Year in Review. Outline of Lecture

Transcription

1 Year in Review Allan I. Pack, M.B.Ch.B., Ph.D. The John Miclot Professor of Medicine Division of Sleep Medicine/Department of Medicine Center for Sleep and Circadian Neurobiology University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania Outline of Lecture Sleep disorders and neurodegeneration New insights from pediatric sleep apnea Sleep medicine in transition New treatment modalities for OSA

2 Sleep-Disordered Breathing A Risk Factor for Development of Mild Cognitive Impairment or Dementia in Older Women (Yaffe K et al, JAMA 306:613, 2011) OR (95% CI) Apnea-hypopnea index >15 events/hour 1.85 ( ) Oxygen desaturation index 1.71 ( ) (ODI >15 events/hour) No association with arousal index Hence, likely related to intermittent hypoxia Cyclical Intermittent Hypoxia and Sleep Deprivation Both Lead to Upregulation of Unfolded Protein Response (UPR) in Mouse Brain UPR occurs in response to stress in endoplasmic reticulum (ER) UPR occurs when there are misfolded proteins proteins are normally folded in ER UPR is mechanism to protect from aggregation of misfolded proteins THERE IS A BIOLOGY AS TO WHY INTERMITTENT HYPOXIA AND SLEEP LOSS COULD ACCELERATE DEVELOPMENT OF DISORDERS OF PROTEIN AGGREGATION (For review, see Naidoo N, Sleep Med Rev 13:195, 2009)

3 Sleep Loss Can Accelerate Development of Neurodegenerative Disease (Kang JE, et al, Science 326:1005, 2009) Control Sleep Reduction Plaques in a mouse model of Alzheimer s disease B/C = Olfactory bulb D/E = Piriform cortex F/G = Entorhinal cortex Question Final Level Amyloid Plaque Burden Years Start of mild cognitive impairment Could early identification of OSA and treatment alter pre-clinical course of Alzheimer s disease (slope of disease progression)

4 New Insights from Studies in Pediatric Sleep Apnea Childhood Adenotonsillectomy Trial (CHAT) (Redline S et al, Sleep 39:1509, 2011) Description of trial design and conduct Proposed n=460 (6 sites) Age: years Pediatric sleep apnea OAI 1 or AH 2 on sleep study and Parental report of habitual snoring >3 nights/week Tonsillar hypertrophy 1 (based on scale 0-4) Deemed to be surgical candidate TO BE RANDOMIZED INTO SURGERY OR WATCHFUL WAITING (7 MONTHS)

5 Childhood Adenotonsillectomy Trial (CHAT) (Redline S et al, Sleep 39:1509, 2011) Primary outcome: Attention/Executive Function Secondary and Mediator Outcomes Sleep apnea: AHI; % of total sleep time with SpO2 >92% Sleep symptoms and QoL: Pediatric Sleep Questionnaire (total score, SRBDS); OSAS-18 (total score); modified Epworth Sleepiness Scale Cognition: GCA total score from DAS-2 Behavior: Regulation Total Score from BRIEF; ADHD Index from the Connors Rating Scale Metabolic: CRP; HOMA-IR Anthropometry: Change in height, weight, and BMI percentiles Blood pressure: mean arterial pressure Generic Quality of Life: PedsQL (total score) Is Childhood Adenotonsillectomy Trial (CHAT) A Model for Other Multi-Center Surgical Studies? When will our adult surgical colleagues follow suit?

