2. Welcome local and national attendees to the first ACRA WEBINAR Sleep Disordered Breathing: A Cardiology Condition – A Sleeping Killer Dr Philip Currie MBBS, FRACP, MBA - Cardiologist and Echocardiographer

3. Local attendees - Emergency exits - Toilet location - Mobile phones (please switch off or turn to silent) - Evaluation forms National attendees -Questions can be typed in left hand side text box -These will be addressed during the presentation -Evaluation to be completed on your screen on completion of event. Next ACRA Webinar THURSDAY 25TH JUNE 2015 - Omega 3 in Cardiovascular Disease Prevention: New Evidence on an old intervention

4. Welcome to country I would like to pay my respects to the Traditional Owners of the land on which we are meeting today. I would also like to pay my respects to elders both past and present.

5. Sleep Important In Wellness and In Disease Sleep Disordered Breathing (SDB) Not Just a Sleep Disorder Heart Condition & Sleeping Killer

6. Maslow’s Hierarchy of Needs Sleep Is Important

7. . Sleep Is Part of Wellness Important to Quality of Life Physiological Effects of Sleep Active physiological state - body repair & variety of important functions: Learning and Memory Important for consolidation of new information & memory formation Growth and Development Secretion of growth hormone & prolactin increased during sleep Blood Pressure Chronic short sleep duration increases the risk of hypertension in adults Stress and Metabolism Cortisol & thyrotropin (thyroid stimulating protein) decrease during sleep Appetite Management Ghrelin & leptin hormone levels influence hunger & satiety

8. Obstructive Sleep Apnea

9. Sleep Disordered Breathing (SDB) More Than OSA - A Social Condition Social Condition Snoring Daytime Sleepiness CV Morbidity & Mortality AF HT CAD CHF Stroke CSA Disease Severity & Lack of Recognition ASV OSA CPAP Mixed Retail CPAP Sleep Dr Cardiology

10. OSA CSA 60 sec 100 % 70 100 % 70 Flow Thorax Abdomen SaO 2 Flow Thorax Abdomen SaO 2 What is Sleep-Disordered Breathing? OSA, CSA, and Mixed Sleep Apnea Effort No Effort

11. Plunging blood oxygen saturation Physiological Consequences of Sleep Apnea Morgan et al., 1996 Sleep Negative swings in intra-thoracic pressure Increase in blood pressure Surge sympathetic nerve activity

12. How Do We Measure SDB? Apnea-Hypopnea Index Based on the total number of complete cessations (apnea) and partial obstructions (hypopnea) of breathing occurring per hour of sleep These pauses in breathing must last for 10 seconds and are associated with a decrease in oxygenation of the blood >3% AHI can be used to classify the severity of disease Mild 5-15 Moderate 15-30 Severe >30

13. Question Why is Sleep Disordered Breathing important in Cardiovascular and Metabolic Diseases?

14. Obesity: A Global Epidemic The Big Elephant (Sumo) in the Room Obesity is Now Socially Accepted

15. Risk Factors for Co-Morbidities OSA Cardiovascular Disease Hyperlipidemia Hypertension Diabetes Obesity

16. Logan et al. J. Hypertension 2001 Javaheri et al. Circulation 1999 Sjostrom et al. Thorax 2002 Schafer et al. Cardiology 1999 Sanner et al. Clin Cardiology 2001 Somers et al. Circulation 2004 80% 70% 50% 35% 30% Einhorn et al. Endocrine Prac 2007 50% Sleep Apnea Prevalence in CV Disease Ubiquitous

17. Cardiovascular Disease Continuum Adapted from Dzau et al, 2006 Circulation

18. Sleep Apnea – A Cardiovascular Disease Jean-Louis et al., 2010 Expert Rev. Cardiovasc. Ther.

19. SDB and Mortality 6,294 participants Average follow up period = 8.2 years 1.46 X more likely TO DIE with severe SDB Predictor of mortality – nocturnal hypoxaemia Punjabi et al., 2009 PLoS Medicine

