Advances in the Evaluation and Management of Adult OSA

Advances in the Evaluation and Management of Adult OSA Michelle Cao, DO Clinical Associate Professor Pulmonary, Critical Care, and Sleep Medicine Stanford University

Conflict of Interest Disclosure I declare that the content for this activity, including any presentation of therapeutic options, is well balanced, unbiased, and to the extent possible, evidence-based.

Learning Objectives Review the latest discoveries in obstructive sleep apnea pathogenesis Detail the clinical work-up for a patient suspected of having OSA Understand the benefits of CPAP in cardiovascular disease prevention Become familiar with novel alternative treatments for obstructive sleep apnea beyond PAP therapy

Case 64 y/o executive requesting a second opinion on sleep apnea treatment. He was diagnosed with severe sleep apnea in Singapore 3 years ago, tried CPAP but did not notice any improvements with use, so he stopped. He denies night time or daytime symptoms of sleep apnea. He sleeps 6 hours per night and states, I go to bed thinking I m wasting my time away for every hour that I m sleeping. His cardiologist is considering adding a third antihypertensive for difficult to control hypertension.

Other Pertinent Info PMH: hypertension, seasonal allergies Social Hx: nonsmoker, social alcohol use PE: BMI 26 kg/m 2, BP 145/85, HR 75, SpO 2 97% ENT: septum midline, Mallampati class 3 airway, tonsils 1+ GEN: pleasant, thin man Cardiovascular: RRR Lungs: CTA Extremities: No peripheral edema

Diagnostic in-lab PSG: Total sleep time: 7 hours 10 minutes Apnea Hypopnea Index (AHI): 70 events per hour Oxygen Desaturation Index (ODI): 61 events per hour Minimum SpO2 76% (REM sleep) T<90: 44 minutes

What would you recommend next? A. Initiate empiric auto bilevel PAP therapy B. Proceed with in-laboratory CPAP / bilevel titration study C. Referral for mandibular advancement device D. Referral to sleep surgery E. Reassure patient that treatment is not required as he is not symptomatic

What would you recommend next? A. Initiate empiric auto bilevel PAP therapy B. Proceed with in-laboratory CPAP / bilevel titration study C. Referral for mandibular advancement device D. Referral to sleep surgery E. Reassure patient that treatment is not required as he is not symptomatic

Questions to think about: Who should be tested? Who should be treated? What are the benefits of treatment?

OSA SLEEP RELATED BREATHING DISORDERS Sleep Hypoventilation Syndromes CSA Syndromes

...and there sat a fat and red-faced boy, in the state of somnolency. C. Dickens

OSA: what it is? Recurrent narrowing or closure of the upper airway during sleep superimposed on an existing narrow upper airway Repetitive obstruction leads to repetitive oxygen desaturations, cortical arousals, consequent sympathetic activation Termination of the obstruction requires arousal from sleep to re-establish upper airway tone and allows ventilation to resume

Anatomy of the Upper Airway PPSM 6 th edition, Chapter 143: Oropharyngeal Growth & Malformations. Quo, Bliska, Hyunh

Eckert et al. Proc Am Thorac Soc 2008

Eckert et al. Proc Am Thorac Soc 2008

Prevalence: 20 years later Wisconsin Sleep Cohort (4% women; 9% men) 2007-2010 Prevalence estimates of moderate to severe OSA 30 49 year old men: 10% 30 49-year old women: 3% 50 70-year old men: 17% 50 70 year old women: 9% Peppard P et al. Am J Epidemiol. 2013.

