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DEFINITIONS
Trial Review
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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.
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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).
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Secondary ID [1]
251872
0
None
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Universal Trial Number (UTN)
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Trial acronym
SAVE
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnea
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Cardiovascular Disease
3542
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Condition category
Condition code
Respiratory
3696
3696
0
0
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Sleep apnoea
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Cardiovascular
3697
3697
0
0
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Coronary heart disease
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Cardiovascular
3698
3698
0
0
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Other cardiovascular diseases
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
3254
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Treatment: Devices
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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.
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Control group
Active
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Outcomes
Primary outcome [1]
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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.
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Assessment method [1]
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Timepoint [1]
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Reviewed 6-monthly; average patient follow up, 4.5 years
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Secondary outcome [1]
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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.
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Assessment method [1]
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Timepoint [1]
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Reviewed 6-monthly; average patient follow up, 4.5 years
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Secondary outcome [2]
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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).
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Assessment method [2]
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Timepoint [2]
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Baseline and at 6-months, 2 and 4 years following randomisation.
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Secondary outcome [3]
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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)).
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Assessment method [3]
264361
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Timepoint [3]
264361
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Randomisation and at 6 months follow-up.
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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
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Minimum age
45
Years
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Maximum age
75
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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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.
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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).
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
22/09/2008
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Actual
28/12/2008
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Date of last participant enrolment
Anticipated
30/11/2013
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Actual
1/12/2013
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Date of last data collection
Anticipated
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Actual
3/04/2016
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Sample size
Target
2500
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Accrual to date
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Final
2717
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Recruitment in Australia
Recruitment state(s)
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Recruitment postcode(s) [1]
1094
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2010
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Recruitment postcode(s) [2]
1087
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2050
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Recruitment postcode(s) [3]
1096
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2065
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Recruitment postcode(s) [4]
1092
0
2138
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Recruitment postcode(s) [5]
1088
0
2139
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Recruitment postcode(s) [6]
1090
0
2145
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Recruitment postcode(s) [7]
1097
0
2170
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Recruitment postcode(s) [8]
1093
0
2217
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Recruitment postcode(s) [9]
1091
0
2250
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Recruitment postcode(s) [10]
1089
0
2310
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Recruitment postcode(s) [11]
1095
0
2606
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Recruitment postcode(s) [12]
1083
0
3004
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Recruitment postcode(s) [13]
1078
0
3050
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Recruitment postcode(s) [14]
1081
0
3084
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Recruitment postcode(s) [15]
1080
0
3128
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Recruitment postcode(s) [16]
1082
0
3168
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Recruitment postcode(s) [17]
1079
0
3181
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Recruitment postcode(s) [18]
1084
0
5041
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Recruitment postcode(s) [19]
1086
0
5042
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Recruitment postcode(s) [20]
1085
0
5112
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Recruitment outside Australia
Country [1]
1131
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New Zealand
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State/province [1]
1131
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Auckland
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Country [2]
1132
0
New Zealand
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State/province [2]
1132
0
Canterbury
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Country [3]
1133
0
New Zealand
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State/province [3]
1133
0
Wellington
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Country [4]
1134
0
New Zealand
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State/province [4]
1134
0
Bay of plenty
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Country [5]
1135
0
India
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State/province [5]
1135
0
Andhra Pradesh
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Country [6]
1136
0
India
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State/province [6]
1136
0
Tamil Nadu
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Country [7]
1137
0
India
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State/province [7]
1137
0
Punjab
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Country [8]
1138
0
India
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State/province [8]
1138
0
Haryana
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Country [9]
1139
0
India
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State/province [9]
1139
0
Karnataka
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Country [10]
1140
0
China
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State/province [10]
1140
0
Shanghai
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Country [11]
1141
0
China
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State/province [11]
1141
0
Guangdong
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Country [12]
1142
0
China
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State/province [12]
1142
0
Beijing
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Country [13]
1143
0
China
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State/province [13]
1143
0
Jiangsu
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Country [14]
1144
0
China
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State/province [14]
1144
0
Tianjin
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Country [15]
1145
0
China
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State/province [15]
1145
0
Inner Mongolia
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Country [16]
1146
0
Brazil
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State/province [16]
