Precision Medicine

Upper Airway Pacing for Obstructive Sleep ApneaCharles W. Atwood, Jr., MD, FCCP, FAASMAssoc Professor of Medicine University of PittsburghSleep Program Director, VA Pittsburgh Healthcare System

Disclosure: Charles W. Atwood, Jr., MDResearch SupportFederalNIH, NIDDK - OSADept of Defense Lung cancerIndustryResearch Grant Philips-Respironics, Inc.Forest Research InstituteIndustry advisoryPhilips-RespironicsCarecore NationalOutlineBackgroundUpper Airway StimulationSTAR Trial Conclusions

Pathogenesis of Obstructive Sleep ApneaAJRCCM 2005 172:13631370Promotion of Airway CollapsePromotion of Airway PatencyNegative pressure oninspirationExtralumenal positive Pressure Fat DepositionSmall mandiblePharyngeal dilator Muscle contraction(genioglossus)Lung volume(longitudinal traction)Risk Mediated by a: Gene (Obesity, Craniofacial Structure, Respiratory Control / Environment (Obesity) Interaction

Sleep 2008 31:1071-78Sleep Disordered Breathing and Mortality: Eighteen-Year Follow-up of the Wisconsin Sleep Cohort (n = 1396) SDB, irrespective of EDS, was associated with increased mortality. The striking high CV mortality risk in untreated severe SDB, suggests that SDB Rx should not be contingent on daytime sleepiness symptomsIncreased Prevalence of Sleep-Disordered Breathing in AdultsThe current prevalence estimates of moderate to severe sleep-disordered breathing (apnea-hypopnea index, measured as events/hour, 15) are:10% (95% CI: 7, 12) among 3049-year-old men17% (95% CI: 15, 21) among 5070-year-old men 3% (95% CI: 2, 4) among 3049-year-old women 9% (95% CI: 7, 11) among 5070 year-old womenThese estimated prevalence rates represent substantial increases over the last 2 decades - relative increases of between 14% and 55% depending on the subgroupAm J Epidemiol. 2013;177(9):10061014OSA and Cardiovascular DiseasePrimary HTN: 35% prevalenceDrug-resistant HTN: 65 to 80% prevalenceMost common secondary cause Coronary Artery Disease: 30% prevalenceHeart failure: 21-37% prevalence Atrial Fibrillation: OSA present 5 X more likelyStroke: 60% prevalence Circulation 2012;126:1495-1510

Cumulative Incidence of Fatal CV EventsCumulative Incidence of Non-fatal CV EventsAIM: Observational study to compare incidence of fatal and non-fatal cardiovascular events in simple snorers, patients with untreated OSA, patients treated with CPAP, and healthy men recruited from the general population.Design: Prospective observational cohort. 264 healthy men, 377 simple snorers, 403 with untreated mild-moderate OSA (AHI 5-30), 235 with untreated severe OSA (AHI > 30), and 372 with OSA and treated with CPAP Lancet 2005 365: 104653MonthsMonths.

Conclusion: In men, severe OSA significantly increases the risk of fatal and non-fatal cardiovascular events. CPAP treatment reduces this risk.Long-term cardiovascular outcomes in men with OSACPAP Therapy and AdherencePAP therapy when used consistently results in decreased daytime sleepiness*, improved HRQOL, and decreased vascular risk.Recent studies of CPAP therapy investigated adherence:APPLES Study largest RCT in sleep medicine to date (1,516 subjects enrolled) and CPAP adherence rate was 39% at 6-months use of CPAP therapy (174 of 443)Home PAP Study Evaluation of standard OSA care vs. home-base diagnostics and titration. Results of 3-month follow-up: CPAP adherence was 39% (Lab titration); CPAP adherence was 50% (Home titration) Conclusion: CPAP is first-line therapy and effective when consistently used by OSA patients. Alternative therapy options for moderate or severe OSA patients who are nonadherent to PAP are desirableOSA Value of Selected Treatment OptionsSnoringMild Sleep ApneaModerate or Severe Sleep ApneaWeight lossNasal decongestantPositional therapySurgery (adults)Surgery (children)Oral appliancePAPDarker more valuable. Upper Airway Stimulation therapy treatment indicationOnly Positive Airway Pressure (PAP) and Surgery indicated for patients with Moderate or Severe OSAhttp://www.sleepapnea.org/diagnosis-and-treatment/treatment-options.htmlOutlineBackgroundUpper Airway StimulationSTAR Trial Conclusions