Proposed Pathophysiology A. Narrow upper airway anatomy (collapsed upper airway with poor neuromuscular reflexes - starting at early age) B. Instability of respiratory control system (high loop gain with resultant unstable ventilatory system) C. Low arousal threshold (propensity to be aroused from sleep) D. Factors that impair upper airway dilator muscle function (neuronal injury, myopathy of genioglossus, pharyngeal sensory impairment, etc)

Obstructive Apnea CPAP Oral Appliance Upper Airway Narrowing, Collapse Decreased UA caliber Low arousal threshold Ventilatory Drive CO2, O2 Increase Arousal Threshold Hypoventilation Reduced UA muscle activity Increased ventilatory response Arousal Increase UA Dilator Muscle Activity Return to Sleep Hyperventilation Decrease Loop Gain

A Systemic Disorder Increased Cancer Incidence Insulin Resistance OSA Cardiovascular Neurodegeneration

Interplay Between Heart Disease and OSA

Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2015

OSA intermittent hypoxia cortical arousals Repetitive Obstructive Apneas Hypopneas increased oxidative stress sleep fragmentation

Two Major Pathophysiological Consequences OSA-arousal Daytime sleepiness Nonrestorative sleep Neurocognitive impairment OSAdesaturation Cardiovascular consequences Metabolic derangements

PHYSIOLOGICAL Pcrit (collapsibility of passive upper airway) Loop gain (measure of instability of ventilatory control system) Arousal threshold to hypoxia, hypercapnia Reflex response of upper airway dilator muscles to negative intraluminal pressure RISK FACTORS STRUCTURAL Craniofacial dimensions Increased upper airway soft tissue Retrognathia Obesity Fat deposition in tongue & lateral pharyngeal wall SUSPECTED Smoking Menopause Alcohol use at bedtime Nighttime nasal congestion Pregnancy

OBESITY and OSA Obese, + OSA Obese, - OSA Sleep. 2014; 37(10):1639 1648

TERMINOLOGY AHI: apnea hypopnea index # of abnormal respiratory events per hour of sleep ODI: oxygen desaturation index # of oxygen desaturation events per hour of sleep RDI: respiratory disturbance index AHI + respiratory effort related arousal (RERA) REI: respiratory event index Used in home sleep testing when there is no EEG

Defining OSA severity AHI < 5 AHI 5-15 AHI 16-30 AHI > 30 OSA should be regarded as a disease spectrum rather than a diagnosis based on AHI cut-off values.

Limitations of AHI Other findings NOT included in AHI could impact overall severity of clinical syndrome: Duration of hypoxemia Duration of hypoventilation Duration of airflow limitation Degree of sympathetic activation

CLINICAL FEATURES Habitual snoring Choking or gasping from sleep Witnessed apneas Disturbed sleep, poor quality sleep Unintentionally falling asleep during the day (high Epworth Sleepiness Scale score) Unrefreshing sleep even after a full night s sleep Chronic daytime fatigue/tiredness Insomnia Morning headaches Neurocognitive impairment

Icelandic Sleep Apnea Cohort: identify distinct clinical subgroups Subgroup 1 Primary complaintinsomnia, not sleepy Subgroup 2 Least symptomatic Normal ESS Highest prevalence of heart disease Ann Am Thorac Soc 2016: 13(9):1456 1467. Subgroup 3 Excessive sleepiness 35% reported drowsy driving

There are different clinical subtypes of OSA: I. Disturbed sleep insomnia II. III. Minimally symptomatic high prevalence of heart disease Excessively sleepy daytime consequences

Physical Examination

CRANIOFACIAL EXAM Small mandible or lower jaw (micrognathia) Short mandible or lower jaw (retrognathia) Recessive maxilla bone Excessive soft tissue in throat Enlarged tonsils Narrow nasal passages Deviated nasal septum Hypertrophied nasal turbinates Nasal valve collapse Large neck size Men = 17 in Women = 16 in

Mallampati Scale

Mallampati I

Mallampati II

Mallampati III

Mallampati IV

Diagnostic Testing

The Sleep Study Overnight in-lab polysomnogram (Gold Standard) Home sleep testing (portable or home studies)

