Precision Sleep Medicine Picking Winners Improves Outcomes and Avoids Side-Effects
North American Dental Sleep Medicine Conference February 17-18, 2017Clearwater Beach, FL
John E. Remmers, MD
• Part owner of a company that manufactures a sleep recorder (Sagatech)
• Part owner and Chief Medical Officer of a company that manufactures a dental titration device (Zephyr Sleep Technologies, Calgary, Alberta CANADA)
Conflict of Interest
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Objectives
• To understand the current balance of patient adherence to therapy versus therapeutic efficacy in outcomes with continuous positive airway pressure (CPAP) and oral appliance therapy (OAT)
• To be familiar with the role of wakefulness in permitting reflex compensation for the pharyngeal anatomic abnormality
• To understand the importance of patient selection in the management of OSA with OAT: what methods work and why
• To learn why mandibular protruding appliances produce a successful outcome in some patients but not others
• To be familiar with the possible role for emerging technologies in enhancing the accuracy of patient selection for OAT
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Apnea– absence of breathing for 10 seconds
or more
Hypopnea– 50% reduction in breathing for 10
seconds followed by a 3% dip in O2 sat or an arousal
Definition of Respiratory Disturbances
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Contraction of Inspiratory Muscles in OSA
Negative luminal pressure
5
Pathophysiology of OSA:Two possibilities
Neural Hypothesis(lazy tongue)
Anatomic Hypothesis(small airway)
Apneics have asub-normal genioglossal
activity during sleep
Apneics have a structurally narrowed
pharyngeal airway
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The Passive Pharyngeal Airway
General Anesthesia
Complete Paralysis
7
Closing pressure is elevated in OSA
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Maximal Area of the Passive Pharynx
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Lazy Tongue Hypothesis
• Tantalizing but fragmentary evidence supports this hypothesis
• Currently, no hard evidence supports the lazy tongue
• In fact, the tongue seems to be working overtime while awake
10
Genioglossal EMG is elevated in OSA while awake
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Here’s the deal -
• OSA is caused by a structural narrowing of the pharynx
• This structural narrowing causes airway obstruction ONLY during sleep
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While Awake - Neuromuscular Compensation
NO Pharyngeal Obstruction
13
Structural
Narrowing
Non-REM Sleep Pharyngeal Obstruction
Structural
Narrowing 14
REM Sleep - Muscle Atonia
Severe Pharyngeal Obstruction
Pharyngeal
Occlusion 15
Oral Appliance TherapyHow Does it Work?
Studies of the passive pharynx reveal that protruding the mandible acts mechanically to open the pharynx
16
Mandibular Protrusion Dilates the Passive Pharynx
Note dependence of nasopharynx and oropharynx 17
OAT eliminates pharyngeal obstruction in OSA by dilating the velo-pharynx and oro-pharynx
No evidence for muscle activation
18
Oral Appliance TherapyHow Does it Work?
Sleep Apnea & Comorbid Disease
Depression
Stroke
Heart Failure
Severe Obesity
Drug-ResistantHypertension
Coronary Artery Disease
A-fib
Type 2 Diabetes
45%
63%
76%
77% 72%
50%
57%
83%
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CV EffectsClearly sleep apnea is associated with CV disease
Marin JM, Carrizo SJ, Vicente E, Agusti AGN. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.
Lancet 2005; 365:1046-53. 20
All CauseMortalityWisconsin Sleep Cohort
Young T; Finn L; Peppard PE; Szklo-Coxe M; Austin D; Nieto FJ; Stubbs R; Hla KM. Sleep disordered breathing and mortality: eighteen-year follow-up of the wisconsin sleep cohort. SLEEP 2008;31(8):1071-1078. 21
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• Barbe et al. JAMA 2012
• Peker et al. Am J Resp Crit Care Med 2016
• McEvoy et al. New Eng J Med 2016
3 recent clinical trials comparing CPAP with usual care
Does CPAP prevent CV disease?
23
McEvoy et al. (n=2687)SAVE Trial
New Eng J Med 2016; 375: 919-931 – SAVE Trial (Sleep Apnea Cardiovascular Endpoints) 24
McEvoy et al. (n=2687)No significant difference in prevention of CV events
comparing CPAP vs. controls
New Eng J Med 2016; 375: 919-931 – SAVE Trial (Sleep Apnea Cardiovascular Endpoints) 25
• CPAP did not significantly reduce the occurrence of serious CV events in non-sleepy patients with moderate to severe OSA
Why not?
Conclusions
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Poor CPAP compliance
3.3 hours per night
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• Prescribing CPAP with the sole purpose of reducing future CV events in asymptomatic patients with OSA and established CV disease cannot be recommended
• Need for novel treatment options
This is why I’m so concerned
Editorial. Mokhlesi B, Ayas N. New Eng J Med 2016; 375(10): 994-996 28
YOU have a treatment that will reduce heart attacks
and strokes
BUT only if you treat the patients who will
respond!29
Which ONES?
