Research Prioritization Topic Brief Topic 19: “ Obstructive Sleep Apnea” Comparative effectiveness of medical and surgical treatment options for obstructive sleep apnea in adults. PCORI Scientific Program Area: Assessment of Prevention, Diagnosis and Treatment Options Dr. Gillian Sanders Schmidler, PhD, and Team The Duke Clinical Research Institute April 18, 2013

PCORI Topic Brief: Assessment of Prevention, Diagnosis and Treatment Options

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Criteria Introduction Overview/definition of topic

Relevance to patient-centered outcomes

Burden on Society Recent incidence and prevalence in populations and subpopulations

Brief Description DESCRIPTION OF CONDITION1 • Individuals with obstructive sleep apnea (OSA) have repeated episodes during sleep where their upper airway collapses and becomes obstructed. This obstruction occurs more frequently among obese individuals, who experience airway narrowing due to fat accumulation. • This results in reduced breathing (hypopnea) or complete stoppage of breathing (apnea). • When breathing stops, oxygen levels drop, causing patients to wake repeatedly through the night. • Over time, poor sleep quality and chronic dropping of oxygen levels lead to many problems. SYMPTOMS/OUTCOMES • Symptoms (many of these may be noticed by spouse more than patient)1,2 o Daytime sleepiness o Snoring o Frequent awakening during the night o Awakening with a choking or smothering sensation, dry mouth, sore throat, or chest pain o Irritability o Difficulty concentrating or mental fogging o Memory problems o Morning headaches o Decreased sex drive o Depression o Body aches o History of high blood pressure, diabetes, heart disease, or kidney disease • Other outcomes1 o Cardiovascular disease (heart disease and stroke) o Hypertension o Diabetes mellitus o Higher rates of motor vehicle accidents o Decreased quality of life o Inability to function at a normal level during day due to sleepiness o Higher mortality INCIDENCE (NEW CASES)/PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • Prevalence of OSA increases with age, from about 10% at age 40 to 20% among those older than age 60.1,3 • Rates of OSA are higher in men than in women and African Americans and Asians may be at risk at younger ages compared with Caucasians.3-6 • Rates of OSA are rising, probably related to increasing rates of obesity; up to 25% of adults are at high risk for OSA.5

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Effects on patients’ quality of life, productivity, functional capacity, mortality, use of health care services

QUALITY OF LIFE • OSA negatively affects patient quality of life, in a large part because of daytime sleepiness.7 PRODUCTIVITY • Studies using work productivity scales show that OSA negatively affects work productivity, even in otherwise healthy patients.8 FUNCTIONAL CAPACITY • OSA appears to negatively impact exercise capacity, although the contribution of OSA is difficult to distinguish from that of obesity.9 MORTALITY • OSA, particularly in severe cases and among elderly patients, increases all-cause mortality.1 Due to its relationship with obesity, OSA is rising in prevalence. OSA is associated with numerous bothersome symptoms such as daytime sleepiness and poor sleep quality, which reduce patient quality of life. Further, OSA is associated with devastating complications, including higher rates of cardiovascular disease and mortality. For all of these reasons, comparative-effectiveness research (CER) to identify optimal treatment approaches should be assigned high priority.

How strongly does this overall societal burden suggest that CER on alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent Systematic reviews: systematic • AHRQ comparative effectiveness review: Diagnosis and Treatment of Obstructive Sleep reviews, what is Apnea in Adults (2011)1 known about the • Two AHRQ future research needs prioritization projects: Future Research Needs for Diagnosis relative benefits of Obstructive Sleep Apnea (2012) and Future Research Needs for Treatment of Obstructive and harms of the Sleep Apnea (2012)10,11 available • Numerous additional systematic reviews are available management SCREENING/EARLY DIAGNOSIS1,2 options? • Diagnostic testing for OSA should be performed on any patient with typical symptoms of OSA, particularly snoring and daytime sleepiness. It is important for medical providers to ask patients about OSA symptoms, particularly patients who have typical risk factors, such as obesity. • Diagnosis of OSA is based on testing to identify episodes of reduced breathing (hypopnea) or complete stoppage of breathing (apnea): o The apnea-hypopnea index (AHI) is the count of the hourly apnea and hypopnea events during sleep. o The American Academy of Sleep Medicine defines OSA by an AHI of at least 15 events per hour (with or without OSA symptoms) or at least five events per hour with OSA symptoms. • There are two main strategies for diagnosing OSA: o Polysomnography (PSG)—Patients sleep in a special lab with comprehensive brain, breathing, heart monitoring and observation by a technologist. Though this is felt to be the most accurate way to diagnose OSA, disadvantages include cost, patient inconvenience, and differences in standards between labs. o Portable monitoring—Smaller monitors that collect data similar to PSG can be used at home or in sleep units.