Sleep Testing Category Unattended Attended Type I: Traditional in-lab attended PSG EEG, Eye, chin EMG, EKG, heart rate, nasal and oral airflow, respiratory effort, SpO 2, legs, arms, and respiratory muscles, respiratory effort, CO 2, video Type II: Minimum of 7 leads (EEG, EOG, chin, ECG/heart rate, airflow, respiratory effort, SpO 2 ) Type III: Minimum 4 leads (airflow, respiratory effort, ECG/heart rate, SpO 2 ) Type IV: Minimum 1 2 leads (oximetry/airflow) **Medicare requires 3+ channels

AASM Indications for Portable Monitoring False negative rates of ~ 17% False positive rates vary; up to 31% Appropriate conditions: High pretest probability of mod-severe OSA NOT for general population screening In lab PSG not possible due to critical illness, immobility, or safety No other cardiopulmonary, neurologic, or sleep disorders Requires comprehensive sleep medicine evaluation by board certified sleep medicine specialist Must follow up to discuss results J Clin Sleep Med. 2007 Dec 15;3(7):737-47.

Contraindications for Portable Monitoring NO comprehensive sleep evaluation prior to study Significant known co-morbid conditions Moderate to severe pulmonary or heart disease Neuromuscular disease Congestive heart failure Neurologic disease To evaluate other sleep disorders o hypoventilation, central sleep apnea, periodic limb movements, parasomnias, seizures, narcolepsy, etc

Advantages & Disadvantages of HST Advantages Increased access for patients and referring providers Lower cost Does not require attendant, easy to set up Disadvantages Less data (fewer channels) Recording time sleep time Leads can fall off before test is completed Can over call or under call abnormalities because of limited detection strategies

Treatment

Goals of Treatment Treatment goals for OSA include: Improvement in daytime symptoms and quality of life Improved sleep quality and reduction in cardiometabolic risks Normalization of AHI and nocturnal oxygen desaturations Individuals may have different treatment goals

FDA Approved I. Positive airway pressure devices (e.g. CPAP, bilevel) II. III. IV. Mandibular advancement devices Sleep surgery (nasal vs. soft tissue vs. bone surgery ) Alternatives Hypoglossal nerve stimulation (Inspire)

CPAP Therapy 38 years later Initial introduction by Dr. Colin Sullivan in 1981 The unit requires a mask interface through which airflow is delivered by an air blower Designed to overcome the obstruction by stenting the upper airway open Established improvements on quality of life, neurocognition, cardiovascular health CPAP continues to be an established gold standard treatment Sullivan C: Nasal Positive Airway Pressure and Sleep Apnea: Reflections on an experimental method that became a therapy. AJRCCM. 2018

Features of CPAP CPAP is very effective in treating OSA, but it is NOT a one size fits all Understanding how each device works allows the clinician to better select the best device and settings for a given patient personalized treatment

The modern CPAP unit CPAP has undergone many changes since 1980 Size and portability (from 15 down to 2 lbs, travel CPAP ~ 1 lb) Noise (26 db ~ equal to whispering) Recognize and differentiate types of breathing events Adjust output to specific events Communicate remotely with treatment team and patient Includes features designed to improve effectiveness and patient comfort Data collection systems can track compliance, pressure, leak, and efficacy

Drawbacks to CPAP Poor adherence (40-85% depending on studies) Nasal discomfort, congestion, mask leak, claustrophobia, aerophagia Adherence defined by CMS as > 4 hours/night, more than 70% of nights in a 30-day period Tied to insurance reimbursement Not a clear threshold for reversal of OSA adverse effects Linear dose response relationship: the greater the usage, the greater improvements in sleepiness, QoL, blood pressure outcomes

Benefits of CPAP Are Dependent on Hours of Use: Normal scores for Epworth Sleepiness Scale (squares) Functional Outcomes of Sleep Questionnaire (diamonds) Multiple Sleep Latency Test (triangles) Terri E. Weaver; Ronald R. Grunstein; Proc Am Thorac Soc 2008, 5, 173-178

CPAP Reduces Cardiovascular Death and Non-fatal Events in Patients With OSA Meta-analysis of 11 studies, 4620 patients with OSA End point: Incidents of cardiovascular deaths, non-fatal cardiovascular events Myocardial infarction, stroke, bypass surgery, PTCA Results: risk reduction Cardiovascular death: 68%, OR 0.32 (0.24-0.41) Nonfatal events: 43%, OR 0.57 (0.43-0.75) Wang J et al. International J Cardiology 2015; 191:128-131.

