sleep apnea and heart failure (2001-06-13)

Sleep Apnea in Heart Failure Update on Prevalence and Treatment Options

S. Javaheri, M.D., FCCP

Professor Emeritus of Medicine, University of Cincinnati, College of Medicine Medical Director, Sleepcare Diagnostics Cincinnati, OhioIndianapolis, 8/2007

Disclosures

I am a consultant and/or have received grant and/or honoraria

and/or travel expenses from:

BI, Cardiac Concept, Cephalon,

GSK, Respironics, Res Med,

Sanofi-Aventis and Takeda

ObstructiveObstructive ApneaApnea

Normal AirwayNormal Airway Obstructed AirwayObstructed Airway

Polysomnographic Breathing Disorders Event

Rib cage

Obstructive apnea

Abdomen

Ribcage

Airflow

Interaction Between Sleep and Heart Pathology

Primary

Secondary

Sleep Apneas & Hypopneas

Secondary

Primary

Cardiovascular Pathology

Polysomnographic Breathing Disorders Event

Rib cage

Abdomen

Ribcage

Airflow

Central apnea

Hunter- Cheyne-Stokes Breathing in SHF

Su

rviv

al %

Months Javaheri et al, JAAC,2007

( N=32 )

( N=56 )

Prevalence of Sleep Apnea inRecent Prospective Studies of SHF

Canada (07) (13)

China (07) (12)

Germany (07) (16)

N Zealand (05) (11)

US (06) (5)

n

%AHI

≥ 10/hr%

β blockers

%AHI

≥ 15/hr

8010

80

30

%OSA

%CSA

2137

46

15

71

68

4749

2612

25

53

52 85

287100

126

56

700

Country (y) (Ref)

9028 43203

54 8037 17102

Germany (07) (15)

Germany (07) (19)

71

UK (07) (18) 7838 1555 53

33 19 8533 19

Complex sleep apnea

The new kid on the block

or

the old guy in the background

Prevalence of Sleep Apnea in Prospective Studies of SHF

• CPAP-resistant Central Sleep Apnea (CSA)– A large number of Patients with Systolic Heart failure – Patients with Atrial Fibrillation– Patients on Opioids– Neuromuscular Disease

• CPAP-emergent CSA– Over-titration – Sleep Fragmentation ( Post-arousal )– S/P UPPP

Complex Sleep ApneaCPAP-resistant CSA and CPAP-emergent CSA

Hunter- Cheyne-Stokes Breathing in SHF

SleepApnea &Hypopnea

H/R

PCO2

Arousals

Ppl

O2 Delivery

RV Afterload

SVR/Others

Changes in R&LVentricular Preload &Afterload

Lung H2O

Vasoconstriction

Thrombosis

Inflammation

OrganDysfunction

Hypoxic & HypercapnicPulmonaryVasoconstriction

EndothelialDysfunctionSyndrome

SympatheticActivation

Transmural P. ofL&R ventricles, and PulmonaryMicrovascular Bed

SA/H: Mechanisms Contributing to Cardiovascular Disease

CSA as a Predictor of Mortality in SHF

• N = 114 eligible

• N = 100 Enrolled

• N = 12 with OSA Excluded

• N = 88

N = 88 : 32 with AHI <5 ; 56 with AHI ≥5/hr

Median F/U : 51 months

Javaheri et al , J Am Coll Cardiol (May, 2007)

Demographic and cardiovascular parameters in 88 heart failure patients

without  and with central sleep apnea Variable AHI<5/hr AHI ≥5/hr P 

Number 32 56 

Age, y 62 67 0.02

BMI, kg/m2 28 26 0.09

SBP, mm Hg 127                119      0.06

DSP, mm Hg 72       70          0.09

Heart rate, n/min 78 80 0.48

SRBD in 88 heart failure patients without  and with central sleep apnea

Variable AHI<5/hr AHI ≥5/hr

AHI, n/hr 2 35

CAI, n/hr 0.6 23

OAI, n/hr 0.1 0.5

CAHI, n/hr 2 32

OAHI, n/hr 0.2 1

Cardiovascular parameters in 88 heart failure patients

without  and with central sleep apnea Variable AHI<5/hr AHI ≥5/hr P 

LVEF, % 27 22 0.006

RVEF, % 49 43 0.048

Atrial fibrillation,% 6 20 0.1    NHYA Class I,% 25  9 0.09 

NHYA Class II, %           53           55 0.09 

NHYA Class III, %  22  36 0.09    

The Predictors of mortality in SHF

Three Variables, RVEF, AHI and DBP

Independently Correlated with Survival:

