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Trial registered on ANZCTR


Registration number
ACTRN12608000409370
Ethics application status
Approved
Date submitted
12/08/2008
Date registered
20/08/2008
Date last updated
30/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Sleep Apnea CardioVascular Endpoints study – An investigation of continuous positive airway pressure for the treatment of obstructive sleep apnea to prevent cardiovascular disease.
Scientific title
SAVE (Sleep Apnea cardioVascular Endpoints) study
An international, multi-centre, open, parallel group, prospective, randomised, controlled trial to determine the effectiveness of treatment with continuous positive airways pressure (CPAP) in addition to standard care in reducing cardiovascular (CV) morbidity and mortality in patients with co-existing CV disease and moderate-severe obstructive sleep apnea (OSA).
Secondary ID [1] 251872 0
None
Universal Trial Number (UTN)
Trial acronym
SAVE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnea 3541 0
Cardiovascular Disease 3542 0
Condition category
Condition code
Respiratory 3696 3696 0 0
Sleep apnoea
Cardiovascular 3697 3697 0 0
Coronary heart disease
Cardiovascular 3698 3698 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients allocated to the CPAP group will be commenced on fixed level CPAP (90th centile of pressures determined during a 1 week treatment period using auto CPAP). Adherence will be monitored using the in-built monitor in each CPAP device. Treatment with CPAP involves a mask placed over the nose, or both the nose and mouth during sleep. The mask is attached via a hose to a CPAP machine, which gently pushes air into the lungs opening the obstructed airways. Treatment will continue for 2-7 years post randomisation depending on the patient’s date of enrolment. In addition, patients will receive standard care of their CV co-morbidities as directed by their regular doctor(s). Patients who continue to use CPAP (even on an intermittent basis) will have the treatment continued indefinitely.
Intervention code [1] 3254 0
Treatment: Devices
Comparator / control treatment
Patients allocated to this group will receive standard care of their CV co-morbidities as directed by their regular doctor(s). Standard care will continue for 2-7 years post randomisation depending on the patient’s date of enrolment.
Control group
Active

Outcomes
Primary outcome [1] 4601 0
The primary outcome will be 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. These reported events will be verified from investigator reports, hospital records (including where applicable results of serial ECGs and cardiac enzymes, CT brain scans, chest radiographs and other investigations) and post-mortem or death certificates.
Timepoint [1] 4601 0
Reviewed 6-monthly; average patient follow up, 4.5 years
Secondary outcome [1] 7765 0
Secondary outcomes will include: a) a composite of CV death, myocardial infarction (MI) and ischaemic stroke, b) the individual components of the primary composite endpoint, c) re-vascularisation procedures, d) all-cause death, e) new onset atrial fibrillation, f) new onset diabetes, g) OSA symptom scores, h) mood i) health-related quality of life.
Timepoint [1] 7765 0
Reviewed 6-monthly; average patient follow up, 4.5 years
Secondary outcome [2] 7766 0
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 (blood pressure, serum lipids and glucose, Haemoglobin A1C, N-terminal fragment of the prohormone Brain-type Natriuretic Peptide and new onset atrial fibrilationand diabetes).
Timepoint [2] 7766 0
Baseline and at 6-months, 2 and 4 years following randomisation.
Secondary outcome [3] 264361 0
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 magnetic resonance imaging (MRI) will be investigated. The sub-study will evaluate left and right ventricular mass, volume and systolic/diastolic function, compliance of the aorta, pathophysiological markers of left ventricular (LV) dysfunction/atherosclerosis (N-terminal prohormone brain natriuretic peptide (NT-proBNP) and high sensitivity C reactive protein (hs-CRP)) and, traditional CV risk factors (blood pressure (BP), serum lipids, glucose and haemoglobin A1c (HbA1c)).
Timepoint [3] 264361 0
Randomisation and at 6 months follow-up.

