFQ, Chalder Fatigue Questionnaire; MCS, Mental Component Summary; PCS, Physical Component Summary. Mean Δ B aseline-6 months Observation MAS adherent only n=6 FOSQ-10 ESS CFQ PCS MCS Adherent to both n= 29 CPAP adherent only n=14 MAS adherent only n=6 Partially adherent n=10 Non-adherent n=5 Adherent to both n= 29 CPAP adherent only n=14 Partially adherent n=10 Non-adherent n=5 MAS adherent only n=6 Adherent to both n= 28 CPAP adherent only n=14 Partially adherent n=10 Non-adherent n=5 MAS adherent only n=6 Adherent to both n= 29 CPAP adherent only n=14 Partially adherent n=10 Non-adherent n=5 MAS adherent only n=6 Adherent to both n= 29 CPAP adherent only n=14 Partially adherent n=10 Non-adherent n=5 Mean Δ Baseline -6 months Observation Mean Δ Baseline -6 months Observation Mean Δ B aseline-6 months Observation Mean Δ B aseline -6 months Observation 100 4.3.8 Correlation Between Frequency and Duration of Treatment Use We examined the strength of the association between the frequency (the percentage of nights treatment was used) and duration of treatment use (number of hours treatment was used on these nights) during each of the 1-month on CPAP, 1-month on MAS and during the 6-months observation period. The correlation between the frequency and duration of use was moderate (r= 0.55, p<0.0001) for CPAP and was strong for MAS (r= 0.74, p<0.0001) indicating that MAS was used for long number of hours during the nights used. The correlation during the 6-months observation period was r= 0.65 (p<0.0001). 4.3.9 Blood Pressure: Just over a quarter of our sample (21 out of the 80 participants) indicated that they were hypertensive at baseline and only 2 of them indicated that they are not on BP medication. 4.3.9.1 Mean SBP (Total Study Population) There was a statistically significant reduction in mean SBP between baseline and 1-month MAS (p=0.02), with a mean difference (95% confidence interval) of 4.6 (0.4-8.8) mmHg and between baseline and 6 months observation (p= 0.046), with a mean difference (95% confidence interval) of 6.7 (0.1-13.2) mmHg. The reduction in mean SBP was not statistically significant for neither the 1-month CPAP (p= 0.7) with a mean difference (95% confidence interval) of 3.5 (-2.0 to 8.9) mmHg nor for the 1-month observation (p= 0.3) with a mean difference (95% confidence interval) of 4.6 (-1.5 to 10.7) mmHg. There was also no statistically significant difference in SBP between all the different treatment timepoints. Figure 4.5A shows the mean SBP at the different timepoints. 4.3.9.2 Mean DBP (Total Study Population) There was a statistically significant reduction in mean DBP between baseline and 1-month CPAP (p= 0.02), 1-month MAS (p=0.002) and 6 months observation (p= 0.03). The mean difference (95% confidence interval) for 1-month 101 CPAP, 1-month MAS and 6 months observation relative to baseline were 4.8 (0.5-9.2) mmHg, 4.7 (1.2-8.3) mmHg and 5.2 (0.3-10.2) mmHg respectively. There was no statistically significant difference in DBP between all the different treatment timepoints. Additionally, there was no effect of sequence of device (MAS-CPAP or CPAP-MAS) or time on neither SBP nor DBP during the cross-over phase. Figure 4.5B shows the mean DBP at the different timepoints. A) Systolic Blood Pressure B) Diastolic Blood Pressure Figure 4.5 Mean Blood Pressure at the Different Timepoints Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; Obs, Observation. *Statistically significant at P<0.05 4.3.9.3 BP Analysis (for the Subset of the Study Population with elevated BP at Baseline) Seventy-four percent of the study participants were considered to be Stage 1 or 2 hypertensive at baseline based on the objective BP measurements. There was a statistically significant reduction (p<0.05) in SBP for the Stage 1 and 2 hypertensive subset of participants relative to baseline at all timepoints except for 1-month CPAP, with a greater mean difference relative to the total population. Mean difference (95% confidence interval) for 1-month MAS, 1-month and 6-months observation were 6.7 (1.8-11.6), 7.6 (0.6-14.6) and 9.6 (2.2-17.1) respectively. Similarly, there was a statistically significant reduction (p<0.001) in DBP for the Stage 1 and 2 hypertensive subset of participants 102 relative to baseline at all timepoints with a greater mean difference relative to the total population. Mean difference (95% confidence interval) for 1-month CPAP, 1-month MAS, 1-month and 6-months observation were 6.9 (2.0-11.7), 5.8 (1.8-9.9), 7.0 (1.8-12.2) and 8.1 (2.6-13.5) respectively. There was no statistically significant differences in SBP and DBP between all the different treatment timepoints. 4.3.10 BMI There was no statistically significant difference in BMI between any of the 5 timepoints. 4.3.11 QoL Questionnaires 4.3.11.1 ESS Scores (Total Study Population) There was an improvement in daytime sleepiness demonstrated by a statistically significant reduction in ESS scores (p<0.0001) at all timepoints relative to baseline. Mean difference (95% confidence interval) for CPAP, MAS, 1-month and 6-months observation relative to baseline of 3.6 (2.2-5.0), 3.2 (2.2-4.3), 3.7 (2.1-5.4) and 3.9 (2.1-5.7) points respectively. There were no statistically significant differences between the treatment timepoints as shown in Table 4.5. 4.3.11.2 ESS Scores (for the Subset of the Study Population who were Highly Symptomatic at Baseline) Forty-six percent of the study participants were considered to be excessively sleepy pre-treatment. There was also a statistically significant reduction in ESS scores (p<0.0001) at all timepoints in the excessively sleepy subset relative to baseline, with a greater mean difference relative to the total population. Mean difference (95% confidence interval) for CPAP, MAS, 1-month and 6-months observation were 6.1 (3.8-8.5), 5.4 (3.5-7.2), 7.1 (4.4-9.7) and 7.0 (4.2-9.8) respectively. 103 4.3.11.3 FOSQ-10, CFQ and MCS Scores of SF-36 FOSQ-10, CFQ and MCS scores of SF-36 followed the same trend with all treatment timepoints showing a statistically significant difference relative to baseline with no significant differences between the treatment timepoints. Similarly, the improvement in scores was higher for the subset of the study population who were considered highly symptomatic at baseline relative to the total study population as assessed by these three questionnaires. Seventy-nine percent of the participants were considered functionally impaired at baseline (as assessed by the FOSQ-10 questionnaire), 41% were considered to have high levels of fatigue at baseline (as assessed by the CFQ questionnaire) and 18% were considered to have low mental scores at baseline (as assessed by the MCS questionnaire) and as shown in Table 4.5. 4.3.11.4 PCS Scores of SF-36 PCS scores of SF-36 did not follow the same trend. There was a statistically significant increase (improvement) in PCS score of SF-36 (p=0.007) for the 1-month MAS, mean difference (95% confidence interval) was 2.4 (0.4-4.5) and for the 1-month observation (p=0.02), mean difference (95% confidence interval) was 3.3 (0.4-6.2). For CPAP and the 6-months observation timepoints, the difference between the PCS score and baseline were not statistically significant (Table 4.5). Cut-off point for highly symptomatic patients for the PCS score of SF-36 has not been determined in the literature and therefore the highly symptomatic group were not assessed separately. 104 Table 4.5 ESS, FOSQ, CFQ and SF-36 questionnaires for the Total Trial Population and for the Subset of Participants Who Were Highly Symptomatic at Baseline Data for PCS is not divided for the highly symptomatic group at baseline as there is no cut off point in the literature Baseline Mean ± SE CPAP Mean ± SE MAS Mean ± SE 1-month observation Mean ± SE 6-months observation Mean ± SE Mean Baseline-Mean CPAP Difference (95% CI) Mean Baseline-Mean MAS Difference (95% CI) Mean MAS- Mean CPAP Difference (95% CI) Mean Baseline – 1-month observation Difference (95% CI) Mean Baseline – 6-months observation Difference (95% CI) ESS ESS Total sample n=68 10.5± 0.6 6.9 ± 0.6 7.2 ± 0.6 6.7 ± 0.6 6.6 ± 0.6 3.6 (2.2 to 5.0) * 3.2 (2.2 to 4.3)* 0.4 (-0.7 to1.4) 3.7 (2.1 to 5.4)* 3.9 (2.1 to 5.7) * > 10 (symptomatic) n= 32, 47% 15.4 ± 0.7 9.2 ± 0.7 10.0 ± 0.7 8.3 ± 0.8 8.4 ± 0.8 6.1 (3.8 to 8.5)* 5.4 (3.5 to 7.2)* 0.8 (-1.1 to 2.7) 7.1 (4.4 to 9.7)* 7.0 (4.2 to 9.8)* FOSQ-10 Total sample (n=68) 15.5± 0.3 17.7 ± 0.3 17.3 ± 0.3 17.8 ± 0.3 18.0 ± 0.3 -2.1 (-3.0 to -1.3)* -1.8 (-2.5 to -1.2)* -0.3 (-1.0 to 0.4) -2.3 (-3.3 to -1.4)* -2.5 (-3.3 to -1.4) * <17.9 (symptomatic) n=54, 79% 14.6 ± 0.3 17.4 ± 0.3 17.1 ± 0.3 17.6 ± 0.3 17.9 ± 0.3 -2.7 (-3.7 to -1.8)* -2.5 (-3.3 to -1.7)* -0.3 (-1.1 to 0.5) -3.0 (-4.1 to -1.9)* -3.3 (-4.4 to -2.1) * CFQ Total sample n=68 16.6 ± 0.6 10.6 ± 0.7 10.9 ± 0.7 10.4 ± 0.7 10.2 ± 0.7 6.0 (3.6 to 8.5)* 5.7 (3.6 to 7.9)* 0.3 (-1.8 to 2.5) 6.3 (3.7 to 8.8)* 6.5 (3.9 to 9.1)* > 17 (symptomatic) n=29, 43% 22.2 ± 1.0 10.7 ± 1.0 11.9 ± 1.0 9.5 ± 1.0 10.3 ± 1.0 11.5 (7.7 to 15.4)* 10.3 (6.9 to 13.7)* 1.2 (-2.2 to 4.6) 12.7 (8.7 to 16.7) * 11.9 (7.8 to 16.0) * SF-36, MCS score Total sample n=68 45.9 ± 1.1 50.0 ± 1.1 49.1 ± 1.1 50.6 ± 1.1 51.3 ± 1.1 -4.1 (-7.8 to -0.4) € -3.2 (-6.2 to -0.2) € -0.8 (-3.9 to 2.2) -4.7 (-8.7 to -0.6) € -5.4 (-9.7 to -1.2) € < 36 (symptomatic) n=14, 21% 30.9 ± 2.1 40.4 ± 2.1 43.6 ± 2.2 45.4 ± 2.3 46.4 ± 2.3 -9.5 (-17.6 to 1.5)€ -12.7 (-19.8 to -5.6)* 3.2 (-3.9 to 10.3) -14.5 (-23.4 to -5.7)* -15.5 (-24.5 to -6.4)* SF-36, PCS score Total sample n=68 50.1 ± 0.8 52.3 ± 0.8 52.6 ± 0.8 53.4 ± 0.9 52.7 ± 0.9 -2.1 (-4.7 to 0.4) -2.4 (-4.5 to -0.4)‡ 0.3 (-1.7 to 2.3) -3.3 (-6.2 to -0.4) € -3.0 (-5.7 to 0.5) *Statistically significant at P<0.0001, ‡Statistically significant at P<0.001, €Statistically significant at P<0.05 Abbreviations: SE, Standard Error; CI, Confidence Interval; ESS, Epworth Sleepiness Scale; FOSQ-10, Functional Outcomes of Sleep Questionnaire; CFQ, Chalder Fatigue Questionnaire; SF-36, Short Form of Health Survey; MCS, Mental Component Summary; PCS, Physical Component Summary; N, Number of Participants; %, Percentage of Participants; CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint. 105 4.3.11.5 Snoring Loudness There was a statistically significant reduction in self-reported snoring (p<0.0001) at all timepoints (1-month on MAS, CPAP, observation and the 6-months observation) relative to baseline. There were no differences between the timepoints after correcting for multiple comparisons (Supplemental Figure 4.4). 4.3.12 Percentage of Symptomatic Participants at the End of 1-month CPAP, 1-month MAS and 6-months Observation from the Total Study Population From the total sample, 14%, 21% and 13% of participants continued to have excessive daytime sleepiness following 1-month CPAP, 1-month MAS and 6-months observation respectively, based on their ESS scores. For FOSQ-10 scores, 41%, 41% and 29% of participants continued to have functional impairment following 1-month CPAP, 1-month MAS and 6-months observation respectively. For CFQ scores, 6%, 9% and 3% of participants continued to experience fatigue following 1-month CPAP, 1-month MAS and 6-months observation respectively. For MCS scores of SF-36, 6%, 2% and 3% of participants continued to have abnormal scores following 1-month CPAP, 1-month MAS and 6-months observation respectively. 4.3.13 Percentages of Highly Symptomatic Participants at Baseline Who Were Able to Achieve Normal Scores with Treatment Among those who had abnormal ESS (>10), FOSQ-10 (<17.9), CFQ (>17) and MCS (<36) scores pre-treatment, 71%, 55% and 72% had normal ESS scores following 1-month CPAP, MAS and 6-months observation respectively; 48%, 48% and 63% had normal FOSQ-10 scores following 1-month CPAP, MAS and 6-months observation respectively; 86%, 79% and 93% had normal CFQ scores following 1-month CPAP, MAS and 6-months observation respectively and 71%, 92% and 83% had normal MCS scores following 1-month CPAP, MAS and 6-months observation respectively. 106 4.3.14 Preference Thirty-nine percent of the participants who completed the decision aid tool (n=79) indicated that they preferred CPAP and 61% preferred MAS. Age, gender, BMI, marital-status, baseline daytime sleepiness, educational-level, employment status, presence of comorbidities and preferred sleep position did not seem to be related to initial preference. However, participants who perceived their OSA as severe were more likely to prefer CPAP over MAS (p<0.001). Furthermore, Patients who considered the ability of treatment to reduce cardiovascular risk of lesser importance to them were more likely to prefer MAS (p <0.05) pre-treatment (Figure 4.6). At the final trial visit 58 participants completed the questionnaire, 38% of them preferred CPAP, 45% preferred MAS and 17% preferred both equally. Initial preference as indicated by the decision aid tool did not seem to match preference at the end of the trial. As shown in Table 4.6A, approximately 16% of the participants who preferred CPAP initially continued to prefer CPAP at the end of the trial and 33% of participants who preferred MAS initially continued to prefer MAS at the end of the trial. Seventeen percent preferred both equally and the remaining participants seemed to switch their preference. Initial preference did not match long term adherence either. As shown in Table 4.6B, approximately 11% of the participants who preferred CPAP initially predominantly used CPAP during the observation period and 5% of participants who preferred MAS initially predominantly used CPAP during the observation period. 4.3.15 Willingness to Pay Out of Pocket for Treatment Seventy-eight percent and seventy-four percent of the 57 participants who competed this questionnaire were willing to pay out of pocket between $500 and $2500 for CPAP and MAS respectively (Supplemental Figure 4.5A). Sixteen percent and 21% were not willing to pay out of pocket for CPAP and MAS respectively. The biggest percentage of participants (26%) indicated that their yearly household income was in the range of $101,000 to $150,000 (Supplemental Figure 4.5B). 107 Figure 4.6 Attributes of Treatment Considered by the Participants to be of Lesser Importance Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; CV, Cardiovascular; OSA, Obstructive Sleep Apnea. 05101520253035404550Reduction in CV RiskDegree of Side-EffectsReduction in Daytime Sleepiness/FatigueReduction in OSA SeverityReduction in SnoringConvenience/TransportCostNumber of ParticipantsAttributes of TreatmentAttributes of Treatment Considered by The Participants to be ofLesser ImportanceCPAPMAS 108 Table 4.6 Preferred Treatment at the End of The Trial and How It Compares to the Preferred Treatment at Baseline Treatment of preference at the end of the trial Treatment of preference as indicated by the decision aid tool (pre-treatment) N (%)* Out of total 58 (100%) CPAP (38%) CPAP 9 (15.5) MAS 13 (22.4) MAS (45%) CPAP 7 (12.1) MAS 19 (32.8) Both (17%) CPAP 5 (8.6) MAS 5 (8.6) *Based on the responses provided by the 58 participants who completed the End of Study Questionnaire Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; N, Number of Participants; %, Percentage of Participants. Table 4.7 Treatment Predominantly Used During the 6-months Observation Period and How It Compares to Pre-treatment Preference. Treatment of preference as indicated by the decision aid tool (pre-treatment) Treatment predominantly used during the observation period N (%)* Out of total 79 (100%) CPAP (39%) CPAP 9 (11.4) MAS 2 (2.5) both 14 (17.7) None 1 (1.3) dropout 5 (6.3) MAS (61%) CPAP 5 (6.3) MAS 4 (5.1) both 25 (31.6) None 4 (5.1) dropout 10 (12.7) *Based on the 79 participants for whom initial preference data was available. Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; N, Number of Participants; %, Percentage of Participants. 109 4.3.16 Measures of Treatment Effectiveness MDA were 64.6%, 43.9%, 57.5% and 55.5% for the 1-month on CPAP, 1-month on MAS, 1-month observation and 6-months observation respectively, SARAH Index values were 6.8, 11.9, 9.6 and 9.6 for the 1-month on CPAP, 1-month on MAS, 1-month observation and 6-months observation respectively (Figure 4.7). Percentage of participants with SARAH index <10 events/hour were 78.8%, 52%, 70% and 65.5% for the 1-month on CPAP, 1-month on MAS, 1-month observation and 6-months observation respectively and the percentage of participants with SARAH index <10 events/hour and a 50% reduction from baseline REI were 65.2%, 32%, 58.3% and 49.1% for the 1-month on CPAP, 1-month on MAS, 1-month observation and 6-months observation respectively (Table 4.4). Figure 4.7 Mean Disease Alleviation (MDA) and Sleep Adjusted Residual Apnea Index (SARAH Index) Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; Obs, Observation. 4.3.17 Relation Between Adherence to Treatment and Symptoms at Baseline Supplemental Table 4.1 shows treatment usage in participants whose values for each of the 4 outcomes (ESS, FOSQ-10, CFQ, SF-36 (MCS)) were normal and for those who were symptomatic at baseline. Treatment usage was not significantly different in any of the groups except for CFQ (p= 0.04), as participants who were symptomatic at baseline used CPAP (during the 1-month on CPAP) on average one hour more (5.9 ± 1.8 hours/night) than those who had a normal baseline CFQ score (4.9 ± 2.1 hours/night). Mean Disease Alleviation SARAH Index 110 4.3.18 Correlation Between Treatment Usage and Changes in Questionnaire Scores As illustrated in Figure 4.8, a weak correlation has been noted between the number of hours of treatment usage and improvement in some symptoms, as indicated by the change in questionnaire scores from baseline. A positive correlation existed between CPAP usage during the 1-month on CPAP and FOSQ-10 score change (r= 0.25, p= 0.04). A positive correlation also existed between MAS usage during the 1-month on MAS and the change in both the FOSQ-10 score (r= 0.25, p= 0.05) and the CFQ score. The correlation with the CFQ score existed with both the mean hours of use over the total duration (r=0.32, p=0.01) and with the mean hours of use when treatment was used (r=0.33, p=0.01). The greatest number of correlations were noted during the observation period, as there was a correlation between the mean number of hours of use over the total duration with the FOSQ-10 score change (r=0.31, p=0.01) and the mean number of hours of use over the total duration with the score change in the MCS subscale of the SF-36 (r=0.26, p=0.04). Additionally, a correlation existed with both the mean hours of use over the total duration (r=0.38, p=0.002) and with the mean hours of use when treatment was used (r=0.31, p=0.01) with the change in the CFQ score. There was a strong correlation between the different variables used to measure adherence, namely the number of hours used over total duration and the number of hours of use (when treatment was used > zero hours) at all the timepoints (p<0.0001). 111 Figure 4.8 Correlation Between Treatment Usage and Changes in Questionnaire Scores and Correlation Between Different Measures of Adherence *Indicates statistical significance P <0.05. Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; ESS, Epworth Sleepiness Scale; FOSQ, Functional Outcomes of Sleep Questionnaire; CFQ, Chalder Fatigue Questionnaire; MCS, Mental Component Summary of SF-36; mean_hr_used, Mean Number of Hours Treatment was Used (> 0 hours); mean_hr_dur, Mean Number of Hours of Treatment Use Over Total Duration. 4.3.19 Effect of Study Centre, Sequence of Treatment and Time on Treatment on the Efficacy, Adherence, Blood-pressure and Questionnaire Scores During the Cross-over Phase There was no effect of treatment sequence (MAS-CPAP) or (CPAP-MAS) during the cross-over phase on any of the aforementioned variables. The effect of the study center was only noted on REI supine and non-supine, as the University of Montreal had lower REI supine and non-supine values (p<0.05) at baseline and with both MAS and CPAP. There was an effect of time since the initiation of treatment (p<0.05) on the FOSQ-10 scores and on MCS score of SF-36 between CPAP and MAS during the cross-over phase of the trial. For the cross-over and observational phases, missing values for efficacy, blood pressure, preference, adherence and QoL questionnaire scores were considered to be missing at random. A) CPAP B) MAS C) 6-months observation * * * * * * * * * * * 112 4.3.20 Side-effects 4.3.20.1 CPAP The nature and frequency of 15 possible side-effects were assessed. The main CPAP reported side-effects were mask leaks, feeling uncomfortable because of wearing CPAP, dry throat, uncomfortable mask pressure, increased awakenings and blocked nose. There was a general trend for side-effects with CPAP to decrease with time (both in number and percentage of participants reporting these side-effects) following titration compared to at the end of the observation period. Nose bleeds, disturbing noises, cold air and runny nose were described as the least frequent occuring side-effects. 4.3.20.2 MAS The nature, frequency and intensity of side-effects were assessed for 21 items. There was a general trend for side-effects with MAS to decrease with time. Exceptions were ‘device causing sensation in the tongue’ which showed a slight increase (n=5 following titaration and n=6 at the end of the observation period), in addition to ‘device breakage’ (n=2 following titaration and n=4 at the end of the observation period). Additionally, ‘Difficulty chewing’ was the most reported side-effect and was persistent over time were 100% of participants reported it as a side-effect at all timepoints however, between 57 and 79% of the participants described the frequency and intensity of this side-effect as being both rare and hardly disturbing. The other most commonly reported side-effects included discomfort or pain in the teeth and jaws, mouth dryness and bite change. 