The Inspire System: Built on a proven, commercial grade technology platform

Stimulation Lead - Self sizing cuff - Multiple stimulation vectors Implanted Pulse Generator (IPG)- 6-8 year projected longevity Effort Sensor - Secure, stable location - Direct measurement of ventilatory effort - Short surgical tunnel12Upper Airway Anatomy & Stimulation Site

Stimulation Site: Medial branch of the hypoglossal nerve, activates only protrusors (genioglossus, geniohyoid), distal to retractors (styloglossus and hyoglossus)Styloglossus (SG)Hypoglossal Nerve (XII)Hyoglossus (HG)Superior root of ansa cervicalisGenioglossus (GG)Geniohyoid (GH)ThyrohyoidStimulation SiteSuperior LongitudinalInferior Longitudinal13

No airway anatomy alterationWorks with patients physiologyStandardized implant techniqueFast post op recoveryPatient Programmer Turn therapy ON/OFF Adjust amplitudeDevice Programmer Adjust Therapy Parameters Bluetooth enables remote adjustmentsduring titration studies in the sleep labUpper Airway Stimulation14Basic Therapy Parameters

Stimulating PulsesAmplitude (V) primary stimulation strength adjustmentRate (Hz) default 33 HzPulse Width (sec) default 90 secOnsetOffsetSensor SignalExpiratoryInspiratory15Upper Airway Stimulation advances tongue to open airway

Airway ObstructedSTIMULATION OFFTongue AdvancedSTIMULATION ONTongue baseEpiglottisTongue base advancement with stimulationTongue baseObserved during sleep endoscopy16Effect of stimulation on the Retropalatal and Retrolingual airway area between awake endoscopy and DISE

Eur Respir J 2014; in pressIncreases in retropalatal and retrolingual area comparing no stimulation with progressively higher levels of stimulation during DISE

No stimulation First sensation Bulk movement Titrated therapeutic Sub-discomfortRetropalatalRetrolingualEur Respir J 2014; in press

PSG: Effect of StimulationTherapy ONTherapy OFF30 secondsEEGEMGNasalPressureThermoChestAbdomenSpO2DOWU, REM19In-lab PSG Titration AlgorithmIncrease amplitude by 0.1 to 0.2 volts if 5 obstructive apneas or hypopneas or loud, unambiguous snoring 10 minStart:0.2 V below Functional ThresholdReduce amplitude by 0.1 to 0.2 volts if stimulation causes persistent arousals or is poorly toleratedAmplitude (volts)Time (minutes)Therapeutic Amplitude Range 30 minutes in the patients preferred sleep position with minimum occurrence of events, preferably with REM sleep observedArousal Threshold20*Adapted from current practice guidelines established for CPAP titration by the American Academy of Sleep Medicine, ref: Journal of Clinical Sleep Medicine, Vol. 4, No 2, 200820Clinical Trial Experience Proof of Principle Trial8 patients4 Centers

Completed in 2001

Demonstrated therapy concept

Feasibility Trial34 patients8 Centers

Completed in 2010

Demonstrated safety and patient selection

References: Operative technique in otolaryngology-head and neck surgery. 2012 23(3): 227-33 Journal of Clinical Sleep Medicine 2013 9 (5) 433-438The Laryngoscope 2012 122(7): 1626-33

Reference: Arch Otolaryngol Head Neck Surg 2001 127:1216-1223Examples collapse at the level of the palate during DISE

Anteroposterior collapseConcentric collapseJCSM 2013 9 (5) 433-438Inspire UAS effect during DISE

PalateTherapy OFFPalateTherapy ONPosterior oropharyngeal wallPosterior UvulaLRPEpiglottisLingual TonsilsLRPLRPLRP

Reference: 2 slicesPalateTongue-BaseTongue BaseTherapy OFFTongue BaseTherapy ON23OutlineBackgroundUpper Airway StimulationSTAR Trial Conclusions

Stimulation Therapy for Apnea Reduction (STAR Trial)ClinicalTrials.gov NCT01161420Hypothesis: Unilateral Stimulation of the Hypoglossal Nerve during sleep will safely and effectively treat Obstructive Sleep ApneaNEJM 2014 370:139-49Outcome Measures: Baseline vs. 12-MonthsCo-PrimaryApnea Hypopnea Index Oxygen desaturation index (ODI4%)Secondary Epworth Sleepiness Scale Functional Outcomes of Sleep QuestionnaireSaO2 < 90%