Eligibility
Key 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;
(a) Coronary artery disease.
i. Previous MI (greater than or equal to 90 days prior to ApneaLinkTM assessment); or
ii. Stable angina or unstable angina (Clinical event greater than or equal to 30 days and confirmatory test equal to or greater than 7 days prior to ApneaLinkTM assessment) defined as either greater than or equal to 70% diameter stenosis of at least one major epicardial artery segment, or greater than or equal to 50% diameter stenosis of the left main coronary artery, or greater than 50% stenosis in at least two major epicardial arteries, or positive stress test (ST depression greater than or equal to 2 mm or a positive nuclear perfusion scintigram); or
iii. Multi-vessel percutaneous angioplasty (PTCA) and/or stent greater than or equal to 90 days prior to ApneaLinkTM assessment; or
iv. Multi-vessel coronary artery bypass surgery (CABG) greater than 1 year prior to ApneaLinkTM assessment
(b) Cerebrovascular disease
i. Previous stroke (includes definite or presumed cerebral ischaemia/infarction and intracerebral but not subarachnoid haemorrhage) greater than or equal to 90 days prior to ApneaLinkTM assessment; or or minor disabling stroke with minimal residual neurological disability (modified Rankin Score of ‘0 equal to no symptoms’ or ‘1 equal to No significant disability despite symptoms, able to carry out all usual duties and activities’ within 7 days of stroke onset) greater than or equal to 7 days prior to ApneaLinkTM assessment; or
ii. Previous transient ischaemic event (TIA) of the brain or retina (symptoms less than 24 hours) but not of presumed vertebrobasilar system ischemia. The TIA diagnosis must be confirmed by a suitably qualified clinician (greater than or equal to 7 days but less than 1 year prior to ApneaLinkTM assessment)
3. Patients have moderate-severe OSA (equivalent to apnea plus hypopneas index [AHI] greater than 30 per hour of sleep) as determined by a greater than 4% oxygen dip rate greater than 12/ h on overnight testing using the ApneaLinkTM device and confirmed by the SAVE corelab in Adelaide upon receipt of the ApneaLink data; and
4. Patients are able and willing to give appropriate informed consent
Minimum age
45 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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,
i. co-morbid disease with severe disability or likelihood of death
ii. significant memory, perceptual, or behavioural disorder
iii. neurological deficit (eg. limb paresis) preventing self administration of the CPAP mask
iv. contraindication to CPAP use e.g. pneumothoraxv 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
i. severe chronic obstructive pulmonary disease (FEV1/FVC greater than 70% and FEV1 less than 50% predicted), or
ii. resting, awake SaO2 less than 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:
i. driver occupation (eg truck, taxi)
ii. ‘fall-asleep’ accident or ‘near miss’ accident in previous 12 months
iii. high (greater than 15) score on the Epworth Sleepiness Scale
8. Severe nocturnal desaturation documented on the ApneaLinkTM device as i. greater than 10% overnight recording time with arterial oxygen saturation of less than 80%
9. Cheyne-Stokes Respiration (CSResp)
i. 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.
ii. patients excluded if greater than 50% of nasal pressure – defined apneas and hypopneas judged to be due to CSResp.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Once CV eligibility criteria are confirmed the subject wil be sent home with a sleep apnea diagnostic device (ApneaLinkTM, ResMed) to make an overnight measurement. Data from the ApneaLink will be reviewed by expert sleep technicians for verification of the OSA diagnostic criteria for entry in the study.
Eligible subjects will undergo a 1-week run-in phase using sham CPAP to determine their level of treatment adherence to the device and study protocol. Subjects who do not accept or adhere to CPAP mask therapy, will be excluded from further participation in the trial.
