Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease

Cardiovascular Disease Clinical Trial

— SAVE  

Official title:

Sleep Apnea cardioVascular Endpoints Study - Investigating the Effectiveness of Treatment With CPAP vs Standard Care in Reducing CV Morbidity and Mortality in Patients With Co-existing CV Disease and Moderate-severe Obstructive Sleep Apnea.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00738179
• Other study ID #: SAVE001
• Secondary ID: ANZCTR 126080004
• Status: Active, not recruiting
• Phase: Phase 3
• First received: August 19, 2008
• Last updated: February 4, 2015
• Start date: September 2008
• Est. completion date: December 2015

Study information

• Verified date: February 2015
• Source: Adelaide Institute for Sleep Health
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Human Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Obstructive Sleep Apnea (OSA) is a condition in which a person stops breathing for several seconds at a time due to relaxation of the throat muscles. This can occur many times during sleep. It is known to cause sleepiness and poor concentration during the day. Research indicates that OSA may be a modifiable risk factor for cardiovascular disease due to its association with hypertension, stroke, heart attack and sudden death. The standard therapy for symptomatic OSA is continuous positive airway pressure (CPAP). CPAP has been shown to effectively reduce snoring, obstructive episodes and daytime sleepiness and to modestly reduce blood pressure and other risk factors for cardiovascular disease. The overall aim of SAVE is to determine if CPAP can reduce the risk of heart attack, stroke or heart failure for people with OSA.

Description:

There is increasing evidence to indicate that OSA is an important modifiable risk factor for CV disease including stroke, MI, and heart failure. Increased nocturnal arterial blood pressure (BP), hypercoagulability, oxidative stress, inflammation, insulin resistance and cardiac arrhythmias are all associated with OSA. These effects are presumed to accelerate the progression of atheromatous disease, particularly within the coronary or cerebral vasculature. Moreover, OSA also appears to increase the risk of sudden death during sleep, which is different from the circadian pattern of sudden death in those without OSA, suggesting that episodes of apnea may have a direct triggering effect for cardiac arrhythmias or MI.

CPAP is now standard therapy for symptomatic OSA, with adherence to treatment comparable to that of other therapies for common chronic diseases. CPAP can eliminate apneas and improve daytime sleepiness, mood and quality of life. Furthermore, short term (1-3 months) randomised controlled trials of CPAP have shown modest reductions in blood pressure (BP) and other markers of CV disease, including C-reactive protein (CRP) and coagulation. However, the epidemiological data is complicated by potential residual confounding factors and the randomised evidence is limited. Thus, a direct causal link between OSA and CV disease remains inconclusive. The management of OSA, therefore, remains principally directed towards symptom control rather than CV risk modification.

The present trial aims to test whether long-term use of CPAP can reduce the incidence of CV events. If the trial shows that CPAP treatment of OSA reduces the incidence of CV events it will influence clinical practice toward the early detection and management of OSA, and add CPAP to the range of strategies available for the prevention of CV disease.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 2500
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 45 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Males and females, any race, and aged between 45 and 75 years

2. Evidence of established coronary or cerebrovascular disease as evident by:

• Coronary artery disease

• Previous MI (equal to or greater than 90 days prior to ApneaLinkTM assessment)

• Stable angina or unstable angina (Clinical event equal to or greater than 30 days and confirmatory test equal to or greater than 7 days prior to ApneaLinkTM assessment) defined as either =70% diameter stenosis of at least one major epicardial artery segment, or =50% diameter stenosis of the left main coronary artery, or >50% stenosis in at least two major epicardial arteries.; or positive stress test (ST depression equal to or greater than 2 mm or a positive nuclear perfusion scintigram)

• Multi-vessel percutaneous angioplasty (PTCA) and/or stent equal to or greater than 90 days prior to ApneaLinkTM assessment

• Multi-vessel coronary artery bypass surgery (CABG) >1 year prior to ApneaLinkTM assessment

• Cerebrovascular disease

• Previous stroke (includes definite or presumed cerebral ischaemia/infarction and intracerebral but not subarachnoid haemorrhage) equal to or greater than 90 days prior to ApneaLinkTM assessment or minor disabling stroke with minimal residual neurological disability (modified Rankin Score of '0 = no symptoms' or '1 = No significant disability despite symptoms, able to carry out all usual duties and activities' within 7 days of stroke onset) =7 days prior to ApneaLinkTM assessment.