4.4 Discussion To the best of our knowledge, this is the first multi-center cross-over randomized trial comparing CPAP to MAS that includes objective adherence monitoring of both CPAP and MAS for the entire study period and in which 94% of the sample recruited are considered moderate or severe OSA patients. It is also the first trial comparing these two therapies that involves a cross-over phase followed by an observational phase. Additionally, this is the first large scale trial objectively assessing the alternating use of CPAP and MAS over a period of 6 months. Furthermore, it is the first trial to assess the effect of adherence to treatment on symptom improvement with both MAS and alternating therapy and shows improvement in daily functioning and a reduction in fatigue scores with longer nightly hours of use of therapy. 113 Our findings demonstrate higher adherence (p<0.0001) to MAS (mean ± SD of 7.0±1.2 hours/night of use) relative to CPAP (5.9±1.6 hours/night). Additionally, the interchangeable use of therapies showed greater overall adherence to therapy relative to CPAP monotherapy, with a greater percentage of regular users (86%) relative to 81% regular users with CPAP and led to a similar improvement in patient centred outcomes. They also show that for ESS, FOSQ-10 and CFQ scores, a combination of therapies may have resulted in a higher percentage of patients achieving normal scores. 4.4.1 Efficacy Our finding of a 42% MAS efficacy is within the range of previously reported MAS efficacy. Barnes et al220 found a 36% efficacy of oral appliance in their study population whose mean baseline apnea-hypopnea index (AHI) was 21.3 events/hour. Sutherland et al279 reported a 50% reduction in AHI by MAS in their study in which the baseline AHI was 27.5 events/hour. In concordance with the findings of Sutherland et el279, our findings also show large inter-individual variability in treatment response with MAS. This may be attributed to the pathophysiology of OSA in the individual participants. While MAS are known to act on anatomical causes of OSA, approximately 69% of patients with OSA have non-anatomical etiological factors contributing to their OSA and hence MAS may not be effective for this group of patients177. Efficacy was highest in the severe OSA group at baseline (51% efficacy) as indicated by the HSAT. These findings are in line with the findings of Henke et al301 who showed a positive correlation between the change in AHI and AHI at baseline. Our findings of a 90% CPAP efficacy is slightly higher than the 86% efficacy reported by a relatively recent systematic review and metanalysis85 in which the mean baseline AHI was 32.7±12.6 events/hours. OSA metrics (REI and ODI 3%) significantly improved with both CPAP and MAS relative to pre-treatment in the current randomized control trial (RCT), with CPAP being significantly more efficacious. This has been a consistent finding over studies comparing CPAP and MAS134,220,279,302 which showed a greater reduction in AHI with CPAP with a mean difference of 6 or 7 events/hour171,280. Our findings demonstrate a greater difference of 10 events/hour due to the slightly higher CPAP efficacy noted in this trial in addition to the large variability in MAS response. We found the recording of the percentage of time spent below an oxygen saturation of 90% (T90%) to be unreliable and have therefore not reported on it. 114 A lower mean OSA severity was noted with HSAT conducted at baseline (21.1 events/hour) compared to the mean severity of OSA obtained from the diagnostic sleep study (mean AHI of 32.4 events/hour with PSG). This can be attributed to the inability of Type III sleep monitors to detect hypopneas due to arousals from sleep and their inability to record sleep. Total sleep time is replaced by total recording time which tends to underestimate the severity of OSA25,27. 4.4.2 Adherence 4.4.2.1 Adherence During the Different Trial Timepoints Our trial shows high adherence to therapy at all the timepoints and the median percentage of nights treatment was used was ≥90% of nights for all the timepoints. Additionally, the mean and median hours of nightly use were highest for MAS relative to both CPAP and the observation period. It has been previously shown that adherence to CPAP and MAS decline with time136,303,304. Our results show that despite the expected decline in adherence with time, adherence to therapy has remained high during the observation period, likely due to the ability to alternate between therapies. Our results show that during the 6-months on observation, 94% of participants were able to maintain adherence to treatment for > 4 hours per night while 87% were able to do so with CPAP monotherapy. Furthermore, the median number of hours therapy was used (when used) was higher during the observation period as compared to the 1-month on CPAP. Our trial shows that providing two therapies is a sound approach to improve adherence to therapy. 4.4.2.2 Correlation Between Frequency and Duration of Treatment Usage A strong correlation existed between the number of hours treatment was used and the percentage of nights treatment was used for both the 1-month on MAS and during the 6-months observation period (r= 0.74 and 0.65, p<0.0001) respectively. This shows that MAS was used for the majority of nights and for a long number of hours during these nights. Similarly, treatment was used for the majority of nights during the observation period and for a long number of hours during these nights. On the other hand, this correlation was weaker during the 1-month on CPAP (r=0.55) indicating that despite CPAP being used for the majority of nights (87%) participants were not able to use it for extended hours during the night, as demonstrated by the number of hours of daily use. The lack of positive effect of 115 treatment on cardiovascular outcomes, as demonstrated by the SAVE trial and the lack of improvement in glycemic control in patients with type 2 diabetes and OSA has been attributed to the suboptimal adherence to CPAP as it is not being used for a sufficient number of hours each night305,306. It is known that the majority of rapid eye movement (REM) sleep takes place during the early hours of the morning306. Obstructive apneas and hypopneas during REM sleep last approximately 30 seconds longer than during NREM sleep and have been associated with greater degrees of hypoxemia and higher REM ODI as compared to NREM ODI, even in non-REM predominant OSA306,307. With sub-optimal adherence to treatment, obstructive events are disproportionately untreated during REM as compared to events that take place during NREM sleep. This may have long term health implications as REM-related OSA has been shown to have greater adverse metabolic consequences308,309. CPAP usage for 3 or 4 hours has been shown to cover only 25 or 40% of REM sleep and therefore leaves most obstructive events during REM sleep untreated. In contrast, 7 hours of CPAP usage covers approximately 87% of REM sleep. Our results show that combination therapy provides patients who are unable to use CPAP for their full sleep duration with alternatives that can allow them to use treatment for prolonged hours, 85.7% of our trial participants were able to use OSA therapy for ≥4 hours/night on ≥70% of nights during the 6-months observation period. Furthermore, having both treatments available allowed participants to alternate between treatments within the same night. Twenty percent of our trial participants who completed the trial used both treatments within the same night. 4.4.2.3 Treatment Usage Pattern During the Observation Phase Given the freedom to choose the treatment of their preference only 7.7% of participants were considered non-users and the majority of participants (60%) chose to use both treatments. The interchangeable use of therapies has allowed 59% of those who used both therapies to reach or exceed the ≥ 4hrs/night on ≥ 70% of nights (the ‘adherent to both’ group). Patients make a decision on a daily basis whether they want to adhere to treatment or not, and our results show that having 2 treatment options available may have allowed our trial participants to maintain high adherence rates over a 6-months period. 116 The 60% of the trial participants who chose to use both treatments is the population for whom we believe that a combination of therapies could help increase their long-term overall adherence to treatment, as compared to having access to a single treatment modality. Despite the ‘partially adherent’ group not reaching the ≥ 4hrs/night on ≥ 70% threshold, it is reasonable to expect that these participants might have otherwise had lower adherence rates if they did not have both treatment options. Even a 0.5 hour/night increase in adherence has been suggested to be a clinically significant difference in adherence25,310. Cistulli et al289 reported on real world data regarding CPAP adherence on over 2.6 million patients during their first 3 month on CPAP and found that mean daily CPAP usage was 6.2 hours/night on days used and 5.5 hours/night over the total duration. Based on a systematic review of studies assessing CPAP adherence over a twenty-year timeframe311, short term adherence (< 6 months) was 4.5 hours/night with a treatment discontinuation rate of 35.5% and long-term adherence (>6 months) was 4.6 hours/night with a discontinuation rate of 34.2%. The authors concluded that CPAP adherence rates remained persistently low over the 20-year period that they assessed, with no clinically significant increase. They described this low adherence rate as being problematic and that these findings question that CPAP is considered the gold-standard for OSA therapy. More recently, only 36% of the patients in the ISAACC study were using CPAP for ≥4 h/night 1 year after starting CPAP and the average adherence was 2.8±2.7 hours/night312. We hypothesize that combination therapy may have an important role in improving treatment adherence relative to CPAP monotherapy. The high adherence rate noted in our trial during the 6 months observation period, which started approximately one year from the time of initiation of treatment and ended 1.5 years from the time of initiation of treatment, is considerably higher than the adherence rates previously reported in the literature. This could be attributed to the freedom of choice, the availability of 2 options and the control that participants had over their own treatment. Participants were able to make an informed decision based on the information that they had objectively received during the trial (prior to the start of the observation period) regarding the efficacy of both treatments, their daytime sleepiness and the effect of treatment on the disease-specific QoL. Daily treatment choices are also related to personal assessment of their values, preferences, treatment side-effects and all other attributes of treatment. Similar to the findings in other fields of medicine161, our findings support the notion that promoting choices and enabling decision making and the personalization of treatment improve acceptance of and adherence to therapy. Likewise, we believe that the high adherence during the observation period with both CPAP and MAS monotherapies (the ‘CPAP- 117 only’ and ‘MAS-only’ groups which constitute 21.5% and 9.5% of participants respectively) is the result of the choice that the participants had and that they willingly chose the treatment that matched their preference and therefore they were also willing to adhere to it. It highlights the importance of choice and patient decision making in treatment adherence. 4.4.3 Effect of Treatment on Patient-Centered Outcomes 4.4.3.1 Effect on the Magnitude of Symptoms The results of our trial show a substantial improvement in symptoms relative to baseline (i.e. severity of symptoms). There was a significant mean difference in ESS, FOSQ, CFQ (p<0.0001) and MCS (p<0.05) scores between pre-treatment and all timepoints: CPAP, MAS and observation, but not between the treatment timepoints. In addition to being statistically significant, the improvement was also clinically significant for ESS, FOSQ-10, CFQ, MCS scores of SF-36 and snoring. For example, there was a reduction of over 3 points in the ESS score with MAS and CPAP and further reduction during the observation period (closer to 4-point reduction). A 2-to-3-point reduction in ESS score has been shown to be a clinically significant reduction63,75,85. Furthermore, all therapies significantly improved symptoms for the subset of the participant population who were highly symptomatic at baseline, showing a larger score change relative to baseline. Using the same ESS example, the score reduction during the observation period was over 7 points for the highly symptomatic group. Our findings and the findings of others have demonstrated the ability of MAS to reduce symptoms such as sleepiness and snoring, improve quality of life and simulated driving performance and modestly reduce blood pressure, all of which are comparable to the effects of CPAP104,134,313. However, our study is among the first to report on the effect of the availability of both treatment modalities and how that helps to alleviate symptoms, especially in the highly symptomatic group of participants. This study demonstrates that an enhancement in the reduction in the severity of symptoms could be achieved with the availability of both treatments for the patients to use interchangeably. This could be a due to the patients being less likely to occasionally drop treatment, and therefore the long-term effects on symptoms were further consolidated. Hence, a combination of treatments likely permitted greater flexibility and improved treatment outcomes. 118 Our findings are in alignment with previous work that shows that both MAS and CPAP are equally capable of reducing daytime sleepiness and improving disease specific QoL assessed via the ESS and FOSQ questionnaires respectively277,314. However, our results also show that there is a greater improvement in the mental health subscore of SF-36 with MAS relative to CPAP in the highly symptomatic group in addition to a greater percentage of participants with normalization of their questionnaire scores with MAS. Some literature reviews indicated similar improvements60,277 or even a tendency for greater improvement with CPAP however, our findings are similar to the findings of Phillips et al134 who showed a statistically significant greater improvement in MCS scores with MAS than with CPAP in their study population. It is important to note that only 17% of our study population were considered to have low MCS scores at baseline. Despite fatigue being one of the main symptoms associated with OSA10 that is of concern to patients as it affects QoL, yet there is paucity of research investigated the effect of OSA treatment on fatigue. Both Walia et al315 and Kazemeini et al79 have shown an improvement in fatigue with CPAP (Fatigue Severity Scale questionnaire used) and MAS (Checklist Individual Strength questionnaire used) respectively. As with the ESS, FOSQ and MCS component of SF-36, CFQ our findings also demonstrate a significant reduction in fatigue at all treatment timepoints of approximately 6 to 7 points and a greater reduction in mean scores in participants who were highly symptomatic pre-treatment of approximately 10 to 13 points from baseline. A minimal clinically important difference for fatigue has not been identified in patients with OSA yet. 4.4.3.2 Percentages of Highly Symptomatic Participants at Baseline Who Were Able to Achieve Normal Scores with Treatment For ESS, FOSQ and CFQ, the interchangeable use of therapies (6-month observation period) resulted in a higher percentage of participants achieving normal scores and a smaller percentage of participants with persistent symptoms and functional impairment. MAS (during the 1-month on MAS) was the treatment most able to improve the mental component of the SF-36 general health survey. Different reasons have been previously suggested to explain the inability of CPAP to normalize sleepiness and FOSQ scores for some patients despite high adherence74. Nevertheless, none of these suggestions have been proven until 119 now. We have noted the same trend in terms of inability to normalize the scores for some participants by both CPAP and MAS monotherapies during the cross-over phase of the trial, specifically for ESS, FOSQ and CFQ, despite the high adherence to both monotherapies noted in our trial during the cross-over phase. However, our results indicate that combination therapy could have the ability to further reduce the number of participants who did not achieve normalization of symptoms with monotherapy. Sixty-three percent of our trial participants were able to normalize FOSQ scores with the interchangeable use of therapies while only 48% of participants were able to achieve normalization of FOSQ scores with both CPAP and MAS monotherapies. Similarly, 86% and 79% of participants were able to normalize CFQ scores with CPAP and MAS respectively while 93% were able to achieve normalized scores with combination therapy. This may be attributed to that a multimodal approach316 to target the different pathophysiological processes involved in sleep disordered breathing provided by the combination therapy may be superior to a unimodal approach (monotherapy). Our findings suggest that combination therapy could be used as a means of alleviating symptoms and normalizing functioning in patients showing persistent symptoms. A second factor that may contribute to the observation period showing the greatest number of participants achieving symptom improvement is that participants have already spent over a year under treatment and good adherence over time my lead to symptom improvement in a greater number of patients, even with monotherapy. However, the decreased burden of treatment resulting from the decreased pressure on the participant’s minds in relying on a single treatment and its inconveniences may have resulted in continued use of treatment in those who are unable to maintain high adherence to monotherapy. This in turn may have allowed for maintaining adherence over time and increased the number of participants who were able to have their symptoms normalized with time. 4.4.4 Treatment Usage Patterns in Participants Who Were Highly Symptomatic at Baseline Similar to the findings of Weaver et al73, there was no statistically significant difference in the number of hours treatment was used between those who were symptomatic and asymptomatic at baseline regarding daytime sleepiness and functional impairment. Our results show that participants who self-reported as having more fatigue at baseline tended to use their CPAP on average 1 hour more than those whose fatigue score was within the normal values. 120 4.4.5 Correlation Between Treatment Usage and Changes in Questionnaire Scores This trial is the first to show the correlation between treatment usage and the effect on symptoms with MAS and with the combination of therapies. Congruent with the finding of Stradling and Davies100 who showed a positive relation between improvement in outcomes and duration of CPAP use, our findings show that a similar relationship exists with MAS. A correlation has been noted between the number of hours treatment was used and in the improvement of some symptoms (p<0.05), as indicated by the questionnaire scores. Specifically, improvement in fatigue and daily functioning were associated with longer nightly hours of use of treatment with MAS monotherapy and with the combination of therapies. There was also a correlation between improvement in daily functioning and hours of nightly CPAP use that were in agreement with the findings of Weaver et al73. Weaver et al73 have demonstrated that 4 hours of nightly CPAP use was associated with improvement in the ESS score and that 7.5 hours of nightly use was required for improvement in both objectively measured sleepiness and FOSQ scores. Antic et al74 also identified a similar trend for subjective sleepiness among moderate to severe CPAP treated OSA patients after three months of treatment. We have attempted to examine the dose-response relationship between hours of treatment use and symptom improvement similar to that conducted by Weaver et al73 however, due to the high adherence to treatment in our trial, very few participants fitted in the low adherence groups and therefore were non-representative samples. Additionally, the aforementioned studies had bigger overall sample sizes making such analysis feasible. 4.4.6 Symptom Improvement Based on Adherence During the Observation Period Mean differences in questionnaire scores (ESS, FOSQ-10, CFQ, MCS and PCS of SF-36) between baseline and the end of the trial were compared based on adherence during the observation period (the 5 adherence groups being those adherent to both, adherent to CPAP-only, MAS-only, partially adherent to both and the non-adherent). Results show that the differences between the groups were not statistically significant. Despite the differences between the groups not being clinically significant, there appears to be some clinically significant differences. For example, not only did the non-adherent group fail to show an improvement in the FOSQ-10, the CFQ, and PCS questionnaires, the mean change indicated a worsening in the outcome of these questionnaires with no treatment, as shown in Figure 4.4. However, due to the small 121 number of participants in this group, the variability in their outcomes and the multiple statistical comparisons, this group did not show a statistically significant difference from the other groups despite showing a clinically significant difference. The partial adherence group showed some improvement in the outcomes of the questionnaires, except for the PCS component of SF-36 which also showed worsening. This partial improvement with partial adherence indicates that it is likely that partial adherence is better than no adherence in terms of symptom improvement and is consistent with the findings reported in the literature that a dose-response effect of adherence on symptoms exists73. Our findings also show that symptom improvement in the group that is highly adherent to combination therapy is comparable to symptom improvement in the groups that are highly adherent to CPAP or MAS monotherapies and indicates that combination therapy is a viable option to increase adherence and achieve similar symptom improvement for patients who are unable to be highly adherent to monotherapy. 