RVEF (HR=0.97, P=0.003)

AHI (HR=2.14, P=0.02)

DBP (HR=0.96, P=0.02)

90

6259 60 60 59

45 44

36 35 35 36

0

10

20

30

40

50

60

70

80

90

100

AHI<5 VS >=5 AHI<10 VS >=10 AHI<15 VS >=15 AHI<20 VS >=20 AHI<25 VS >=25 AHI<30 VS >=30

Med

ian

Su

rviv

al

Less than cutoff point Greater or equal to cutoff point

44

36353536

45

P=0.0190

P=0.0162 P=0.02

59

P=0.00360

P=0.00260

P=0.00259

Med

ian

su

rviv

al (

mo

nth

s)

AHI<5 VS ≥5 AHI<10 VS≥10 AHI<15 VS ≥15 AHI<20 VS ≥20 AHI<25 VS ≥25 AHI<30 VS≥30

■ Less than the cutoff point■ Greater or equal than the cutoff point

0

10

20

30

40

50

60

70

80

90

100

Javaheri et al, JAAC, 2007

Prevalence of Sleep apnea Stable Systolic Heart Failure

Prospective Studies

Variable

Apnea-Hypopnea Index > 15/hr

Central Sleep Apnea

Obstructive Sleep Apnea

Range, %

47 - 49

15 - 46

12 - 53

Prevalence of SRBD in Systolic Heart Failure

100 out of 114 consecutive patients

– 68% with AHI ≥ 5/h ; 49% with AHI ≥ 15/h

– 56% CSA

– 12% OSA

– Javaheri, Ann Intern Med, 1995, Circulation 1998– and Int J cardiol 2006

Prevalence of Sleep Apnea in Prospective Studies of SHF

68

4947

68 71 70

82

53

0

20

40

60

80

100

%

CanadaUS NZ ChinaGermanyDCM ICM

AHI ≥5/hr AHI ≥10/hr AHI ≥15/hr

Germany

Prevalence of Sleep Apnea in Prospective Studies of SHF

12

37

2621

53

15

20

37 3835

32

46

17

37

0

10

20

30

40

50

60

%

OSA CSA

CanadaUS NZ ChinaGermany

DCM ICM Germany

Heart Failure in U.S.

• 1.5–2% of population (5 million)

• 6–10% of population >65 y old

• 400,000–700,000 new cases annually

• 20 million with asymptomatic cardiac impairment

• 11 million physician office visits annually

• 3.5 million hospitalizations annually

• Leading cause of hospitalization in people >65 y

• 250,000 deaths annually (direct and indirect)

• $27 billion (annual cost), 2003

• $8–15 billion per for hospitalization

Mortality Trends in Heart Failure U.S.

• Framingham Study (2002)

59% in men and 43% in women

• Olmsted Study (2004)

43%

• Worcester (2007)

79%

Treatment of CSA in SHF(No Guidelines)

1. Promote sleep hygiene

2. Avoiding ETOH and benzodiazepines

3. Optimization of medical thereapy of CP functions

lockers vs- melatonin secretion

4. Treatment algorithm for CSA

5. Treatment of RLS/PLM

Optimize Therapy:

ACEI; ß-Blockers; Diuretics; Digoxin; CRT

SRBD Eliminated

Persistent SRBD

Follow-up Clinically

Consider Treatment

Cardiac TransplantationMedications

TheophyllineNocturnal Nasal Oxygen

Acetazolamide

APSSV HFV

Medical Devices

nCPAPMandibular

AdvancementCardiacPacing

Optimize Therapy:

ACEI; ß-Blockers; Diuretics; Digoxin

SRBD Eliminated

Persistent SRBD

Follow-up Clinically

Consider Treatment

Cardiac TransplantationMedications

TheophyllineNocturnal Nasal Oxygen

Acetazolamide

APSSV HFV

Medical Devices

nCPAPMandibular

AdvancementCardiacPacing

Study Design-Inclusion Criteria

• Subjects transplanted between 1995-1999

• At least 5 months post- transplant

• 59 Eligible patients

• 45 Participated (76%)

