Comparative Effectiveness of Oral Appliances vs CPAP in the Treatment of OSA Christopher Lettieri, MD, FCCP, FAASM Colonel, Medical Corps, US Army Professor of Medicine, Uniformed Services University Pulmonary & Critical Care Medicine Consultant to the Surgeon General The views stated in this presentation reflect those of the author and do not represent official policy of the US Army or Department of Defense

Conflict of Interest Disclosures 1. I do not have any potential conflicts of interest to disclose, OR 2. I wish to disclose the following potential conflicts of interest Type of Potential Conflict Details of Potential Conflict Grant/Research Support Consultant Speakers’ Bureaus Financial support Other 3. The material presented in this lecture has no relationship with any of these potential conflicts, OR 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

OAs vs CPAP for Treating OSA Both OAs and CPAP are approved/recommended as 1st line therapy for mild-moderate OSA Clear benefits of OAs in severe OSA, but lower rates of successful therapy c/w CPAP Both have been shown to improve measures of sleep quality, symptoms, function, and health outcomes CPAP remains reference standard and often considered superior to OAs Not necessarily true by direct comparisons Improved efficacy partially offset by lower adherence rates with CPAP

Oral Appliances So Many to Chose From Tongue retaining vs Mandibular advancement Pre-fabricated vs Customized Fixed vs Titratable Monobloc vs Duobloc

Oral Appliances So Many to Chose From How can we communicate with other providers (or bill payers) if we don’t use consistent language? How does effectiveness differ with different devices? How do we balance costs vs effect? How do we ensure proper patient selection and individualization of care? When is an OTC, pre-fabricated device ok? When is a non-titratable device ok?

Differences in OA Devices

Variability in OA Efficacy OA outcome trials limited by Different devices (titratable vs fixed, custom vs pre-fab) Inadequate titration/ablation Bias towards CPAP failures Underestimates success rates Our trial Custom adjustable devices, not CPAP failures OAs comparable to, but not as efficacious as CPAP Success rates (AHI < 5) Mild OSA - 70% Moderate OSA – 48% Severe OSA – 42% Final AHI Mean P CI OA CPAP 9.67 ± 12.8 5.34 ± 10.6 0.0001 2.83 – 5.83 Holley, et al. Chest 2013

Oral Appliance Efficacy OSA severity Mild Moderate Severe Success - Study A 62.3% 50.8% 39.9% - Study B 56.6% 48.1% 21.2% Partial Success 8% 26.3% 21.7% 13% 25 % 24.3% Failure 29.7% 22.9% 38.4% 30.4% 26.9% 54.5% Success = AHI < 5 Partial success = > 50% reduction in AHI but >5 Study A: Holley et al. Chest 2011 retrospective, CPAP vs MAS n=378 Study B: Phillips et al. AJRCCM 2013 RCT crossover CPAP vs MAS n=108 Lettieri, Almeida, Cistulli and Carra. Principles and Practice Parameters of Sleep Medicine, 2015. Chapter 151

Fixed versus Adjustable OAs Success Rates Baseline Apnea-Hypopnea Index (events/hour) OTC “boil and bite” should be avoided Adjustable, customized OAs most effective Fixed OAs not as effective OK for mild OSA Lettieri, et al. JCSM 2011

Effect on the Apnea-Hypopnea Index

Snoring In snoring patients without OSA CPAP and OAs both effective in reducing the frequency and intensity of snoring Prospective, randomized crossover trial - Snoring Outcomes similar between OAs and CPAP OA was superior to CPAP in improving sleep quality among bed partners More patients preferred OAs to CPAP for long-term treatment of snoring Robertson et al., 2008

Apnea Hypopnea Index OAs and CPAP are effective at reducing the AHI However, CPAP consistently more efficacious Lam et al, 2007 – RCT assessing reduction in AHI CPAP: 23.8±1.9 to 2.8±1.1 OA: 20.9±1.7 to 10.6±1.7, p<0.001 Gagnadoux et al, 2009 - >50% reduction in AHI< 5 73.2% w/ CPAP vs.42.8% w/ OA Ferguson et al, 1997 -- achieving an AHI ≤ 10 was 1.9 times greater w/ CPAP than OA

Efficacy CPAP vs OAs CPAP OA Lettieri, Almeida, Cistulli and Carra. Principles and Practice Parameters of Sleep Medicine, 2015. Chapter 151