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Patient questionnaires may also have a role in identifying patients in whom testing for OSA is indicated.

What could new research contribute to achieving better patient-centered outcomes?

TREATMENT1,2 • Continuous positive airway pressure (CPAP) is the standard first-line treatment for OSA. CPAP machines improve the airway obstruction that causes OSA by delivering compressed air into the airway (via a nasal or oral mask) to hold it open. o CPAP improves sleep patterns and quality of life when used as directed.1 o Optimal CPAP settings can be determined during PSG. Biphasic positive airway pressure (BiPAP) masks may be tolerated better by some patient subgroups. o The biggest drawback with CPAP is that patients have trouble tolerating it, often because they find the CPAP mask to be uncomfortable. CPAP only benefits those who use it correctly. Greater adherence is predicted by worse severity as measured by AHI or Epworth Sleepiness Scale.1 o The systematic review suggests CPAP is more effective than dental/mandibular devices.1 • Dental/mandibular devices are fitted by a dentist and worn overnight in the mouth to hold the airway open and prevent collapse. The systematic review suggests moderate effectiveness, but lower than with CPAP.1 o PSG or portable monitoring is recommended to confirm effectiveness of a patient’s device. o Device is generally used in cases where CPAP cannot be tolerated or the patient prefers an oral device. • Surgery can be performed to open up/widen the airway. The most common procedure is uvulopalatopharyngoplasty, in which the soft tissue at the back of the throat is removed, as well as the tonsils and adenoids, if present. o Surgery is generally only performed in cases where CPAP or oral devices have not worked. o The systematic review concluded that there is insufficient evidence to evaluate comparative effectiveness with CPAP or other interventions. • Weight loss—since obesity is a common underlying cause for OSA, weight loss can be effective in reducing symptoms if successful; options include lifestyle interventions and bariatric surgery. • Other treatments—less used treatments for OSA may include devices that hold the head/neck in a certain position, as well as pharmacotherapy. New research could contribute to achieving better patient-centered outcomes: • Diagnosis-related research:10 o How do different available tests compare in their ability to diagnose OSA in adults with symptoms suggestive of disordered sleep? o How do these tests compare in different subgroups of patients based on race, sex, body mass index, existing noninsulin-dependent diabetes mellitus, existing cardiovascular disease, existing hypertension, clinical symptoms, previous stroke, or airway characteristics? o How does phased testing (screening tests or battery followed by full test) compare with full testing alone? o In adults being screened for OSA, what are the relationships between AHI or oxygen desaturation index and patient characteristics with long-term clinical and functional

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outcomes? Treatment-related research:11 o What is the comparative effectiveness of different treatments for OSA in adults? o Does the comparative effect of treatments vary based on presenting patient characteristics, severity of OSA, or other pretreatment factors? o Are any of these characteristics or factors predictive of treatment success? o Does the comparative effect of treatments vary based on the definitions of OSA used by study investigators? o In patients with OSA who were prescribed nonsurgical treatments, what are the associations between pretreatment patient-level characteristics and treatment adherence? o What is the effect of interventions to improve adherence with device use (positive airway pressure, oral appliances, and positional therapy) on clinical and intermediate outcomes? Recent innovations: Recently, some improvements in CPAP masks have been developed to improve patient adherence to therapy.

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Have recent innovations made research on this topic especially compelling? How widely does care now vary?

What is the pace of other research on this topic (as indicated by recent publications and ongoing trials)? How likely is it that new CER on this topic would provide better information to guide clinical decision making?