4.4.7 Patient Preferences and the Decision Aid Tool Prior to initiation of treatment, 61% of the newly diagnosed, treatment naïve participants preferred MAS and 39% preferred CPAP. Participants who perceived their OSA as severe were more likely to prefer CPAP over MAS. Conversely, participants were more likely to prefer MAS pre-treatment if they thought that the impact of treatment on cardiovascular health was of lesser importance to them. Our findings are in line with previous studies that showed a preference for MAS over CPAP179. At the end of the trial, more participants continued to prefer MAS (45%) over CPAP (38%) and 17% preferred both MAS and CPAP equally. These results show that more participants preferred CPAP at the end of the trial as compared to pre-treatment preference, since 17% preferred both at the end of the trial. This may be attributed to the close monitoring and troubleshooting of issues as they arise that were part of this clinical trial and shows that it is possible to increase preference for CPAP with positive experience. The combination of treatments may have also attributed to an increase in preference for CPAP as it may have helped alleviate some of its potential side-effects, discomfort and the burden of having only one cumbersome treatment that is required to be used for every single night. Initial preference is not the sole determinant of long-term preference, rather positive experience with treatment is what may shape latter preference. It may be only when a patient experiences a specific treatment that they formulate their true 122 preference or lack of preference towards it. This emphasizes the importance of positive experience in both long term preference and adherence and can be translated to the clinical setting by ensuring that patients have good initial support with their treatments and a timely resolution of problems with their CPAP or MAS. Our findings are in agreement with the findings of others who also noted the relation between the importance of initial experience and adherence with both CPAP and MAS104,317. The Decision Aid tool has shown that there is marked heterogeneity of goals among patients seeking OSA treatment and hence, application of an a priori general policy that gives more relevance to an outcome related to a given objective (ie, reduction in AHI) may not be effective for the patients who have other priorities (reduction in snoring for example). In order to apply a policy that favors the “best” treatment option, a main treatment goal must be clearly outlined so that the different alternatives can be analyzed and evaluated according to this objective as part of the shared decision-making process. Our trial has highlighted different aspects which may be used in the future to improve decision aid tools. 4.4.8 Measures of Effectiveness Different measures of effectiveness have been introduced including MDA, SARAH index, apnea burden and effective AHI (eAHI)205,216,221,297. There are no differences in the variables used to calculate the SARAH Index, apnea burden or eAHI. The utilization of these measures of effectiveness in the comparison between CPAP and MAS is relatively recent and has been made possible with objective MAS adherence monitoring. While a few studies have attempted to calculate the MDA, to the best of our knowledge, no studies have reported the SARAH Index based on a prospective trial and hence, we are the first trial to report on both the short and long-term measures of effectiveness. The two key elements of effectiveness are efficacy and adherence205. Since treatment is efficacious only when used, adherence is an important factor in determining effectiveness. The importance of adherence should not be underestimated in chronic conditions for which treatment is not curative and is life-long. While the efficacy of MAS exhibits variability279, adherence to MAS therapy has shown to be high and on average, a one hour difference between CPAP and MAS adherence has been demonstrated in our work and in previous studies277. This higher adherence to MAS works towards counteracting its suboptimal efficacy. 123 The limitations of these methods of measuring effectiveness are that they assume that the AHI or REI fully rebounds to the pre-treatment AHI/REI, which may not be accurate205. On the other hand, important aspects of these measures are that they are personalized to the individual and take into consideration the individual’s habitual sleep time, instead of the standard 8 hours of sleep per night and some of them also take into consideration the individual’s baseline disease severity. The reasons behind our trial finding a lower MAS (43.9%) and a higher CPAP MDA (64.6%) than previously reported in the literature can be attributed to the higher adherence to CPAP noted in our study relative to the other studies that calculated the MDA for CPAP205,215. The lower MDA for MAS reported in the current trial relative to other studies216,318 can be attributed firstly to the great inter-individual variability that was found with MAS efficacy in this trial, that resulted in a lower overall MAS effectiveness. Secondly, it could be due to the current trial performing a single night of HSAT with MAS while Stern et al318 performed three consecutive nights of testing. It is known that there is night to night variability in AHI/RDI319. A few of our participants (mostly those with mild OSA) showed an increase in REI, for example from 14.4 events/hour at baseline to 17.8 events/hour with MAS and this has been translated to a negative MDA, despite minimal clinical significance in some. Our findings show a similar SARAH index for MAS (11.9 events/hour) to that calculated by Dissanayake et al320. However, their calculation was based on subjectively measured adherence and was reported retrospectively for some participants from their previously conducted randomized controlled trial comparing one month of CPAP to MAS134. Interestingly the SARAH index reported by Dissanayake et al320 for CPAP (10.1 events/hour) was higher than that calculated for our trial participants (6.8 events/hour) indicating higher effectiveness of CPAP in our trial. As with the MDA, this can be attributed to the higher CPAP efficacy and adherence observed by our current trial relative to that reported in the literature85,312. Nevertheless, the combination of both treatments during the observation period has shown to maintain a high MDA (57.5% for 1-month observation and 55.5% for 6-months observation) and a low SARAH index (9.6 for both the 1-month and 6-months observation) over time (Figure 4.7). This highlights that combination therapy could have high effectiveness as indicated by the currently available methods of measuring effectiveness. 124 4.4.9 Effect of Treatment on Blood Pressure OSA is known to be an independent risk factor for hypertension and cardiovascular disease321,322 therefore, the relevance of BP in OSA management should not be underestimated. Similar to the sample studied by Pamidi et al323, our sample consisted mainly of non-hypertensive participants (74%) and similar to their findings, our findings showed greater than average decrease in daytime systolic and diastolic BP (3.5 mmHg and 4.8 mmHg respectively during the 1-month on CPAP and 6.7mmHg and 5.2mmHg respectively during the 6-months observation) relative to what has been otherwise reported in the literature (average SBP and DBP reduction were 2.5mmHg and 2.0mmHg respectively with CPAP)324. The common factor between the Pamidi et al323 trial and our trial is the high level of treatment adherence in both studies, as participants used CPAP for the total sleep duration in the Pamidi et al study. Our findings add to the body of evidence showing that higher adherence results in greater BP reduction and are in alignment with the findings of Bratton et al324 who suggested a dose-response relationship between adherence and BP reduction. Additionally, Barbe´ et al325 have showed that the BP lowering effect of CPAP is evident only in patients who use CPAP for greater than 5.6 hours/night. Our findings show that the 1-month on MAS and 6-months observation were able to significantly reduce SBP relative to baseline and that 1-month on MAS, 1-month on CPAP and 6-months observation were able to significantly reduce DBP relative to baseline. Sutherland et al326 have reported that there is no significant relationship between changes in AHI and ambulatory BP measurements which is in line with our findings, as efficacy of MAS was significantly lower than that of CPAP in our trial nevertheless, there was a statistically significant reduction in SBP with MAS but not with CPAP in our trial. The mean change is SBP in our trial appears to follow the same trend as the hours/night of treatment use (when used), which also tended to be at its highest during the 1-month on MAS and during the 6-months observation. Interestingly, the trial that compared BP changes with both MAS and CPAP while objectively monitoring adherence did not find a significant reduction in BP with either CPAP or MAS relative to baseline135. Our results also show further reduction in both SBP and DBP during the 6-months observation relative to all the other timepoints with a 6.7mmHg reduction in SBP and 4.6mmHg reduction in DBP. This may be a result of an incremental reduction in BP with sustained high adherence to treatment. 125 Our findings with regards to BP are promising however, it is noteworthy to mention that they are based on in office BP measurements. Future studies should assess the effect of combination therapy on 24-hour BP measurements. The effect of BMI as a confounding factor has been assessed by comparing participants’ BMI at the different time points. The results of this analysis show that there were no statistically significant differences in BMI at the different timepoints, indicating that the observed changes in BP, efficacy and symptom improvement are most likely an effect of treatment. It has been previously shown that patients on CPAP tend to gain weight with treatment327. Contrary to these findings, our trial did not find any change in weight and may be due to our mean BMI being smaller than other CPAP only studies. 4.4.10 MAS and CPAP Side-effects The side-effects most commonly reported by our trial participants with MAS in descending order included difficulty chewing, discomfort or pain in the teeth and jaws, mouth dryness and bite changes. There was a tendency for 18 out of the 21 side-effects to decrease with time as indicated by the number and percentage of participants reporting the side-effect. This was likely achieved with MAS adjustments and the participants getting used to treatment. Dental discomfort, mouth dryness, excessive salivation and TMJ pain have been previously reported as being common side-effects of MAS therapy223,226. TMJ pain was only assessed using a questionnaire in this trial and did not show to be highly prevalent. Our findings are in agreement with the findings of others who described these short term side-effects as being mild, transient and reversible in nature178,203. Unlike short-term side-effects which tend to become less of an issue with time, long-terms side effects are progressive and are associated with the duration of use. The long-term side-effects of MAS have been described in our previous publication328 (chapter 3 of this thesis) and in the work of others as being mainly dental changes in the form of decreased overbite and overjet, retroclination of the upper incisors and proclination of the lower incisors233,257,329. The current trial has followed-up participants for approximately 1.5 years, a time period during which long term side-effects may still be unnoticed328. 126 The main self-reported CPAP side-effects observed in our trial were mask leaks, feeling uncomfortable because of wearing CPAP, dry throat, uncomfortable mask pressure, increased awakenings and blocked nose. Similar to MAS, there was a general trend for all the side-effects to decrease with time or with mask and/or pressure adjustments. Rotty et al330 have described the most frequent side-effect in long-term CPAP-treated patients as being patient-reported mask leaks. Patient reported leaks did not show a correlation with device-reported leaks, however there was a correlation between patient reported mask leaks and dry mouth to low CPAP adherence. Other common side effects included dry mouth, increased number of awakenings, blocked up nose, mask pressure and mask leaks, claustrophobia and difficulties exhaling294,331. Additionally, oro-nasal masks were shown to be associated with more mask related side-effects compared to nasal masks330. In our trial, participants were started on nasal masks and were switched to or-nasal masks or nasal pillows if needed. Long-term dental side-effects have also been described with CPAP mainly retrusion of the anterior maxilla, reduction in overjet and overbite, retroclination of the upper incisors and setback of the supramentale and chin positions295,329. As with the long-terms dental side-effects of MAS, the long-term dental side-effects of CPAP are also progressive in nature although less pronounced than the dental long-term side-effects caused by MAS329. These side-effects, similar to MAS, start to be noticed after 2 years of use and therefore were not to be expected to be present in our current trial. As mentioned earlier, the reduction in the frequency and intensity of the short-term side-effects with time can be attributed to the nature of these side-effects which tend to be both short-term and to decrease with time, as previously reported in the literature203. Other explanations for the reduction in the frequency of the side-effects for both MAS and CPAP could be that the participants who were bothered by these side-effects may have stopped using the device of concern during the observation period, some side-effects have been previously shown to affect adherence330,331. However, during the observation period, approximately 31% of participants choose to only use monotherapy and approximately 8% were considered non-users. Another explanation for why the frequency and intensity of side-effects decreased with time could be attributed to the alternating use of therapies, which may have indirectly led to a reduction in the perception of these side-effects since each device was not used full time and there was time to partially ‘recover’ from these side-effects. As such, it could be speculated that the alternating use of therapies may also reduce the magnitude and rate of progression of the long-term dental side-effects of MAS, as the appliance will be used for shorter 127 durations than if a patient were to only use MAS-monotherapy. Hence, a potential benefit of alternating therapies could be the possible reduction in the side-effects of both therapies without compromising treatment effectiveness. 4.4.11 Choices and Shared Decision Making Despite cost-effectiveness studies assuming that adherence after 2 or 5 years of treatment will be stable332, we know that in OSA, this is not the reality. The attributes of treatment that patients may be seeking are subject to change due to social, personal and medical factors. It has been previously alluded to by Platt and Kuna333 that patients may adhere selectively to treatment. The medical literature shows that treatment choices could change over time334 and having options and alternatives allows patients to make choices based on their priorities at any given time. It has been shown that giving choices and allowing patients to make their own decisions increases their sense of control and ownership of their own treatment, which makes them more willing to adhere160,162,335. Shared decision making requires that the patient have a degree of health literacy that allows them to make informed decisions334. Tools have been developed to increase patients’ health literacy regarding their medical condition and to provide them with information about the different treatment options336. They are meant to transfer information to the patient, encourage direct two-way communication between the patient and clinician and are a good tool for relationship-building, which is an important component of shared decision-making336. In the field of OSA, 71% of a sample indicated that a communication tool helped them make a decision regarding their treatment163. Similarly, in a previous study conducted to develop the currently used decision aid tool, 96 % of the participants thought that the decision aid tool was useful for them in making a decision furthermore, 96% of them would recommend it to others164. In the current trial, despite the decision aid tool not being able to predict the treatment that the participants would adhere to long term, we believe that it has served multiple purposes: it contributed to increasing the treatment naïve participants’ knowledge and awareness regarding their medical condition and the different treatment options available for them. Recently diagnosed patients are seeking information regarding their condition and the available treatment options and providing information to them from a trust-worthy source is important. Furthermore, it also provides the potential harms and benefits of the treatment options from a trust-worthy source. Additionally, it helps patients elucidate their preferences and helps them think about the attributes of treatment that matter most to them and the goals that they are seeking to accomplish from their treatment all of which increase. 128 We consider the Decision Aid tool as the first tool that was used in the current trial to engage participants in the decision-making process. The second tool that was used in our trial was the disclosure of the results at the end of the randomized control part of our trial. It enabled participants to better understand the efficacy of each treatment on their REI and ODI as well as the effects of both treatments on their symptoms. It is known that human behavior is multifactorial and includes complex interactions in which individual factors, in addition to the interplay of factors could affect adherence337. Multiple factors may cause patients to favor CPAP over MAS, such as concerns over teeth alignment (dental side effects), suboptimal efficacy of MAS and the development or presence of comorbidities. Factors that may cause patients to favor MAS over CPAP include psychosocial aspects such as patient and bed partner preference, a life-style that includes frequent travel and camping, convenience and the presence of airway infections or diseases. More recently, the recall on some CPAP machines338 has also been a factor impacting CPAP usage. Barriers to adherence can be minimized by giving choices. The reasons that prevent patients from adhering to treatment could be different for the different treatment modalities. The interchangeable use of therapies addresses this problem by providing an alternative therapy that may not have the same issues or gives the patients a ‘break’ from the issues experienced with the other treatment modality. The decision to use an alternative therapy rather than no therapy may be a small daily decision that patients make that could led to a compound effect on the long-term. The interchangeable use of therapies could also be a strategy for reducing side effects long term as each treatment is used for a shorter duration overall, without compromising long-term effectiveness. The reduction in the MCS scores that have been demonstrated at the different timepoints in this trial and especially during the observation period, could be a reflection of the reduction in the burden of treatment that we hypothesize is associated with the availability of more than one treatment option. A recently published data analysis from 789,260 adult patients shows that CPAP usage pattern over the first 3 months demonstrated that the younger age group (18-30 years old) had the lowest adherence rate compared to all the other age groups. This age group also demonstrated the greatest decay in use over time and abandoning treatment102. These findings are concerning as this group of patients will require treatment for many more decades to come. Matching treatment to needs and preferences and possibly providing them with both CPAP and MAS may increase adherence in this age group, that can be sustained long term. Since the early days after the invention of CPAP, many strategies have 129 been researched and implemented to improve adherence to CPAP. While multiple strategies have been more recently utilized to augment adherence such as different machine pressure delivery modes (examples include flexible pressure and Bi-level) cognitive behavioural therapy, educational programs, telemedicine and device applications86,96,104, the success rate seems to be currently comparable to our findings with regards to combination therapy. Therefore, we propose a combination of therapies as one of the methods that may be utilized to augment overall adherence to OSA therapy. A meta-analysis that assessed the impact of educational, behavioural, troubleshooting and telemedicine interventions on CPAP adherence demonstrated an improvement in CPAP usage of 0.6 hours/night, 1.2 hours/night, 0.7 hours/night and 1.0 hour/night respectively during a follow-up period of <1 year85. Our results show that at 1.5 years of treatment, both mean and median adherence were higher (by 0.4 hours/night and 0.5 hours/night respectively) with combination therapy relative to CPAP monotherapy, taking into consideration that CPAP adherence would have likely further decreased otherwise if it was to be used solely as a monotherapy for 1.5 years. Furthermore 85.7% of our trial participants were able to use OSA therapy for ≥4 hours/night on ≥70% of nights compared to 80.6% who were able to achieve this criterion with CPAP monotherapy. 