Apnea Hypopnea Index Meta-analysis of 15 RCTs comparing AHI reduction btw OAs and PAP Both effective at reducing the AHI Custom, titratable devices have best efficacy PAP better at reducing AHI than OAs Mean reduction in AHI was 6.24 events/hr greater with PAP (95% CI: 8.14 – 4.34) AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

OAs vs. CPAP: Reduction in AHI AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Apnea Hypopnea Index - Summary CPAP reduces AHI and RDI more than OAs in adult patients with OSA Level of evidence: Moderate AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Reduction in Daytime Somnolence

Daytime Somnolence Both OAs and PAP are effective in reducing subjective daytime sleepiness Outcomes appear equivalent between both treatments Neither consistently resolves symptoms

Daytime Somnolence Barnes et al, 2004 – RCT comparing OAs and PAP on daytime sleepiness Both lead to significant improvements (p < 0.001 for both) Greater effects noted with PAP therapy Alertness improved with PAP (p < 0.001) but unchanged with OAs

Daytime Somnolence Hoekema, et al – RCT comparing OAs to PAP OAs performed similarly to PAP in improving daytime sleepiness ESS changed from 12.9±5.6 to 6.9±5.5 w/OA vs. 14.2±5.6 to 5.9±4.8 with PAP

OAs vs. CPAP: Improvements in Somnolence Meta-analyses of 10 RCTs comparing measures of daytime sleepiness between OAs and CPAP AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Daytime Somnolence - Summary OAs are equivalent to CPAP in reducing subjective daytime sleepiness in adult patients with OSA Level of evidence: Low Meta-analyses performed on 8 RCTs changes in the ESS between OAs and CPAP Insignificant difference of -0.50 (95% CI: -1.05, 0.06) in post-treatment measures of subjective sleepiness between these two therapies AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Improvements in Quality of Life Measures

Quality of Life OAs are equivalent to PAP for improving QOL measures Barnes et al., 2004 -- Both treatments lead to clinically and statistically significant improvements in QOL greater effects noted with PAP Neither significantly improved neuropsych fnc or mood Hoekema et al., 2008 -- OAs performed similarly to PAP in improving QOL (FOSQ) OA: 13.7±3.1 to 16.6±2.8 CPAP: 13.9±3.7 to 16.7±3.1 Phillips et al., 2013 FOSQ improvements and SF-36 scores equal between OA and PAP

OA Appliance vs CPAP in OSAS: A 2-Year Follow-up SF-36 –no difference between OA and PAP ESS similar (4 vs. 5) FOSQ similar (16.3 vs 17.1) More treatment discontinuation w/ OA (47% vs 33%) PAP more effective in lowering AHI AHI: 0 vs. 2 vs 0, p<0.05 Tx success at 2 years 52.9% w/OA vs 67.3% w/ PAP Doff. SLEEP 2013

OAs vs. PAP: Quality of Life Meta-analaysis of RCTs comparing OAs to PAP for QOL measures found that both therapies performed similarly AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Quality of Life - Summary OAs are equivalent to PAP for improving QOL Level of evidence: Moderate Meta-analyses performed on 8 RCTs changes in the ESS between OAs and CPAP Insignificant difference of -0.50 (95% CI: -1.05, 0.06) in post-treatment measures of subjective sleepiness between these two therapies AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Effect on Blood Pressure & Health Outcomes

Blood Pressure OAs are equivalent to CPAP in reducing BP Neither results in significant improvements Trend towards better outcomes with OAs Trzepizur et al. -- no significant difference in post-treatment BP changes btw OAs and CPAP mean SBP  from 149.3±4 to 140.5±7 w/ OAs Gotsopolous et al -- modest  in BP w/ OAs SBP 127.3±1.3 to 125.2±1.3 mmHg DBP 77.7±0.9 to 76.4±0.9 mmHg

OAs vs CPAP: Blood Pressure Systolic BP Diastolic BP AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Blood Pressure - Summary Custom, titratable OAs modestly reduce BP in adult patients with OSA Level of evidence: Moderate Slightly superior to PAP Meta-analysis showed the mean reduction in BP for custom, titratable OAs Systolic BP: -2.37 mmHg (95% CI:-3.55,-1.20) Diastolic BP: -2.72 mmHg (95% CI:-3.81,-1.64) AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Health Outcomes: OAs vs CPAP Neurobehavioral function, FOSQ, SF-36, ESS, and driving simulator performance similarly improved with both therapies PAP was more efficacious in reducing AHI OAs superior to PAP for improving general QoL domains Compliance higher with OAs 6.5 ± 1.3 vs. 5.2 ± 2.0 h/night, p < 0.0001 51% preferred MAD vs 23% preferred PAP Doff, et al. SLEEP 2013 White, et al J Clin Sleep Med 2013 Phillips. Am J Respir Crit Care Med 2013

