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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