6 Epigenetic Mechanisms Methylation Can Be Permanent and Passed to Next Generation Histone Modification More Dynamic DNA Methylation in Inflammatory Genes Among Children with OSA (Kim J et al, AJRCCM 185:330, 2012) Hypermethylation of FOXP3 INITIAL DISCOVERY STRATEGY FOLLOWED BY VALIDATION

7 Lab Approach to Diagnosis and Treatment of OSA vs. Approach in the Home The plot thickens Noninferiority of Ambulatory Management of Obstructive Sleep Apnea (Kuna ST et al, AJRCCM 183:1238, 2011) Referral for OSA randomized into in-home or in-lab pathway In-lab (AHI=47.3±29.4) Home Pathway (AHI=42.9±23.2) PSG Home diagnostic study CPAP titration Auto-CPAP at home (4-5 nights) 1-month follow-up (n=92) 3-month follow-up (n=88) Fixed CPAP 1-month follow-up (n=103) 3-month follow-up (n=96) OUTCOMES: FOSQ, SF12, Epworth, PVT, CES-D and CPAP adherence

8 Noninferiority of Ambulatory Management of Obstructive Sleep Apnea (Kuna ST et al, AJRCCM 183:1238, 2011) Changes in Some Outcomes Home Group Lab Group Differences in change scores between groups FOSQ 1.74±2.81* 1.85±2.46* NS Epworth -2.6±5.2* -2.9±4.4* NS *All p< Noninferiority of Ambulatory Management of Obstructive Sleep Apnea (Kuna ST et al, AJRCCM 183:1238, 2011) CPAP Adherence Data Lab Home Mean CPAP use was higher in home group (p=0.08); CPAP pressure was higher in home group (p<0.001) (11.1±3.2 cm H 2 O compared to 9.4 ±2.9 cm H2O) QUESTION: IS CPAP TITRATION IN HOME STUDIES SUPERIOR?

9 Assessing Concordance of Decision- Making to Use CPAP or Not Based on Home Studies or In-Lab Studies (Masa J et al, AJRCCM 184:964, 2011) Large multi-center study in Spain (8 centers) Patients intermediate or high suspicion of sleep apnea-hypopnea syndrome (n=348) All patients had both home studies and lab studies (random order) at initial assessment and one month later Assessing Concordance of Decision- Making to Use CPAP or Not Based on Home Studies or In-Lab Studies (Masa J et al, AJRCCM 184:964, 2011) Decision-making agreement is decreased at AHI<25 events/hour

10 Health-Economic Analysis of Diagnostic and Therapeutic Strategies in Treatment of Moderate-to-Severe OSA (Pietzsch JB et al, Sleep 34:695, 2011) Modeled cost of different diagnostic strategies for OSA over 10 years In-lab PSG + CPAP most cost-effective! Seems counter-intuitive why? Health-Economic Analysis of Diagnostic and Therapeutic Strategies in Treatment of Moderate-to-Severe OSA (Pietzsch JB et al, Sleep 34:695, 2011) Reasons in-lab sleep study had lowest cost Patient missed would incur health care costs (CV disease, etc.) False positives by HST CPAP costs (unnecessary) Technical failures on HST all assumed lost DOUBTFUL ASSUMPTIONS (Ayas NT et al, Sleep 34:691, 2011)

11 Home Approach vs. In-lab Approach Clearly home-based approach can work Concern about home approach is more in mild-to-moderate OSA Perhaps question is not optimal both can be used where appropriate Need to develop and test a comprehensive algorithm QUESTION IS SOMEWHAT MUTE HORSE IS OUT OF THE BARN Sleep Management Solutions (SMS) - Working for Payers SMS has developed a robust solution for payers to better manage the escalating costs associated with sleep-disordered breathing via our Utilization Management (UM) services and new clinical management model. The executive team at SMS has developed multiple options for payers to choose from. Regardless of which model is chosen, each payer will realize a decrease in their annual sleep spend and an increase in the oversight of the clinical services being administered to their membership.

