APPROACHES TO THERAPY APPROACHES TO THERAPY OF CENTRAL SLEEP APNEA OF CENTRAL SLEEP APNEA

IN HEART FAILUREIN HEART FAILURE

T. Douglas Bradley, MDT. Douglas Bradley, MDDirector, Centre for Sleep Medicine and Director, Centre for Sleep Medicine and

Circadian Biology,Circadian Biology,

Toronto General Hospital and Toronto Toronto General Hospital and Toronto Rehabilitation Institute, University of TorontoRehabilitation Institute, University of Toronto

0 6 12 18 24 30 36 42 48 54 600

20

40

60

80

100

Time from randomization (months)

Tra

nsp

lan

t-fr

ee s

urv

ival

(%

)

P=0.032

Non-CSR-CSA

CSR-CSA

Sin D et al. Circulation 2000

Transplant Free Survival: CSR-CSA vs non-CSR-CSA Transplant Free Survival: CSR-CSA vs non-CSR-CSA

N = 66

Types of Mechanical Ventilation Types of Mechanical Ventilation Tested in Cheyne-Stokes RespirationTested in Cheyne-Stokes Respiration

Adaptive Pressure Support Servo-Adaptive Pressure Support Servo-Ventilation (ASV)Ventilation (ASV)

Bilevel Pressure Support Ventilation Bilevel Pressure Support Ventilation (BPSV)(BPSV)

Continuous Positive Airway Pressure Continuous Positive Airway Pressure (CPAP)(CPAP)

Teschler H et al. Am J Respir Crit Care Med 2001

RESULTSRESULTS

ASV:ASV: Reduced BNP and urinary Reduced BNP and urinary

metnorepinephrinemetnorepinephrine Improved alertness on the Osler Test Improved alertness on the Osler Test

ASV had no effect on:ASV had no effect on: LVEF LVEF Quality of life Quality of life Performance on a driving simulator testPerformance on a driving simulator test

Pepperell J et al. AJRCCM 2003

CONCLUSIONSCONCLUSIONS

In HF Patients with CSA:In HF Patients with CSA: Effect of ASV for 1 month on CSA was not assessed, Effect of ASV for 1 month on CSA was not assessed,

so we cannot say whether it improved CSA so we cannot say whether it improved CSA compared to sham ASVcompared to sham ASV

ASV increased alertness (Osler), and reduced BNP ASV increased alertness (Osler), and reduced BNP and 24 hr urinary metnorepinephrineand 24 hr urinary metnorepinephrine

ASV had no effect on LVEFASV had no effect on LVEF Clinical cardiovascular endpoints were not assessed Clinical cardiovascular endpoints were not assessed Accordingly, there is insufficient evidence to Accordingly, there is insufficient evidence to

support the use of ASV to treat CSA in patients with support the use of ASV to treat CSA in patients with HFHF

RANDOMIZATIONRANDOMIZATION(to detect HR of 0.65) (to detect HR of 0.65)

n = 408n = 408

RANDOMIZATIONRANDOMIZATION(to detect HR of 0.65) (to detect HR of 0.65)

n = 408n = 408

Optimal Medical Therapy AloneOptimal Medical Therapy Alonen = 204n = 204

Optimal Medical Therapy AloneOptimal Medical Therapy Alonen = 204n = 204

Optimal Medical Therapy & Optimal Medical Therapy & CPAP CPAP n = 204n = 204

Optimal Medical Therapy & Optimal Medical Therapy & CPAP CPAP n = 204n = 204

Predicted Mean Follow Up Period = 2.5 yrsPredicted Max Follow Up Period = 5 yrs

Primary OutcomePrimary Outcome Cumulative combined all cause mortality-heart Cumulative combined all cause mortality-heart transplant rate during study periodtransplant rate during study period

Primary OutcomePrimary Outcome Cumulative combined all cause mortality-heart Cumulative combined all cause mortality-heart transplant rate during study periodtransplant rate during study period

Secondary Outcomes Secondary Outcomes AHI and mean nocturnal SaO AHI and mean nocturnal SaO2 2

Resting LVEF Resting LVEF

6-minute walk distance6-minute walk distance Plasma Norepinephrine (PNE)Plasma Norepinephrine (PNE) Atrial Natriuretic Peptide (ANP)Atrial Natriuretic Peptide (ANP) Hospital admissionsHospital admissions Chronic Heart Failure Questionnaire ScoresChronic Heart Failure Questionnaire Scores

Secondary Outcomes Secondary Outcomes AHI and mean nocturnal SaO AHI and mean nocturnal SaO2 2

Resting LVEF Resting LVEF

6-minute walk distance6-minute walk distance Plasma Norepinephrine (PNE)Plasma Norepinephrine (PNE) Atrial Natriuretic Peptide (ANP)Atrial Natriuretic Peptide (ANP) Hospital admissionsHospital admissions Chronic Heart Failure Questionnaire ScoresChronic Heart Failure Questionnaire Scores

Eligible PatientsEligible PatientsHF, LVEF <40%, CSA (AHI HF, LVEF <40%, CSA (AHI 15/hr)15/hr)