4.4.12 Disadvantages of Combination Therapy Despite all the potential advantages of combination therapy, there are also disadvantages. For example, the increased cost of purchasing two treatments versus one is one of the main issues. An interdisciplinary team of professionals needs to be involved in the patient management which may not be widely available. Additionally, time is needed to explain the different treatment options and both treatments require evaluation and long-term maintenance. The availability of two options may also lead some patients to stay on a non-effective therapy. 4.4.13 Study Limitations and Strength We acknowledge a number of limitations in our trial. We were unable to conduct polysomnography (PSG) to assess respiratory parameters during the study and used level III HSAT instead. This is due to technical issues as in our overburdened health care system, the priority for in-hospital overnight sleep studies goes to those who require a diagnosis, and the waitlist is usually in months. This would have not fitted with our study protocol which required 130 testing at specific time points during the study that were not flexible, in order to maintain standardization of our protocol. Hence, we resorted to the use of the home sleep studies. To overcome some of the shortcomings of the home sleep studies, all participants had a baseline assessment with the level III portable sleep monitor, and re-assessment with the same level III monitor at the end of each treatment period (i.e. under CPAP and MAS treatment) to minimize measurement bias. Furthermore, scoring of the sleep studies was done centrally for all sleep studies by one sleep technologist blinded to treatment group and trial timelines. An important limitation was the inability to use actigraphy as a measure of sleep time and instead home sleep diaries were used. Nevertheless, sleep diaries have been deemed appropriate for clinical use339 and participants were strongly encouraged to complete the sleep diary every morning upon awakening in order to minimize recall bias. Actigraphy also has its limitations, as it is known to overestimate sleep when movement is the only input, this is due to quiet wake time appearing similar to sleep27. Another limitation was the loss of some MAS adherence data due to adherence smartchip failure. Additionally, participants were aware that their adherence to treatment is being monitored. However, we believe that while this may be an important factor in short-term trials, it is less significant in long-term trials such as the current trial, as many other more important factors may be contributing to the decision of whether to adhere or not adhere to treatment. As per the nature of clinical trials, those who agreed to participate where willing to try both treatments and may not represent all OSA patients. Overall trial completion rate was 78% based on the initial number randomized and upon excluding the participant who was incorrectly initially randomized despite being ineligible for the trial, the true drop-out rate would be 20%. Due to the long total duration of the trial, the complex protocol and with 14 clinic visits in total per participant at strict intervals over a 1.5-year period, we believe that the drop-out rate was acceptable and comparable to other studies. Additionally, we had recruited considerably more participants than required as per the sample size calculation in anticipation of high drop-out rates commonly encountered in long term trials. This trial had many strengths, it had a unique study design that involved both a randomized cross-over phase and a prospective observational phase. The randomized cross-over phase allowed for a head-to-head comparison between the 2 main therapeutic interventions for OSA and an observational phase for the assessment of the real-world long-term measures of effectiveness. Multiple measures were taken to minimize potential biases; randomization minimized bias in 131 allocating subjects to the initial treatment groups which was followed by re-randomizing patients after adaptation/titration, prior to the start of the cross-over phase. This second randomization minimized bias due to withdrawals during adaptation/titration (i.e. versus a single randomization at time of recruitment). Allocation concealment protected against possible treatment allocation bias. Contamination bias was eliminated by collecting the therapy from the participants when not intended to be used as per protocol. Carry-over effect was minimized by employing 1-week washout periods. The effect of confounding was minimized via the cross-over design were each participant acted as his\her own control. Additionally, adherence was measured objectively for both therapies which minimized self-reporting bias. At the end of the cross-over trial phase, efficacy and adherence were disclosed to the participants. To minimize the influence of the dentists or physicians over the participant’s decision prior to the observational phase, participants received the disclosure of treatment outcomes via a standard lay language written report. Moreover, all members of the research team were given instructions not to share information at any time during the trial with the participants in favor of one treatment or the other and rather encourage them to decide for themselves. Site visits and regular communication between the study centers helped ensure standardization. Moreover, being a multi-center trial, this improved generalizability of the results. In summary, A holistic approach to patient management involves not only improving AHI or REI and other disease indices, which are necessary but not sufficient, and rather involves a treatment that can alleviate symptoms, improve QoL and improve long term health outcomes while at the same time take patient preferences, life-style and psychosocial factors into consideration. Furthermore, a multimodal treatment approach seems to have an important role in patient-centred medicine. 4.5 Conclusions During the cross-over phase and the observation phase of this trial, overall adherence to treatment was high with a greater number of hours of use of MAS compared to CPAP during the cross-over phase. During the observation phase, the majority of the trial participants were using both CPAP and MAS. This multimodal treatment approach with the alternating use of CPAP and MAS helped maintain the high level of adherence observed during the cross-over phase which may also be attributed to the availability of choices and the flexibility that these choices provide. The high 132 adherence has likely contributed to the clinically significant improvement in quality-of-life, blood pressure and patient-centered outcomes that was more profound during the observation phase. Not only was there a greater reduction in the magnitude of symptoms during the observation phase, there was also a reduction in the number of participants who experienced these symptoms. The subset of the study population who were highly symptomatic at baseline have benefited the most in terms of improving their quality of life with the availability of the two therapies. FUNDING SOURCE: This study was supported by a Canadian Institute of Health Research (CIHR) grant. MOP-136987, ISU-157533 133 Chapter 5: Continuous Positive Airway Pressure and Mandibular Advancement Splint Monotherapies Versus Combination Therapy: A Clinical Trial (DOT study) Summary To compare continuous positive airway pressure (CPAP) and mandibular advancement splint (MAS) as monotherapies, with two forms of combination therapy. CPAP and MAS used interchangeably (alternating therapy) and used simultaneously (dual therapy) for obstructive sleep apnea (OSA) management. This four-phase clinical trial aimed to compare the effects of 1-month each of CPAP, MAS, alternating therapy and dual therapy, following optimal titration to both CPAP and MAS. CPAP and MAS monotherapy (Phases I and II) were double-randomized cross-over, followed by combined therapies, alternating therapy (III) and dual therapy (IV) phases. Outcomes included CPAP pressure, objective adherence, blood pressure (BP), oxygen desaturation index (ODI), sleepiness, quality-of-life, comfort and treatment preference. Thirteen participants completed phase IV. These were predominantly middle-aged (55±13years) Caucasian (62%) males (71%) with severe OSA (apnea-hypopnea index= 33events/hour). CPAP pressure requirements were reduced by dual therapy compared to CPAP-monotherapy for the high pressure on CPAP-monotherapy (N=7) group (≥10cmH2O) p=0.04, but not for the total sample (p=0.25). CPAP-monotherapy, MAS-monotherapy, and dual therapy each significantly reduced ODI relative to baseline (p<0.001). CPAP-monotherapy and dual therapy were more effective than MAS-monotherapy (p=0.002). Objective adherence was significantly lower for CPAP-monotherapy compared to MAS-monotherapy and dual therapy (p<0.001). 134 There were non-significant changes in sleepiness and BP in all groups following treatment. MAS, alternating therapy and dual therapy, but not CPAP-monotherapy resulted in significant improvement in quality-of-life scores relative to baseline (p=0.001). These results demonstrate that dual therapy is beneficial for patients who require high CPAP pressure (≥10cmH2O) with CPAP-monotherapy. They also show that both dual therapy and alternating therapy improve symptoms and increase adherence to treatment compared to CPAP-monotherapy. 5.1 Introduction Combining therapies with different mechanisms of action is an option frequently utilized in medicine under circumstances in which a single treatment on its own does not provide the desired therapeutic outcome, either due to lack of efficacy or adherence to treatment. Combination treatment for systemic hypertension for example dates back to the 1960s140. In obstructive sleep apnea (OSA) management, there are limited studies on the effect of combination therapy. The combination of therapies has been undertaken when a single therapy improves but does not resolve OSA, attempts include combining two pharmacological agents147, the combination of supplemental oxygen with hypnotic medication123 and the combination of positional therapy with mandibular advancement splint (MAS) in patients with positional OSA229. Combining OSA therapies has also been undertaken when one therapy, continuous positive airway pressure (CPAP), albeit being highly efficacious, may have low adherence and high intolerance340. It has been postulated that high CPAP pressure may lead to intolerance to therapy, and that pressure can be reduced when CPAP is concomitantly used with a mandibular advancement splint (MAS). The pressure reduction will in turn lead to increased comfort and higher adherence341. MAS therapy has been shown to be the preferred OSA treatment option as reported in multiple studies comparing CPAP to MAS patient preference179. However, MAS-monotherapy is only partially effective 135 in some OSA patients. Therefore, it has also been postulated that for patients with a residual apnea-hypopnea index (AHI) or residual symptoms despite maximum appliance titration, a combination of therapies may be beneficial342. Prehn and Swick (2017)343 described 2 ways in which CPAP and MAS could be used simultaneously: (1) by integrating them into one device so that they are inseparable. This has been named ‘integrated therapy’ and (2) by maintaining them in their original form as two distinct therapies that are used at the same time ‘dual therapy’343. The combination of CPAP and MAS can also take other forms, such as their alternating (or interchangeable) use which has been done by patients on a short-term basis when traveling for example154 but has not been used as an ongoing treatment approach. The combination of therapies for the treatment of OSA has been underestimated and underinvestigated344. The aim of this clinical trial is to compare the alternating use of MAS and CPAP to their simultaneous use (dual therapy) and to their conventional use (MAS and CPAP as monotherapies). 5.2 Materials and Methods 5.2.1 Study Design and Setting This is a 4-phase open-label prospective clinical trial aimed to compare the effects of 1 month of each of the following: CPAP, MAS, alternating therapy and dual therapy. Alternating therapy refers to the interchangeable use of CPAP and MAS, at the participant’s own will, over a 1-month period and corresponds to the 1-month observation period described in chapter 4. Dual therapy refers to the simultaneous use of CPAP and MAS also for a 1-month period. The first three phases were described in detail in chapter 4 and were part of an initial trial, a cross-over randomized trial comparing MAS to CPAP, registered (ClinicalTrials.gov Identifier: NCT02242617), approved by the institutional ethics board (H14-01215) and conducted at three research centers. Phase I was a titration phase to both CPAP 136 and MAS. Phase II was a cross-over phase in which participants used both monotherapies, CPAP and MAS for 1-month each, separated by a 1-week washout period. Phase III was the alternating therapy phase where participants would alternate therapy on a nightly basis at their discretion, without any specific clinician’s recommendations. Participants who completed the initial trial at the University of British Columbia site were invited to participate in the fourth phase (Phase IV) which was also prospectively registered (ClinicalTrials.gov Identifier: NCT03435731) and ethically approved (H18-00175). Recruitment for phase IV took place between February and September 2018. 5.2.2 Participants Participants aged 19-75 years who were recently diagnosed with OSA and treatment naïve were invited to participate in the initial trial described in chapter 4 (phases I to III). Before consenting to the initial trial, participants were told that they will be provided with both CPAP and MAS at no cost. There were no further incentives provided for phase IV of the trial. 5.2.3 Eligibility Criteria Eligibility criteria for Phases I to III are outlined in Supplemental Figure 5.1. Inclusion criteria for Phase IV included: (1) age 19-75 years old who are able to freely provide informed consent; (2) prior participation in the previous three phases of the trial; (3) have been optimally titrated to both CPAP and MAS; (4) have both CPAP and MAS devices at home. Exclusion criteria included the use of a full-face mask as the CPAP interface during phases I to III of the trial. 5.2.4 Interventions The interventions used were a MAS and a CPAP. The MAS was a custom-made and titratable bibloc oral appliance (SomnoDent Flex G2, SomnoMed Ltd., Australia) that was initially set at 75% of the participant’s maximum advancement203,283 and had an embedded adherence monitoring smart-chip 137 (DentiTrac ®, Braebon Medical Corporation, Ontario, Canada). This temperature-sensitive adherence smart-chip was 10.5×8.5×4 in dimension. The smart-chip sampling rate is 1 measurement every 5 minutes and stores data for up to 180 days and has been shown to be highly accurate and reliable in objectively measuring adherence217. The CPAP (DreamStation AutoCPAP, Koninklijke Philips N.V. Netherlands) had built-in adherence monitoring. 5.2.5 Procedures Following eligibility assessment and collection of baseline information, participants were randomized to either monotherapy for adaptation/titration order in a cross-over design (first randomization) for phase I. Participants were given their CPAP by a standardized respiratory therapist (RT) and their mask adjusted. All participants were using nasal masks or nasal pillows as the CPAP interface. Automatic pressure changes were set from 6 to 16cmH2O during the first week of titration and again during the first week of dual therapy (phase IV). After 1-week, the RT assessed the pressure data and set a fixed pressure at the 95th percentile pressure. Participants had their custom-made MAS inserted by a trained and standardized dentist. Daily mandibular advancements were done until the maximum comfortable mandibular advancement was achieved134. Titration extended for a period of 2 to 4 months on each treatment modality and was objectively assessed by overnight oximetry. Adequate titration on either treatment was defined as an oxygen desaturation index (ODI) <5 events/hour. Following a 1-week washout period, participants were re-randomized and entered the cross-over phase of the study (phase II). Participants were on CPAP and MAS-monotherapies for 1-month each, separated by a 1-week washout. To avoid contamination during titration (phase I) and cross-over (phase II) phases, the other treatment modality was temporarily returned to the research team. At the end of phase II, participants received a written report of their results on both monotherapies. Following another 1-week washout, they were given both therapies to take home to use at their own discretion, and outcomes were assessed after 1-month (phase III, alternating therapy) which corresponds to the 1-month observation period 138 described in chapter 4. Following completion of the initial study (phases I to III), eligible participants were invited to participate in phase IV. For 1-month, participants were instructed to use dual therapy. Outcomes were assessed at the end of the 1-month on MAS, CPAP, alternating and dual therapy. Supplemental Figure 5.1 outlines the main data acquisition timepoints for the current trial. 5.2.6 Objective Measures 5.2.6.1 CPAP Pressure Requirements CPAP pressure requirements were assessed with both CPAP-monotherapy and with dual therapy and the changes in CPAP pressure between these two timepoints was the primary outcome of this trial. Participants were divided into two groups based on their pressure requirements with CPAP-monotherapy, the high pressure group, requiring a pressure of (≥10cmH2O)151, and the low-pressure group (<10cmH2O). 5.2.6.2 Portable Monitoring and Body Mass Index (BMI) Type III Home sleep apnea testing (HSAT) device was utilized to assess the ODI (Alice NightOne, Respironics Inc., IL, USA). Testing was conducted at baseline and the end of each of the 1-month on CPAP-monotherapy, MAS-monotherapy and dual therapy. Recordings were acceptable if they were ≥4 hours at all previously mentioned timepoints. BMI was recorded on the day of the baseline sleep study and the day following the sleep study for CPAP-monotherapy, MAS-monotherapy and dual therapy. 5.2.6.3 Adherence Calculation The following variables were calculated for CPAP and/or MAS for each of the 1-month periods: (1) objective adherence (h/night) calculated over the nights the device was used (>0 hours), (2) percentage of nights used from the total duration and, (3) participants were then classified into 139 compliant users if the mean treatment usage rate was ≥4 hours/night and into (4) regular users if there were ≥70% of nights with at least 4 hours/night of use99,215,223. 5.2.6.4 Blood Pressure (BP) Office BP readings were measured on the dental chair using an automated Omron BP monitor HEM-780 (OMRON Healthcare, Kyoto, Japan) at baseline and at all subsequent time points. Participants were in the seated position for at least 10 minutes prior to the first BP reading, and reporting was on the average of two measurements of the left arm taken five minutes apart, following the guidelines of the American Heart Association290. 5.2.7 Self-reported Measures Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS), a widely used questionnaire with good internal consistency (Cronbach’s alpha statistic= 0.74 to 0.88), lower scores indicate less daytime sleepiness72. A score of ≥10 indicates excessive daytime sleepiness74,152. Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10) was used to assess the impact of OSA on everyday activities and the related impact of treatment (internal consistency of FOSQ-10 is alpha = 0.87)69,70. Higher scores indicate better outcomes69 and a score of <17.9 indicates sleep-related disease specific functional impairment73. Claustrophobia, comfort, preference, willingness to use long term and side-effects were assessed with questionnaires. Claustrophobia and willingness to use long term were assessed using a 3-point Likert scale293 and participants were asked to choose whether they were very, somewhat or not claustrophobic. Similarly, they were asked to indicate their willingness to use dual therapy long term by choosing one of the following options (will definitely use regularly, may use regularly and will not use regularly). Comfort was assessed using a horizontal visual analogue scale (VAS)346. Side-effects were assessed using a standardized self-reported questionnaire. 140 5.2.8 Sample Size An a priori sample size calculation was powered to CPAP pressure changes as the primary outcome. Previous studies have shown a difference of 1cmH2O as a clinically significant difference343,347. To detect a CPAP pressure difference of 1cmH2O (effect size) at 90% power and Type 1 error of 0.05 (2-sided), using the standard deviation of the difference for matched samples and continuous outcome, a sample size of 13 participants was required. 5.2.9 Randomization 5.2.9.1 Sequence Generation Computer generated randomization lists were prepared by a statistician. Randomization was stratified by disease severity (mild/moderate versus severe) for the first randomization and by disease severity and treatment adaptation/titration order for the second randomization. 