CPAP on Cardiovascular Death Reduction Wang J et al. International J Cardiology 2015; 191:128-131.

Moderate-Severe OSA Wang J et al. International J Cardiology 2015; 191:128-131.

Association of PAP Therapy With Cardiovascular Events and Death in Adults with OSA Meta-analysis of 10 RCTs (PAP versus Control) N=7266, 80.5% men, mean age 60.9 years, mean BMI 30 kg/m 2 Moderate to severe OSA (AHI>15) Results: no difference Major cardiovascular events, RR 0.7 (0.53-1.13) Cardiac death, RR 1.15 (0.88-1.5) All cause death, RR 1.13 (0.99-1.29) Yu J et al. JAMA 2017; 38(2):156-166.

Meta-analysis of 10 RCTs (PAP versus control) N=7266 5683 OSA 1583 central sleep apnea 7 RCTs met criteria for OSA and PAP intervention Heterogeneous group of primary vs. secondary prevention Mean follow up of 6 months 6 years Mean PAP adherence of 1.4-6.6 hours per night N= 4562, with 356 outcomes events 73% derived from a single study (SAVE trial)

Sleep Apnea Cardiovascular Endpoints (SAVE) Study Secondary Prevention Trial Largest RCT evaluating effectiveness of CPAP in reducing rate of cardiovascular events in OSA patients 2717 patients (81% men) with mod-severe OSA + coronary or cerebrovascular disease, age 45-75 years, minimal daytime sleepiness Randomized to CPAP + Usual Care or Usual Care alone 3.7 years follow up Primary endpoint: death or hospitalization from cardiovascular causes, MI, stroke Secondary endpoint: QoL, sleepiness, snoring, mood McEvoy D, et al. N Engl J Med 2016;375:919-31.

Results: Average CPAP use: 3.3 hours/night AHI improved from mean 29 to 3.7 events/hour CPAP did not prevent cardiovascular events compared to usual care 229 primary endpoint events occurred in CPAP group (17%) vs. 207 in UC group (15.4%), P=0.34 CPAP did reduced snoring, daytime sleepiness, improved quality of life and mood

CPAP Had No Effect on Secondary Prevention of Cardiovascular Events N Engl J Med 2016;375:919-31.

Sub-group Analysis in CPAP-Adherent Patients 42% used 4 hours per night CPAP Adherent + UC (n=561) Usual Care (n=561) HR (95% CI) P value Stroke 19 (3.4) 31 (5.5) 0.56 (0.32-1.0) 0.05 Major cerebral events 20 (3.6) 35 (6.2) 0.52 (0.30-0.90) 0.02

Mandibular Advancement Devices Predictors of success Lower baseline AHI Lower BMI Younger age Appropriate for Mild to moderate OSA Patients who prefer oral appliance to PAP Unsuitable candidates for PAP Treatment attempts with PAP failed

2-Year Follow Up of Oral Appliance vs CPAP for OSA Oral appliance trended towards decreased compliance Oral appliance dropped out 47% vs. 33% CPAP dropped out) Deterioration in success based on lowering of AHI. Why? Loosening and adaptation of soft tissue structures and musculature Genioglossus muscle tone negatively correlates with age Sleep 2013; 36(9):1289-1296.

