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1 Obrigada por ver esta apresentação Lembramos que esta apresentação é propriedade do autor É-lhe proporcionada pela Associação Portuguesa de Sono no contexto da Lufada 2016, para seu uso pessoal, tal como submetido pelo autor 2016 pelo autor

2 Adaptative servoventilation Clinical inidications and conteroversies Joaquín Durán-Cantolla, MD, PhD Chair of Research Bioaraba Research Institute OSI Araba University Hospital Vitoria-Gasteiz (Spain)

3 CONFLICT OF INTEREST I am actively participating of on-going study of ADVENT-ASV for the treatment of pacients with HF and aymptomatic OSA and CSA, and I am member of the steering committee of this study

4 Adaptative Servoventilation (ASV) 1. ASV utilizes PAP ventilatory support that is adjusted based on the detection of apneas, or pauses in breathing, during sleep. 2. It is primarily used in the treatment of Central Sleep Apnea. It is also used for complex sleep apnea, mixed sleep apnea, periodic breathing and Cheyne-Stokes respiration 3. The device resembles CPAP machines and uses the same masks, hoses, and attachments 4. While CPAP provides one continuous pressure, and BiPAP provides two pressures, ASV adjusts the pressure based on an algorithm

5 HF, OSA and CSA 1. HF es one of the most prevalent disease, specially in the elderly 2. OSA afects more than 25% of the population and more than 50% in patients with HF 3. CSA y relatively frequent and it is a well known consequence of HF 4. Therefore, in patients with HF frequently coexist with OSA and/or CSA

6 Hipothesis 1: During sleep patients with HF: 1. OSA will acutely reduce SV and CO 2. CSA will have no acute effect on SV and CO Effect of Obstructive Apneas on Stroke Volume in a Patient with Heart Failure Effect of Central Apneas on Stroke Volume in a Patient with Heart Failure Yumino, D et al. Am J Respir Crit Care Med 2013

7 Change in Stroke Volume (% of baseline) Effect of OSA and CSA on SV in 40 patients with HF 4 * ** ** OA ** OH OA = obstructive apnea OH = obstructive hypopnea CH = central hypopnea CA = central apnea CH CA Yumino, D et al. Am J Respir Crit Care Med 2013

8 Overnight changes (%) Overnight changes (%) Hypothesis 2: During sleep patients with HF: 1. OSA will cause and overnight reduction in SV and CO 2. Treatment OSA by CPAP will prevent these effects Influence of OSA on Overnight Change in CV Variables Effects of CPAP on SV, CO and TPR In HF Patients with OSA Figure 1 NSA OSA Figure 3 P= % % * P=0.002 P= * % % % % Systolic BP Diastolic BP SV HR CO TPR Baseline CPAP % SV Baseline CPAP % CO Baseline CPAP % TPR Kasai T, et al. Can J Cardiol 2015;7:832-8

9 Hypothesis 3: In patients with HF, treatment of coexisting OSA with CPAP will: 1. Improve cardiac mechanics (LVEF) 2. Reduce sympathetic nervous activity LVEF and fractional shortening p= ns p<0.001 p=0.044 Baseline 1 mo ns p= Control CPAP Control CPAP LVEF, % FS, % Kaneko et al. NEJM 2003;358: Usui et al. JACC 2005

10 1. OSA has adverse effects on survival in patients with HF, that appear bo be at least partially reversible with CPAP treatment 2. HF patients with OSA, generally do not complain EDS and CPAP treatment for mild-moderate OSA without EDS do not reduce CV events Wang et al. JACC 2007 Arzt et al. Arch Int Med 2006

11 LEFT VENTRICULAR FAILURE: CARDIAC OUTPUT LV FILLING PRESSURE Fatigue Pulmonary edema Hypersomnolence Pulmonary afferent stimulation Chemosensitivity Sleep disruption Hyperventilation Arousal SNA Catecholamines HR BP Cardiac O 2 supply Cardiac O 2 demand PaCO2 PaO 2 PaCO 2 CENTRAL APNEA Courtesy of Douglas Bradley