5.2.9.2 Allocation Concealment The randomization list was concealed in the data capturing system (REDCap) and could only be accessed by the clinical trial coordinator who was not involved in participant management. The order of titration generated by the initial randomization was not revealed to the clinician or participant until all baseline information was collected. Likewise, the treatment sequence generated from the second randomization was revealed only after the titration phase was complete. 5.2.10 Blinding Neither the participants nor investigators were blinded to treatment due to the nature of the therapies. 141 5.2.11 Statistical Analysis Data is reported as means ± SD or median with interquartile ranges for non-normally distributed data. Continuous variables were tested for normal distribution using the Shapiro-Wilk test. Repeated measures analysis of variance (ANOVA) followed by post hoc analysis with Bonferroni correction were conducted for parametric variables and Friedman’s test with post hoc analysis (Wilcoxon) were conducted for non-parametric variables. Within subject analyses were corrected for multiple comparisons. Independent sample t-test (for parametric variables) and Mann Whitney-U test (for non-parametric variables) were performed to assess the differences between the groups in terms of their indication for long term use of dual therapy. Independent sample t-test was also used to compare between the characteristics of individuals who participated in phase IV of the trial and those who did not participate. SPSS software (SPSS version 28, Statistical Package for Social Sciences, SPSS Inc., Chicago, Illinois, USA) was used for analyzing data. 5.3 Results 5.3.1 Participants Twenty-eight participants were randomized for phase I of the trial and 25 of them completed the trial to phase III260. Twenty-one of those who completed phase III were eligible for phase IV. Three of the ineligible four were ineligible due to use of a full-face mask as the CPAP interface during phases I to III, and one was ineligible due to return of the CPAP machine following Phase III (as he did not want to use it again). Fourteen of the twenty-one who were eligible agreed to participate (detailed study flow chart in Figure 5.1). Of the seven who did not agree to participate, 4 did not want to commit their time to another trial (following phases I to III) and 3 did not want to use one of the treatments or the other. After consenting to participate, one participant was unable to start phase IV due to family circumstances. Table 5.1 describes the baseline characteristics of the participants who completed phase IV. The sample was predominantly Caucasian, male, had severe OSA and were middle-aged adults. 142 Figure 5.1 Study flow-chart of the four phases of the trial 143 Table 5.1 Baseline Characteristics for The Thirteen Participants Included in The Trial (phase IV) Parameter Mean (SD) Range Age, years 55.1 (13.4) 30 - 74 Sex, M/F 10/3 -- Diagnostic OSA Severity* Type I sleep study (N= 12) AHI, events/hour 32.9 (16.3) 11-58 Type IV (N= 1) ODI, events/hour 32.8 -- Baseline OSA Severity** ODI, events/hour 25.6 (13.5) 8.5 - 46.8 BMI, kg/m2 28.6 (5.5) 18.6 - 34.8 Neck circumference, inches 39.4 (3.8) 34 - 46.5 Bed partner (Y/N) 7/6 -- Snorer (Y/N) 12/1 -- Educational level (high school/higher education) 2/11 -- Occupational status (employed/retired/sick leave) 9/3/1 -- Preferred sleep position (lateral/supine/not sure) 7/5/1 -- Mean Office Systolic BP, mmHg 129.6 (12.0) 108 - 142 Mean Office Diastolic BP, mmHg 82.8 (8.5) 68 - 94 ESS, score 11.2 (7) 1 - 21 High ESS score (N=8) 15.4 (5.3) 10 - 21 FOSQ-10, score 15.2 (3.2) 9.7-19 Low FOSQ-10 score (N=11) 14.6 (3.1) 9.7-17.7 Data are presented as mean ± SD. N=13 unless otherwise indicated. *Diagnostic OSA severity is based on the initial method of OSA diagnosis- Type I or IV sleep study and the number of participants diagnosed by each method. ** Baseline OSA severity is the severity as indicated by the Type III sleep study done at baseline for Phase I of the trial. Abbreviations: OSA, Obstructive Sleep Apnea; AHI, Apnea-Hypopnea Index; REI, Respiratory Event Index; ODI, Oxygen Desaturation Index; BMI, Body Mass Index; M, Male; F, Female; Y, Yes; N, No; BP, Blood Pressure; ESS, Epworth Sleepiness Scale; FOSQ-10, Functional Outcomes of Sleep Questionnaire; SD, Standard Deviation. 5.3.2 Outcomes 5.3.2.1 Objective Outcomes 5.3.2.1.1 Effect of Dual-Therapy on Therapeutic CPAP Pressure Requirements, Mask Air Leaks and Machine Estimated Apnea-Hypopnea Index 144 The reduction in median CPAP pressure requirement with dual therapy was non-significant (p= 0.25) as compared to CPAP-monotherapy for the total sample. Reduction in CPAP pressure was more profound and was statistically significant (p=0.04) for the high CPAP pressure group (N=7), from a median pressure of 12 (10-13) cmH2O to a median pressure of 10 (9-12) cmH2O. Conversely, in the low CPAP pressure group, 2 participants demonstrated an increase in pressure with dual therapy compared to CPAP-monotherapy and 3 remained on the same pressure with dual therapy as on CPAP-monotherapy. Figure 5.2 outlines the changes in the pressure requirements. There was no significant difference in median mask air leaks (software measured) between CPAP-monotherapy and dual therapy (p=0.93). Likewise, the difference in machine estimated Apnea-Hypopnea Index (AHI) between the 1-month CPAP (3.6±2.2 events/hour) and the 1-month dual therapy (3±1.7 events/hour) was non-significant (p= 0.28). Figure 5.2 CPAP Pressure Requirements For (A) Total Sample, (B) Pressure ≥ 10cmH2O with CPAP-monotherapy, (C) Pressure <10cmH2O with CPAP-monotherapy Abbreviation: CPAP, Continuous Positive Airway Pressure. Mean 145 5.3.2.1.1 Oxygen Desaturation Index (ODI) 3% and BMI CPAP-monotherapy, MAS-monotherapy and dual therapy were all able to significantly reduce the ODI relative to baseline. The improvement was significantly (p=0.002) greater with CPAP-monotherapy and dual therapy than with MAS-monotherapy (Table 5.2). Additionally, there was no significant difference in BMI (p=0.64) at the different timepoints. 146 Table 5.2 Treatment Outcomes Divided by The Trial Timepoints: CPAP-monotherapy, MAS-monotherapy, Alternating and Dual therapy Baseline CPAP MAS Alternating therapy Dual therapy N P value Mask air leaks in second -- 42.2 (8.2-552.7) -- -- 72 (0-288) 13 0.93 b CPAP Pressure CPAP Pressure-total sample -- 10 (8 -12.5) -- -- 9 (8 -10) 13 0.25 b High Pressure ³ 10cmH2O -- 12 (10 -13) -- -- 10 (9-12) 7 0.04 b ODI 3% 25.6 (12.8-40.2) 2.6 (0.5-4.1) * 10.7 (4.7-14.1) *€ -- 2.8 (0.5-3.9) *  13 <0.001 b Adherence Mean adherence (h/night) when used -- 5.8 (1.7) 7.2 (1.1) € 6.7 (1.7) 7.1 (1.1) ‡ 11 <0.001 a Percentage of nights on therapy -- 100 (90-100) 96.3 (82.5-100) 97.5 (91.4-100) 100 (94-100) 11 0.11 b Office Systolic BP, mmHg 130 (119-139.5) 123 (115-128) 124.5(118.5-126.8) 122 (119-128) 124 (112-129) 13 0.54 b Office Diastolic BP, mmHg 84 (75-88.5) 76 (72.5-78) 79.5 (69.5-87.8) 80 (74.5-82.5) 78 (72-85.5) 13 0.24 b ESS score (0-24) ESS-total sample 10 (5-19.5) 7 (4-9) 9 (4-12) 7 (5-11) 6 (4-8.5) 13 0.10 b High ESS at baseline ³ 10 15 (10-21) 8 (4.8-13.5) 11 (8.3-13.5) 8 (7-12.3) 7 (4.3-9.8) 8 <0.001 b FOSQ-10 score (0-20) FOSQ-10 (total sample) 16.8 (12.6-17.6) 17.8 (15.3-19) 18.2 (14.5-19.1) * 18 (14.9-19.1) 18.7 (16.9-19.3) * 13 0.001 b Low FOSQ-10 score at baseline <17.9 16.2 (12.2-17.5) 17.7 (13.7-19) 18.2 (14-19.2) * 18 (14.3-19.6) * 17.3 (16.8-19.2) * 11 <0.001 b BMI 28.6 (18.6-34.8) 29.0 (19.3-36.0) 28.7 (19.1-35.9) 28.9 (19.0-36.0) 29.2 (18.8-35.2) 13 0.33 b CPAP machine estimated AHI, events/hour -- 3.6 (2.2) -- -- 3.0 (1.7) 13 0.28 a 147 Data are presented as mean (standard deviation) or median (interquartile range) based on normality of the data a Parametric test b Non-parametric test * Statistically significant difference compared to baseline after correction for multiple comparisons (p<0.005) € Statistically significant difference between MAS and CPAP Statistically significant difference between MAS and dual therapy ‡ Statistically significant difference between CPAP and dual therapy Abbreviations: CPAP, Continuous Positive airway Pressure; MAS, Mandibular Advancement Splint; BMI, Body Mass Index; ODI, Oxygen desaturation Index; ESS, Epworth Sleepiness Scale; FOSQ-10, Functional Outcomes of Sleep Questionnaire; BP, Blood Pressure; AHI, Apnea-Hypopnea Index. 5.3.2.1.2 Adherence During 1-month on CPAP, MAS, Alternating Therapy and Dual Therapy During the 1-month on alternating therapy, 9(69%) participants were alternating between CPAP and MAS. Two (15.4%) were using CPAP-monotherapy exclusively and 2(15.4%) were using MAS-monotherapy exclusively. During the 1-month on dual therapy, participants used both devices simultaneously for 69% of the time on treatment, CPAP-monotherapy for 11% of the time and MAS-monotherapy for 20% of the time. As seen in Figure 5.3, overall mean ± SD, objectively measured adherence to therapy was 5.8±1.7, 7.2±1.1, 6.7±1.7 and 7.1±1.1(h/night) during the 1-month on CPAP-monotherapy, MAS-monotherapy, alternating and dual therapies respectively. There was a statistically significant difference between mean therapy usage (when used), showing less adherence for the 1-month on CPAP-monotherapy as compared to 1-month on MAS-monotherapy (p=0.01) and to the 1-month on dual therapy (p=0.04). There was no difference in mean usage between the 1-month on MAS-monotherapy, 1-month alternating therapy and 1-month dual therapy. Median percentage of nights therapy was used were 100 (90-100), 96.3 (82.5-100), 97.5 (91.4-100) and 100 (94-100) for the 1-month on CPAP-monotherapy, MAS-monotherapy, alternating and dual therapies respectively. Differences were not statistically significant (p=0.11). 148 One participant had an adherence chip failure during the 1-month on MAS-monotherapy and 1 had an adherence chip failure during the 1-month on dual therapy. 1-month on MAS-monotherapy and 1-month on dual therapy showed the highest adherence rates, with 100% of the participants being compliant to treatment. Eighty-two percent of participants were compliant during the 1-month on CPAP-monotherapy and during the alternating therapy month. The l-month on MAS-monotherapy also had the highest percentage of regular users, with 100% considered regular users. Ninety-one percent of the participants were regular users of treatment during the 1-month on dual therapy. Eighty-two percent of participants were considered regular users during the 1-month on CPAP-monotherapy and during the alternating therapy month. Figure 5.3 Mean Objectively Measured Adherence: Number of Hours Per Night (When Used) During Each of The Trial Phases Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; Alternating, the alternating use of CPAP and MAS; Dual, the simultaneous use of CPAP and MAS. 0123456789101 2 3 4 5 6 7 8 9 10 11 12Mean number of hours used (when used)/hourParticipant IDMean AdherenceCPAPMASAlternatingDual 149 5.3.2.1.3 Blood Pressure Compared to baseline SBP [130 (119-139.5) mmHg], there was a reduction in SBP with CPAP [123 (115-128) mmHg], MAS [124.5 (118.5-126.8) mmHg], with alternating therapy [122 (119-128) mmHg] and with dual therapy [124 (112-129) mmHg]. However, this reduction was not statistically significant (p=0.54). Similarly, compared to baseline DBP [84 (75-88.5) mmHg], there was a reduction in DBP with CPAP [76 (72.5-78) mmHg], MAS [79.5 (69.5-87.8) mmHg], with alternating therapy [80 (74.5-82.5) mmHg] and with dual therapy [78 (72-85.5) mmHg]. This reduction was also not statistically significant (p=0.24). 5.3.2.2 Self-reported Outcomes 5.3.2.2.1 ESS Scores There was no statistically significant effect of treatment on reducing the ESS scores at the different timepoints for the total sample. For the 8 participants who presented with excessive sleepiness pre-treatment, there was a statistically significant reduction in their ESS score with CPAP-monotherapy, MAS-monotherapy, alternating therapy and dual therapy at the p<0.05 level. There was more reduction in ESS median score with dual therapy and with alternating therapy relative to MAS-monotherapy. However, after adjusting for multiple comparisons (p<0.005), the difference between the baseline ESS score and the ESS score at all the timepoints was not statistically significant (Figure 5.4A and B). 150 5.3.2.2.2 FOSQ-10 Scores MAS-monotherapy and dual therapy resulted in a statistically significant improvement in FOSQ-10 scores relative to baseline for both the total sample and for the subset of participants who presented with low scores at baseline (N=11) at the p<0.005 level (adjusted for multiple comparisons). CPAP-monotherapy resulted in an increase in FOSQ-10 score for the total sample and for participants who presented with low baseline scores (Figure 5.4C and D), which was not statistically significant after adjustment to multiple comparisons. Likewise, the increase in mean score for the total sample during the 1-month on alternating therapy was not statistically significant after adjusting for multiple comparisons. Figure 5.4 ESS and FOSQ-10 Scores for The Total Sample (A and C Respectively) and for Participants Who Are Highly Symptomatic at Baseline, (B) Baseline ESS ≥10 and (D) Baseline FOSQ-10 <17.9 *Statistically significant difference compared to baseline, p<0.005 Abbreviations: ESS, Epworth Sleepiness Scale; FOSQ-10, Functional Outcomes of Sleep Questionnaire; CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint; Alternating, the alternating use of CPAP and MAS; Dual, the simultaneous use of CPAP and MAS. 151 5.3.2.2.3 Participants’ Perceptions with MAS-monotherapy, CPAP-monotherapy and Dual Therapy Only one of the 13 participants who completed this trial reported being very claustrophobic with CPAP and was only somewhat claustrophobic with dual therapy. One felt somewhat claustrophobic with both MAS and dual therapy. No participants felt very claustrophobic with either MAS or dual therapy. In total, 4 (31%) participants felt somewhat claustrophobic with dual therapy. Perceived comfort with CPAP, MAS and dual therapy were 71, 73 and 55% respectively on the VAS. Four (31%) participants preferred dual therapy over CPAP-monotherapy and 3 (23%) preferred dual therapy over MAS-monotherapy. All participants indicated that they would continue to use MAS and CPAP regularly and 7 (53.8%) of them reported that they would continue to use dual therapy long term. There were no statistically significant differences between those who indicated that they would continue to use dual therapy long term and those who indicated that they would not (Table 5.3). 152 Table 5.3 Characteristics of Participants Based on Their Willingness to Continue to Use Dual Therapy Long Term Will use dual therapy long term N= 7 Will not use dual therapy long term N= 6 P (95% CI) Baseline characteristics Diagnostic AHI (events/h) 38.9 (16.8) 26 (11.7) 0.15 a (-30.9 to 5.2) OSA severity (mild/moderate/severe) 1/2/4 1/3/2 -- Sex (M/F) 5/2 5/1 -- Bed partner (Y/N) 5/2 2/4 -- Age (years) 58 (11.3) 51.7 (15.8) 0.4a (-22.9 to 1.2) BMI (kg/m2) 28.5 (5.6) 28.7 (5.3) 0.93 a (-6,4 to 7.0) Baseline FOSQ score 16.1 (3.3) 14.3 (3.1) 0.33a (-5.8 to 2.1) Baseline ESS score 11.7 (8.3) 10.5 (5.9) 0.77a (-10.1 to 7.7) Treatment related factors Adherence (mean hours/night) 6.4 (1.4) d 7.4 (1.1) 0.20 a (-0.6 to 2.6) Dual therapy FOSQ-10 score 18.0 (1.2) 17.7 (2.5) 0.89 b Δ FOSQ-10 1.9 (2.7) 3.5 (1.9) 0.25 a (-1.3 to 4.4) Dual therapy ESS score 6.1 (2.4) 7.7 (6.1) 0.94 b Δ ESS 5.6 (7.9) 2.8 (2.6) 0.44 a (-10.2 to 4.7) Pressure on CPAP-monotherapy (cmH20) 11.1 (2.7) 8.5 (1.8) 0.07 a (-5.5 to 0.2) Pressure on dual therapy (cmH20) 9.7 (2.0) 8.5 (1.2) 0.66 b Δ Pressure (cmH20) 1.4 (2.4) 0 (1.3) 0.16 b Comfort with dual therapy (%) 64.9 (22.5) 43.7 (23.8) 0.13 a (-49.5 to 7.2) Somewhat claustrophobic with dual therapy (Y/N) 2/5 2/4 -- Self-reported effectiveness (not effective/effective) 0/7 3/3 -- Data are presented as mean (standard deviation) a Parametric test b Non-parametric test d N=6 Abbreviations: CI, Confidence Interval; BMI, Body Mass Index; AHI, Apnea-Hypopnea Index; ESS, Epworth Sleepiness Scale; FOSQ, Functional Outcomes of Sleep Questionnaire; M, Male; F, Female; Y, Yes; N, No; h, Hours; Δ= Baseline Variable-Dual Therapy Variable; %, Percentage. 153 5.3.2.2.4 Side-effects with Dual Therapy Seven participants did not complain of side-effects with dual therapy while 6 complained of transient side-effects. The main complaints were dry mouth (n= 2), excessive salivation (n=1), drooling (n=1), chapped lips (n=1) and being more intrusive (n=1). 5.3.2.2.5 Comparison Between Individuals Who Participated and Those Who Did Not Participate in Phase IV Participants who completed phase III (n=25) and completed phase IV (n=13) were compared to those who completed phase III but did not participate in phase IV (n=12). There was no difference between the two groups in terms of their diagnostic AHI, age or baseline FOSQ-10 scores. However, there was a significant difference in their baseline ESS score and their pressure on CPAP-monotherapy. Those who participated in phase IV had a significantly higher mean baseline ESS score (p=0.03) and a higher mean pressure on CPAP-monotherapy (p=0.04). 5.4 Discussion To our knowledge, this is the first trial to compare the alternating use of CPAP and MAS to their simultaneous use in patients who are tolerant to both CPAP and MAS conventional therapies. It is also the first trial to objectively measure adherence to alternating and simultaneous use. It shows that combination therapy, whether alternating or simultaneous use, has advantages over monotherapy and can improve overall adherence to therapy and further reduce symptoms. Previous reports have described the utility of simultaneous use of CPAP with MAS (whether integrated or dual therapy) for patients who are intolerant to CPAP monotherapy due to the high pressure and for those who are sub-optimal responders to MAS monotherapy149,150,152,342,343,348. Results of our study confirm the findings of the literature and show that CPAP pressure requirements are reduced by dual therapy 154 compared to CPAP-monotherapy for patients who require high CPAP pressure on monotherapy (≥10cmH2O). A CPAP pressure change of <0.5 cmH2O was shown to be the most useful intervention to increase adherence to CPAP in a recently published study investigating interventions to improve adherence to CPAP310. Similar to the findings of Premaraj et al347, our results show that there was a non-significant difference in mean pressure for the total sample between CPAP-monotherapy and dual therapy. In the current trial, pressure requirements remained the same or increased on dual therapy for 4 out of the 6 participants who were on low (<10cmH2O) pressure with CPAP-monotherapy. Similarly, De Vries et al151 have shown that three of their seven patients had a pressure increase from 6 cmH2O to 7 cmH2O with dual therapy. Premaraj et al347 reported that six out of their thirteen patients exhibited an increase in pressure with dual therapy, while the data from El-Solh et al150 also showed a similar increase in CPAP pressure for a participant whose pressure on monotherapy was <10cmH2O. Our study confirms the findings that not every patient’s CPAP pressure will decrease with dual therapy, especially those who are on low pressure with CPAP-monotherapy. It has been hypothesized that the reduction in pressure requirements with the simultaneous use of CPAP and MAS can be attributed to the MAS reducing upper airway collapsibility149, as the anterior displacement of the mandible and tongue base widen the retropalatal airway349. The reason for an increase in CPAP pressure on dual therapy is unknown. Our results also show that the simultaneous use of CPAP and MAS did not lead to a significant increase in CPAP mask air leaks, despite the use of a MAS that allowed for mouth opening. However, this may be attributed to the close monitoring and troubleshooting as part of a clinical trial and may not reflect routine clinical practice. 