After eligibility in the study has been confirmed, subjects will be randomised via a centralised web-based system. The treatment group is concealed until assigned.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A minimisation program will stratify treatment allocation by type of CV disease (cardiac or cerebrovascular) and by a measure of OSA severity( minimisation cut off for OSA severity on the Epworth sleepiness scale is >=11 and <11).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 1078 0
3050
Recruitment postcode(s) [2] 1079 0
3181
Recruitment postcode(s) [3] 1080 0
3128
Recruitment postcode(s) [4] 1081 0
3084
Recruitment postcode(s) [5] 1082 0
3168
Recruitment postcode(s) [6] 1083 0
3004
Recruitment postcode(s) [7] 1084 0
5041
Recruitment postcode(s) [8] 1085 0
5112
Recruitment postcode(s) [9] 1086 0
5042
Recruitment postcode(s) [10] 1087 0
2050
Recruitment postcode(s) [11] 1088 0
2139
Recruitment postcode(s) [12] 1089 0
2310
Recruitment postcode(s) [13] 1090 0
2145
Recruitment postcode(s) [14] 1091 0
2250
Recruitment postcode(s) [15] 1092 0
2138
Recruitment postcode(s) [16] 1093 0
2217
Recruitment postcode(s) [17] 1094 0
2010
Recruitment postcode(s) [18] 1095 0
2606
Recruitment postcode(s) [19] 1096 0
2065
Recruitment postcode(s) [20] 1097 0
2170
Recruitment outside Australia
Country [1] 1131 0
New Zealand
State/province [1] 1131 0
Auckland
Country [2] 1132 0
New Zealand
State/province [2] 1132 0
Canterbury
Country [3] 1133 0
New Zealand
State/province [3] 1133 0
Wellington
Country [4] 1134 0
New Zealand
State/province [4] 1134 0
Bay of plenty
Country [5] 1135 0
India
State/province [5] 1135 0
Andhra Pradesh
Country [6] 1136 0
India
State/province [6] 1136 0
Tamil Nadu
Country [7] 1137 0
India
State/province [7] 1137 0
Punjab
Country [8] 1138 0
India
State/province [8] 1138 0
Haryana
Country [9] 1139 0
India
State/province [9] 1139 0
Karnataka
Country [10] 1140 0
China
State/province [10] 1140 0
Shanghai
Country [11] 1141 0
China
State/province [11] 1141 0
Guangdong
Country [12] 1142 0
China
State/province [12] 1142 0
Beijing
Country [13] 1143 0
China
State/province [13] 1143 0
Jiangsu
Country [14] 1144 0
China
State/province [14] 1144 0
Tianjin
Country [15] 1145 0
China
State/province [15] 1145 0
Inner Mongolia
Country [16] 1146 0
Brazil
State/province [16] 1146 0
Sao Paulo
Country [17] 1147 0
Brazil
State/province [17] 1147 0
Porto Alegre
Country [18] 5172 0
Brazil
State/province [18] 5172 0
Maringá
Country [19] 5173 0
Brazil
State/province [19] 5173 0
Pernambuco
Country [20] 5174 0
Brazil
State/province [20] 5174 0
Rio de Janeiro
Country [21] 5175 0
Spain
State/province [21] 5175 0
Álava
Country [22] 5176 0
Spain
State/province [22] 5176 0
Barcelona
Country [23] 5177 0
Spain
State/province [23] 5177 0
Madrid
Country [24] 5178 0
Spain
State/province [24] 5178 0
Asturias
Country [25] 5179 0
Spain
State/province [25] 5179 0
Guadalajara

Funding & Sponsors
Funding source category [1] 3723 0
Charities/Societies/Foundations
Name [1] 3723 0
Respironics Sleep and Respiratory Research Foundation
Address [1] 3723 0
Murrayville, Pennsylvania, 15668
Country [1] 3723 0
United States of America
Funding source category [2] 287585 0
Government body
Name [2] 287585 0
National Health and Medical Research Council
Address [2] 287585 0
Level 1, 16 Marcus Clarke Street, Canberra ACT 2601
Country [2] 287585 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Respironics Sleep and Respiratory Research Foundation