Eligible PatientsEligible PatientsHF, LVEF <40%, CSA (AHI HF, LVEF <40%, CSA (AHI 15/hr)15/hr)

CANPAP

Calendar YearCalendar Year

Eve

nt

Rat

e/10

0 p

erso

n-y

ears

Eve

nt

Rat

e/10

0 p

erso

n-y

ears

1998/1999 2000 2001 2002 2003 2004

05

1015

2025

Observed Event Rate

Constant Anticipated Event Rate (Control Group)

PRIMARY EVENT RATE OVER TIMEPRIMARY EVENT RATE OVER TIME

Bradley et al. NEJM 2005Bradley et al. NEJM 2005

CANPAP

TERMINATION OF THE TRIALTERMINATION OF THE TRIAL

• Interim analysis on the 1Interim analysis on the 1stst 200 patients: a) a 200 patients: a) a post hocpost hoc subgroup analysis of NYHA class 3 & 4 subgroup analysis of NYHA class 3 & 4 patients revealed an early divergence of event patients revealed an early divergence of event rates favouring the control group, rates favouring the control group, b) enrollment only 50% of predicted, b) enrollment only 50% of predicted, and c) >50% decline in the event rate over the and c) >50% decline in the event rate over the course of the trial.course of the trial.

• The DSMC recommended stopping the trial even The DSMC recommended stopping the trial even though the event rate crossed over to favour the though the event rate crossed over to favour the CPAP group after 18 months.CPAP group after 18 months.

• The trial was stopped in May, 2004The trial was stopped in May, 2004

Bradley et al. NEJM 2005Bradley et al. NEJM 2005

CANPAP

Enrollment, Drop-outs and Enrollment, Drop-outs and ComplianceCompliance

• Enrollment began in December, 1998Enrollment began in December, 1998• 258 patients were enrolled at the time 258 patients were enrolled at the time

the trial was stopped in May, 2004 the trial was stopped in May, 2004 • Mean 24 month follow-up (range 0-64 Mean 24 month follow-up (range 0-64

months)months)• Only 15% of subjects dropped-out (20 Only 15% of subjects dropped-out (20

in each group)in each group)• Average daily CPAP use was Average daily CPAP use was ≈ ≈ 4 hr at 4 hr at

8-9 cm H8-9 cm H22O throughout the trialO throughout the trialBradley et al. NEJM 2005Bradley et al. NEJM 2005

CANPAP

Effects of CPAP on CSAEffects of CPAP on CSA

A

HI (

no

. /h

r)A

HI (

no

. /h

r)

00

1010

2020

3030

4040

CPAP groupCPAP group

ControlControl groupgroup

P<0.001P<0.001

Time From Randomization (mo)Time From Randomization (mo)

Sa

OS

aO

22 (%

) (

%)

00919192929393949495959696 CPAP groupCPAP group

Control groupControl group

P<0.001P<0.001

00 33 2424

CANPAPBradley et al. NEJM 2005Bradley et al. NEJM 2005

Effects of CPAP on LVEFEffects of CPAP on LVEF

CANPAPBradley et al., NEJM 2005Bradley et al., NEJM 2005

Time From Randomization (mo)

LV

EF

(%

)

0

20

25

30

35

0 3 6 24

CPAP group

Control group

P=0.007

Effect of CPAP on Transplant-free SurvivalEffect of CPAP on Transplant-free Survival

CANPAPBradley et al., NEJM 2005Bradley et al., NEJM 2005

Tra

nsp

lan

tati

on

-fre

e S

urv

ival

(%

)T

ran

spla

nta

tio

n-f

ree

Su

rviv

al (

%)

Time from Enrollment (mo)Time from Enrollment (mo)

00 1212 2424 3636 4848 606000

2020

4040

6060

8080

100100

128128 104104 7979 5959 4949 4242 3333 2424 2020 1212 66

130130 117117 9696 7979 5959 4646 3737 2727 1919 1212 44

CPAPCPAP

ControlControl

No. at RiskNo. at Risk

Control groupControl group(32 events)(32 events)

CPAP groupCPAP group(32 events)(32 events)

P=0.54P=0.54

Time From Randomization (months)Time From Randomization (months)

Cu

mu

lati

ve T

ota

l Nu

mb

er o

f H

osp

ital

izat

ion

sC

um

ula

tive

To

tal N

um

ber

of

Ho

spit

aliz

atio

ns

0 12 24 36 48 60

050

100

150

Group

CPAPControl

Compare Total Hospitalizations

P = 0.83

Cumulative Number of HospitalizationsCumulative Number of Hospitalizations

Bradley et al. NEJM 2005Bradley et al. NEJM 2005

CANPAP

OTHER SECONDARY OUTCOMESOTHER SECONDARY OUTCOMES

• 6-Minute Walking Distance:6-Minute Walking Distance: increased increased more in CPAP than in control group at 12 more in CPAP than in control group at 12 weeks (20.0 weeks (20.0 ± 55.0 vs –0.8 ± 64.8 m, P = ± 55.0 vs –0.8 ± 64.8 m, P = 0.016) 0.016)