155 During the 1-month on alternating therapy participants had the flexibility to use both therapies as they wish, and it was observed that the majority of participants (69%) were alternating between CPAP and MAS. During the 1-month on dual therapy, participants were asked to try to use the treatments together and were using dual therapy for 69% of their hours on treatment, in addition to the use of MAS (20%) and CPAP (11%) separately. The combined effect was an improved adherence to therapy during that 1-month period. Similarly, having both therapies to alternate, increased overall adherence to OSA therapy relative to CPAP-monotherapy as evident during the 1-month on alternating therapy. The results of our trial enlighten us that CPAP-monotherapy, despite it being the most efficacious OSA therapy282, was the one with the least hours/night of use. The literature shows that adherence to CPAP-monotherapy is generally low and is approximately 4.5 hours/night311. In our trial, adherence to CPAP-monotherapy was higher, likely due to the close follow-up done during the trial. It has been previously shown that adherence to CPAP declines with time303. Our results demonstrate that despite the high adherence noted with CPAP-monotherapy in our trial compared to that reported in the literature, adherence to OSA therapy has remained high and was even higher than with CPAP-monotherapy, due to the ability to alternate between treatments and the ability to use them simultaneously. Premaraj et al347 also found an increase in adherence with dual therapy relative to CPAP albeit adherence being self-reported in their study. An intervention that can increase CPAP adherence by ³ 0.5 hours/night has been considered to be a clinically significant difference85,310 and the findings of our work show that both forms of combination therapy were able to do so relative to CPAP monotherapy. Adherence was 5.8±1.7, 6.7±1.7 and 7.1±1.1(h/night) during the 1-month on CPAP-monotherapy, alternating and dual therapies respectively. In agreement with previous findings, CPAP, MAS and dual therapy were all able to improve respiratory parameters relative to baseline278,282. CPAP and dual therapy provided greater ODI improvement than MAS monotherapy134,152,278,282,302 while CPAP and dual therapy showed similar improvement150,151. The AHI values reported in the current trial were obtained from the CPAP machine, and similar to the findings 156 of Premaraj et al347 who also obtained the AHI values from the CPAP machine, both studies showed no significant difference in the residual AHI between CPAP-monotherapy and dual therapy. While CPAP machine estimated AHI may not be as accurate as polysomnography (PSG) derived AHI, it can serve the purpose of comparing residual AHI on CPAP-monotherapy and dual therapy. Contrary to the findings of a previous network meta-analysis313, our findings did not show a statistically significant difference in SBP or DBP with CPAP or MAS. Despite our trial showing a reduction in the mean SBP and DBP at all timepoints relative to pre-treatment values, the differences did not reach statistical significance. This may be attributed to the present trial being inadequately powered to detect a statistically significant difference with regards to blood pressure, or that our sample was too small to be divided into high and normal blood pressure groups at baseline. Notably, individual studies included in Bratton’s et al313 network meta-analysis followed up their patients between 1 and 157 weeks. Similar to our findings, Liu et al152 on their sample of 14 patients, did not find a difference in overnight BP between dual therapy, MAS, CPAP and pre-treatment. The results of this study show a significant increase in the FOSQ-10 scores for the total sample and for participants who were symptomatic at baseline during the 1-month on MAS, alternating and dual therapies. This indicates that both the alternating and simultaneous use of therapies helped alleviate symptoms relative to CPAP-monotherapy. Due to the multiple comparisons and the small sample size, some self-reported outcome findings were not statistically significant at the p<0.005 level but were statistically significant at the p<0.05 level and are also clinically significant. For example, there was a considerable improvement in FOSQ-10 scores with CPAP-monotherapy compared to pre-treatment score that was noted when the p-value was not corrected for multiple comparisons. Similarly, for the group of participants who had high pre-treatment ESS scores, treatment with CPAP-monotherapy, MAS-monotherapy, alternating and dual therapies lead to a substantial reduction of 4 to 8 points in their ESS scores that was statistically significant only at the p<0.05 level. Alternating and dual therapies were also further able to reduce daytime sleepiness relative to MAS-monotherapy. 157 None of our trial participants on dual therapy were using oronasal masks (ONM) however, ONM have been previously associated with increased residual AHI compared to nasal masks (NM)84. This has been attributed to the tongue and mandible being displaced posteriorly with the ONM, subsequently narrowing the oropharynx and contributing to pharyngeal collapse341,350. On the other hand, NMs have been associated with lower pressure requirements341,351,352 and better tolerability352. Borel et al353 have demonstrated that combining a NM with a MAS reduced velopharyngeal resistance compared to ONM and NM alone and that together they acted synergistically to improve velopharyngeal patency. Our trial confirms the feasibility of use and high efficacy of NM with MAS. Attempts have been made to integrate CPAP and MAS for their simultaneous use151,153,343. Both integrated/attached and non-integrated simultaneous use provide the same advantages of improving respiratory parameters and reducing the required CPAP pressure343. However, in our opinion, the additional advantage of non-integrated over integrated is the ability to continue to use each of the CPAP and MAS separately when not using them simultaneously. Consequently, this flexibility could increase overall adherence to therapy. In our current trial, CPAP and MAS were used separately 31% of the time during the dual therapy phase, despite participants being advised to use them together. Additionally, non-integrated simultaneous use eliminates the added customization required and reduces the associated complexity. Unlike the findings of DeVries et al151, study participants did not perceive dual therapy as being more comfortable than CPAP or MAS monotherapy. In their study, DeVries et al attributed the increased comfort with dual therapy over CPAP-monotherapy as being due to their patients having more complaints with CPAP-monotherapy151. Our participants did not have substantial complaints with CPAP or MAS monotherapy (results not shown) and therefore may have not perceived dual therapy as being more comfortable. Nevertheless, 54% of our participants preferred dual therapy over either CPAP or MAS monotherapy, possibly due to the added benefits, and approximately half of them indicated that they would use dual therapy on occasion in the long term. 158 No single factor appeared to be a determinant of whether participants will continue to use dual therapy long term and it may be due to a combination of factors. Nevertheless, there was a tendency for those who had severe OSA pre-treatment, had a bed partner, reported higher perceived effectiveness with dual therapy and perceived dual therapy as being comfortable, to indicate that they would use dual therapy long term. Participants who likely will continue to use dual therapy also tended to have a higher mean pre-treatment AHI, be older in age and present higher mean ESS and lower FOSQ-10 pre-treatment scores. They also had a greater reduction in their daytime sleepiness and CPAP pressure with dual therapy than the group who indicated they would not use dual therapy long term. However, the differences between the two groups were not statistically significant. Two participants who were claustrophobic with either MAS or CPAP felt somewhat claustrophobic with dual therapy and two participants who were not claustrophobic with neither MAS nor CPAP felt somewhat claustrophobic with dual therapy. Therefore, claustrophobia should be considered as a possible side-effect of all the treatment modalities available in our current trial. However, it did not deter participants from adhering to treatment. A comparison between the individuals who participated in phase IV and those who did not participate in phase IV of this trial shows that the former group were experiencing, on average, more daytime sleepiness at baseline and had a higher mean CPAP pressure on CPAP-monotherapy. These factors may have encouraged them to be more willing to seek additional treatment. This study has potential limitations, patients who agreed to participate in Phase IV of the study (1-month of dual therapy) were those who were tolerant to both MAS and CPAP and willing to use both simultaneously therefore, may not represent all patients with OSA. This study was conducted at a single center and it lacks a PSG assessment for treatment efficacy. Our study protocol required assessment of efficacy at specific time points throughout the trial and logistically a PSG assessment was not feasible. Additionally, a larger sample size would have increased the generalizability of the findings. It is also 159 important to note that the subgroup analyses need to be interpreted with caution as the trial was not powered to detect differences in these subgroups. Despite these potential limitations, this prospective clinical trial had a unique and robust design that helped minimize potential biases. Our findings indicate that outcomes on both alternating therapy and dual therapy are comparable and the decision to choose one modality or the other may be based on the individual patient’s needs, lifestyle and preferences. Both forms of combination therapy appear to reduce the shortcomings of CPAP and MAS monotherapy. Dual therapy provides a unique advantage over alternating therapy in cases where a reduction in CPAP pressure requirement is a goal. In spite of the perceived effectiveness of combination therapy, its major drawback is the cost of purchasing both treatment modalities and the time required for titration and adjustment of both therapies. Future research with a larger sample should investigate the long-term effectiveness of combination therapies for the management of OSA and its cost-effectiveness. 5.5 Conclusions Our results demonstrate that dual therapy may be beneficial for patients who require high CPAP pressure (≥10cmH2O) with CPAP-monotherapy. Our findings also show that dual therapy along with the alternating use of therapies increase adherence to treatment. Furthermore, dual and alternating therapies could be effective in reducing symptoms in patients who are highly symptomatic pre-treatment and for whom monotherapy is not sufficient to completely resolve symptoms, despite adequate treatment. 160 Chapter 6: Discussion, Summary, Overall limitations and Strengths, Clinical Implications, Future Directions and Conclusions 6.1 Discussion OSA is a highly prevalent yet underdiagnosed chronic condition11. Not only is it underdiagnosed, it is also undertreated in patients who have received a diagnosis, as only a few are adhering to treatment long term. Both the underdiagnosis and the undertreatment lead to considerable reduction in the overall numbers of those who are effectively treated for OSA. The two main disease specific therapies for OSA are CPAP and MAS. Effective treatment by CPAP is limited by its low adherence and effective treatment by MAS is limited by its suboptimal efficacy134, in addition to concerns regarding its long-term side effects243. Medication adherence in chronic conditions is a concerning issue and it is estimated that 40 to 60% of patients do not take their medications as prescribed335,354. Adherence is very important in all nonsurgical OSA treatment modalities. Both CPAP and MAS are treatments that do not eliminate the underlying cause of OSA and are therefore life-long therapies. In non-surgical treatment modalities, the patient makes a daily decision to put on and remove the treatment device. The effectiveness of treatment is dependent on adherence and entails an effective reduction of the apneic events and symptoms and an improvement in the quality of life205. 6.1.1 Beyond the AHI Despite the undeniable importance of AHI as a treatment outcome, a therapy for which patient improvements are assessed based on a single outcome is far from the current precision medicine paradigm355. A more holistic approach that involves patient centered treatment outcome parameters should be utilized to assess a patient’s benefit from an intervention356. In the last few decades, there has been a broadening of focus in the measurement of health beyond mortality and morbidity, the traditional 161 health indicators, to include measures of the impact of disease and impairment on daily activities, perceived health and disability/functional status357. The traditional disease-centered mechanistic model of medicine, concerned primarily with the eradication of disease, is being balanced by a shift of focus to the humanistic element of health care. Health care is becoming increasingly recognized as a humanistic transaction where the patient's well-being is a primary aim357. By incorporating quality of life assessments, attention is being focused onto this aspect of health, and on patients' well-being357. The research presented in this thesis has integrated quality of life measures and measurement of the impact of OSA on functional status and impairment of daily activities. Our findings indicate that CPAP, MAS and a combination of both are equally able to improve quality of life, reduce functional impairment and reduce symptoms for patients with OSA. 6.1.2 Patient Centered Care Approach and Shared Decision-making A shared decision-making process requires patients to know the benefits and be aware of the risks of each alternative. Additionally, the patients need to identify their concerns, preferences, needs, values and goals in a bidirectional communication process between the patient and the clinican158,358. The Agency for Healthcare Research and Quality (AHRQ) has proposed a framework for shared decision making named the SHARE approach359. SHARE stands for: “Seek your patient’s participation, Help your patient explore and compare treatment options, Assess your patient’s values and preferences, Reach a decision with your patient, Evaluate your patient’s decision”. Similarly, Hilbert and Yaggi156 have described the patient-centered care approach in OSA to include: “1) determining patient-specific needs to guide treatment decisions, 2) understanding patient values, preferences, and other factors impacting treatment decisions and using shared decision-making, 3) enhancing patient education and support to improve treatment adherence, 4) promoting patient engagement, 5) optimizing care coordination, continuity of care, and access to care, and 6) determining and assessing patient-centered outcomes”. 162 In the work presented in this thesis, we believe that we have, at least in part, applied a patient centered care approach156 and have shown that it is feasible in the context of OSA. We have utilized the decision aid tool to educate the participants about OSA, the treatment options available to them and the pros and cons of these options. We also utilized this interactive tool to identify patient values, needs and preferences. The disclosure of the treatment results also helped the participants in their decision-making process. Additionally, we took a multidisciplinary team care approach and provided the participants the support that they needed with both therapies. We also included patient centered outcomes in our assessment of the different treatment modalities. 6.1.3 Comparison of CPAP and MAS: Although MAS has been compared to CPAP in several head to head comparison studies134,220,282,360–364, these studies either mostly enrolled patients in the mild to moderate scale of OSA severity220,360,363, did not have a titration/adaptation period before measuring outcomes220,361,362,364, or did not use custom made titratable MAS360. Furthermore, all the previously mentioned comparison studies lacked objective adherence monitoring for MAS. Our work represents the first multi-center, cross-over randomized trial comparing MAS to CPAP that includes objective monitoring for both MAS and CPAP for the entire study period. Phillips et al134 has conducted a pivotal randomized controlled trial comparing CPAP and MAS that assessed a variety of outcomes. Our findings were similar to their findings with regards to several aspects. Our results show that both CPAP and MAS were able to improve respiratory parameters relative to baseline and that CPAP was superior in doing so. These findings are consistent among all randomized controlled trials that have compared the efficacy of the two treatments. Our findings regarding adherence were also consistent with the findings of Phillips et al134 in terms of higher adherence to MAS over CPAP being noted, despite our findings being based on an objective assessment and their assessment being based on patient self-reported data. Additionally, our assessment of 163 adherence was more thorough and included different measures of adherence and showed that adherence to MAS was on average 1.1 hours/night greater than CPAP. Adherence to CPAP was lower in their study134 in comparison to the current work. Furthermore, a higher preference for MAS over CPAP was also consistent between our study and the Phillips et al134 study and was consistent with the findings of several other studies as reviewed by Sutherland et al226. Our work included multiple measures to assess QoL, some of which are disease specific (FOSQ) and others assess general QoL (SF-36) in addition to assessing symptom specific outcomes (ESS, CFQ and snoring). This variability in the assessment tools attempted to provide a comprehensive assessment and comparison of treatments with regards to patient centered outcomes. Our findings are congruent with those of Phillips et al134 which showed that changes in both ESS and FOSQ were comparable between the two treatments and that MAS but not CPAP was able to improve the Mental Component Score of SF-36. Blood pressure findings however were not consistent between the two studies and while their assessment 134 was of the 24-hour blood pressure, our assessment was based on in-office blood pressure readings. Their analysis 134 showed a comparable reduction in blood pressure between CPAP and MAS that was not statistically significant from baseline for both treatments. Only a subset of their study population who were initially hypertensive at baseline showed a significant reduction with both treatments as compared to baseline134. Our results show that MAS was able to significantly reduce systolic blood pressure relative to baseline with a mean difference of 4.6mmHg and that both CPAP and MAS were both able to significantly reduce diastolic blood pressure by 4.8mmHg and 4.7mmHg respectively compared to baseline. These findings are in line with the findings of a meta-analysis that showed that both CPAP and MAS were equally able to reduce blood pressure relative to the control group and that each hour per night increase in mean CPAP use was associated with an additional reduction in systolic blood pressure by 1.5 mm Hg and an additional reduction in diastolic blood 164 pressure by 0.9 mm Hg. Since adherence was high in our study population, it is reasonable to expect the magnitude of reduction in blood pressure that we observed in our study. 6.1.4 Comparison of CPAP Adherence Between Studies As described by Cistulli et al289 “It is not sufficient simply to prescribe a PAP machine and consider the patient to be treated”. Studies have reported short term CPAP adherence (<6 months) to be approximately an average of 4.5 hours/night311. Cistulli et al289 reported relatively higher adherence to CPAP compared to the previously reported averages (mean daily CPAP use of 6.2 hours/night on days used and 5.5 hours/night over the total duration during the first 90 days of use). This higher than average adherence could be related to the recent advances in the CPAP machines or could also be related to third party insurer policies and the fear that the patients may have had of not meeting the criteria for reimbursement during the first 90 days of use96. We attribute the high CPAP adherence rates observed in our trial during the cross-over phase (mean daily CPAP use was 5.9 hours/night on days used and 5.3 hours/night over the total duration) to the continuous support that our trial participants received, the education that they received regarding treatments (delivered via the decision aid tool) and the frequent follow-ups during the adaptation/titration and cross-over phases of the trial. Patient education, frequent follow-ups and troubleshooting have all been previously identified as factors that may improve adherence86,96,104. Similarly, we attribute the high CPAP adherence observed during the observational phase to the aforementioned factors, in addition to the ability given to the participants to decide for themselves which treatment they want to use and to the disclosure of the results that helped participants in their decision-making process. The disclosure of the results helped quantify for the participants the symptom improvement and showed them treatment efficacy. However, we believe that the effects of close monitoring and follow-ups during this phase of the trial have been downplayed due to the long duration 165 between follow-up visits and due to the fact that it is a long trial and the need to please the research personnel is not of importance, as there were no benefits gained or lost with high or low adherence. Our findings show that adherence is the key to improve all objectively measured and self-reported outcomes, except for efficacy. Nevertheless, even efficacy can be sustained by improving adherence and some studies on oral appliances have found further improvement in AHI after 2-4 years, in patients who were highly adherence to treatment365. Our work highlights some strategies to improve adherence, these include support and troubleshooting that help minimize side-effects, providing participants with more than one therapy (giving choices and alternatives), including participants in the decision-making process and inclusion of a multidisciplinary team in patient care. Interestingly, numerous studies since CPAP was first described in the literature over 40 years ago have raised concerns regarding the generally low adherence rates to CPAP and the potential consequences of this low adherence85,98,102,311. Moreover, numerous studies have discussed methods to augment adherence86,96,104,105,310, yet to the best of our knowledge, none have investigated combination therapy as a potential method to increase adherence to therapy. We are the first to propose combination therapy as a means of increasing overall adherence. Our results show that the percentage of participants who were using CPAP for ≥4 hours/night was 87% during the 1-month on CPAP and 94% during the 6-months observation period (the time during which the majority of participants were using combination therapy). Furthermore, the percentage of regular users (≥4 hours of nightly use on ≥70% of nights) was 81% during the 1-month on CPAP and 86% during the 6-months observation period. Considering that adherence is known to decline with time, it would have been otherwise expected for adherence during the observation period to be lower than adherence during the 1-month on CPAP, yet the opposite was noted in our study when the combination was used. These findings confirm our hypothesis that the interchangeable use of therapies can increase overall adherence to therapy. 