12 Events in Massachusetts Sleep Management Solutions got contract for exclusive management of sleep studies with small insurance plan Fallon Spread to Tufts Health Plan and Harvard Pilgrim Blue Cross in Massachusetts will adopt in next few months SMS mandates home studies For some plans they are exclusive Provider of HST and CPAP (DME) Sleep centers are now challenged financially. Many patients do not get studied. SMS goal is to cost of diagnosis. Responses American Academy of Sleep Medicine Have proposed integrated sleep center model to Medicare (CMS) Propose center provides sleep studies, including home studies and CPAP delivery Submitted grant as part of CMS Innovation Our strategy (Pack AI, J Clin Sleep Med 7:577, 2011) Focus on outcomes Seek new model of reimbursement care, bundled payment model Advocate to change accreditation make it OUTCOMES-BASED

13 Two Relatively New Therapies Hypoglossal nerve stimulation Expiratory positive airway pressure (EPAP) Hypoglossal Nerve Stimulation Acute Studies (Schwartz AR, et al, AJRCCM Dec 1, 2011, epub ahead of print) (n=30) Progressive increases in stimulation progressive increases in flow Inspiratory flow limitation abolished in 57% of patients Produced increases in flow without arousals

14 Hypoglossal Nerve Stimulation Chronic Studies (Eastwood PR et al, Sleep 34:1479, 2011); n=21 (CPAP failures) Used 89%±15% of nights Improvements from baseline to 6 months AHI: 43.1± ±16.7* Epworth score: 12.1± ±4.4* FOSQ: 14.4± ±2.2* *p< serious AEs: infection (device removed); lead dislodgement (needed replacement) Expiratory Positive Airway Pressure (EPAP) Device (Berry RB et al, Sleep 34:479, 2011) Nasal EPAP device. Single use valves are inserted into each nostril and sealed with adhesive.

15 Expiratory Positive Airway Pressure (EPAP) Device (Berry RB et al, Sleep 34:479, 2011) AHI Device (n=92) Sham (n=81) Baseline 16.7 (9.5, 26.3) 15.1 (10.3, 24.1) 1 week 7.1 (2.2, 17.1)* 13.6 (8.6, 25.8) 3 months 8.1 (3.8, 17.6)* 13.3 (5.9, 25.0) *p<0.001 Expiratory Positive Airway Pressure (EPAP) Device (Berry RB et al, Sleep 34:479, 2011) Changes in Epworth Sleepiness Score

16 Conclusions Does sleep-disordered breathing affect progression of Alzheimer s disease in preclinical stage a MAJOR QUESTION Pediatric field is taking the lead in multicenter randomized trials for surgical intervention and consideration of epigenetic changes Home diagnostic studies with auto-cpap titration at home is a viable strategy Conclusions Current sleep medicine model is challenged NEED TO CHANGE ASAP FOCUS ON OUTCOMES New therapies are emerging for OSA Hypoglossal nerve stimulation EPAP

17 YEAR IN REVIEW Allan I. Pack, M.B.Ch.B., Ph.D. Center for Sleep and Respiratory Neurobiology University of Pennsylvania Philadelphia, Pennsylvania Ayas NT, Pack A, Marra C. The demise of portable monitoring to diagnose OSA? Not so fast! Sleep 34: , An editorial on the study of Pietzch JD et al on health care economic analysis of diagnostic and therapeutic strategies for the treatment of moderate to severe OSA (Sleep 34:695, 2011). Editorial makes the point that the conclusion that in-laboratory studies are the most cost-effective strategy is based on some dubious assumptions. Berry RB, Kryger MH, Massie CA. A novel nasal expiratory positive airway pressure (EPAP) device for the treatment of obstructive sleep apnea: a randomized controlled trial. Sleep 34: , Multi-center study (19 sites) that evaluated efficacy of a novel nasal expiratory positive airway pressure device (EPAP) for treatment of OSA. Patients studied had relatively mild disease with average AHI events/hour. Compared to sham treatment over 3 months, the device improved AHI, ODI and Epworth Sleepiness Score significantly. There was high self-reported adherence. Could be option for patients with mild-tomoderate OSA who cannot tolerate CPAP. Canessa N, Castronovo V, Cappa SF, Aloia MS, Marelli S, Falini A, Alemanno F, Ferini- Strambi L. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med 183: , Investigation of 17 sleep apnea patients and 15 controls. Patients with OSA had impairments in most cognitive functions. Impairments were associated with focal reductions in grey matter volume, e.g., in the left hippocampus. With treatment, behavioral impairment improved. This improvement paralleled increases in grey matter volume in structures such as the hippocampus. Collop N, Fleishman SA. The future of sleep medicine: will you be a part of it? J Clin Sleep Med 7: , Response of the current leadership of the American Academy of Sleep Medicine to the commentary by Pack AI (J Clin Sleep Med 7: , 2011). Academy leadership argue that Pack articulated the wrong question and that for accreditation one size does not fit all. Do agree that we need to move to a field focused on outcomes of care.

