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Adaptative servoventilationClinical inidications and conteroversies

Joaquín Durán-Cantolla, MD, PhDChair of ResearchBioaraba Research InstituteOSI Araba University HospitalVitoria-Gasteiz (Spain)

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

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

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

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

Yumino, D et al. Am J Respir Crit Care Med 2013

Effect of Central Apneas on Stroke

Volume in a Patient with Heart Failure

Hipothesis 1: During sleep patients with HF:

-12

-10

-8

-6

-4

-2

0

2

4C

han

ge in

Str

oke V

olu

me

(%

of

baselin

e)

OAOA OHOH CHCH CACA

**

**

***

Effect of OSA and CSA on SV in 40 patients with HF

OA = obstructive apnea

OH = obstructive hypopnea

CH = central hypopnea

CA = central apnea

Yumino, D et al. Am J Respir Crit Care Med 2013

1. OSA will cause and overnight reduction in SV and CO

2. Treatment OSA by CPAP will prevent these effects

Hypothesis 2: During sleep patients with HF:

Figure 1

-30

-20

-10

0

10

20

30

40

50

60

70

Ove

rnig

ht

ch

an

ge

s (

%)

Systolic

BP

Diastolic

BPTPR

†

SV

†

CO

†

NSA OSA

*

†

HR

*

Influence of OSA on Overnight

Change in CV Variables

Kasai T, et al. Can J Cardiol 2015;7:832-8

Baseline CPAP

%△CO

P=0.042

-17.2 9.0%

-9.7 10.7%

Baseline CPAP

%△SV

-14.0 7.9%

-3.4 9.8%

P=0.002

Figure 3

Ove

rnig

ht

ch

an

ge

s(%

)

-20

-10

0

10

20

30

40

Baseline CPAP

%△TPR

38.3 23.4%

22.3 16.5%

P=0.016

Effects of CPAP on SV, CO and TPR

In HF Patients with OSA

1. Improve cardiac mechanics (LVEF)

2. Reduce sympathetic nervous activity

Hypothesis 3: In patients with HF, treatment of

coexisting OSA with CPAP will:

0

5

10

15

20

25

30

35

40

Control ControlCPAP CPAP

LVEF, % FS, %

Baseline

1 mo

nsp=0.002

ns

p<0.001

p=0.009

p=0.044

LVEF and fractional shortening

Kaneko et al. NEJM 2003;358:1233-41 Usui et al. JACC 2005

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

LEFT VENTRICULAR FAILURE:

CARDIAC OUTPUT

LV FILLING PRESSURE

Fatigue

Pulmonary edema

Hypersomnolence

Pulmonary

afferent

stimulation

Hyperventilation

CENTRAL APNEA

PaCO2

Sleep disruption

Cardiac O2

supply

Cardiac O2

demandArousal

Chemosensitivity

PaO2

PaCO2

SNA

Catecholamines

HR

BP

Courtesy of Douglas Bradley

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.

VPAP Adapt SV

(ASV mode on)

AirflowHYPOPNEA

APNEA

Adapt SV responds to apnea by increasing pressure support

(Apnea converted to a hypopnea & breathing quickly normalized)

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

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

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

SERVE-HF: Design

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

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

INCLUSION CRITERIA

• Age ≥ 22 years

• Chronic stable HF (ESC guidelines,

no hospitalization within 4 weeks)

• LV systolic 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 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

INCLUSION AND EXCLUSION CRITERIA

FLOW-CHART OF THE STUDY

Cowi MR et al. NEJM 2015

PATIENTS AT BASELINE

Cowi MR et al. NEJM 2015

RESPIRATORY CHARACTERISTICS AT BASELINE

Cowi MR et al. NEJM 2015

ADHERENCE AND CSA CONTROL

Cowi MR et al. NEJM 2015

SYMPTOMS AND QUALITY OF LIFE

Cowi MR et al. NEJM 2015

PRIMARY END POINT: Neutral

Cowi MR et al. NEJM 2015

ALL CAUSE OF MORTALITY

Cowi MR et al. NEJM 2015

CARDIOVASCULAR DEATH

Cowi MR et al. NEJM 2015

10% of CV mortality for ASV7.5% of CV mortality for control group(HR =1.335; 95% CI: 1-070-1.666; p = 0.010).

1. The increased risk appears to be grater in more severe ventricular disfunction2. Deaths mainly happened out of the hospital (sudencardiac death)3. The risk does not diminish with the time therapyand it is independent of perceived symtomaticbenefit from therapy

CONCLUSIONS

Cowi MR et al. NEJM 2015

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

HF patients 18 yrs of age with LVEF 45% on optimal HF therapy, undergo a sleep study

ASV FOR TREATMENT OF OSA AND CSA IN HFJointly funded by CIHR and an unrestricted grant from PHILIPS/RESPIRONICS

AHI 15 ( 50% obstructive = OSA, >50% central = CSA)

RandomizationControl – no ASV, n = 430ASV – titrated on sleep study to

eliminate OSA and/or CSA, n = 430

Baseline QOL, NT-pro-BNP, 6MWT, LVEF, LVEDV and LV mass

• 1 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)

THE STUDIES ARE SIMILILAR BUT THEY

HAVE SOME DIFFERENCES

DIFFERENCES IN DESIGN

DIFFERENCES IN DESIGN

DIFFERENCES IN RESULTS

DIFFERENCES IN

RECOMENDATIONS

REFLECTIONSSERVE-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

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

LOSING HEARTBEN MACNEVIN MAY 15, 2015 |

¡WE HAVE HAD OTHERS IMPORTANT

HISTORIC WARNINGS!

BMJ 2011;342:d3215

doi:10.1136/bmj.d3215

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

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

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