166 While combination therapy may seem to be a costly option to increase adherence, other interventions that aim to increase adherence are also considered costly, such as behavioural therapy that requires the presence of a specialized therapist. Additionally, it is not expected that the patients will continue on behavioural or educational interventions for many decades and the long-term effect of such interventions is unknown, as the positive effect may subside following terminated of the intervention. Furthermore, a recently published study assessing interventions to increase CPAP adherence showed that attendance to educational session was poor310. Our findings show that a combination of CPAP and MAS can lead to a higher percentage of time on treatment (independent of which) compared to CPAP monotherapy. Moreover, the benefits of this combination are twofold, as another advantage that is unique to the combination is its ability to reduce the burden of treatment which is sometimes under-estimated by health care providers366. 6.1.5 Combination Therapy Combination therapy is a well-established concept in many health disciplines and is even regarded as the standard of care in some of them, yet the literature describing combination therapy for the management of OSA is scarce. Combining two or more therapies with different mechanisms of action or that target different pathways of the disease is a cornerstone in cancer therapy and many chronic conditions, since monotherapies rarely provide the desired therapeutic outcome. In addition to increased efficacy, a combination of therapies allows for a reduction in the required dose of any single therapy which reduces side-effects and toxicity367,368. This in turn can increase treatment acceptance. Few studies describe combination therapy for the management of OSA. These can be divided into studies that investigate the combination of CPAP with other therapies, the combination of MAS with other therapies and those that involve the combination of different pharmacotherapies. MAS has been combined with positional therapy229, surgery146, genioglossus muscle stimulation143, medications144 and expiratory positive airway pressure145. CPAP has been combined with weight loss148, MAS150,151 and 167 with modafinil369 (pharmacological agent) in addition to the combination of different pharmacological agents together147. Combining therapies which target different physiological traits that contribute to the pathophysiology of OSA has been attempted. A trial assessing a single night of a combination of a noradrenergic and an antimuscarinic agent found that the combination was able to reduce the AHI and increase muscle responsiveness while neither was able to reduce the AHI when administered separately147. Similarly, one night of a combination targeted towards lowering loop gain (by means of supplemental oxygen) and raising the arousal threshold (by administering eszopiclone) led to a reduction in the AHI in patients who had less severe OSA, a less collapsible upper airway and greater upper airway muscle effectiveness123. Therapies that target the physiological traits (anatomical and non-anatomical) based on endotype help to personalize treatment however, their application in routine clinical practice is far from being feasible at the current time due to the difficulty in determining both the endotype and the specific contribution of each non-anatomical trait in the pathophysiology of OSA at the level of the individual. Additionally, they may be of benefit to a selective patient population who have these traits. To improve the efficacy of MAS, few studies have attempted to combine it with surgery146, genioglossus muscle stimulation143, medications and expiratory positive airway pressure145. Results of split night polysomnography showed that compared to baseline and MAS monotherapy, MAS plus oral expiratory positive airway pressure significantly reduced the median AHI, with further reductions for the MAS plus oral/nasal expiratory positive airway pressure combination in comparison to the other groups (22, 15, 10 and 7 events/hour respectively)145. In another study, further improvement in the AHI were also noted in patients who had undergone uvulopalatopharyngoplasty and were under MAS therapy in comparison to those who had only undergone uvulopalatopharyngoplasty146. However, uvulopalatopharyngoplasty is an invasive procedure and not all patients with OSA are good candidates for, limiting the applicability of this combination. The combination of MAS with positional therapy has shown to have higher therapeutic efficacy than either MAS or positional therapy when used as 168 monotherapies229. AHI at baseline, with MAS alone, with positional therapy alone and with the combination were 20.8, 11.0, 11.1 and 5.7 events/hour respectively229. Even though this combination seems to be promising, it is useful for only a subset of the patient population who predominantly have positional OSA. Only eighteen to thirty-four percent of patients treated with MAS showed supine dependent OSA under MAS therapy370. Of note is that the aforementioned proof-of-concept studies show that these combinations seem to be promising yet the majority have solely assessed efficacy. Currently there continues to be a lack of studies that thoroughly evaluate these combinations and their effect on patient centered outcomes, long term effectiveness and side-effects. A direct comparison of our findings to the previously published work on combination therapy is not possible. This is due to that there is no single AHI/REI for the combination in our trial investigating the alternating use of therapies (chapter 4), since both treatments were not used simultaneously but rather interchangeable. However, we were able calculate metrics for effectiveness such as the MDA and SARAH index which adjust for hours of usage over total sleep time205. Hence, not only do these metrics include a measure of efficacy (REI in our study) but rather they extend beyond that and measure real world effectiveness, since efficacy by itself is not synonymous for ‘being treated’, as all the aforementioned interventions are of no benefit if not used. In our trial, the SARAH index for CPAP monotherapy and for the predominantly interchangeable use of therapies were comparable as it was 7 events/hour for CPAP monotherapy and 10 events/hour for the interchangeable use of therapies. This comparable effectiveness noted in our study was mainly due to the high efficacy and adherence to CPAP and the variability in the response to MAS. Moreover, our investigation of combinational therapy (presented in chapter 4) is more rigorous compared to the aforementioned studies. Additionally, we have studied the combination of the two most widely used treatments for OSA (CPAP and MAS) that have proven to be safe treatments leading to no 169 serious risks. The combination was investigated longer term (for 6 months) relative to the other studies, on a large sampler size, in a multi-center setting, with an objective assessment of adherence to both therapies and involving an assessment of a variety of patient centered outcomes, making our trial unique from the aforementioned trials assessing combination therapy. Studies investigating the combination of CPAP to other interventions include a 6-months parallel group randomized trial on the effects of CPAP, a weight loss intervention and their combination in obese adults with moderate to severe OSA148. The CPAP-weight loss combination did not have a significant incremental effect on C-reactive protein, the primary outcome however, it showed an effect on insulin resistance and serum triglyceride levels, as compared to CPAP monotherapy but not to the weight-loss intervention alone148. While the effects of weight loss are undeniably important for many aspects of health, weight loss is both hard to achieve and to maintain371, limiting the applicability of this combination. To minimize excessive daytime sleepiness in patients who have persistent sleepiness despite optimized CPAP, the combination of CPAP with modafinil or armodafinil has also been studied369. A meta-analysis showed that Modafinil/armodafinil were able to improve both objective and subjective measures of daytime sleepiness in patients with residual symptoms with a 2.2-point improvement on the ESS score however, there are concerns about long term or possible serious risks369. Additionally, this combination aims to reduce or eliminate a single symptom, which is increased daytime sleepiness and may not reduce other symptoms such as fatigue if present. Several researchers have previously investigated the simultaneous use of CPAP and MAS and similar to all previous studies assessing the respiratory parameters with the combination relative to each of the monotherapies150–152, our trial showed that the respiratory parameters were significantly improved on dual therapy relative to MAS monotherapy. Our findings were also similar to those of El-Solh et al150 and De Vries et al151 who showed that these improvements were not significantly different between 170 CPAP monotherapy and dual therapy. Additionally, dual therapy has been shown to reduce CPAP pressure requirement relative to CPAP monotherapy150. While our findings did not demonstrate a statistically significant reduction in CPAP pressure for the total sample, they showed that there was a significant pressure reduction (of 2 cmH2O) for the subgroup who were on high pressure with CPAP monotherapy. The high pressure group are the patients who are likely to benefit the most from pressure reduction. Furthermore, a pressure difference of 0.5 cmH2O has been shown to increase adherence310. Congruent with the findings of de Vries et al151 and Liu et al152, our findings showed an increase in objective adherence with dual therapy relative to CPAP monotherapy. Liu et al152 showed that the mean daily use of CPAP was 2.9±1.1 hours/night with CPAP, 6.4±1.1 hours/night with MAS and 5.9 ± 1.7 hours/night with dual therapy. Despite the high adherence to CPAP monotherapy noted in our trial, our results demonstrate higher adherence with dual therapy relative to CPAP monotherapy, as mean adherence was 5.8±1.7, 7.2±1.1 and 7.1±1.1 hours/night for CPAP, MAS and dual therapy respectively (as shown in chapter 5). 6.1.6 Burden of Treatment: Chronic Illness Comes with Chronic Patient Workload The burden of chronic illness is well recognized and is a major focus of health care professionals. The burden of chronic illness represents the impact of the illness on the individual, their family and the healthcare system372. Strategies that have been developed to manage chronic conditions however, these have created a growing burden for the patients366. Treatment burden refers to the consequences that patients experience as a result of undertaking or engaging in treatment, such as medications, therapies, medical interventions, etc373. With chronic illness the aim of treatment is the life-long management of the condition, as there is no permanent cure. Unfortunately, chronic illness also comes with chronic workload for the patient and a lifetime burden of treatment366. This treatment burden induces poor adherence, wasted resources, poor outcomes and negative consequences on the well-being of the patients366,373. 171 We believe that the combination of CPAP and MAS can be a strategy to ease this treatment burden. The interchangeable use of therapies can reduce the burden of standalone therapy, whether CPAP or MAS and reduce the burden of treatment on the lifestyle in general (psychosocial aspects). The burden of CPAP lies in that it is a constraining treatment374, it requires cleaning by the patient and has side-effects. This burden can be reduced with the interchangeable use of therapies due to the ability to take a ‘medication holiday’335 from one treatment modality while still being ‘on treatment’. Likewise, there is less burden of MAS (caused by its suboptimal efficacy and its side-effects) if it is used interchangeably with CPAP. Therefore, the availability of alternative therapies has a twofold effect, it can minimize disruptions to the lifestyle (hence reduce the burden of treatment) and minimize disruptions to treatment (hence increase adherence). The flexibility provided by having both treatments allows the patient to choose the treatment that best matches their life-style at any point in time, they are therefore less likely to occasionally drop treatment and consequently disrupt their treatment due to these everyday life situations. For example, a patient may choose to use one treatment on nights in which there is a bed partner or roommate versus the other treatment on nights without a bed partner or roommate. The patient may prefer MAS during travel and camping trips or for early morning meetings (to avoid CPAP strap marks on the face). The patient may choose CPAP if they feel it is improving a certain symptom that is particularly important in a certain situation (such as daytime sleepiness and going on a long drive the next day). The patient may resort to using CPAP while waiting for a replacement oral appliance or resort to using MAS in the case of CPAP recalls. In addition to many more everyday situations where the patient may prefer one treatment over the other. While we believe that the combination of CPAP and MAS can be regarded as an individualized approach to alleviating treatment burden, it is important to note that for this combination therapy approach to truly reduce the treatment burden, good coordination of care between the members of a 172 multidisciplinary team is necessary. Since uncoordinated care is a source of increased workload on the patient and can in itself contribute to treatment burden366. 6.1.7 Treatment side-effects One of the factors that can increase the burden of treatment is side-effects. With CPAP and MAS, these side-effects can be reversible or irreversible, short or long-term. Our work and the work of others shows that both CPAP and MAS lead to both short and long-term side-effects240,241,268,295,330. Therefore, patients need to be informed about possible side-effects prior to the initiation of therapy. As described in chapter 3, our results regarding the long-term side-effects of MAS demonstrate that the changes that occur are mainly dental, and they are in the form of retroclination of the upper incisors and proclination of the lower incisors. Furthermore, approximately 44% of our study population had a negative overjet at the end of their follow-up duration. These findings are congruent with the findings of Araie et al243 who identified in their systematic review and meta-analysis the side-effects of long-term MAS use. Furthermore, our findings indicate that the changes that take place are mainly dental and not skeletal, which is confirmed by their analysis. Despite these dental movements, a previous study found that the increase in lower incisor angulation did not induce periodontal disease or bone loss375. Patients could feel the changes in their bite with less posterior contacts nevertheless they were not aware of the decrease in masticatory function. Since long-term side-effects may only become noticeable many years after the initiation of treatment, patients’ preference and adherence may also change in response to the perceived side-effects. We propose that a combination of therapies may reduce these side-effects, as the alternating use of therapies can reduce overall duration of use of any of the two monotherapies. Duration of use has been previously linked to the magnitude of side-effects250,253. Similarly, the simultaneous use of both CPAP and MAS can allow the mandible to be in a less advanced (protrusive) position150. The amount of advancement has also been shown to be related to the severity of the long-term side-effects253. 173 Overall, our work demonstrates that combination therapy (in the form of the interchangeable use of CPAP and MAS), and in comparison to the consequences of suboptimal adherence to monotherapy that has been repeatedly reported in the literature, can augment adherence, reduce treatment burden, allow for flexibility that matches the lifestyle, reduce symptoms and blood pressure, improve QoL and overall treatment effectiveness and possibly reduce side effects. Combination therapy in the form of the simultaneous use of CPAP and MAS can improve efficacy (relative to MAS), reduce CPAP pressure (for patients who require high CPAP pressure), improve adherence relative to CPAP and improve symptoms and disease specific QoL. 6.1.8 CPAP, MAS or a Combination of Both? Each of the treatment alternatives has its pros and cons and the preferable alternative can be recognized as the one that, on average, provides a positive benefit to risk trade-off on measurable clinical outcomes. In order to select the “best” option, the main goal(s) need to be identified so that different alternatives may be analyzed and evaluated according to this/these goal(s)154. Based on the findings of this thesis, we provide a simple framework (Figure 6.1) that could guide in the decision-making process of whether CPAP, MAS or a combination of both could be selected for a patient. This framework does not take into consideration the OSA endotypes and is only suitable for patients who are willing to use one or both therapies (CPAP and MAS). For treatment naïve (previously untreated) patients we propose a staggered or sequential combination of therapies if needed, with the first line therapeutic option still being monotherapy for the majority of patients. A discussion between the patient and the physician should be the first step in order to educate the patient about the condition, consequences and treatment options along with their benefits and harms. The patient should be able to voice their preferences, goals for seeking treatment and attributes of treatment that matter most to them. Decision aid tools can be utilized to streamline the decision making 174 process in this shared decision making model. Treatment expectations are to be discussed and based on an agreement between the patient and health care provider, the ‘best’ therapy for the patient should be selected and initiated, with adequate patient support by a multidisciplinary team. A re-evaluation of treatment adherence, efficacy, goals, symptoms, preferences and side effects should be a point of determination if another therapy should be introduced. Since adherence patterns are established early on as well as the other measures of effectiveness, patients should not spend years undertreated before the decision to add another therapy is made. 6.1.9 When is Monotherapy Sufficient? For patients who are well treated (in terms of efficacy, symptoms and QoL), are highly adherent and have minimal discomfort and side-effects on their treatment of choice. 6.1.10 Who May Benefit from Combination Therapy? The following groups of patients may benefit from combination therapy: 1- Suboptimal adherence to monotherapy: those for whom adherence to monotherapy is not ideal, in terms of duration (hours per night) and/or frequency of use (number of nights/week) could benefit from the interchangeable use of therapies. Factors that affect the duration of use include the inability to tolerate the device for the total sleep time. Alternating therapies within the same night could increase adherence for this group of patients. Factors that could affect frequency of use could include the inability to tolerate the device on a daily basis due to side-effects for example or patients who are unable to fully adhere to treatment due to a lifestyle that includes frequent travel, nights with or without a bed partner, body pain, etc. Alternating therapies between nights could increase adherence for this group of patients. 175 2- Suboptimal efficacy with monotherapy: A) Suboptimal efficacy despite maximum appliance titration: patients with residual OSA under a given therapy often need further adjustment (titration) of the therapy. If there is inability to advance the MAS any further (as it is not tolerated by the patient or no further advancement of the mandible is possible) and efficacy is suboptimal, the simultaneous use of CPAP and MAS could improve efficacy without the need for further advancement. Alternatively, the interchangeable use of therapies could allow for patients to not be exclusively on a treatment that is not fully efficacious. B) The effective management of OSA is a moving target that requires constant follow up and re-assessment. Both age376 and weight gain377 could increase the AHI and both situations may be an indication for combination therapy. Additionally, the efficacy of MAS has been shown to decline with time for some patients378. A reduction in MAS efficacy with time would require further mandibular advancement, this in turn could be both not well tolerated by the patient and could lead to more side-effects. Therefore, a reduction in MAS efficacy could also be managed by the simultaneous use of both therapies and as mentioned above, the interchangeable use of therapies could allow for patients to not be exclusively on a treatment that is not fully efficacious. 3- High CPAP pressure that is causing discomfort and low adherence: patients who are on high CPAP pressure that they are unable to tolerate and/or is causing reduced adherence or discontinued treatment can benefit from combination therapy. Dual therapy (the simultaneous use of CPAP and MAS) can reduce the CPAP pressure requirement and hence increase comfort and adherence. 176 4- Patients who are highly symptomatic pretreatment: those who are highly symptomatic at baseline could benefit from a combination of therapies, whether interchangeably or simultaneously used. Our results show that combination therapy was able to reduce the number of participants experiencing more severe symptoms (60% of our sample were using a combination of both therapies during the observation period). 