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13 VPAP Auto SV (ResMed) 1. Algorithm directed at measuring baseline TV and respiratory rate 2. Can titrate for EPAP or use fefault setting of 5 cm. 3. IPAP suggestions: a) Set minimal PS at 3 cm; b) Set maximal PS at 10 cm. Adapt SV responds to apnea by increasing pressure support Airflow APNEA HYPOPNEA VPAP Adapt SV (ASV mode on) (Apnea converted to a hypopnea & breathing quickly normalized)

14 BiPAP Auto SV (Respironics) 1. Respond to Peak-flow ASV and adjusts Pressure Support accordingly 2. Manufactures suggestions for settings: a) Set EPAP or minimal EPAP; b) Set PS from 2-15 cm; c) Set maximal EPAP at 25 cm; d) Automatic respiratory breath

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16 1. Post-hoc data from a RCT (CANPAP; N=258) suggest that CPAP might improve mortality when CSA is controlled (AHI <15/h) in HF patients with CSA and EF <40% 2. Small and/or uncontrolled studies (and meta-analyses) suggest multiple beneficial effects of ASV on surrogate markers in HF patients with CSA: Improvements in LVEF, plasma BNP levels, quality of life and functional outcomes

17 SERVE-HF: Objetive To investigate the effects of adding ASV to guideline-based medical management on survival and CV outcomes in patients with HF with reduced ejection fraction and predominant CSA

18 SERVE-HF: Design

19 SERVE-HF: Design 91 centres in 11 countries Randomized, parallel, event-driven design Guideline-based medical management: Alone (control group) Plus ASV (Auto Set CSTM, ResMed) ASV titration in hospital (PG or PSG) Starting at default settings EPAP manually increased to control OSA and maximum PS increased to control CSA

20 SERVE-HF: End-points Primary composite endpoint: Time to first event of all-cause death, life-saving CV intervention*, or unplanned hospitalization for worsening chronic HF Secondary endpoints: CV death vs. all-cause death All cause unplanned hospitalization for worsening chronic HF Time to death (all-cause) Time to cardiovascular death Change in NYHA class Change in 6 min walking test Quality of life *heart transplant, long-term ventricular assist device, resuscitation of sudden cardiac arrest, or appropriate ICD shock

21 INCLUSION AND EXCLUSION CRITERIA INCLUSION CRITERIA Age 22 years 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 Chronic stable HF (ESC guidelines, Oxygen saturation <90% at rest no hospitalization within 4 weeks) during the day LV systolic dysfunction LVEF 45% Current use of CPAP 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

22 FLOW-CHART OF THE STUDY Cowi MR et al. NEJM 2015

23 PATIENTS AT BASELINE Cowi MR et al. NEJM 2015

24 RESPIRATORY CHARACTERISTICS AT BASELINE Cowi MR et al. NEJM 2015

25 ADHERENCE AND CSA CONTROL Cowi MR et al. NEJM 2015

26 SYMPTOMS AND QUALITY OF LIFE Cowi MR et al. NEJM 2015

27 PRIMARY END POINT: Neutral Cowi MR et al. NEJM 2015

28 ALL CAUSE OF MORTALITY Cowi MR et al. NEJM 2015

29 CARDIOVASCULAR DEATH 10% of CV mortality for ASV 7.5% of CV mortality for control group (HR =1.335; 95% CI: ; p = 0.010). 1. The increased risk appears to be grater in more severe ventricular disfunction 2. Deaths mainly happened out of the hospital (suden cardiac death) 3. The risk does not diminish with the time therapy and it is independent of perceived symtomatic benefit from therapy Cowi MR et al. NEJM 2015