18 Eastwood PR, Barnes M, Walsh JH, Maddison KJ, Hee G, Schwartz AR, Smith PL, Malhotra A, McEvoy RD, Wheatley JR, O Donoghue FJ, Rochford PD, Churchward T, Campbell MC, Palme CE, Robinson S, Goding GS, Eckert DJ, Jordan AS, Catcheside PG, Tyler L, Antic NA, Worsnop CJ, Kezirian EJ, Hillman DR. Treating obstructive sleep apnea with hypoglossal nerve stimulation. Sleep 34: , Study that assessed value of chronic use of hypoglossal nerve stimulation during sleep in 21 patients with OSA who had failed CPAP. Showed that device was used in 89% of nights. Over 6 months, there was significant improvement from baseline in AHI, Epworth Sleepiness Score and FOSQ. The mean Epworth score normalized. AHI was reduced from 43.1±17.5 to 19.5±16.7 events/hour. There were, however, two serious adverse events. There was an infection of one device that required removal. There was another patient where the lead cuff from the device became dislodged requiring replacement. Seems that this approach will need more work but could be an option for patients failing CPAP. Kim J, Bhattacharjee R, Khalyfa A, Hkeirandish-Gozal L, Capdevila OS, Wang Y, Gozal D. DNA methylation in inflammatory genes among children with obstructive sleep apnea. Am J Respir Crit Care Med 185: , First study to examine whether DNA methylation occurs in obstructive sleep apnea. Study was done in children with OSA. In children with OSA and high CRP levels there is evidence of hypermethylation of the Forkhead box P3 (FOXP3) gene. This gene regulates expression of T regulatory lymphocytes. This raises interesting concept that OSA might lead to more permanent modifications of DNA. Kimoff RJ. To treat or not to treat: can a portable monitor reliably guide decision-making in sleep apnea? Am J Respir Crit Care Med 184: , Brief editorial by John Kimoff about the important studies of JF Masa et al (AJRCCM 184:964, 2011). Points out the complexities of the study design and argues that further work is needed on use of home studies in individuals with an AHI in range of 5-30 events/hour. Kuna ST, Gurubhagavatula I, Maislin G, Hin S, Hartwig KC, McCloskey S, Hachadoorian R, Hurley S, Gupta R, Staley B, Atwood CW. Noninferiority of functional outcome in ambulatory management of obstructive sleep apnea. Am J Respir Crit Care Med 183: , Important study that shows that in patients suspected of having OSA you can obtain results that are not inferior from using an entirely home pathway for diagnosis and treatment compared to a traditional in-lab pathway. The main outcome assessed was self-report functional outcomes. The CPAP pressure found in the home group was about 2.0 cm H 2 O higher than that from lab-based titration. CPAP adherence was higher in the home group, but not significantly so. Page 2