• PNE:PNE: Decreased more in the CPAP than Decreased more in the CPAP than the control group over course of the trial the control group over course of the trial (-1.03 (-1.03 ±± 1.84 vs 0.02 1.84 vs 0.02 ±± 0.99 nmol/L, P = 0.99 nmol/L, P = 0.009)0.009)

• ANP and ANP and Quality of Life:Quality of Life: No significant No significant change in either groupchange in either group

Bradley et al. NEJM 2005Bradley et al. NEJM 2005

CANPAP

HypothesisHypothesis

CPAP will improve LVEF and transplant-CPAP will improve LVEF and transplant-

free survival of HF patients with CSA, if it free survival of HF patients with CSA, if it

causes attenuation of CSAcauses attenuation of CSA

Transplant-free survival in HF patients according to effect of CPAP on CSA

CANPAP

CPAP suppressed*(AHI at 3 months < 15/hr)

CPAP unsuppressedCPAP unsuppressed(AHI at 3 months (AHI at 3 months 15/hr) 15/hr)

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060

Time from enrollment (mo)Time from enrollment (mo)

ControlControl

00

2020

4040

6060

8080

100100T

ran

spla

nt-

free

su

rviv

al (

%)

Tra

nsp

lan

t-fr

ee s

urv

ival

(%

)

*versus control: HR=0.36, *versus control: HR=0.36, p=0.040p=0.040

Arzt M et al. Circulation 2007

SummarySummary

CPAP improved LVEF and transplant-free CPAP improved LVEF and transplant-free survival in those HF patients in whom CPAP survival in those HF patients in whom CPAP attenuated CSAattenuated CSA

In contrast, HF patients, whose CSA was not In contrast, HF patients, whose CSA was not attenuated in response to CPAP, did not attenuated in response to CPAP, did not improve their LVEF and had reduced improve their LVEF and had reduced transplant-free survival ratestransplant-free survival rates

CONCLUSIONS ICONCLUSIONS I

CPAP was well tolerated, alleviated CPAP was well tolerated, alleviated CSA and improved cardiovascular CSA and improved cardiovascular functionfunction

However, the primary analysis However, the primary analysis showed no difference in showed no difference in transplant-free survival or transplant-free survival or hospitalizations between the two hospitalizations between the two groupsgroups

Bradley et al. NEJM 2005Bradley et al. NEJM 2005

CANPAP

CONCLUSIONS IICONCLUSIONS II

Our data demonstrate that early reduction in Our data demonstrate that early reduction in the AHI (within 3 months) in response to the AHI (within 3 months) in response to CPAP occurs in conjunction with CPAP occurs in conjunction with improvement in LVEF, and is a predictor of improvement in LVEF, and is a predictor of improved transplant-free survival in HF improved transplant-free survival in HF patients with CSApatients with CSA

Alleviation of CSA by CPAP may be an Alleviation of CSA by CPAP may be an important therapeutic target to improve important therapeutic target to improve transplant-free survival in such patientstransplant-free survival in such patients

CONCLUSIONS IIICONCLUSIONS III

Our data demonstrate that the failure to Our data demonstrate that the failure to attenuate CSA by CPAP within 3 months is attenuate CSA by CPAP within 3 months is not associated with an improvement in LVEF, not associated with an improvement in LVEF, and is a predictor of reduced transplant-free and is a predictor of reduced transplant-free survival in HF patients with CSAsurvival in HF patients with CSA

CPAP may have adverse effects in HF patients CPAP may have adverse effects in HF patients whose CSA does not improve with CPAPwhose CSA does not improve with CPAP

PerspectivePerspective Based on our observation that in HF patients with Based on our observation that in HF patients with

CSA, an early reduction in AHI is accompanied by CSA, an early reduction in AHI is accompanied by improvement in LVEF and higher improvement in LVEF and higher transplant-free transplant-free survival, survival, we believe that it may be reasonable to we believe that it may be reasonable to provide a trial of CPAP to such patients, and to provide a trial of CPAP to such patients, and to reassess CSA 1 to 3 months later by PSGreassess CSA 1 to 3 months later by PSG

If the AHI does not decrease, then CPAP should be If the AHI does not decrease, then CPAP should be stoppedstopped

If the AHI decreases substantially, then one could If the AHI decreases substantially, then one could recommend continuation of CPAP with close recommend continuation of CPAP with close follow-upfollow-up

FellowsFellows• Ruzena TkacovaRuzena Tkacova• Don SinDon Sin• Matt NaughtonMatt Naughton• Michael ArztMichael Arzt

ColleaguesColleagues• John FlorasJohn Floras• Sandy LoganSandy Logan

Research AssistantsResearch Assistants • Fabia FitzgeraldFabia Fitzgerald• Nicole CatherineNicole Catherine• Gisella HopkinsGisella Hopkins• Fiona Rankin Fiona Rankin • Ruth RutherfordRuth Rutherford

ACKNOWLEDGMENTSACKNOWLEDGMENTS