20. Young et al., 2008 SLEEP Wisconsin Sleep Cohort – 18 year Follow up n = 1396

21. Long Term Fatal and Non-fatal CV Events Worse with More OSA & Better with CPAP Marin et al., 2005 Lancet 200-400 subjects per group Followed for a mean of 10.1 years

22. Cumulative Incidence of Hypertension Worse With More Severe OSA Marin et al., 2012 JAMA n = 1889

23. Atrial Fibrillation and SDB Multiple mechanistic factors contribute to SDB suggesting SDB induces AF High incidence of OSA in patients with AF High incidence of recurrence of AP in first year post DC cardioversion in pts not Rx with CPAP Risk factor modification reduces recurrent AF post AF ablation (symptoms, AF burden, recurrent ablation)

24. The ARREST-AF Cohort Study Aggressive Risk Factor Reduction Post AF Ablation Pathak et al J Am Coll Cardiol 2014;64:2222

26. Single-procedure, drug-free, AF-free & Total AF-free Survival

27. Obstructive Sleep Apnea and the Risk of Sudden Cardiac Death (SCD) 10,701 consecutive adults first PSG 1987-2003 15 yr follow up SCD - average follow-up of 5.3 yrs, 142 pts had resuscitated or fatal SCD (annual rate 0.27%) Independent risk factors for SCD - age, hypertension, CAD, cardiomyopathy, heart failure, ventricular ectopy or nonsustained VT, & lowest nocturnal O 2 sat SCD was best predicted by age >60 years (HR: 5.53), AHI >20 (HR: 1.60), mean nocturnal O 2 sat <93% (HR: 2.93), & lowest nocturnal O 2 sat <78% (HR: 2.60; all p < 0.0001) J Am Coll Cardiol 2013;62:610–6)

28. Obstructive Sleep Apnea and the Risk of Sudden Cardiac Death J Am Coll Cardiol 2013;62:610–6)

29. Obstructive Sleep Apnea and the Risk of Sudden Cardiac Death J Am Coll Cardiol 2013;62:610–6)

30. Effect of OSA in Metabolic Syndrome Bonsignore MR et al ERJ 2012

31. 31 © ResMed 2012 07 Sleep Disordered Breathing Increases Mortality CARDIOVASCULAR –SDB is very common and affects prognosis –Cardiovascular diseases are probably the most important consequence of OSA –Assessment of SDB is rapidly becoming a routine part of the management of cardiology patients DIABETES –OSA and type 2 diabetes frequently coexist –Accumulating evidence that OSA impairs glucose metabolism –Rapidly increasing awareness of OSA in the diabetes community and assessment/management should INCREASE Summary

32. 32 © ResMed 2012 07 Where Else to Go In Heart Failure? Lets Invite A Colleague and Sleep On It Well, this is just going from bad to worse!

33. Outline Heart failure – big problem, need more Rx Traditional Epiphenomena - LBBB, AF Sleep Disordered Breathing – more than OSA ? another epiphenomenon ASV – Adaptive Servo Controlled Ventilation Schal-HF Registry SERVE-HF Trial

34. Heart Failure 300,000 patients in Australia have CHF Despite recent advances in treatment CHF continues to cause debilitating symptoms Congestive heart failure leading cause of hospitalisation in >65 years CHF costly with frequent hospital admissions and deadly. 5 year mortality remains high at 50%

35. Heart Failure – We Need More ! New interventions that reduce symptoms, increase quality of life, reduce hospital admissions and mortality are needed It is likely that new interventions will be targeted at specific subgroups of chronic HF patients rather than all CHF pts

36. Heart Failure Management Primary Cardiac Problem Blocking RAS (ACE, ARB, Spironolactone) Blocking SNS (Beta Blocker) LBBB Atrial fibrillation (PVI) SDB (ASV)

37. Add-on Therapy in Heart Failure Each Added Therapy Incrementally Decreases Mortality ?? LVAD Destination Therapy CHARM AR2B ?? ASV Therapy for SDB There remains a 50% 5 year mortality