30 CONCLUSIONS Cowi MR et al. NEJM 2015

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32 HYPOTHESIS In patients with HF on optimal medical therapy, treatment of CSA and non-sleepy patients with OSA by ASV will reduce the composite primary endopoint of all-cause mortality, CV hospitalizations, appropriate ICD shocks and atrial fibrillation requiring anticoagulation but no hospitalization compared to an untreated control group

33 ASV FOR TREATMENT OF OSA AND CSA IN HF Jointly funded by CIHR and an unrestricted grant from PHILIPS/RESPIRONICS HF patients 18 yrs of age with LVEF 45% on optimal HF therapy, undergo a sleep study AHI 15 ( 50% obstructive = OSA, >50% central = CSA) Baseline QOL, NT-pro-BNP, 6MWT, LVEF, LVEDV and LV mass Control no ASV, n = 430 Randomization ASV titrated on sleep study to eliminate OSA and/or CSA, n = month clinic visit, sleep study and QOL 3 month clinic visit 6 month clinic visit, QOL, NT-pro-BNP, 6MWT, LVEF, LVEDV and LV mass 6 monthly clinic visits and QOL until end of trial at 60 months Primary outcome: composite of deaths, CV hospitalizations, appropriate ICD shocks and AF requiring anticoagulation over the follow-up period Endpoint is 540 primary events which we estimate will require a 3-year accrual time with minimum and maximum follow up times of 2 and 5 years 2 interim analyses after 50% (n=270) and 75% (n=405) of the predicted number of primary events have occurred CENTERS: n=53 (Canadá = 12; USA = 4; Brazil =4; Spain = 9; Germany = 5; Italy = 5; UK = 1; Japan = 6; France = 8)

34 THE STUDIES ARE SIMILILAR BUT THEY HAVE SOME DIFFERENCES

35 DIFFERENCES IN DESIGN

36 DIFFERENCES IN DESIGN

37 DIFFERENCES IN RESULTS

38 DIFFERENCES IN RECOMENDATIONS

39 REFLECTIONS SERVE-HF data, showed an increase of mortality probably related to the use of ASV in patients with severe HF and asymptomatic CSA BUT: 1. We do not know the mechanism causing this increased mortality (PAP; ASV; Type of device; Supressed Cheynes- Stokes respiration, etc.) 2. We really do not know if the mortality is due to the disease or the treatment 3. Regarding the treatment we not know if it is due to the PAP or the ASV itself, the type of device or the settings

40 LOSING HEART BEN MACNEVIN MAY 15, 2015 Cardiologists are responsible for prescribing devices to patients with HF. Despite the substantial number of secondary endpoints in the SERVE-HF study, it is highly unlikely that a cardiologist would consider prescribing a ventilation device given the failure to meet the primary endpoints. As such, we conclude that Resmed will be unable to make a meaningful impact in this market

41 BMJ 2011;342:d3215 doi: /bmj.d321 5 WE HAVE HAD OTHERS IMPORTANT HISTORIC WARNINGS!

42 CONCLUSIONS (1) 1. Based on SERVE-HF data, it is advisable to avoid, at least for now, the use of ASV in patients with severe HF and asymptomatic CSA until we have more data 2. If you have patients under ASV keeping the treatment should be individualized and carefully monitorized. Patients should receive very detailed explanations about the balance risk-benefit and we recommend asking the patients to sign inform consent to continue the treatment

43 CONCLUSIONS (2) 3. For now it will be very difficult to launch new studies for the treatment of CSA in patients with HF 4. Therefore, it is very important that on going studies like ADVENT-ASV can be completed to allows us to confirm or reject the results of SERVE-HF 5. We need more data to know if the ASV could be a useful treatment for patients with CSA and HF 6. Every body, companies, providers and professionals, must be specially prudent

44 WE NEED MORE STUDIES A few observations and much reasoning lead to error; many observations and a little reasoning lead to truth Dr. Alexis Carrel French surgeon and 1912 Nobel Prize in Medicine recipient

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