SHOULD ALL OBSTRUCTIVE SLEEP APNEA PATIENTS BE TREATED? “YES!” Yüksel Peker MD*, PhD**

SHOULD ALL OBSTRUCTIVE SLEEP APNEA PATIENTS BE TREATED?

YES!

Yksel PekerMD*, PhD**

*Sleep Medicine Unit, Skaraborg Hospital, Skvde & **University of Gothenburg, Sweden

OSA (Asymptomatic OSA; Non-sleepy sleep apnoeics)

OSAS (Symptomatic OSA; Sleepy sleep-apnoeics)

Wisconsin Sleep Cohort (age 30-60 yrs)Men Women OSA 24 %9 % OSAS4 %2 % Young et al, N Engl J Med 1993; 328: 1230-1235

Majority of the OSA patients do not report daytime sleepiness

Eight-year follow-up AHI versus baseline AHI in the Wisconsin Sleep Cohort Study (n= 282) Young T et al, AJRCCM 2002OSA increases by age

Bixler et al, AJRCCM 1998%OSAS decreases after age of 64?Do theybecome asymptomatic? die?

OSA

Immediate changes

Long-term effects

Modified from Grote L, Schneider H, 1997

Acute Blood Pressure Changes in OSA - Mechanisms -

Part

SaO2

EMG

EEG

EOG

Flow

Effort

30 sec

REM-sleepapneatachycardiacomplete AV blockarousalmodified from Becker et al, AJRCCM 1995

Cardiovascular mechanisms (I)

Repeated nocturnal hypoxemiaCoccogna G et al, 1972; Podszus T et al, 1986

Sympathetic nervous activity Fletcher EC et al, 1987; Hedner J et al, 1988; Narkiewicz K & Somers VK 2003 Vascular endothelial dysfunction Carlson J et al, 1996; Remsburg S et al, 1999; Kraiczi H et al, 2000

Cardiovascular mechanisms (II)

Enhanced release of superoxide from polymorphonuclear neutrophils in OSA. Impact of CPAP. Schulz R et al, AJRCCM 2000

Plasma vascular endothelial growth factor in OSAS: Effects of CPAP. Lavie L et al, AJRCCM 2002 Elevated levels of C-reactive protein and interleukin-6 in patients with OSAS are decreased by CPAP. Yokoe T et al, Circulation 2003

OSA & CVD

Immediate changes

Long-term effects

Hypnogram

00:0002:0004:0006:0008:00S4S3S2S1REMWakeMTLights Out00:0001:0002:0003:0004:0005:0006:0007:00S4S3S2S1REMWakeMTLights OutNormalOSA

Long-term complications

Cognitive dysfunctionDaytime sleepiness

Cardiovascular dysfunction

DAYTIME SLEEPINESS

Sleepy OSA patients should be treated!

No doubt!

Evidence based data on impact of treatment regarding daytime sleepiness, quality of life!

Ballester E, et al, AJRCCM 1999Farre R, et al, Lancet 1999Benson K, Hartz AJ. N Engl J Med 2000

How to treat?

CVD OSAObesity

Treatment of sleep apnea

Weight reductionGastric by-passCPAPPalatal surgeryOral devicesTracheostomyDrugs?

Why to treat all OSA patients regardless daytime sleepiness?

Clinical and epidemiological aspects

Obstructive sleep apnea is associated withHypertensionCoronary heart diseaseCardiac arrhythmias Heart failureStrokeDiabetes and Insulin ResistanceMortality

MORTALITY

%Mortality in severe OSAS patients at 5 to 7-yr follow-up(AHI 5527, age 5310 yrs, BMI 325 kg/m2 at baseline)modified from Marti S et al, ERJ 2002

Long-term cardiovascular outcomes in men with OSA with or without treatment with CPAP: an observational study

Marin JM et al Lancet 2005; 365:1046-53

Long-term cardiovascular outcomes in men with OSA with or without CPAP

Sleep clinic (1992-1994), PSG 1465 Simple snorers (n=377) OSA (n=1071) CPAP recommended (n=667) CPAP accepted (n=426) Untreated severe OSA (AHI>30, n=235)

Healthy controls (n=264) individually matched with the severe untreated OSA for age and BMI (AHI

Variables HealthySnorersMild Severe CPAP men OSA OSA treated at baseline (AHI 5-30) (AHI>30)

Patients (n) 264 377 403 235 372

AHI* n/h 1 4 18 43 42 Age yrs 49 50 50 50 50BMI* kg/m2 30 26 28 30 31Hypertens.* (%) 15 18 25 35 35Diabetes (%) 7 7 7 8 8Smokers (%) 23 23 24 25 25

Marin JM et al, Lancet 2005

%Cardiovascular events in men during 10 yearsmodified from Marin JM et al, Lancet 2005******

Fully adjusted Odds Ratios for cardiovascular death associated with clinical variables

OR (95% CI)p

Age, yrs1.09 (1.04-1.12)0.001Snoring1.03 (0.31-1.84)0.88Mild OSA1.15 (0.34-2.69)0.71Severe OSA2.87 (1.17-7.51)0.025CPAP1.05 (0.39-2.21)0.74Cardiovascular disease2.54 (1.31-4.99)0.005Marin JM et al, Lancet 2005

OVERALL CARDIOVASCULAR DISEASE

Peker et al, AJRCCM 2002; 166: 159-65

FOURVARIABLES

6.56.756.8

4.16.727

3.3021.6

1.6016.2

Non OSA (n=122)

Efficiently treated OSA (n=15)

Incompletely treated OSA (n=37)

%

Incidence of cardiovascular disease during a 7-year follow-upin otherwise healthy middle-aged men at baseline

Blad1

OSA (ineffectively treated)OSA (effectively treated)Non OSA

Coronary Artery Disease804

Hypertension1015

Cardiovascular Disease2118

Non OSA (n=122)Efficiently treated OSA (n=15)Incompletely treated OSA (n=37)

Cardiovascular disease6.56.756.8

Hypertension4.16.727.0

Coronary artery disease3.3021.6

Cardiovascular event1.6016.2

HYPERTENSION

OSA as an independent risk factor for hypertension (sleep-clinic population, n=599)

Grote et al., AJRCCM, 1999

Chart1

11.522.072.154.15

BMI (kg/m2)123.24.96

Age (years)11.831.982.98

GenderGender11.1Gender

= 40Systolic and diastolic hypertension72.654.833.919.44.8

% hypertensive patients41.660.369.170.386.2

% controlled hypertensives28.814.724.613.9811.96

< 55 -< 1010 - < 2020 - < 40> = 40

% hypertensive patients20.533.738.53553.4

< 55 -< 1010 - < 2020 - < 40> = 40

% controlled hypertensives28.814.724.613.9811.96

5 = 405 = 40

% hypertensive patients on treatment25.545.654.470.4% hypertensive patients (total 798)41.666.770.386.2

% controlled hypertension on treatment28.820.913.9811.96% hypertensive patients on treatment (total 599)25.545.654.470.4

% controlled hypertension on treatment (total 100 out of 599)33.825.82117.7

Sheet3

Control of Hypertension in OSA

Grote et al., J. Hypertension, 2000

Chart3

130.1

132.9

137.3

146.2

Systolic Blood Pressure

Age

mmHg

Systolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591 patients, no antihypertensive medication)

Chart4

83.6

86.2

88

85.1

Diastolic Blood Pressure

Age

mmHg

Diastolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart5

69.8

71.2

72.6

72.5

Heart Rate

Age

bpmin-1

Heart Rate and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart6

46.5

46.8

49.4

57.1

Pulse Pressure

age

mmHg

Pulse Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart7

13.9

19.5

20.7

22.1

RDI

age

events/hour of sleep

OSA activity (RDI) and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive mediaction)

Chart8

130.183.669.8

132.986.271.2

137.38872.6

146.285.172.5

&A

Page &P



Heart Rate

Age

mmHg/bpmin-1

Blood Pressure and Heart Rate in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart9

21.527.715.410.824.6

20.611.82517.625

25.417.516.717.522.8

14.719.619.621.724.5

1114.416.724.933

RDI-Classes

sys bp = 170

% patients

Control of systolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart10

15.423.19.227.724.6

10.313.210.329.436.8

14.921.99.627.226.3

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% patients

Control of diastolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart11

10.833.8

5.920.6

9.628.9

4.221

4.817.7

controlled hypertension < 140/90


RDI Classes

% patients

Control of hypertension in relation to OSA activity (n=599)

Chart1

51.212.70.613.921.7

37.613.9216.829.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

RDI-Classes

% patients

Type of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centrewith no previous history of hypertension (n=591)

Chart2

51.24161.8

37.643.616.82

32.853.410.32.6

30.850.815.82.5

34.134.1255.7

normotension

stage 1 hypertension



RDI Classes

% patients

Stage of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart18

21.527.715.410.824.6

23.615.419.817.623.6

14.719.619.621.724.5

1114.416.724.933

sys bp = 170

RDI-Classes

% Patients

Chart23

15.423.19.227.724.6

13.218.79.92830.2

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% patients

Chart24

10.833.8

8.225.8

4.221

4.817.7



RDI-Classes

% patients

Chart25

51.212.70.613.921.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension



diastolic hpt


DI-Classes

% patients

Type of Hypertension and OSA ActivityPatients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart26

51.24161.8

3548.813.42.3

30.850.815.82.5

34.134.1255.7

normotension




RDI-Classes

% patients

Stage of Hyperetnsion and OSA Activity Patients from the Marurg Sleep Disorders Clinic with no previous history of hypertension (n=591)

Chart28

12.70.613.921.7

14.70.921.630.2

102.521.735

6.83.411.444.3



diastolic hpt


RDI Classes

% patients

Type of Hypertension and OSA Activity Newly diagnosed hypertensive Patients referred to the Marburg Sleep Disorders Centre (n=363)

Chart29

4161.8

48.813.42.3

50.815.82.5

34.1255.7




RDI-Classes

% patients

Stage of Hypertension and OSA Activity Newly diagnosed hypertensive patients referred to the Marburg Sleep Disorders Centre (n=363)

Sheet1

Stage of Hypertension and OSA

Grote et al., J Hypertens. 2001

Chart3

130.1

132.9

137.3

146.2


Age

mmHg

Systolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591 patients, no antihypertensive medication)

Chart4

83.6

86.2

88

85.1


Age

mmHg

Diastolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart5

69.8

71.2

72.6

72.5

Heart Rate

Age

bpmin-1

Heart Rate and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart6

46.5

46.8

49.4

57.1

Pulse Pressure

age

mmHg

Pulse Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart7

13.9

19.5

20.7

22.1

RDI

age

events/hour of sleep

OSA activity (RDI) and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive mediaction)

Chart8

130.183.669.8

132.986.271.2

137.38872.6

146.285.172.5

&A

Page &P



Heart Rate

Age

mmHg/bpmin-1

Blood Pressure and Heart Rate in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart9

21.527.715.410.824.6

20.611.82517.625

25.417.516.717.522.8

14.719.619.621.724.5

1114.416.724.933

RDI-Classes

sys bp = 170

% patients

Control of systolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart10

15.423.19.227.724.6

10.313.210.329.436.8

14.921.99.627.226.3

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% patients

Control of diastolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart11

10.833.8

5.920.6

9.628.9

4.221

4.817.7



RDI Classes

% patients

Control of hypertension in relation to OSA activity (n=599)

Chart1

51.212.70.613.921.7

37.613.9216.829.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension



diastolic hpt


RDI-Classes

% patients

Type of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centrewith no previous history of hypertension (n=591)

Chart2

51.24161.8

37.643.616.82

32.853.410.32.6

30.850.815.82.5

34.134.1255.7

normotension




RDI Classes

% patients

Stage of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart18

21.527.715.410.824.6

23.615.419.817.623.6

14.719.619.621.724.5

1114.416.724.933

sys bp = 170

RDI-Classes

% Patients

Chart23

15.423.19.227.724.6

13.218.79.92830.2

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% Patients

Chart24

10.833.8

8.225.8

4.221

4.817.7



RDI-Classes

% patients

Chart25

51.212.70.613.921.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension



diastolic hpt


DI-Classes

% patients

Type of Hypertension and OSA ActivityPatients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart26

51.24161.8

3548.813.42.3

30.850.815.82.5

34.134.1255.7

normotension




RDI-Classes

% patients

Stage of Hyperetnsion and OSA Activity Patients from the Marurg Sleep Disorders Clinic with no previous history of hypertension (n=591)

Chart28

12.70.613.921.7

14.70.921.630.2

102.521.735

6.83.411.444.3



diastolic hpt

combined systolic and diastolic hpt

RDI-Classes

% patients

Chart29

4161.8

48.813.42.3

50.815.82.5

34.1255.7

grade 1 hypertension



RDI-Classes

% patients

Sheet1

Lavie P et al; BMJ 2000;320:479-482OSA as a risk factor for hypertension (sleep-clinic population, n=2677)

OR FOR HYPERTENSION

Odds ratio

Wald 95% CI

3.5

3.0

2.5

2.0

1.5

1.0

5

10

15

20

30

40

50

60

70

APN-HYPOPNINDEX (per hour)

Samband mellan hypertoni och apn-hypopn index hos 2452 oselekterade patienter remitterade till ett smnlaboratorium under en 10-rs period. Odds ratio och Wald 95% KI fr hypertension associerad med AHI niver av 5,15,30,40,50,60,och 70predikterade genom bst anpassad multipel logistisk modell: T=e.012apn-hypopn index+.081lder+.161manligt kn+.067BMI . Omarbetad frn Lavie et al. BMJ 2000; 320:479-82.

OSA & HT in a general population

Sleep Heart Health Study Cross-sectional analysis (n=6,132) Adjusted OR for HT 1.37 (95% CI 1.03-1.83) (AHI>30 versus AHI

Incidence of HT in a general population

Wisconsin Sleep Cohort Prospective 4-yr follow-up (n=893)

AHI Adj. OR95% CI0 10.1-4.9 1.41.1-1.85.0-14.9 2.01.3-3.2>=15 2.91.5-5.6

Peppard PE et al, N Engl J Med 2000;342:1378-1384

Pepperell J et al, LANCET 2001; 359: 204-210Ambulatory BP after therapeutic and subtherapeutic CPAP for OSA: a randomised parallel trial

Normotensive & HypertensiveOSAS (n=118)More BP-reduction in hypertensivesMore BP-reduction in severe OSAS

CORONARY ARTERY DISEASE

OSA & CAD in a general population

Sleep Heart Health Study Cross-sectional analysis (n=6,132) Adjusted OR for CAD 1.27 (95% CI 0.99-1.62) (AHI>11 versus AHI

Peker et al, Eur Resp J 1999; 14: 179-84Prevalence of risk factors (%) OSA & Coronary Artery Disease

Explanatory variables associated with CAD (multivariate analysis) ______________________________________________________________ Odds Ratio 95 % CI p values ______________________________________________________________Current smoking9.82.6-36.50.001Diabetes mellitus4.21.1-17.10.045Obstructive sleep apnea3.11.2-8.30.025______________________________________________________________

Peker et al, Eur Resp J 1999; 14: 179-84

Prevalence of OSA in CAD

First author; publ yrnAHI>10controlsDe Olazabal; 1982 Andreas S; 1996Mooe T; 1996Mooe T; 1996Koehler U; 1996Peker Y; 1999Moruzzi P; 1999Sanner BM; 200117501421027462224976%50%37%30%35%31%9%27%nonoyesyesnoyesnono

Total51837%

Peker et al, AJRCCM 2000; 162:81-86

Hazard function of death estimated by use of Poisson modelPeker et al, AJRCCM 2000; 162:81-86

Eur Resp J, in press

CAD incidence in a sleep-clinic cohort at a 7-yr follow-up***%Eur Resp J, in press

Probability of CAD incidence estimated by Poisson model

(Start age 49 yrs, Systolic BP 133 mmHg and Sat. min 86%)

Eur Resp J, in press.

Eur Resp J, in press

CONCLUSIONS (I)

Recurrent obstructive events during sleep, independently or in concert with other recognized risk factors, have harmful effects on vascular structure and function.

CVD development and proneness to CVD complications are likely to depend on genotypic and phenotypic factors.

Not only may OSA induce a CVD but also the events in themselves may aggravate an already existing CVD.

CONCLUSIONS (II)

OSA should be included among factors considered in the primary and secondary prevention models of CVD.

OSA should be treated not only to eliminate daytime sleepiness. Treatment may also have a beneficial prognostic impact by reducing cardiovascular morbidity in OSA.

SHOULD ALL OBSTRUCTIVE SLEEP APNEA PATIENTS BE TREATED?

YES!

*********************

Documents

SHOULD ALL OBSTRUCTIVE SLEEP APNEA PATIENTS BE TREATED? “YES!” Yüksel Peker MD*, PhD**