5- Concerns about long-term side-effects: while maximizing adherence is the means to achieve the desired effectiveness. Long-term adherence to monotherapy has its side-effects136. We believe that these side-effects could be reduced or mitigated, at least in part, by combination therapy. Both forms of combination therapy could achieve this purpose as the interchangeable use allows for reduced overall duration of use of any of the two monotherapies and the simultaneous use could allow for avoiding any further advancement of the MAS. The amount of advancement has been shown to be related to the severity of the long-term side-effects234. 6- Patient prefers one treatment while the other treatment is more efficacious: the interchangeable use of both therapies could lead to high overall effectiveness due to the high overall adherence, while respecting patient preference. The availability of alternatives can reduce the burden of treatment as it reduces the inconveniences associated with treatment. 177 Figure 6.1 A Simplistic Representation of the Decision-making Scheme Apply the decision aid tool and have conversations with health care providers to determine the initial preferred therapy 178 6.2 Summary of the Work Done and of the Main Findings The overarching goal of this thesis was to explore the combination of CPAP and MAS. In order to better understand the effects of this combination, it was necessary to fill some of the literature gaps. In chapter2 we reviewed the literature and identified some of the existing gaps which included a lack of long-term studies assessing MAS side effects and lack of a comparison of the effect of CPAP and MAS on multiple outcomes based on objective adherence. In chapter 3 we conducted a retrospective trial investigating the long-term side effects of MAS. This trial has one of the longest follow up periods for MAS use published in the literature and it shows that there are dental side-effects associated with long-term use. These findings are in agreement with the most recently published meta-analysis on oral appliance side-effects243. While these long-term side-effects may be well tolerated by some patients, they may not be well tolerated by others and could lead to discontinuation of treatment. In chapter 4, we conducted a multi-center, randomized cross-over trial (CHOICE trial) that compared the effectiveness of CPAP and MAS with regards to multiple outcomes and which was followed by an observational phase to assess the combination of both CPAP and MAS. In agreement with the findings of others, our results show that CPAP was able to consistently and effectively normalize respiratory parameters and was superior to MAS in doing so134,171,220,302. Additionally, both CPAP and MAS demonstrated comparable improvements in symptoms and QoL measures, that were both clinically and statistically significant. This has also been a consistent finding in the literature208,277,314. Furthermore, this improvement in patient centered outcomes was associated with longer nightly hours of use of therapy and the improvement was more profound for patients who were highly symptomatic pre-treatment. While these findings were previously recognized for CPAP therapy73, we are among the first to report them regarding MAS and combination therapy. 179 Our findings indicate that CPAP led to a reduction in the in-office diastolic BP and MAS lead to a reduction in both systolic and diastolic BP compared to baseline. A meta-analysis313 showed that both CPAP and MAS were comparable in their reduction of both systolic and diastolic BP however, Phillips et al134 and Yamamoto et al135 did not find significant changes in blood pressure with either CPAP or MAS compared to baseline. Patient preference has been previously proposed as a key component of patient centered care226. Our findings show that matching treatment to preference increased acceptance and adherence to therapy. Furthermore, our results are in agreement with the literature showing a preference by patients for MAS over CPAP179. Similar to the recently published findings of Braun et al166, we identified marked heterogeneity in treatment goals between patients who were seeking treatment. This highlights the importance of the decision aid tool or an interactive discussion between patient and clinician in order to provide a personalized treatment. Contrary to what has been previously suggested in the literature regarding Mean Disease Alleviation (MDA)205,216, our findings show that the MDA and Sleep Adjusted Residual AHI (SARAH) Index were not comparable between CPAP and MAS, as CPAP showed better outcomes with both metrics. This was attributed to the higher efficacy and adherence demonstrated by CPAP in our work relative to other studies311. However, our findings demonstrated that these measures were comparable for CPAP and for the long-term interchangeable use of both therapies (during the observation period). Our findings regarding the self-reported side-effects during the trial period were congruent with the side-effects of both CPAP and MAS reported in the literature223,226,294,331. The main CPAP side-effects were mask leaks, feeling uncomfortable because of wearing CPAP, dry throat, uncomfortable mask pressure, increased awakenings and blocked nose294,331. There was a general trend for the side-effects to decrease in frequency with time. Similarly, the side-effects most commonly reported with MAS included difficulty chewing, discomfort or pain in the teeth and jaws, mouth dryness and bite changes223,226. The majority of 180 these side-effects were described as occurring rarely and being hardly disturbing. There was a trend for most of the side-effects to decrease in frequency with time. To the best of our knowledge, we were the first to report the following findings; objectively measured adherence for MAS and when participants had a choice of treatment (during the observation period) were higher than for CPAP (in terms of number of hours treatment was used). Additionally, a greater percentage of participants were considered compliant and regular users during the long-term observation period relative to the 1-month on CPAP. Interestingly, during the observation period (when participants had the freedom of choice of treatment), 60% used a combination of both therapies, 31% used monotherapy (CPAP or MAS) and 8% did not adhere to treatment. This trial is the largest trial to describe the effects of offering treatment choices in the management of OSA. We were the first to show that preferences to OSA therapy changed with experience and changed based on outcomes. Additionally, we have noted that when there was freedom of choice, participants matched treatment(s) to their preference, and this was associated with high adherence, which in turn has likely resulted in the clinically relevant symptom improvement observed and the reduction in BP. Furthermore, we were the first to show that a combination of therapies can have a similar effect to CPAP and MAS monotherapies on symptoms and QoL. Our results also show that a greater percentage of participants were able to achieve normal values on ESS, FOSQ and CFQ questionnaires during the observation period (predominantly combination therapy) compared to CPAP or MAS. Therefore, based on our findings, we are the first to propose combination therapy as a means of increasing overall adherence to therapy and as a means of reducing the burden of treatment in the management of OSA. The combination of CPAP and MAS can take two forms, either the alternating use of both, or their simultaneous use. In chapter 5 we conducted a prospective trial to compare CPAP, MAS and their 181 alternating use (CHOICE trial described in chapter 4) to their simultaneous use (dual therapy) in a subset of the same study population. Our trial was the first to objectively assess adherence with the simultaneous use of both therapies and our findings showed increased adherence with both forms of combination therapy relative to CPAP monotherapy. Additionally, our trial was the first to compare the interchangeable use of therapies to their simultaneous use and showed that both forms of combination therapy are able to achieve a high level of treatment adherence and improve symptoms. Furthermore, dual therapy was able to improve respiratory parameters (as assessed by the ODI) and reduce CPAP pressure in the high pressure group compared to CPAP monotherapy. A reduction in CPAP pressure by dual therapy has been previously suggested in the literature150–152 while the study conducted by Premaraj et al347 did not find a significant reduction in pressure with dual therapy relative to CPAP monotherapy. 6.3 Clinical implications of our findings The findings of our trials have both clinical relevance and important implications in the field of OSA management and bring us a step closer towards personalized medicine. Our work provides a comparison of the two most commonly used, disease specific OSA treatments with regards to adherence, patient-centered outcomes (symptoms and QoL measures), efficacy, effects on BP and measures of effectiveness (MDA and SARAH Index). It provides insight into the importance of treatment adherence in long term effectiveness as well as the side-effects that are involved with long-term adherence to MAS. It improves awareness regarding the impact of patient participation on treatment adherence and the importance of patient participation in the decision-making process. Additionally, our work highlights the role of offering two therapies to the patients to be used interchangeably or simultaneously, moving away from the monotherapy approach to multimodality treatment, all of which will aid in the development of a more targeted treatment approach. In the context of the P4 medicine, an approach to medicine that includes 182 predictive, preventive, personalized and participatory aspects133, our work has contributed to the advancement of knowledge in the personalized and participatory aspects of this approach. 6.4 Overall Limitations and Strengths 6.4.1 Limitations We acknowledge some limitations in our work. Despite the retrospective study described in chapter 3 being one of the longest follow-ups of MAS therapy, it lacks an objective measurement of adherence. This was unavoidable as there was no reliable means of tracking adherence objectively when these patients started their treatment many years ago. However, we could assume with confidence that these patients were actively using MAS therapy as we asked if they were using their devices at least 4 days/week (subjective compliance), and there would be no reason for them to show up for follow-ups and purchase more oral appliances (mostly paid out of pocket) if they were not using them. Due to logistic and financial constraints, the trial described in chapter 5 comparing dual therapy to CPAP monotherapy, MAS monotherapy and alternating therapy was conducted at only one centre (UBC) despite our efforts to conduct it as a multi-centre trial. This resulted in a reduced sample size nevertheless, the a priori sample size calculation deemed that our sample size based on our primary outcome was sufficient to detect statistically significant differences. Additionally, both the dual-therapy trial (described in chapter 5) and the CHOICE trial (described in chapter 4) lack a PSG assessment of efficacy. Again, this was due to logistic issues as efficacy assessments were scheduled to be conducted at very specific timepoints that did not allow for flexibility and long waiting times were required for in hospital PSGs. Furthermore, in hospital PSG assessments also have their limitations, in addition to the availability of an in-patient bed which was a challenge, the high costs involved, and the high labor requirements are also limitations. There is also the possibility of lower sleep efficiency due to the patient’s anxiety and the restriction of movements due to the 183 abundance of monitoring sensors/wires. A huge deterrent to in hospital PSGs in our trials also included the inconvenience to the participants, as participants who completed both of our trials required 4 nights of efficacy assessment and the need to spend 4 nights in hospital may have deterred many from participating and could have led to more drop-outs. Hence, in our opinion, the use of HSAT instead of PSG was justifiable. To make sure the results were reliable, we have used a state-of-the-art type III monitor and had all results scored by an experience sleep technician who was blinded to the treatment protocol and to the results. Our research lacks an assessment of cost-effectiveness and focuses purely on the clinical aspects of the different treatment modalities. Published literature shows that both CPAP and MAS are highly cost-effective when compared to no treatment and while some studies have shown that CPAP is the better option with regards to cost-effectiveness379 as MAS is a less efficacious treatment compared to CPAP, costs per quality adjusted life years were better with MAS as compared to CPAP in another study380. Despite the cost of combination therapy being inevitably high, the cost of non-adherence to therapy is higher and its economic burden is substantial43. As our data has some components necessary to do cost analysis, we will be further evaluating our work with this new focus. We do hope that our work and the work of others could reshape policies in the future and provide sufficient evidence for policy makers and third-party insurance companies to cover the costs of more than one treatment modality for OSA at the same time. Our trials have been subject to limitations that are common to the majority of prospective clinical trials. Firstly, our study population may not represent all OSA patients. As per the nature of prospective trials, those who agreed to participate are those who are willing to try the treatments involved and may not represent the whole OSA patient population. Secondly, our findings are susceptible to the ‘healthy user effect” which describes the likelihood that adherent participants have other unmeasured healthy behaviors381. 184 6.4.2 Strengths While most studies are considered to be either efficacy or effectiveness studies, our CHOICE study (described in chapter 4) comparing CPAP and MAS encompasses both. The cross-over phase of our trial provided more stringent control over treatment conditions while the observational phase took the approach of effectiveness studies that seek to examine the outcomes of interventions under circumstances that more closely resemble both the ‘real world’ and routine clinical settings382. While well-designed and conducted randomized controlled efficacy studies are known for their good internal validity, effectiveness studies are known for their good external validity. We believe that the main research conducted for this thesis combines both good internal and external validity. While our trial was methodologically strong, and was done in 3 different centres across Canada, the results have good generalizability. Our research has added to the currently available evidence in many ways; we have conducted the longest assessment of oral appliance side-effects, with follow up of up to 21 years for some patients. Additionally, we were the first to objectively compare both CPAP and MAS to a combination of both therapies and our prospective trials included an objective measurement of adherence. Furthermore, we compared different forms of combination therapy, alternating and simultaneous use. Comparing CPAP to MAS to their alternating and simultaneous use within the same group of individuals has allowed for an accurate comparison of the treatment modalities while minimizing the effects of inter-individual variability on the outcomes. Making the differences observed more likely attributable to the therapies rather than an effect to inter-individual differences. Additionally, our work assessed a broad range of clinical measures that are both objectively and subjectively assessed. 6.5 Future Directions OSA is being increasingly recognized as a heterogenous condition, both in terms of its endotype and phenotype. Our findings do not suggest that a combination of therapies is to be recommended for every 185 OSA patient. However, it does seem to be a viable option for many patients. While our work provides insight into the potential benefits of combination therapy and focuses on the effect of treatment on specific OSA phenotypes, further research needs to determine which subgroups of patients will benefit from a combination of therapies based on OSA endotypes. A more personalized and targeted approach would take into consideration both the phenotype and endotype of the patient as well as desired outcomes of seeking treatment. It might be that monotherapy is all that is needed for a particular patient while for another patient, a combination/multimodality of therapies will better achieve the desired outcomes. Currently, some multimodal approaches such as positional therapy with oral appliance, or weight loss with CPAP are often prescribed in the clinical setting. A new form of combination therapy, described in this thesis, should also be taken into consideration by clinicians in the future. In addition to the above, the long-term effect of combination therapy on potential consequences such as cardiovascular consequences needs to be explored. Lastly, we hope that our work and the work of others will provide insight into the potential benefits of combination therapy, which in turn will help inform policy makers and insurance companies and trigger policy changes. combination therapy would not become an option only available for those who can afford to pay for it out of pocket. 6.6 Conclusions Long-term effectiveness was increased by increasing adherence, high adherence in turn led to an improvement in patient-centered outcomes and a reduction in the in-office blood pressure. An acceptably high MDA and low SARAH index (in comparison to CPAP) were achieved with high adherence. These results indicate that combination therapy is a viable option for patients who are experiencing sub-optimal efficacy, outcomes or adherence to monotherapy and for patients who are concerned about long-terms side-effects. The combination of CPAP and MAS can take two forms, either the alternating use of both treatments to improve overall treatment adherence, or their simultaneous use which provides a reduction in CPAP pressure requirements. Due to combination therapy showing similar improvements to CPAP 186 regarding many measurable outcomes while showing better adherence, we suggest that a model of care in which patients have access to both MAS and CPAP to use could be an alternative model of care. Finally, combination therapy is not for everyone. If the patient can tolerate a single treatment with minimal side-effects and optimal outcomes, efficacy and adherence, then monotherapy is sufficient. 187 Bibliography 1. Zielinski MR, McKenna JT, McCarley RW. 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Effectiveness Versus Efficacy: More Than a Debate Over Language.; 2003. www.jospt.org 240 Appendix A Appendices from chapter 4. A.1 Supplemental Figure 4.1. A custom-made Mandibular Advancement Splint (SomnoDent®) with Dentitrac® adherence monitor, fabricated for one of the trial participants 241 A.2 Supplemental Figure 4.2. Study Protocol Abbreviations: ESS, Epworth Sleepiness Scale; FOSQ, Functional Outcomes of Sleep Questionnaire; SF-36, Short Form of Health Survey; PAP, positive airway pressure; MAS, mandibular advancement splint. O1, observation visit 1; O2, observation visit 2. 242 A.3 Supplemental Figure 4.3. Disclosure Letter 243 244 A.4 Supplemental Figure 4.4. Snoring Scores at the Different Timepoints Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint. 245 A.5 Supplemental Figure 4.5. A) Willingness to Pay Out of Pocket for CPAP and MAS B) Self-reported Total Yearly Household Income Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint. A B 246 A.6 Supplemental Table 4.1. Hours of Treatment Usage Per Night for Participants with Values Above or Below the Threshold Defining Normalcy at Baseline for ESS, FOSQ-10, CFQ and SF-36 (MCS) Measurements are described as mean ± SD. *Statistically significant at P ≤0.05. Abbreviations: ESS, Epworth Sleepiness Scale; FOSQ-10, Functional Outcomes of Sleep Questionnaire; CFQ, Chalder Fatigue Questionnaire; SF-36, Short Form of Health Survey; MCS, Mental Component Summary; SD, Standard Deviation; N, Number of Participants; CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint. Variables at baseline CPAP Use, hours/night MAS Use, hours/night Treatment Use during the 6 months observation, hours/night N Mean ± SD P-Value N Mean ± SD P-Value N Mean ± SD P-Value ESS score > 10 (symptomatic) 31 5.3 ± 2.0 0.95 25 6.2 ±1.9 0.481 29 5.4 ± 2.3 0.84 ≤ 10 36 5.3 ± 2.2 35 5.8 ± 2.2 35 5.2 ± 2.4 FOSQ-10 score <17.9 (symptomatic) 53 5.2 ± 2.1 0.53 47 6.1 ± 2.0 0.44 50 5.3 ± 2.4 0.79 ≥ 17.9 14 5.6 ± 1.7 13 5.6 ± 2.5 14 5.1 ± 2.1 CFQ score > 17 (symptomatic) 29 5.9 ± 1.8 0.037* 27 6.4 ± 1.9 0.18 28 5.8 ± 1.8 0.12 ≤ 17 38 4.9 ± 2.1 33 5.7 ± 2.2 36 4.9 ± 2.6 SF-36, MCS score < 36 (symptomatic) 13 5.5 ± 1.9 0.70 12 6.1 ± 2.2 0.87 12 6.4 ± 1.7 0.84 ≥ 36 54 5.3 ± 2.1 48 6.0 ± 2.1 52 6.3 ± 1.6 247 Appendix B Appendix from chapter 5. B.1 Supplemental Figure 5.1: Time Points for Assessment of Eligibility and For Data Collection Abbreviations: CPAP, Continuous Positive Airway Pressure; MAS, Mandibular Advancement Splint.
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eng
Craniofacial Science
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Almeida, Fernanda
Mandibular advancement splints, continuous positive airway pressure and a combination of both for the management of obstructive sleep apnea
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