Sleep Apnea Surgery Maxillo-mandibular advancement (MMA) most effective long-term Success dependent on severity of sleep apnea, age, BMI, surgeon s experience and expertise Nasal surgery (septoplasty, turbinectomy, nasal valve reconstruction): corrects nasal valve collapse, improves CPAP comfort, nasal breathing, sleep quality UPPP or palatal surgery less and variable effectiveness, not long-term solution

Comparison on Surgical Efficacy Holty and Guilleminault. Med Clin N Am 2010

Bariatric surgery Long term elimination of OSA varies by studies Studies show OSA re-emerges or persists after surgery Weight loss 10 kg reduction in body weight can yield a reduction in AHI roughly about 5 events/hour (Foster, the Sleep AHEAD Study, Arch Intern Med, 2009) OSA resolved in 63% of patients with mild OSA 13% of severe OSA had remission

Novel Therapies

Hypoglossal Nerve Stimulation STAR Trial Multicenter, single group cross-over design sponsored by Inspire Medical Systems (STAR Trial) Surgical implantation of upper airway stimulation device Exclusion: BMI>32, AHI<20>50, complete concentric collapse of upper airway N=126, 83% men, mean age 54.5 years, BMI 28.4 Primary outcomes: AHI, ODI Strollo PJ et al. Upper Airway Stimulation for OSA. NEJM 2014;370:139-149.

Eligibility FDA approved 2015, insurance coverage is determined on a case by case basis Currently recommended specifically for PAP intolerance > 22 years of age or older BMI < 32 kg/m 2 AHI range 15-65 (< 25% central apneas) Requires drug induced sleep endoscopy to rule out retropalatal complete concentric collapse

Results: Outcome Baseline 12 months P value AHI 32.0±11.8 15.3±16.1 <0.001 Median AHI 29.3 9.0 ODI 28.9±12.0 13.9±15.7 <0.001 Response in 64% of participants at 18 months Median ODI 25.4 8.6 FOSQ 14.3±3.2 17.3±2.9 <0.001 Epworth 11.6±5.0 7.0±4.2 <0.001 T<90 (%) 8.7±10.2 5.9±12.4 0.01 Strollo PJ et al. NEJM 2014;370:139-149.

OSA Screening in the Primary Care Setting US Preventive Task Force Recommendations 110 studies (N = 46,188) Asymptomatic adults including those with unrecognized symptoms Screening Tools: ESS, STOP Questionnaire, STOP-BANG, Berlin, Wisconsin Sleep, MVAP No RCTs compared screening with no screening 2 studies (n = 702), the screening accuracy of the multivariable apnea prediction score (MVAP) followed by HST for detecting severe OSA syndrome (AHI 30 and ESS score >10) showed AUC 0.80 (0.78-0.82) and 0.83 (0.77-0.90) These studies oversampled high-risk participants JAMA. 2017;317(4):415-433.

Recommendations I II III Evidence on use of validated screening questionnaires in asymptomatic or patients with unrecognized symptoms to identify who will benefit from diagnostic testing is insufficient. Treatment with CPAP or MAD improves intermediate outcomes (AHI, daytime sleepiness, BP). However the applicability of this evidence to screen populations is limited. Current evidence is insufficient to assess the balance of benefits and harms of screening for OSA in asymptomatic adults.

IN SUMMARY CPAP is recommended for symptomatic benefit in any OSA severity CPAP is recommended for OSA and resistant hypertension CPAP should be considered for those with established or with risk factors for vascular/heart disease CMS mandated adherence criteria of 4 hours of nightly use for 70% of the nights in a 30-day period should be reconsidered The cardiovascular benefits of CPAP may not be achieved with a typical use of 3 4 hours at the beginning of the night

My Algorithm Suspect OSA HST vs In Lab PSG Mild (AHI 5-14) Asymptomatic Mild (AHI 5-14) Symptomatic Moderate to Severe (AHI>15) Consider holding treatment, monitor Recommend treatment Highly recommend treatment