Treatment of sleep apnea in heart failure patients after SERVE-HF results

Treatment of sleep apnea in heart failure patients after SERVE-HF results Martin R Cowie Professor of Cardiology National Heart & Lung Institute Imperial College London (Royal Brompton Hospital Campus) m.cowie@imperial.ac.uk @ProfMartinCowie

Declaration of interests Research grants from ResMed, Boston Scientific, St Jude Medical, Bayer Consultancy advice and speaker s fees from Medtronic, ResMed, Boston Scientific, St Jude Medical, Respicardia, Sorin, Servier, Pfizer, Novartis, Daiichi-Sankyo Co-Principal Investigator of SERVE-HF Study (NCT00733343)

Airflow Impedance It is easy to screen for SDB

SDB prevalence and type varies by HF symptom severity Oldenburg et al. Eur J Heart Fail 2007;9:251-7

Does treatment of sleep apnea really make a difference in heart failure?

Building the evidence 2005 CANPAP trial: CPAP treatment of CSA/CSR in HF patients (n=258) 1 Improvements in LVEF, plasma BNP levels, and functional outcomes No beneficial effect on hospitalization, quality of life, or survival 1. Bradley et al. NEJM 2005;353:2025-33.

Building the evidence 2007 CANPAP post-hoc analysis suggested that CPAP might improve mortality when CSA is controlled (AHI <15/h) in HF patients with CSA and ejection fraction <40% 1 * Unadjusted p=0.043 1. Arzt et al. Circulation 2007;115:3173-809.

Using more modern technologies? ASV is more effective than CPAP for treating CSA/CSR 1,2 HF patients comply better with ASV vs CPAP therapy 2,3 Patients prefer ASV over both CPAP and bilevel PAP 1 1. Teschler et al. AJRCCM 2001;164:614-9; 2. Philippe et al. Heart 2006;92:337; 3. Kasai et al. Circ Heart Fail 2010;3:140-8.

SERVE HF: Objective To investigate the effects of adding ASV to guideline-based medical management on survival and cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF) and predominant CSA 1,2 1. Cowie et al. Eur J Heart Fail 2013;15:937-43; 2. Cowie et al. NEJM 2015; 373: 1095-105

SERVE-HF: Design 91 centres (Germany, France, Sweden, UK, Australia, Denmark, Norway, Czech Republic, Finland, Switzerland, Netherlands) Randomized, parallel, event-driven design Guideline-based medical management: Alone (control group) Plus ASV (Auto Set CS, ResMed) ASV titration in hospital (PG or PSG) Starting at default settings Expiratory positive airway pressure manually increased to control OSA and maximum pressure support increased to control CSA Cowie et al. Eur J Heart Fail 2013;15:937-43; Cowie et al. NEJM 2015; 373: 1095-105

SERVE-HF: Patients Inclusion Criteria Age 22 years Chronic stable HF (ESC guidelines, no hospitalization within 4 weeks) LV dysfunction LVEF 45% NYHA class III or IV Or NYHA class II with 1 hospitalization for HF in previous 24 months Predominant CSA (AHI >15/h with 50% central events and central AHI 10/h Exclusion Criteria Significant COPD Oxygen saturation <90% at rest during the day Current use of positive airway pressure therapy Cardiac surgery or resynchronization therapy within the previous 6 months TIA or stroke in previous 3 months Significant valvular heart disease Contraindications to ASV 1325 patients enrolled between Feb 2008 and May 2013 Cowie et al. Eur J Heart Fail 2013;15:937-43; Cowie et al. NEJM 2015; 373: 1095-105

Primary Endpoint (2015): Neutral Time to first event of all-cause death, life-saving cardiovascular intervention, or unplanned hospitalization for worsening chronic HF Cowie et al. NEJM 2015; 373: 1095-105

Subgroup Analysis: 1 Endpoint Cowie et al. NEJM 2015; 373: 1095-105

Cowie et al. NEJM 2015; 373: 1095-105 All-Cause Death

Cowie et al. NEJM 2015; 373: 1095-105 Cardiovascular Death

Subgroup Analysis: CV Death Cowie et al. NEJM 2015; 373: 1095-105

Post-hoc Analysis Cardiovascular death without prior hospitalization for worsening heart failure Between-group difference in cardiovascular death was largely accounted for by death without prior hospitalization for worsening HF

8x more events than CANPAP 425 deaths 357 CV deaths 559 pts WHF hosp 20 heart tx 26 VAD Cowie et al. NEJM 2015; 373: 1095 105

SERVE-HF more evidence to come MRI and biomarker sub-study Multi-state modelling On-treatment analysis ICD data analysis Sleep Study data analysis And many other topics.

SERVE (interim) conclusions Addition of ASV to guideline-based medical management does not improve morbidity and heart function in patients with HFrEF There is a safety signal for all-cause and cardiovascular mortality Significantly increased in the ASV group vs control Pathophysiology of the increased cardiovascular mortality remains to be elucidated: likely sudden death (?arrhythmic) The SERVE-HF results apply only to the population studied Cannot be generalised to patients with HF with preserved ejection fraction, acute HF, or those with predominant OSA Cowie et al. NEJM 2015; 373: 1095 105

What might mechanisms of harm of (mask-based) therapy in CSR be? Naughton MT. Thorax 2012; 67: 357 60 End-expiratory lung volume (and therefore oxygen stores) hyperventilation-associated vagal and sympathetic tone hyperventilation-associated respiratory alkalosis which may be protecting myocytes hyperventilation-associated intrathoracic pressure assist to cardiac pump action hyperventilation over-ride of bronchial oedema apnoea-associated 5-10mmHg intrinsic PEEP respiratory muscle fatigue due to abolishing apnoea

SERVE (interim) conclusions Addition of ASV to guideline-based medical management does not improve morbidity and heart function in patients with HFrEF There is a safety signal for all-cause and cardiovascular mortality Significantly increased in the ASV group vs control Pathophysiology of the increased cardiovascular mortality remains to be elucidated: likely sudden death (?arrhythmic) The SERVE-HF results apply only to the population studied Cannot be generalised to patients with HF with preserved ejection fraction, acute HF, or those with predominant OSA Cowie et al. NEJM 2015; 373: 1095 105

Sub-group Analysis of Global Rank Endpoint Central SDB in hospitalised patients HFpEF HR (95%CI) p-value Global rank endpoint 0.38 (0.15, 0.98) 0.045 NCT01953874

ADVENT-HF more evidence to come NCT 01128816 ASV effect on survival and hospital admission in heart failure LVEF 45%; AHI 15; ESS 10 OSA or CSA RCT Event driven: 540 endpoints death, or first hospitalisation, or onset of new Afib/flutter requiring anticoagulation, or appropriate ICD shock not leading to hospitalisation

Sleep Apnoea and Heart Failure Not airway pressure currently for CSA IF daytime sleepiness and severe OSA treat with CPAP Individualised approach consult the sleep/resp physician What to do?