Mortality Mortality in severe OSA, compared CPAP OA Those who refused therapy Normal controls Residual AHI higher w/ OAs vs CPAP 16.3 ± 5.1/h vs. 4.5 ± 2.3/h; P < 0.001 Despite inadequate titration of OAs, cardiovascular mortality similarly reduced HR: 1.08 (95% CI: 0.55-1.74; p=0.71)  Event Rate 95% CI Controls 0.28 0.08-0.71 CPAP 0.56 0.20-1.23 OAs 0.61 0.13-1.78 Untreated OSA 2.1 1.37-2.92 Variable Adjusted HR (95% CI) P-value Hypertension 1.65 (0.83–3.26) 0.15 Current smoking 1.99 (1.08–3.67) 0.02 Previous heart disease 2.37 (1.15–4.87) 0.01 CPAP-treated OSA 0.87 (0.16–2.04) 0.39 MAD-treated OSA 0.98 (0.13–2.69) 0.48 Untreated OSA 6.53 (2.30–18.54) 0.004 Non-apnoeic controls 1.00 (reference) Anandam. Respirology 2013

Adherence Efficacy vs Effectiveness

Side Effects and Discontinuation of Therapy Both treatments generally well-tolerated with minimal significant side-effects However, less D/C OAs due to side-effects AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

PAP Adherence Despite its benefits, PAP adherence remains problematic Largely related to PAP intolerance (or unwillingness) 20% don’t initiate therapy Approx 30% discontinue in first month By 3 years, only ¼ are “regular users” of PAP Patients often struggle to use PAP therapy in an ideal manner. When patients are asked to self-report PAP use, they tend to overestimate the hours that PAP is being used. In multiple articles, there are data suggesting that average self-reported use is approximately 1 hour greater than their objectively measured use. Engleman HM, Asgari-Jirandeh N, McLeod AL, Ramsay CF, Deary IJ, Douglas NJ. Self-reported use of CPAP and benefits of CPAP therapy. Chest 1996; 109 : 1470-6. Rauscher H, Formanek D, Popp W, Zwick H. Self-reported vs. measured compliance with nasal CPAP for obstructive sleep apnea. Chest 1993; 103 : 1675-80.

Adherence Rates Between OA and PAP Subjective measures of adherence consistently greater w/ OAs compared with CPAP AASM Clinical Practice Guidelines for the Treatment of OSA and Snoring with Oral Appliance Therapy: An Update for 2015

Efficacy vs Effectiveness 8 RCTs OA vs Placebo 10 RCTs OA vs CPAP Health outcomes are similar between the therapies, despite a lower efficacy of OAs Chan & Cistulli, 2007

Agency for Healthcare Research and Quality AHRQ Statement on OAs Strength of evidence is moderate that MADs are an effective treatment for OSA patients without comorbidities or excessive sleepiness Insufficient evidence regarding comparisons of different devices Strength of evidence is moderate that PAP is superior to MAD

Medical Society Statements American Academy of Sleep Medicine (AASM) PAP is the preferred first line therapy for OSA OAs are indicated for mild to moderate OSA patients who Prefer OAs to CPAP Do not respond to CPAP Are not appropriate candidates for CPAP Fail treatment attempts with CPAP Fail treatment with behavioral measures Patients with severe OSA should have an initial trial of nasal CPAP. CPAP is indicated whenever possible for patients with severe OSA before consideration of OAs

Medical Society Statements American College of Physicians (ACP) PAP is recommended as the initial therapy (Grade: strong recommendation; moderate-quality evidence) OAs can be used as an alternative to PAP in those who prefer OAs or have adverse effects associated with PAP (Grade: weak recommendation; low-quality evidence)

“The best bat is the one you can hit the ball with” – Yogi Berra OAs and PAP have similar efficacies The best treatment for OSA is one that the patient will actually use Patient education, treatment selection, and individualization of care are key to improving outcomes

Comparative Effectiveness of Oral Appliances vs CPAP in the Treatment of OSA Christopher Lettieri, MD, FCCP, FAASM Colonel, Medical Corps, US Army Professor of Medicine, Uniformed Services University Pulmonary & Critical Care Medicine Consultant to the Surgeon General The views stated in this presentation reflect those of the author and do not represent official policy of the US Army or Department of Defense