38. Biventricular Pacing Resynchronising Therapy

39. Current Clinical Trajectory of Patients with HF time NYHA Class I II III IV Death Optimal Medical Management Acute events Death Major costs are incurred for each acute cardiac decompensation inpatient hospital admission Major costs are incurred for each acute cardiac decompensation inpatient hospital admission

40. LVAD – Left Ventricular Assist Device Bridge to TransplantBridge to Transplant Destination TherapyDestination Therapy Bridge to RecoveryBridge to Recovery LVAD starting to approach transplant survival in pts not previously transplant candidatesLVAD starting to approach transplant survival in pts not previously transplant candidates

41. International Cardiology Guidelines Committee Sleep Disordered Breathing in Cardiology & CHF “We Await the Evidence of CV Mortality RCT” SBD

42. Why is The Disconnect? The Elephant in The Room Often OSA overlooked as a reversible CV risk factor No large-scale, multicentre, randomised control trials of PAP therapy (cholesterol – pre statin) Ethical challenges (long term no active treatment for symptomatic OSA at risk for car accidents) Reduced adherence in nonsleepy pts CSA is indeed Silent But Deadly as the clinical markers of OSA (snoring, witnessed apnoea, daytime sleepiness) are not common No positive mortality RCT

43. Principal Mechanisms Contributing to SDB in CHF - Important Differences Central Sleep Apnea Pulmonary vagal afferent receptor stimulation Increased central chemo-responsiveness Abnormal cerebrovascular reactivity to pCO 2 Obstructive Sleep Apnea Obesity Reduced neural output to upper airway muscles Pharyngeal oedema Upper airway anatomical abnormalities

44. Kasai, T. et al. J Am Coll Cardiol 2011;57:119-127 Bad Cardiovascular Autonomic Effects of OSA

45. OSA - All Roads Lead to HF Brisco et al., Curr Heart Fail Rep 2010

46. Pathophysiologic Consequences of CSA in Heart Failure J Am Coll Cardiol. 2015;65(1):72-84

47. SchlaHF Registry of the SERVE-HF Trial High Prevalence of SDB in CHF High prevalence of SDB (46%) in stable chronic HF patients Male gender, age, BMI, severity of both symptoms and LV dysfunction clinical predictors for SDB Chronic HF patients with SDB often do not show characteristic SDB symptoms Presence of one or more predictors of SDB (e.g. male, older, obesity, LVEF <25%, NYHA class III/IV or AF) should prompt clinicians to perform device-based screening for SDB

48. Risk factors for SDB in Chronic HF Gender, Age, AF, High BMI Low LVEF -

49. Prevalence of SDB in Stable CHF Populations

50. SchlaHF Registry: PSG data CSA prevalence increases with worsening LV systolic function and increasing NYHA

51. ASV Keywords Adaptive Servo-Ventilation Adaptive: the (pressure) target is adjusted according to the input from the patient, i.e. the target is not a fixed value but instead adapts to patient’s demand Servo-ventilation: closed feedback loop where therapy is designed to achieve a target ventilation (PPM analogy: CPAP =PPM, ASV=PPM, ICD)

52. ASV Flow HYPOPNEAAPNEA Adaptive Servoventilation ASV Auto

53. Key Principals of Adaptive Servo-Ventilation ASV Used to regulate or maintain normal ventilation by correcting the ventilatory pattern of a patient with central sleep apnea (CSA and/or Cheyne-Stokes) Specifically by: Stabilizing the upper airway when required, by offering a base level of pressure (EPAP) Deliver pressure support to stabilise ventilation Provide patient-machine synchrony

54. On a breath by breath basis minute ventilation is calculated Minute ventilation is monitored using a weighted average mean (3 min window) weighted average mean (3 min) How the ASV Determines a Target