• 14 Refused (24%)

Javaheri et. al., EHJ, 2004

21

1

7

0

5 4

7

5

10

15

20

0- 5 5- 10 10- 15 15- 20 20- 30 30- 40 40

47% 53%

51%

36%

36%

24%

16%

AHI, no./hr

Nu

mb

er o

f S

ub

ject

s

Javaheri et. al., EHJ, 2004

Demographics and Physical Examination Findings in 45 Heart Transplant Subjects Without Sleep Disorders (Group I, n=15),

With PLM (Group II, n=14)or With Sleep Related Breathing Disorders (Group III, n=16)

Variable

Age, yMale/Female, nHt, cmWt, kgWt gain since transplant, kgBMI, kg/m2

Neck size, cm

Group II 55

12/2179•

909

28•

42.4

Group I 58

13/217685 4

27 41.1

Values are means ± SD; * p<0.05 when compared to Group I; • p<0.05 when compared to Group III.

Group III 58

15/117299*16*

33* 43.9

p 0.7 — 0.03 0.045 0.03

<0.001 0.1

10

20

30

40

50

60

80

HabitualSnoring

ExcessiveDaytime

Sleepiness

UnrefreshedSleep

Restless LegsSyndrome

PhysicalComponent

Scale

MentalComponent

Scale

P=0.02 P=0.002 P=0.03 P=0.04 P=0.01 P=0.7

*

*

*

*

Group I

Group 2

Group 3

0

%%

% %

70

Javaheri et. al., EHJ, 2004

Optimize Therapy:

ACEI; ß-Blockers; Diuretics; Digoxin

SRBD Eliminated

Persistent SRBD

Follow-up Clinically

Consider Treatment

Cardiac TransplantationMedications

TheophyllineNocturnal Nasal Oxygen

Acetazolamide

APSSV HFV

Medical Devices

nCPAPMandibular

AdvancementCardiacPacing

Ap

nea

-Hyp

op

nea

In

dex

(n

/hr)

0

10

20

30

40

50

60

70

80 Changes in AHI with low flow nasal O2 in CSA patientswith heart failure and systolic dysfunction

Room Air

Oxygen

N=9 N=7 N=11 N=7 N=22 N=29Hanly FranklinStaniforthWalsh Andreas Javaheri

p<0.0001

p<0.01

p<0.001

p=0.02

p=0.01

p<0.05

MeansSD

Effects of Supplemental Nasal O2 on CSA in SHF

• Decreases PB and central apneas

• Improves hypnogram

Ar; S1; S2

• Improves exercise capacity

• Decreases sympathetic activity

urinary norepinephrine

SMNA by microneurography

• Increases LVEF

• Improves Quality of life

• Decreases BNP

Optimize Therapy:

ACEI; ß-Blockers; Diuretics; Digoxin ,CRT

SRBD Eliminated

Persistent SRBD

Follow-up Clinically

Consider Treatment

Cardiac TransplantationMedications

TheophyllineNocturnal Nasal Oxygen

Acetazolamide

APSSV HFV

Medical Devices

nCPAPMandibular

AdvancementCardiacPacing

Data of HF Patients Undergoing Theophylline Trial

Placebo

15 15/0

66 175

88 ND

Theo

15 15/0

66 175 88 11 Values are means; ND=not detectable

Javaheri et al., NEJM, 1996, 335, 562-7

Baseline

15 15/0 66 175 89

ND

Variable

NGender, M/FAge, yHt, cmWt, kgTheo, ug/ml

Periodic Breathing at Baseline, With Placebo and Theophylline in 15 HF Patients

Placebo

37 26 2 2

17

Theo

18* 6* 2 1 8* Values are means; * p < 0.05

Javaheri et al., NEJM, 1996, 335, 562-7

Baseline

47 26 2 2

24

Variable

AHI, n/hCAI, n/hOAI, n/hMAI, n/hDBArI, n/h

Optimize Therapy:

ACEI; ß-Blockers; Diuretics; Digoxin;CRT

SRBD Eliminated

Persistent SRBD

Follow-up Clinically

Consider Treatment

Cardiac TransplantationMedications

TheophyllineNocturnal Nasal Oxygen

Acetazolamide

APSSV HFV

Medical Devices

nCPAPMandibular

AdvancementCardiacPacing

Demographics and Cardiovascular Findings in 12 SHF Patients with Central Sleep Apnea Treated

with Acetazolamide

Variable

Patients, n Age, yBMI, kg/m2

SBP, mm HgDBP, mm HgLVEF, %

Placebo

126626

1136921

ACTZ

126626

1086920

Values are means.Javaheri, AJRCCM, 2006

Baseline

126626

1106719

p

----0.91.00.80.90.5

Variable

AHI, n/h

CAI, n/h

Placebo

57

49

ACTZ

34*†

23*†

Disordered Breathing Events of 12 SHF Patients with Central Sleep Apnea Treated with Acetazolamide

Baseline

55

44

p

0.002

0.004

* p < 0.05 versus baseline † = p < 0.05 versus placebo

Patients’ Perception of Their Sleep Quality and Daytime Symptoms Comparing Acetazolamide

with Placebo

Variable

Sleep qualityWaking up refreshedDaytime fatigueFall asleep

unintentionally

Javaheri, Am J Respir Crit Care Med,2006

Acetazolamide

ImprovedImprovedImproved

Decreased

p

0.0030.0070.020.002

• The Canadian Continuous Positive Airway Pressure for Patients with CSA and Heart Failure trial tested the hypothesis that CPAP would improve the survival rate without heart transplantation of patients who have CSA and heart failure

Background

Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure

Bradley TD et al., N Engl J Med 2005;353:2025-33.

• After medical therapy was optimized, 258 patients who had heart failure, were randomly assigned to receive CPAP (128) or no CPAP (130)

• CAHI = 40/hr , LVEF = 25%, age = 63 yr

• Patients were followed for a mean of two yr

Methods

Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure

Bradley TD et al., N Engl J Med 2005

Effect of CPAP on the Frequency of Episodes of Apnea and Hypopnea

Bradley TD et al., N Engl J Med 2005

P<0.001

Control group

CPAP group

Time from Randomization (mo)

Ep

iso

des

of

Ap

ne

a a

nd

H

yp

op

ne

a (

no

. pe

r h

r o

f s

lee

p)

50

40

30

20

10

00 3 24

Bradley TD et al., N Engl J Med 2005

Heart-Transplantation-Free Survival

Tra

nsp

lan

tati

on

-fre

e S

urv

ival

(%

)

Time from Enrollment (mo)

Control group(32 events)

CPAP group(32 events)

P=0.54

100

80

60

40

20

00 12 24 36 48 60

Potential Mechanisms of CPAP Failure

1. Hemodynamic Consequences:Effects on RV Function, LV Stroke Volume, BP and CBF. Hemodynamic Effects of Atrial Fibrillation

2. Nonresponsive Patients Importance of Hpocapnia and Failure of PAP Devices to Correct it

Javaheri, JCSM, 2006

The Predictors of mortality in SHF

• N = 88; 32 with AHI <5; 56 with AHI ≥5/hr

• Mean AHI 2/hr vs. 32/hr (CAI = 23/hr)

• Median F/U : 51 months

• RVEF (HR=0.97,P=0.003), AHI (HR=2.14,P=0.01) and DBP (HR=0.96,P=0.02) independently correlated with

survival

RV Systolic dysfunction is a predictor of mortality in SHF

1. Palak, J Am Coll Cardiol, 1983

2. Disalvo, J Am Coll Cardiol, 1995

3. Gavazzi, J Heart Lung Transplant, 1997

4. Mehta, J Am Coll Cardiol, 2001

5. Karatasakis, J Am Cardiol. 1998

6. Meluzin, Int J Cardiol, 2005

7. De Groote, J Am Coll Cardiol, 1998

8. Ghio, J Am Coll Cardiol, 2001

CVD mortality in the elderlyThe lower the DBP the worse

• CV effects of SBP and DBP depend on the age

• In the Fram study, there was a gradual transition from DBP to SBP as the more important predictor of CV mortality

• After age 60 yr, the risk of CHD correlated positively with SBP and negatively with DBP

• After age 60 yr, the lower DBP was associated with a worsening CV prognosis

Franklin et al, Circulation, 2001

The risk with aggressively lowering blood pressure in HTN patients with CAD

• Low DBP and Mortality; Post hoc analysis of INVEST

• N = 22576 patients with CAD, CHF (I,II) and HTN

• The risk for the primary outcome, all-cause death and MI, but not stroke, progressively increased with low diastolic blood pressure.

• Excessive reduction in diastolic pressure should be avoided in patients with CAD who are being treated for hypertension.

• Messerli et al, AIM, 2006

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

CPAP responders*(AHI at 3 months < 15/hr, n = 57)

CPAP non-respondersCPAP non-responders(AHI at 3 months (AHI at 3 months 15/hr, n = 43) 15/hr, n = 43)

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060

Time from enrollment (months)Time from enrollment (months)

ControlControl

00

2020

4040

6060

8080

100100

Tra

nsp

lan

t-fr

ee s

urv

ival

(%

)T

ran

spla

nt-

free

su

rviv

al (

%)

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

Optimize Therapy:

ACEI; ß-Blockers; Diuretics; Digoxin

SRBD Eliminated

Persistent SRBD

Follow-up Clinically

Consider Treatment

Cardiac TransplantationMedications

TheophyllineNocturnal Nasal Oxygen

Acetazolamide

APSSV HFV

Medical Devices

nCPAPMandibular

AdvancementCardiacPacing

APSSV in CSA (mean values)

AHI

ArI

PtCO2

45*

67*

32

28*

32*

37*

6

17

34

27*

32*

35

15*

18

35

(n/hr)

(n/hr)

(mm Hg)

BaselineO2

2l/minCPAP 8-11

Bilevel IP:11-15 EP: 5-6

APSSV PI:4-10 EP: 4-6

*Significant vs. APSSV. Teschler et al., AJRCCM, 2001

APSSV in SHF/ CSA

• A randomized parallel trial using Therapeutic and Sub-therapeutic APSSV for one month

• 15 patients with SHF in each group; mean AHI = 20/hr

• AHI decreased to 5/hr in Ther. and 15 /hr in Subther. arm

• In the Ther. arm: Objective (but not subjective) EDS, BNP and urinary metadrenaline excretion decreased

Pepperell et al, AJRCCM, 2003

Studies with ASV in SHFa

Szollosi

Phillips

Pepperell*

Teschler

nAge(Y)

LVEF%

(2006)

(2001)

(2006)

(2003)

Baseline AHIn/hr

14

8

<10

5

Durationnights

30

47

47

25

ASV AHIn/hr

67

69

64

71

32

NR

29

30

1

1

180

30

10

14

12

15

Kasai (2006) 66372 38 14

CPAP vs. APSSV in Patients on Opioids

BaselinePSG

CPAP Final Setting

ADAPT Final Settings

AHI OAI CAI AHI OAI CAI AHI OAI CAI

1 74 45 29 101 0.0 101 6 0.0 0.0

2 17 0.5 3 27 0.0 22 12 0.0 0.0

3 44 4 3 61 0.0 56 1 0.0 0.0

4 83 1 60 34 0.0 33 5 0.0 0.0

Prevalence of Sleep Apnea inRecent Prospective Studies of SHF

Canada (07) (13)

China (07) (12)

Germany (07) (16)

N Zealand (05) (11)

US (06) (5)

n

%AHI

≥ 10/hr%

β blockers

%AHI

≥ 15/hr

8010

80

30

%OSA

%CSA

2137

46

15

71

68

4749

2612

25

53

52 85

287100

126

56

700

Country (y) (Ref)

9028 43203

54 8037 17102

Germany (07) (15)

Germany (07) (19)

71

UK (07) (18) 7838 1555 53

33 19 8533 19

OSA as a Cause of Mortality in SHF (Wang, JAAC, 2007)

N=37

N=113

Treatment of OSA in CHF

• Promote sleep hygiene

• Avoid ETOH , benzodiazepines and Viagra

• Weight loss• Positive airway pressure devices CPAP, bilevel• Mandibular advancement devices• Upper airway procedures• Nocturnal use of supplemental oxygen

Effects of CPAP on Systolic Heart Failure in OSA

• 24 patients with systolic HF and OSA (AHI ~40/h) were randomized to CPAP (n = 12) or a control group (n = 12)

• LVEF increased significantly following one month of CPAP therapy (25% to 34%)

• LVEF did not change significantly in the control group

Kaneko Y et al. N Engl J Med. 2003;348:1233.

CPAP = continuous positive airway pressureHF = heart failureLVEF = left ventricular ejection fraction

A controlled study of mild to moderate OSA (AHI~25, low SaO2~78%) with CPAP (9cm H2O) for 3 months in SHF

VariablesNAHI, n/hrLVEFUNEESSSF36CHF?

Control2121 181.5%21No changeNo change

CPAP1925 35% (P=0.04)10 (P=0.04)3 (P=0.01)ImprovedImproved

No change in BP, Dyspnea, VO2, NYHA, BMI or MedsMansfield et al, Am J Respir Crit Care Med, 2004

CPAP Improves Cardiac Efficiency

Open study of 7 HF /OSA compared to 5 HF/No OSA

Yoshinaga et al; JAAC, 2007

SHF/OSA

LVEFBMI AHIAge

61 37 31 38

SHF/No OSA 62 30 27 3

%Kg/m2 /hryrs

• 2D-ECHO and “C acetate PET (K mono) baseline and 6 W

• K mono = Monoexponential function fit to myocardial clearance

(rate of oxidative metabolism reflecting MVO2)

• Myocardial efficiency: LV WMI = SVI *SBP/K mono)

Yoshinaga et al; JAAC, 2007

Long-term CPAP Improves Cardiac Efficiency

CPAP Improves Cardiac Efficiency

Yoshinaga et al; JAAC, 2007

SVI

Heart rate

SHF/No OSASHF/OSA (CPAP)

59

37

141

60

42

129SBP

58

38

141

42

121

55

WMI

LVEF 38

7.1

0.047

43

8.2

0.039Kmono

43*

8.2*

0.04*

7.0

0.036

44

Base line Base line 6 wk 6 wk

38 43*

Effects of CPAP on LVEF in OSA/SHF

AHI, n / h

Duration

CPAP titration

LVEF, %

n

MansfieldKaneko SmithYoshinaga

6W

30

38

yes

3.5

19 7

3M

35

21

23

yes

NR

36

6W

38

6.2Compliance, h

40

12

4W

25

yes

5.6

Auto

Change in LVEF, % N05 59

Treatment of OSA in CHF

• Promote sleep hygiene.

• Avoid ETOH and benzodiazepines.• Weight loss.• Positive airway pressure devices, CPAP, bilevel.• Mandibular advancement devices.• Upper airway procedures.• Nocturnal use of supplemental oxygen. • Pacing does not improve OSA.

Pacing does not improve OSA

OSA without Heart Failure

1. Pepin et al, Eur Respir J, 2005

2. Luthye et al, Am J Respir Crit Med, 2005

3. Simantrikis et al, NEJM, 2005

OSA with Heart Failure

1. Garrigue et al, NEJM, 2002

2. Gabor et al, Eur Respir J, 2005

3. Pepin et al ,Eur Respir J, 2005

HR /min 64 75

Pacing Does Not Improve OSA

Baseline Pacing

AHI /hr 43 50

CAI /hr 1 2

Minimum SaO2 % 83 84

n=15; BMI=28 kg/m2; LVEF=64 % (5<56 %)

Pepin et al, ERJ;2005

Treatment of OSA in CHF

• Promote sleep hygiene.

• Avoid ETOH and benzodiazepines.• Weight loss.• Positive airway pressure devices, CPAP, bilevel.• Mandibular advancement devices.• Upper airway procedures.• Nocturnal use of supplemental oxygen.

Heart Failure in U.S.

• 1.5–2% of population (5 million)

• 6–10% of population >65 y old

• 400,000–700,000 new cases annually

• 20 million with asymptomatic cardiac impairment

• 11 million physician office visits annually

• 3.5 million hospitalizations annually

• Leading cause of hospitalization in people >65 y

• 250,000 deaths annually (direct and indirect)

• $27 billion (annual cost), 2003

• $8–15 billion per for hospitalization