19 Macey PM. Is brain injury in obstructive sleep apnea reversible? Sleep 35:9-10, A very helpful commentary on the study by O Donoghue FJ et al (Sleep 35:41-48, 2012). Argues that this study provides further evidence that OSA leads to injury to white matter, activation of glia and inflammatory change in hippocampus. Inflammatory changes resolve with CPAP therapy but white matter injury persists. Masa JF, Corral J, Pereira R, Duran-Cantolla J, Cabello M, Hernandez-Blasco L, Monasterio C, Alonso A, Chiner E, Zamorano J, Aizpuru F, Montserrat JM, Spanish Sleep Network. Therapeutic decision-making for sleep apnea and hypopnea syndrome using home respiratory polysomnography. A large multicentric study. Am J Respir Crit Care Med 184: , Complex multi-center study that assessed the agreement between decisions to use CPAP or not in the same patient based on data obtained from home studies or in-laboratory studies. All patients who had intermediate to high clinical suspicion of OSA had both types of studies. At AHI<25 events/hour the agreement whether to use CPAP or not was not great but was good in patients with severe disease. Thus, there needs to be some level of concern about the use of only home studies for patients with mild-to-moderate disease. Morrell MJ, Glasser M. The brain in sleep-disordered breathing. A vote for the chicken? Am J Respir Crit Care Med 183: , Helpful commentary on studies that have examined changes in brain morphology in patients with obstructive sleep apnea. Morrell MJ, Jackson ML, Twigg GL, Ghiassi R, Mcrobbie DW, Quest RA, Pardoe H, Pell GS, Abbott DF, Rochford PD, Jackson GD, Pierce RJ, O Donoghue FJ, Corfield DR. Thorax 65: , Case-control study of changes in brain morphology in patients with OSA. In OSA there was evidence of focal loss of grey matter. Pack AI. Sleep medicine: strategies for change. J Clin Sleep Med 7: , Article the lays out the immediate threats to our field. Also suggests the opportunities. Develops the argument that the time to change is now and proposes strategies for change. The vision for sleep medicine should be a field based on obtaining quality outcomes of chronic management of chronic disorders. Argues that the accreditation process for sleep centers needs to change to be one focused on outcomes of care. Page 3

20 Pietzsch JB, Garner A, Gipriano LE, Linehan JH. An integrated health-economic analysis of diagnostic and therapeutic strategies in the treatment of moderate-to-severe obstructive sleep apnea. Sleep 34: , A very detailed economic analysis of the benefits gained and costs of different methods to diagnose and treat obstructive sleep apnea. Comes to the somewhat surprising result that the most cost-effective strategy is in-laboratory sleep studies. Rajaratnam SMW, Barger LK, Lockley SW, Shea SA, Wang W, Landrigan CP, O Brien CS, Qadri S, Sullivan JP, Cade BE, Epstein LJ, White DP, Czeisler CA, Harvard Work Hours, Health and Safety Group. JAMA 306: , Study in large sample of police in different regions. Mostly based on questionnaires. Showed a high prevalence of excessive sleepiness. Also showed that those who screened positive for sleep disorders, albeit by questionnaires, had an increased risk of medical issues and of problems at work. Redline S, Amin R, Beebe D, Chervin RD, Garetz SL, Giordani B, Marcus CL, Moore RH, Rosen CL, Arens R, Gozal D, Katz ES, Mitchell RB, Muzumdar H, Taylor HG, Thomas N, Ellenberg S. The childhood adenotonsillectomy trial (CHAT): rationale, design, and challenges of a randomized controlled trial evaluating a standard surgical procedure in a pediatric population. Sleep 34: , Very detailed description of an ongoing randomized trial of adenotonsillectomy for pediatric sleep apnea (CHAT study). Study will involve 6 sites. Indicates that this study design will provide framework for other studies that might evaluate other surgical interventions for OSA. Schwartz AR, Barnes M, Hillman D, Malhotra A, Kezirian E, Smith PL, Hoegh T, Parrish D, Eastwood PR. Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea. Am J Respir Crit Care Med 2011 Dec 1 (Epub ahead of print). Study that examined the effect of hypoglossal nerve stimulating during one night of sleep in 30 patients with OSA. Increasing stimulation led to increasing peak inspiratory flow. Inspiratory flow limitation was abolished by nerve stimulation in 57% of patients studied. Flow increased in the absence of an arousal. Page 4