• Previous transient ischaemic event (TIA) of the brain or retina (symptoms <24 hours) but not of presumed vertebrobasilar system ischemia. The TIA diagnosis must be confirmed by a suitably qualified clinician (=7 days but <1year prior to ApneaLinkTM assessment)

3. Patients have moderate-severe OSA (equivalent to apnea plus hypopneas index [AHI] >30 per hour of sleep) as determined by a = 4% oxygen dip rate > 12/ h on overnight testing using the ApneaLinkTM device and confirmed by the SAVE core lab in Adelaide upon receipt of the ApneaLinkTM data

4. Patients are able and willing to give appropriate informed consent

Exclusion Criteria:

Patients will be excluded from entry if ANY of the criteria listed below are met:

1. Any condition that in the opinion of the responsible physician or investigator makes the potential participant unsuitable for the study. For example,

• co-morbid disease with severe disability or likelihood of death

• significant memory, perceptual, or behavioural disorder

• neurological deficit (e.g. limb paresis) preventing self administration of the CPAP mask

• contraindication to CPAP use e.g. pneumothorax

• residence sufficiently remote from the clinic to preclude follow-up clinic visits

2. Any planned coronary or carotid revascularisation procedure in the next 6 months

3. Severe respiratory disease defined as

• severe chronic obstructive pulmonary disease (FEV1/FVC < 70% and FEV1 < 50% predicted), or

• resting, awake SaO2 < 90% by ApneaLinkTM device

4. New York Heart Association (NYHA) categories III-IV of heart failure

5. Other household member enrolled in SAVE trial or using CPAP

6. Prior use of CPAP treatment for OSA

7. Increased risk of a sleep-related accident and/or excessive daytime sleepiness, defined by any one of the following:

• driver occupation (eg truck, taxi)

• 'fall-asleep' accident or 'near miss' accident in previous 12 months

• high (> 15) score on the Epworth Sleepiness Scale

8. Severe nocturnal desaturation documented on the ApneaLinkTM device as > 10% overnight recording time with arterial oxygen saturation of < 80%

9. Cheyne-Stokes Respiration (CSResp)

• CSResp identified on ApneaLinkTM nasal pressure recording by typical crescendo-decrescendo pattern of respiration with associated apneas and/or hypopneas in the absence of inspiratory flow limitation.

• patients excluded if > 50% of nasal pressure - defined apneas and hypopneas judged to be due to CSResp.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Apnea
• Cardiovascular Disease
• Cardiovascular Diseases
• Sleep Apnea
• Sleep Apnea Syndromes
• Sleep Apnea, Obstructive

Intervention

Device:
• Continuous Positive Airway Pressure (CPAP)
CPAP worn nightly

Other:
• Standard care
Standard care of cardiovascular risk factors

Locations

Country	Name	City	State
Australia	Adelaide Institute for Sleep Health, Repatriation General Hospital	Adelaide	South Australia
Brazil	Brazil Principal Investigator: Geraldo Lorenzi Filho, Heart Institute, University of São Paulo	São Paulo
China	Regional Coordinating Centre China: The George Institute China Beijing	Beijing	Beijing
India	Regional Coordinating Centre India: The George Institute India 839C, Road No. 44A Jubilee Hills	Hyderabad	Andhra Pradesh
Spain	Regional Coordinating Centre Spain: Spanish Respiratory Society (Sociedad Española de Neumología y Cirugía Torácica) (SEPAR)	Barcelona

Sponsors (7)

Lead Sponsor	Collaborator
Adelaide Institute for Sleep Health	Fisher and Paykel Healthcare, Health Research Council, New Zealand, National Health and Medical Research Council, Australia, Philips Respironics, ResMed, The George Institute

Countries where clinical trial is conducted

Australia,  Brazil,  China,  India,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	A composite of the CV endpoints of CV death, non-fatal acute myocardial infarction, non-fatal stroke, hospital admission for heart failure, and new hospitalisation for unstable angina or transient ischaemic attack.		Reviewed 6-monthly; average patient follow up, 4.5 years	No
Secondary	Composite of CV death, MI & ischaemic stroke; components of primary composite endpoint; re-vascularisation procedures; all-cause death; new onset atrial fibrillation; new onset diabetes; OSA symptom scores; mood; health-related quality of life.		Reviewed 6-monthly; average patient follow up, 4.5 years.	No
Secondary	In a sub-sample of 600 subjects pathophysiological mechanisms of CPAP-induced CV event reduction will be explored by assessing various intermediate markers of CV risk		baseline and at 6-months, 2 and 4 years following randomisation	No
Secondary	Cardiac MRI to assess effects of CPAP on cardiac structure and function.	In a sub-sample of 150 participants (75 from the CPAP plus standard treatment and 75 from the standard treatment arms) the effect of CPAP on cardiac and vascular function using cardiac MRI will be investigated. The sub-study will evaluate left and right ventricular mass, volume and systolic/diastolic function and compliance of the aorta.	Randomisation and at 6 months follow-up	No

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