VARIABILITY IN CARE • Though the American Academy of Sleep Medicine uses a standardized definition for diagnosis of OSA based on AHI,2 different research studies have used different AHI cutoffs.1 • Some differences exist in diagnostic equipment and protocols used by sleep labs as well as in patterns of treatment utilization. RECENT PUBLICATIONS • MEDLINE search 1/1/08-4/9/13—Total: 2,269 o Tagged as randomized controlled trial (RCT): 267 o Tagged as meta-analysis or systematic reviews: 158 ONGOING TRIALS • Clinicaltrials.gov—Total ongoing trials: 269, completed trials: 262 • NIH reporter—Projects: 166, publications: 232 KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • Should there be age- and sex-specific criteria for defining OSA? • What is the optimal test to identify and diagnose OSA? Should this differ in different subgroups (eg, age, obese vs. nonobese, patients with jaw abnormalities)? • What is the role for routine (or selected) preoperative screening for OSA? • When is it appropriate to skip PSG in diagnosing OSA? • What are the available objectively-measured predictors of OSA diagnosis (eg, AHI), and which ones are the best? • What are consumer preferences for strategies to diagnose OSA? • What is the value of less common strategies for diagnosing OSA (eg, scoring nasal flow limitation in recognizing mild OSA, brain MRI, 4-phase rhinomanometry in identifying patients with high nasal resistance and OSA)? • What is the impact of different available strategies for OSA treatment on major long-term clinical outcomes (including CPAP, dental devices, different surgeries, weight-loss strategies such as lifestyle modification or bariatric surgery, pharmaceutical strategies)?

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How do patient characteristics (demographics, comorbidities, OSA severity) affect the likelihood of long-term clinical outcomes? • What is the optimal treatment for OSA in different patient subgroups (differing disease severity, patients who do not tolerate CPAP)? • What is the role of weight-loss programs and bariatric surgery as an adjunctive treatment for OSA? • What CPAP and/or BiPAP masks are optimal for different patient subgroups, and how do they affect adherence to therapy? • What is the role of postoperative CPAP for patients with OSA or at high risk of OSA undergoing any surgery with sedation? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • Appropriately designed studies would have a high likelihood of answering these questions and reducing key areas of uncertainty. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • OSA is a common clinical problem with rising prevalence, so there is high societal motivation barriers that to improve care. would affect the • OSA is associated with many serious clinical complications; these complications may be implementation of prevented or treated through appropriate therapy. new findings in BARRIERS practice? • Diagnostic strategies may inconvenience patients (time, costs, and other factors). • Treatments are costly and often poorly tolerated by patients, which reduces effectiveness. • Many different treatment options are available; effects may differ by patient subgroups, which may make designing good trials challenging. How likely is it that EVIDENCE OF BENEFIT the results of new • It is likely that research would be implemented widely if there is evidence of better patientresearch on this centered outcomes topic would be EVIDENCE OF NO BENEFIT OR HARM implemented in • It is likely that research demonstrating no evidence of benefit would also have an impact on practice right practice, particularly because many strategies for diagnosing and treating OSA are costly. away? Would new OSA is a very common problem, and it is increasing in prevalence. Information from wellinformation from designed randomized controlled trials on this CER topic would likely remain relevant for several CER on this topic years. remain current for several years, or would it be rendered obsolete quickly by subsequent studies? REFERENCES 1. Balk EM, Moorthy D, Obadan NO, Patel K, Ip S,Chung M, Bannuru RR, Kitsios GD, Sen S, Iovin RC, Gaylor JM, D’Ambrosio C, Lau J. Diagnosis and Treatment of Obstructive Sleep Apnea in Adults. Comparative Effectiveness