Address
Murrayville, Pennsylvania, 15668
Country
United States of America
Secondary sponsor category [1] 3339 0
Commercial sector/Industry
Name [1] 3339 0
ResMed Ltd
Address [1] 3339 0
14040 Danielson Street , Poway , CA 92064-6857 , SAN FRANCISCO , 94107
Country [1] 3339 0
United States of America
Secondary sponsor category [2] 3340 0
Commercial sector/Industry
Name [2] 3340 0
Fisher & Paykel Healthcare corporation limited
Address [2] 3340 0
PO Box 14 348, Panmure, Auckland, 1741
Country [2] 3340 0
New Zealand
Secondary sponsor category [3] 3341 0
Charities/Societies/Foundations
Name [3] 3341 0
Adelaide Institute for Sleep Health
Address [3] 3341 0
c/o Repatriation General Hospital, Daws Rd., Daw Park, SA, 5041, Australia
Country [3] 3341 0
Australia
Secondary sponsor category [4] 256312 0
Government body
Name [4] 256312 0
Health Research Council of New Zealand (HRC) Trans Tasman Clinical Trials Collaboration Grant ( for the Cardiac MRI sub-study)
Address [4] 256312 0
PO Box 5541, Wellesley Street, Auckland, 1141
Country [4] 256312 0
New Zealand
Other collaborator category [1] 368 0
University
Name [1] 368 0
Professor Craig Anderson
Address [1] 368 0
The George Institute for International Health, Level 10, King George V Building
Royal Prince Alfred Hospital Missenden Road, Camperdown NSW 2050
Country [1] 368 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5775 0
Repatriation General Hospital Research and Ethics Committee
Ethics committee address [1] 5775 0
Daws Road, Daw Park, SA, 5041
Ethics committee country [1] 5775 0
Australia
Date submitted for ethics approval [1] 5775 0
22/11/2007
Approval date [1] 5775 0
05/03/2008
Ethics approval number [1] 5775 0
RGH 03/07

Summary
Brief summary
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 over 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 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.
Trial website
www.savetrial.org
Trial related presentations / publications
McEvoy, R., Antic, N., Heeley, E., Luo, Y., Ou, Q., Zhang, X., Mediano, O., Chen, R., Drager, L., Liu, Z., Chen, G., Du, B., McArdle, N., Mukherjee, S., Tripathi, M., Billot, L., Li, Q., Lorenzi-Filho, G., Barbe, F., Redline, S., Wang, J., Arima, H., Neal, B., White, D., Grunstein, R., Zhong, N. and Anderson, C. (2016). CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. New England Journal of Medicine, 375(10), pp.919-931.
Public notes

Contacts
Principal investigator
Name 28831 0
Prof Doug McEvoy
Address 28831 0
c/o Adelaide Institute for Sleep Health, Repatriation General Hospital, Daws Rd., Daw Park, SA, 5041
Country 28831 0
Australia
Phone 28831 0
+61 8 8275 1359
Fax 28831 0
Email 28831 0
doug.mcevoy@health.sa.gov.au
Contact person for public queries
Name 11988 0
Prof Doug McEvoy
Address 11988 0
c/o Adelaide Institute for Sleep Health, Repatriation General Hospital, Daws Rd., Daw Park, SA, 5041, Australia
Country 11988 0
Australia
Phone 11988 0
+61 8 8275 1359
Fax 11988 0
Email 11988 0
doug.mcevoy@health.sa.gov.au
Contact person for scientific queries
Name 2916 0
Prof Doug McEvoy
Address 2916 0
c/o Adelaide Institute for Sleep Health, Repatriation General Hospital, Daws Rd., Daw Park, SA, 5041, Australia
Country 2916 0
Australia
Phone 2916 0
+61 8 8275 1359
Fax 2916 0
Email 2916 0
doug.mcevoy@health.sa.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary