Obstructive Sleep Apnea and Obstructive Sleep Apnea and Cardiovascular Disease: A Tale of Cardiovascular Disease: A Tale of

Two Unhappy BedfellowsTwo Unhappy Bedfellows

Najib Ayas MD MPHNajib Ayas MD MPH

Associate Professor of MedicineAssociate Professor of Medicine

Sleep Disorders ProgramSleep Disorders Program

Critical Care and Respiratory Divisions Critical Care and Respiratory Divisions

University of British ColumbiaUniversity of British Columbia

Multiple Lines of Evidence Suggest that OSA Multiple Lines of Evidence Suggest that OSA causes Cardio Vascular Disease (CVD)causes Cardio Vascular Disease (CVD)

1.1. Biologic Plausibility: Basic science/animal Biologic Plausibility: Basic science/animal studies demonstrating a potential studies demonstrating a potential pathophysiologic link between OSA and CVD. pathophysiologic link between OSA and CVD.

2.2. Associations: OSA is strongly and independently Associations: OSA is strongly and independently associated with CV Risk Factors and CVD in associated with CV Risk Factors and CVD in epidemiologic studies across many populations.epidemiologic studies across many populations.

3.3. Experimental: Treatment of OSA leading to Experimental: Treatment of OSA leading to improved outcomes.improved outcomes.

Pathophysiology of Cardiovascular Disease Caused by OSA

Recurrent upper airway obstruction

Arousal From Sleep/Sleep

Fragmentation

Hypoxemia/Reoxygenation

Changes in Pleural Pressure/

Hemodynamic stress

Activation of the Sympathetic Nervous SystemOxidative Stress

Activation of Systematic InflammationHypercoagulabilityPlatelet ActivationHormonal changes

Endothelial dysfunction

HypertensionAcute strokesHeart failure

Aortic DissectionCoronary events

Glucose intoleranceObesity

Animal studies Some have focused on simulating upper airway

closure– Dogs with tracheostomies– English bulldog– Recent cat model different head positions

Most are focused on the effect of intermittent hypoxia (IH) in rats/mice– Easier to do– Don’t reproduce all the aspects of human OSA– Degree of hypoxia greater than that commonly seen in

patients with OSA– IH associated with oxidative stress, hypertension

Intermittent Hypoxia and AtherosclerosisIntermittent Hypoxia and Atherosclerosis

40 mice exposed to 12 weeks of:40 mice exposed to 12 weeks of: CIH (12 hrs/day, 5% FiO2) plus high cholesterol CIH (12 hrs/day, 5% FiO2) plus high cholesterol

dietdiet CIH plus normal dietCIH plus normal diet IA plus high cholesterol dietIA plus high cholesterol diet IA plus normal dietIA plus normal diet

Savransy et al. AJRCCM 2007.

Aortic plaques found 9/10 mice in CIH Aortic plaques found 9/10 mice in CIH plus high cholesterol groupplus high cholesterol group

Associated with increased lipids, Associated with increased lipids, increased markers of inflammation in increased markers of inflammation in the liverthe liver

No plaques in other groupsNo plaques in other groups

Human Studies:Human Studies:

Presence of OSA Associated with a Variety of CV Presence of OSA Associated with a Variety of CV Risk Markers: Risk Markers:

Catecholamine levelsCatecholamine levels CRP CRP Endothelial dysfunctionEndothelial dysfunction Leptin, adhesion Molecules (serum ICAM-1, Leptin, adhesion Molecules (serum ICAM-1,

sVCAM-1), Carotid intima media thickeningsVCAM-1), Carotid intima media thickening Markers of oxidative stressMarkers of oxidative stress

2. Association studies:2. Association studies:

Spanish study:Spanish study: 264 healthy men 264 healthy men 377 snorers without sleep apnea377 snorers without sleep apnea 403 untreated mild/moderate disease403 untreated mild/moderate disease 235 untreated severe disease235 untreated severe disease 372 treated patients372 treated patients patients followed for 10 years for incident CVD patients followed for 10 years for incident CVD

(stroke,MI, PTCA, CABG)(stroke,MI, PTCA, CABG)

Marin et al, Lancet 2005

Fatal Cardiovascular Events

Non-Fatal Cardiovascular Events

Untreated severe OSA compared to healthy Untreated severe OSA compared to healthy subjects: subjects: – increased odds ratio of fatal CVD by 2.87 (1.17-7.51)increased odds ratio of fatal CVD by 2.87 (1.17-7.51)

– nonfatal CVD by 3.17 (1.12-7.51)nonfatal CVD by 3.17 (1.12-7.51)

Odds ratios were not increased in treated patientsOdds ratios were not increased in treated patients Similar findings in older patients and women Similar findings in older patients and women

(unpublished)(unpublished)

Epidemiologic Studies Linking OSA to Vascular Epidemiologic Studies Linking OSA to Vascular OutcomesOutcomes

Aortic Dissection/Dilation: Kohler, Thorax 2009; Aortic Dissection/Dilation: Kohler, Thorax 2009; Sampol AJRCCM 2003 Sampol AJRCCM 2003

Stroke : Arzt, AJRCCM, 2005; Yaggi, NEJM 2005Stroke : Arzt, AJRCCM, 2005; Yaggi, NEJM 2005

Myocardial Infarction: Peker, Eur Respir J, 2006Myocardial Infarction: Peker, Eur Respir J, 2006

Sudden Cardiac Death: Gami, NEJM 2005Sudden Cardiac Death: Gami, NEJM 2005

Atrial Fibrillation: Gami, Circulation 2004 Atrial Fibrillation: Gami, Circulation 2004

Hypertension: Peppard, NEJM 2000Hypertension: Peppard, NEJM 2000

Major problem with non-randomized Major problem with non-randomized observational studies:observational studies:

ConfoundingConfounding– Confounding by indication/complianceConfounding by indication/compliance

– Other factors associated with sleep apnea and Other factors associated with sleep apnea and CVD CVD

Cardiovascular Outcomes

Confounding?

Central Obesity-Hypertension-Diabetes-Lipids

Confounding by Indication/Compliance

Sleep Heart Health Study Between 1995-1998, 6000 subjects enrolled in a variety of

epidemiologic cardiovascular cohorts had PSG Followed for 9 years for incident CH disease (MI,

revascularization, death from CHD)– Signal only in men <70 years (HR=1.10 for every 10 increase in

AHI; for AHI>30, 68% increased risk)

– Not in women, age>70

– Gottlieb et al. Circulation 2010

For stroke, – AHI>19 (4th quartile) had a HR of 2.86 for stroke in men

– In women, association not as robust

– Redline et al. AJRCCM 2010.

?Difference in community (survival) based vs. clinic cohort

3. Experimental Studies (RCT) in OSA: 3. Experimental Studies (RCT) in OSA:

1.1. short-term studies of surrogate endpointsshort-term studies of surrogate endpoints

2.2. Measurements of atherosclerosis in carotidMeasurements of atherosclerosis in carotid

3.3. long-term studies with clinically relevant long-term studies with clinically relevant endpointsendpoints

• Stroke, heart attacksStroke, heart attacks

Surrogate Endpoints: BPSurrogate Endpoints: BP

Blood Pressure: Reasonable surrogate as it is highly correlated with

future CV risks Effect consistent across most (but not all) drug

classes

CPAP (compared to the control group) reduces BP but effect is overall effect fairly modest (2

mm Hg) though effect greater in patients with more severe disease

Majority of studies were less than one month

AlAjmi et al, Lung 2007.; Haentjens, Arch Int Med, 2007

Two Recent Spanish RCT are consistent with these results Non-sleepy patients (ESS<11) with AHI>19/hr

– 359 hypertensive patients randomized to CPAP vs. control for 12 months

– Decreased systolic BP by 1.89 mm Hg, diastolic by 2.19 mm Hg (signal greatest if used CPAP>5.6 hrs/night)

– Barbe et al. AJRCCM 2010.

Patients with systemic hypertension and AHI>15/hr– Randomized 340 patients to CPAP vs. sham CPAP for 3 months

– 24 hr systolic BP decreased by 2.1 mm Hg, diastolic by 1.3 mm Hg

– Mean nocturnal BP decreased by 2.1 mm Hg

– Duran –Cantolla et al. BMJ 2010.

Other Surrogate Endpoints Positively Other Surrogate Endpoints Positively Impacted by CPAP:Impacted by CPAP:

Markers of inflammation (CRP), Metabolic derangements Markers of inflammation (CRP), Metabolic derangements (glucose/insulin, lipids), oxidative stress markers, (glucose/insulin, lipids), oxidative stress markers, endothelial dysfunctionendothelial dysfunction

Most of these outcomes have less robust independent Most of these outcomes have less robust independent associations with target outcomes than BPassociations with target outcomes than BP

Most of these studied small numbers of subjects, were one Most of these studied small numbers of subjects, were one month or lessmonth or less

Many were non-randomized studies (before and after)Many were non-randomized studies (before and after) Effects are inconsistentEffects are inconsistent

Direct Measurements of AtherosclerosisDirect Measurements of Atherosclerosis

24 patients with severe OSA24 patients with severe OSA Randomized to 4 months of CPAP vs. no CPAPRandomized to 4 months of CPAP vs. no CPAP After 4 months of CPAP:After 4 months of CPAP:

– Improved CRP, catecholaminesImproved CRP, catecholamines

– Reduction of CIMT with CPAPReduction of CIMT with CPAP

Drager et al. AJRCCM 2007.

Long-term studies with clinically relevant Long-term studies with clinically relevant outcomes:outcomes:

Many are ongoing:Many are ongoing: SAVESAVE

– 5000 person RCT (McEvoy, Australia)5000 person RCT (McEvoy, Australia)

MOSAICMOSAIC– Cardiac risk factors in non-sleepy patients with OSA Cardiac risk factors in non-sleepy patients with OSA

(Stradling, UK)(Stradling, UK)

ADVENTADVENT– Sleep disordered breathing in patients with CHF Sleep disordered breathing in patients with CHF

(Bradley, Toronto)(Bradley, Toronto)

Other Unanswered Questions: Impact of Non-CPAP treatments for OSA in

preventing CVD:– Dental appliances

– Anti-oxidants

– Statins

– Weight loss

Take-Home MessageTake-Home Message Accumulating data implicate OSA as a cause of Accumulating data implicate OSA as a cause of

CVDCVD Larger RCT needed and in progressLarger RCT needed and in progress Consider treatment in:Consider treatment in:

– Sleepy patients regardless of disease severitySleepy patients regardless of disease severity

– In non-sleepy patients, consider treatment if:In non-sleepy patients, consider treatment if: Moderate to severe sleep apnea (especially in the setting of Moderate to severe sleep apnea (especially in the setting of

hypoxemia)hypoxemia) Underlying CVD/risk factorsUnderlying CVD/risk factors

Treat underlying risk factors Treat underlying risk factors