55. On a breath by breath basis minute ventilation is calculated Minute ventilation is monitored using a weighted average mean (3 min window) – continually adjusting across the night Calculates 90% of minute ventilation – target ventilation If instantaneous minute ventilation < target ventilation (  PS) If instantaneous minute ventilation > target ventilation (  PS) weighted average mean (3 min) How the ASV Determines a Target

56. After ~10-30 mins… …and SpO2 stable Breathing normalised …

57. PAP Therapy in CSA ASV Abolishes CSA Teschler H et. al; AJRCCM 2001

58. HF – ASV and AHI Meta-Analysis Reduction in AHI Sharma et al., 2012 CHEST

59. HF – ASV and LVEF Improvement in LVEF Sharma et al., 2012 CHEST

60. Pts With Severe Advanced Heart Failure – ASV Decreases CHF Events: A Pooled Meta Analysis Of 629 Pts With CSA J Am Coll Cardiol. 2015;65(10_S)

61. Current Clinical Trajectory of Patients with HF time NYHA Class I II III IV Death Optimal Medical Management Acute events Death Major costs are incurred for each acute cardiac decompensation inpatient hospital admission Major costs are incurred for each acute cardiac decompensation inpatient hospital admission

62. Current Clinical Trajectory of Patients with HF time Optimal Medical Management Patient with Cheyne Stokes Respiration Prognosis poor Acute events Death Trajectory without Cheyne Stokes NYHA Class I II III IV Death

63. Possible Trajectory of HF Patients using ASV Potential for Dramatic Improvement in Economics of Management of Cardiac Failure Routine Clinical Management Patient with Central Sleep Apnea Acute events Trajectory without Central Sleep Apnea *ASV? NYHA Class I II III IV Death time *Await final results of SERVE-HF trial & the ADVENT-HF trial late 2016

64. Treatment Of SDB In Pts Admitted For Decompensated HF Reduces 6 Mth Hospital Visits 64 patients admitted with CHF underwent PSG within 4 weeks discharge 60yrs old, BMI 38, 48% male, mean AHI 33 29/59 pts (49%) compliant PAP therapy mean change in hospital visits decreased to - 0.7 ± 1.8 visits compliant group vs mean increase of 0.2 ± 1.8 visits for the non- compliant group (paired Wilcoxon test, p=0.03) J Am Coll Cardiol. 2015;65(10_S)

65. SERVE-HF Study Treatment of sleep-disordered breathing with predominant central sleep apnea by adaptive servo ventilation in pts with heart failure

66. SERVE-HF Design Randomised, multi-centre, outcome study Parallel group design, comparing control (optimal medical management) with active treatment (optimal medical treatment plus adaptive servoventilation). Sample size: approx. 1260 patients 80 active centres Estimated 20% drop out rate Estimated minimum follow up of 24 months.

67.  Chronic heart failure  LVEF <45%  NYHA class III or IV  Optimised medical treatment  SDB (AHI ≥ 15/h) with > 50% central events and a central AHI ≥ 10/h SERVE-HF-Study Inclusion Criteria

68. SERVE-HF-Study Preliminary Results 1325 pts Primary end point – All cause mortality or hospitalisation NS difference Preliminary analysis – significant 2.5% absolute increase in CV mortality in ASV Rx group (10% ASV vs 7.5% per year in control group) Current ResMed response - avoid ASV in patients who fulfill entry criteria of SERVE-HF trial Awaiting detailed analysis

69. SDB is very common and increases mortality CV diseases the most important consequence of OSA Recognition and management of SDB must become routine in the management of cardiology pts SDB diagnostics in CV patients (PSG, home based PSG and type 3 screeners) CSA needs to be recognised due to its prevalence, cheap effective treatment (by cardiology standards) Greater understanding of ASV – will have greater use Await cardiology trials (large randomised trials with hard end points (mortality and hospitalisation) Sleep and SDB major consideration in the holistic management of pts Summary Sleep is Important in Wellness and In Disease

70. Final Message - Connect the Dots Specifically SDB is a CV Problem Which Kills It must be considered, diagnosed & aggressively managed