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Review No. 32. (Prepared by Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-1). AHRQ Publication No. 11-EHC052-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published July 2011. 2. Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, Weinstein MD, Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5(3):263-276. 3. Young T, Finn L, Peppard PE et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-1078. 4. Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Medicine/Public Library of Science 2009;6:e1000132. 5. Hiestand DM, Britz P, Goldman M, et al. Prevalence of symptoms and risk of sleep apnea in the US population: Results from the national sleep foundation sleep in America 2005 poll. Chest 2006;130:780-786. 6. Villaneuva AT, Buchanan PR, Yee BJ, Grunstein RR. Ethnicity and obstructive sleep apnoea. Sleep Med Rev. 2005;9(6):419-436. 7. Bulcun E, Ekici A, Ekici M. Quality of life and metabolic disorders in patients with obstructive sleep apnea. Clin Invest Med. 2012;35(2):E105-113. 8. Nena E, Steiropoulos P, Constantinidis TC, Perantoni E, Tsara V. Work productivity in obstructive sleep apnea patients. J Occup Environ Med. 2010;52(6):622-625. 9. Przybyłowski T, Bielicki P, Kumor M, et al. Exercise capacity in patients with obstructive sleep apnea syndrome. J Physiol Pharmacol. 2007;58(suppl 5):563-574. 10. Balk EM, Chung M, Moorthy D, Chan JA, Patel K, Concannon TW, Ratichek SJ, Chang LKW. Future Research Needs for Diagnosis of Obstructive Sleep Apnea. Future Research Needs Paper No. 11. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055 I.) AHRQ Publication No. 12-EHC031-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.gov/reports/final.cfm. Published February 2012. 11. Balk EM, Chung M, Chan JA, Moorthy D, Patel K, Concannon TW, Ratichek SJ, Chang LKW. Future Research Needs for Treatment of Obstructive Sleep Apnea. Future Research Needs Paper No. 12. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055 I.) AHRQ Publication No. 12-EHC033-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.gov/reports/final.cfm. Published February 2012. APPENDIX: Topic Questions Nominated by ‘Web’ 1) A sleep study confirmed I have sleep apnea. I failed CPAP, oral appliances, and other noninvasive measures. Surgery is my next step. What information can you provide to help me decide what type of surgery has the best outcome and the lowest cost, based on my history, morphology, and age. Population: an infant/adolescent; a teenager, adult 25-65 or over 65, regardless of sex or ethnicity Importance: It is well known obstructive sleep apnea leads to decrease day time alertness, physical and mental functioning, mental illness, motor vehicle accidence, and if untreated, diabetes, obesity, heart disease and other diseases or disabilities in the longer term. AHRQ conducted a comparative effectiveness analysis between CPAP and other appliances. Soft-tissue surgery is performed routinely but published study showed it has limited effectiveness and is associated with significant postoperative morbidity and even mortality. Maxillo-mandibular advancement (MMA) surgery, while more costly,

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appears to be associated with a much higher efficacy rate than soft-tissue surgery. That all surgical studies had limited sample size is part of the issue. Most insurers, however, would only approve MMA after a trial and failure of soft-tissue surgery even though its efficacy is low, increasing cost and subjecting many patients with two surgeries in order to attain relief. Nominated by Agency for Healthcare Research and Quality (AHRQ) 1) Age- and gender-specific criteria for defining the OSA syndrome (and abnormal breathing)? 2) Effect of routine (or selected) preoperative screening for sleep apnea? 3) Diagnostic approaches to OSA in obese and nonobese patients? 4) Can PSG be skipped in making the diagnosis of sleep apnea? 5) Head-to-head comparisons of portable monitors, questionnaires, and prediction rules? 6) What are the available, objectively-measured predictors of sleep apnea diagnosis? 7) What is consumer willingness to pay for screening and to identify consumer preferences for strategies to diagnose sleep apnea? 8) Value of scoring nasal flow limitation in recognizing mild OSA? 9) Value of brain MRI in evaluating OSA patients? 10) Value of using 4-phase rhinomanometry in recognition of patients with high nasal resistance and OSA? 11) Diagnostic approach to OSA in micrognathia and retrognathia? 12) What is the impact of treatment of sleep-disordered breathing on major long-term clinical outcomes, including mortality, cardiovascular disease, and diabetes? 13) What are long-term outcomes of mandibular advancement devices (MAD) treatment? 14) Comparative studies of different sleep apnea treatments based on patient characteristics a. Analyses of CPAP stratified by disease severity b. Analyses of non-CPAP treatments stratified by disease severity 15) Comparison of alternative treatments for patients who do not tolerate CPAP? 16) What is the association between sleep apnea severity and long-term clinical outcomes? 17) Trials to evaluate weight-loss programs as an adjunctive treatment for sleep apnea? 18) What is the value of bariatric surgery for treatment of sleep apnea? 19) Role of surgery for treatment of OSA? 20) Comparison of surgery vs. CPAP? 21) Role of orthognathic surgery (corrective jaw surgery)? 22) Comparison of genio-tubercle advancement vs. dental devices? 23) Evaluation of postoperative CPAP for all patients with OSA or at high risk of OSA undergoing any surgery with sedation a. Trials comparing CPAP vs. pharmaceutical interventions b. Trials comparing different CPAP masks c. Trials comparing CPAP vs. oropharyngeal exercises d. Trials comparing different degrees of mandibular advancement e. Studies of factors influencing therapist decisions concerning CPAP mask choice

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