1. The Sleep Apnea cardioVascular Endpoints study (SAVE) R. Doug McEvoy Professor of Medicine, Adelaide Institute for Sleep Health Flinders University, AUSTRALIA doug.mcevoy@flinders.edu.au For the SAVE Investigators and Coordinators, on behalf of the SAVE Executive, Operations, and Advisory Committees

2. Disclosures Personal disclosure: Research funding - Philips Respironics, AirLiquide, ResMed and National Health and Medical Research Council (NHMRC) of Australia Main funding for SAVE - Philips Respironics and NHMRC Additional support - ResMed, Fisher&Paykel, Australasian Sleep Trials Network, Spanish Respiratory Society, and Fondo de Investigaciones Sanitarias

3. Rationale – obstructive sleep apnea (OSA) OSA causes repetitive night-time hypoxic episodes, sympathetic activation, BP surges, and cardiac stress OSA associated with elevated BP, insulin resistance and endothelial dysfunction - improved by continuous positive airway pressure (CPAP) OSA associated with an increased CV risk (stroke, coronary artery disease, heart failure) and sudden death (most at night) – reduced in observational studies with CPAP treatment OSA affects 40-60% of CV patients RCT clinical endpoint data lacking

4. Objective To determine if CPAP treatment of moderate to severe OSA in patients with CV disease would reduce the incidence of CV events

5. Design International, multicentre, prospective, open-label with blinded adjudication of endpoints, randomised controlled trial – CPAP + usual care – Usual care alone

6. Patients Inclusion criteria Age 45-75 years Coronary or cerebrovascular disease Moderate-severe OSA – ApneaLink™, ResMed; 4% oxygen desaturation index, ODI, ≥ 12 events/hr 1 Able to use CPAP mask – Av. >3hrs/night during 1-week sham-CPAP run-in Able and willing to give informed consent 1. Ganter D et al. Respirology 2010;15:952-60 Exclusion criteria Severe sleepiness or risk of fall-asleep accident – Epworth sleepiness score >15; fall-asleep or near miss accident last 12 months; or commercial driver Severe oxygen desaturation – >10% recording time with SaO 2 <80% Heart Failure NYHA Class III-IV Cheyne Stokes respiration Prior CPAP use Other condition which in opinion of investigator made patient unsuitable

7. Outcomes Primary outcome - composite of MI, stroke, hospitalisation for unstable angina, TIA or heart failure, and CV death Secondary CV outcomes – Other composites: ischaemic CV events; major CV events; cardiac events; cerebral events – Individual components of primary outcome – New-onset atrial fibrillation, diabetes – All cause mortality

8. Other outcomes OSA symptoms - snoring, sleepiness (ESS), mood (HADS) Health related quality of life (SF36) Days off work due to sickness Safety outcomes – Serious adverse events – Accidents causing personal injury, fall-asleep accidents or near miss accidents, traffic accidents

9. Statistics Sample size - revised from 5,000 to 2,500 in 2012 – Challenges with recruitment - meta-regression showed strong relationship of AHI and CV events; blinded data of high event rates; good CPAP adherence – Power - 25% RR reduction for primary endpoint (α 0.05, 1-β 0.90) for av. 4.5 years FU; 6.86% annual event rate with usual care, av. CPAP 3 hr/night - for total of 533 events Statistics – ITT, P<0.047 for primary outcome (1 formal interim analysis) – Unadjusted survival analysis for time to first (adjudicated) event in Cox model – Sensitivity analyses - Covariate adjustments - stratification factors, region, severity of OSA; multiple events; events as clinician-reported – CPAP complier (>4 hrs/night) PP-matched

10. Dec 2008 - Dec 2015  2717 patients from 89 centres in 7 countries  International Coordinating Centre  Core sleep laboratory Recruitment and Management

11. Patient Flow 2717 Randomised 1359 CPAP + Usual Care 1358 Usual Care 15,325 Screened 5844 ApneaLink sleep study 9481 Ineligible or declined 2598 Excluded 17 Withdrew consent or were excluded 13 Withdrew consent or were excluded 1346 included in ITT 1341 included in ITT 3246 Sham CPAP run-in 529 Excluded

12. Baseline Characteristics CPAP + usual care N=1346 Usual care N=1341 Age, mean, years61 Male %81 Ethnicity -Asian %6463 BMI, kg/m 2 29 Snoring almost every day %8481 ODI 4% SaO 2 dips/hr282828 AHI events/hr2930 Epworth sleepiness Score mean (0-24)7.37.5

13. Baseline characteristics CPAP + Usual Care N=1346 Usual Care N=1341 Coronary artery disease, %51 TIA/Stroke, %49 Systolic/ diastolic BP, mmHg132/ 80131/ 79 Medical history, % Past or Current Smoking57 55 Hypertension7978 Diabetes mellitus3029 Medications, % BP lowering drugs,78 Lipid lowering drugs60 Antiplatelet/antithrombotic75 Oral anti-diabetic22 Insulin66

14. CPAP adherence and OSA control

15. Primary endpoint – neutral Hazard ratio (95% CI) 1.10 (0.91 - 1.32)

16. Sensitivity and secondary CV analyses No significant differences in primary outcome sensitivity analyses No significant differences in analyses of: – Individual components of primary endpoint Except rate of TIA hospital admissions higher in CPAP group, P=0.04 – Other CV composites – New-onset diabetes or newly diagnosed AF – All cause mortality

17. Primary endpoint - subgroups

18. Sleepiness, mood, QoL, work and safety CPAP+Usual Care versus Usual Care Improved – Epworth sleepiness score (p<0.001) – HADS anxiety (p=0.002) and depression (p<0.001) scores – SF36 physical (p=0.002 ) and mental (p<0.001) component scores – Work days lost because of ill-health (p<0.001) No significant difference – Serious adverse events – Accidents

19. Per protocol analysis Hazard Ratio (95% CI) P Composite primary outcome, no. (%)0.80 (0.60 to 1.07)0.13 Components of primary endpoint CV Death0.90 (0.41 to 2.01)0.81 Myocardial infarction1.19 (0.59 to 2.39)0.63 Stroke0.56 (0.32 to 1.00)0.05 Hospitalisation for heart failure0.82 (0.34 to 2.03)0.67 Hospitalisation for unstable angina0.99 (0.64 to 1.51)0.95 Hospitalisation for TIA0.22 (0.03 to 2.01)0.18 Other vascular endpoints Composite of ischaemic CV events0.81 (0.59 to 1.10)0.17 Composite of major CV events0.69 (0.46 to 1.04)0.08 Composite for cerebral events0.52 (0.30 to 0.90)0.02 Composite for cardiac events1.01 (0.74 to 1.39)0.93 CPAP good compliers (i.e. >4 hrs/night; n=561) matched 1:1 with usual care patients by propensity scores

20. Conclusions Addition of CPAP to usual care did not reduce CV events in patients with OSA and coronary or cerebrovascular disease – Risk of stroke may be reduced in patients with high levels of CPAP adherence CPAP significantly improved daytime alertness, mood, quality of life, and reduced work-days lost because of ill-health

21. McEvoy RD et al. NEJM 2016, 28 August [Epub ahead of print].