30
Selection
Selection
Selection31
We need a validated method to prospectively select
patients for OAT
• More efficient delivery of therapy
• Better outcomes
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Available Methods for Selecting Patients for OAT
• Clinical features
• Imaging the pharynx
• Mandibular titration
• OSA is caused by a structural narrowing of the pharynx
• This structural narrowing is not apparent while awake because of neuromuscular compensations
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Here’s the deal -
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Available Methods for Selecting Patients for OAT
• Clinical features
• Imaging the pharynx
• Mandibular titration – during sleep
Mandibular TitrationDuring Sleep in the Lab
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1. Accurately selects patients who will respond to OAT and
2. Identifies an efficacious protrusive position for each responder
Single-night, Attended
Polysomnographic Test
MATRx
Remmers J, Charkhandeh S, Grosse J, Topor Z, Brant R, Santosham P, Bruehlmann S. Remotely controlled mandibular protrusion during sleep predicts therapeutic success with oral appliances in patients with obstructive sleep apnea. SLEEP 2013; 36(10): 1517-25. 37
Mandibular TitrationDuring Sleep at Home
Replacing the Tech with a Computer
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1. Accurately selects patients who will respond to OAT and
2. Identifies an efficacious protrusive position for each responder
Home Sleep Test
MATRx plus
Note: This device is approved by Health Canada for sale in Canada. This device is pending 510(k) and 513(f)(2) clearance and is not available for sale in the United States. 39
The MATRx plus Difference
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Every other HST device only supports the diagnosis of OSA
MATRx plus does it all
• Auto-titrating mandibular positioner
• MATRx style dental trays
• Feedback signals:‒Oxyhemoglobin saturation‒Respiratory airflow
• Real-time detection of respiratory events
• Automated analysis of data
MATRx plus: A-MP Technology
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MATRx plus
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43
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MATRx plus Patient Information Portal
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Night 1
• Dynamic interaction between respiratory events and mandibular movement
Night 2
• Refinement of mandibular position in response to respiratory events
MATRx plus Titration: A two night study in the home
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Time (h)
0 1 2 3 4 5 6 7 8
8
10
1
2
14
1
6
Pro
tru
sive
po
siti
on
(m
m)
47
MATRx plus Results: Responder
Time (h)
0 1 2 3 4 5 6 7 8
6
8
10
12
14
16
18
Pro
tru
sive
po
siti
on
(m
m)
48
MATRx plus Results: Non-Responder
Obese Patient with Severe OSA
Patient Profile62 year old malePre-study AHI = 40.2BMI = 34.3
Tray FittingLower Limit (Resting Position) - 3.5mmUpper Limit (Maximum Protrusion) + 5.5mm
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Case Study
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Night 1 - Dynamic Theragnostic Study
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Night 2 - Static Theragnostic Study
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Night 3 - Static Theragnostic Study
3.1mm
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Theragnostic Study Summary
Objective
To assess the ability of an auto-titrating mandibular positioner test in:
• Prospectively identifying therapeutic responders
• Determining an efficacious protrusive position
MATRx plus Clinical Investigation
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All participants received:
2-night auto-titrating mandibular positioner test
Custom oral appliance (SomnoMed G2, MicrO2)
MATRx plus Trial Study Design
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Broad inclusion criteria:
• ODI > 10 hr-1
• BMI < 45 kg/m2
Inclusion Criteria
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Distribution of BaselineODI and BMI
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MATRx plus
Machine Learning
(Random Forest)
Prediction of
Outcome with OAT
Auto-titration + Machine Learning
58
Training and Validation of Predictive Model
Phase 1:
n = 131
Phase 2:
n = 48
Extract
266
feature
s
Extract
266
feature
s
Training of
Random Forest
Machine
Trained
Random Forest
Machine
Responder
or Non-
Responder
Therapeutic
Outcome
59
Baseline and Outcome ODI
n=48
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Therapeutic success defined as ODI < 10hr-1
Predictive Accuracy:Patient Selection
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0
20
40
60
80
100
0 10 20 30 40 50 60 70 80 90 100
Effi
caci
ou
s P
rotr
usi
on
(%
)
Target Protrusion (%)
PPV=86%
Predictive Accuracy:Efficacious Protrusive Position
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Test circumstances mimic the outcome situation
Why does MATRx work so well?
Test
Prediction
Outcome
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Efficiency: Fewer Clinic Visits
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Efficiency: Reduced Time-to-Treatment
Days from OA Insertion to
Therapeutic Success
Prediction Mean±SD Range
Predicted Success 29.3±27.1 6.0-111.0
Predicted Failure 76.9±56.7 8.0-243.0
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Conclusions
•CPAP is still standard treatment for OSA but it has “clay feet”
•OAT is great treatment for OSA BUTit must incorporate patient selection
•The at-home sleep test, MATRx plus, provides accurate patient selection for OAT
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Know, in advance, OSA patients who will be effectively treated with an oral appliance
Improve your efficiency of appliance fitting at target
Decrease the time-to-therapy
Minimize the risk of over-titration
MATRx plus Empowering the Sleep Dentist
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Acknowledgements
• National Research Council Canada –Industrial Research Assistance Program
• Alberta Innovates Technology Futures
• SomnoMed
• MicroDental Laboratories
• Zephyr Sleep Technologies
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