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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

2

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

3

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

6

The Passive Pharyngeal Airway

General Anesthesia

Complete Paralysis

7

Closing pressure is elevated in OSA

8

Maximal Area of the Passive Pharynx

9

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

32

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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 -

35

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

42

43

44

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

50

Night 1 - Dynamic Theragnostic Study

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Night 2 - Static Theragnostic Study

52

Night 3 - Static Theragnostic Study

3.1mm

53

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

54

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

56

Distribution of BaselineODI and BMI

57

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

61

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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