NEJM 2014 370:139-49Methods IProspective, multicenter trial with randomized therapy withdrawal arm in participants with moderate to severe OSA who had failed or had not tolerated CPAP. All underwent a screening polysomnographic (PSG) study, surgical consultation, and drug-induced sedation endoscopy (DISE). Participants without complete concentric collapse at the retropalatal airway received an implanted neurostimulatorNEJM 2014 370:139-49Inclusion CriteriaAHI between 20 and 50Have failed or have not tolerated CPAPCentral and mixed sleep apnea accounted for < 25% of all AHI eventsAbsence of significant apnea when sleeping in a non-supine position (AHInon-supine > 10)28NEJM 2014 370:139-49Exclusion CriteriaBMI > 32Neuromuscular diseases Severe Co-Morbid Cardiopulmonary DiseaseOther chronic sleep disordersComplete concentric collapse at the level of soft palate during drug-induced sedation endoscopy (DISE)29NEJM 2014 370:139-49Examples collapse at the level of the palate during DISE

Anteroposterior collapseConcentric collapseJCSM 2013 9 (5) 433-438Methods IIParticipants were followed for 12 months to assess efficacy and adverse events. PSG (AHI and ODI)Quality of life measures Epworth Sleepiness Scale (ESS)Functional Outcomes of Sleep Questionnaire (FOSQ) Responders after 12 months of continuous therapy were randomized to one week of therapy suspension (OFF) vs. therapy maintenance (ON) and evaluated with PSG.

NEJM 2014 370:139-4931

Consort Flow ChartNEJM 2014 370:139-49 Baseline Characteristics of the Study Population (N = 126)CharacteristicsMean SD or N (%)Age, year54.5 10.2Male sex, no. (%)83%Caucasian race, no. (%)97%Body Mass Index, kg/m228.4 2.6Neck size, cm41.2 3.2Systolic BP, mmHg128.7 16.1Diastolic BP, mmHg81.5 9.7Hypertension, no. (%)38%Diabetes9%Asthma5%Congestive heart failure2%Prior UPPP, no. (%)18%NEJM 2014 370:139-49

Primary Outcome Measures: AHI and ODI (n = 124) 68% reduction in AHI from baseline to Month-12 70% reduction in ODI from baseline to Month-12AHI ODI*Median and error bar in standard errorp < 0.0001p < 0.0001NEJM 2014 370:139-49

Secondary Outcome Measures: FOSQ & ESS (n = 123)FOSQ ScoreESS Scale*Median and error bar in standard errorp < 0.0001p < 0.0001NEJM 2014 370:139-49Secondary Outcome Measure: SaO2 < 90%p < 0.05NEJM 2014 370:139-49

Randomized Controlled Therapy Withdrawal*mean and error bar in standard errorp < 0.0001p = n.s.NEJM 2014 370:139-49Relevant Adverse EventsSerious: Device related 1% Device revisionNon Serious: Procedure related~ 25% Pain (minimal, most did not require narcotics - substantially less than UPPP)Non-Serious: Device related~ 33% Tongue discomfort / abrasion (time limited)1% Mild or Mod Infection (cellulitis)* One Death Unrelated to the TrialNEJM 2014 370:139-49Adherence DataAfter 12 months follow up of 126 implanted participants, 124 participants (98%) remained active users of UAS therapy. One participant died unexpectedly due to an unrelated cause, and one participant requested a device removal for personal reasons. Based on self reports from 123 participants at 12 months, 86% (106 of 123) used the device daily and 93% (115 of 123) used the device at least 5 days a week. The UAS device registers the cumulative hours of stimulating pulses duration since last device interrogation. At the 12-month visit, the average stimulation pulses time was 2.6 hours per night. The stimulating pulses were not delivered continuously during sleep, and were only delivered during the late expiratory and inspiratory phases of respiration.

NEJM 2014 370:139-49Measurement of Use of Therapy

NEJM 2014 370:139-49Upper Airway Stimulation effect on SleepBaselineN = 12612 MonthN = 124Sleep Time, minMean(SD)% of Total SleepMean(SD)% of Total SleepP valueTotal Sleep364.8 (68.0)333.7 (69.3)