1146
0
Sao Paulo
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Country [17]
1147
0
Brazil
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State/province [17]
1147
0
Porto Alegre
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Country [18]
5172
0
Brazil
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State/province [18]
5172
0
Maringá
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Country [19]
5173
0
Brazil
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State/province [19]
5173
0
Pernambuco
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Country [20]
5174
0
Brazil
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State/province [20]
5174
0
Rio de Janeiro
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Country [21]
5175
0
Spain
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State/province [21]
5175
0
Álava
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Country [22]
5176
0
Spain
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State/province [22]
5176
0
Barcelona
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Country [23]
5177
0
Spain
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State/province [23]
5177
0
Madrid
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Country [24]
5178
0
Spain
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State/province [24]
5178
0
Asturias
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Country [25]
5179
0
Spain
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State/province [25]
5179
0
Guadalajara
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Funding & Sponsors
Funding source category [1]
3723
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Charities/Societies/Foundations
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Name [1]
3723
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Respironics Sleep and Respiratory Research Foundation
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Address [1]
3723
0
Murrayville, Pennsylvania, 15668
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Country [1]
3723
0
United States of America
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Funding source category [2]
287585
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Government body
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Name [2]
287585
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National Health and Medical Research Council
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Address [2]
287585
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Level 1, 16 Marcus Clarke Street, Canberra ACT 2601
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Country [2]
287585
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Australia
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Primary sponsor type
Charities/Societies/Foundations
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Name
Respironics Sleep and Respiratory Research Foundation
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Address
Murrayville, Pennsylvania, 15668
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Country
United States of America
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Secondary sponsor category [1]
3339
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Commercial sector/Industry
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Name [1]
3339
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ResMed Ltd
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Address [1]
3339
0
14040 Danielson Street , Poway , CA 92064-6857 , SAN FRANCISCO , 94107
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Country [1]
3339
0
United States of America
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Secondary sponsor category [2]
3340
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Commercial sector/Industry
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Name [2]
3340
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Fisher & Paykel Healthcare corporation limited
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Address [2]
3340
0
PO Box 14 348, Panmure, Auckland, 1741
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Country [2]
3340
0
New Zealand
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Secondary sponsor category [3]
3341
0
Charities/Societies/Foundations
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Name [3]
3341
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Adelaide Institute for Sleep Health
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Address [3]
3341
0
c/o Repatriation General Hospital, Daws Rd., Daw Park, SA, 5041, Australia
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Country [3]
3341
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Australia
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Secondary sponsor category [4]
256312
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Government body
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Name [4]
256312
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Health Research Council of New Zealand (HRC) Trans Tasman Clinical Trials Collaboration Grant ( for the Cardiac MRI sub-study)
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Address [4]
256312
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PO Box 5541, Wellesley Street, Auckland, 1141
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Country [4]
256312
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New Zealand
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Other collaborator category [1]
368
0
University
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Name [1]
368
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Professor Craig Anderson
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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
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Country [1]
368
0
Australia
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
5775
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Repatriation General Hospital Research and Ethics Committee
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Ethics committee address [1]
5775
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Daws Road, Daw Park, SA, 5041
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Ethics committee country [1]
5775
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Australia
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Date submitted for ethics approval [1]
5775
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22/11/2007
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Approval date [1]
5775
0
05/03/2008
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Ethics approval number [1]
5775
0
RGH 03/07
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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.
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Trial website
www.savetrial.org
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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.
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Public notes
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Contacts
Principal investigator
Name
28831
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Prof Doug McEvoy
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Address
28831
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c/o Adelaide Institute for Sleep Health, Repatriation General Hospital, Daws Rd., Daw Park, SA, 5041
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Country
28831
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Australia
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Phone
28831
0
+61 8 8275 1359
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Fax
28831
0
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Email
28831
0
doug.mcevoy@health.sa.gov.au
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Contact person for public queries
Name
11988
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Doug McEvoy
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Address
11988
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c/o Adelaide Institute for Sleep Health, Repatriation General Hospital, Daws Rd., Daw Park, SA, 5041, Australia
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Country
11988
0
Australia
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Phone
11988
0
+61 8 8275 1359
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Fax
11988
0
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Email
11988
0
doug.mcevoy@health.sa.gov.au
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Contact person for scientific queries
Name
2916
0
Doug McEvoy
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Address
2916
0
c/o Adelaide Institute for Sleep Health, Repatriation General Hospital, Daws Rd., Daw Park, SA, 5041, Australia
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Country
2916
0
Australia
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Phone
2916
0
+61 8 8275 1359
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Fax
2916
0
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Email
2916
0
doug.mcevoy@health.sa.gov.au
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No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
Impact of obstructive sleep apnoea on diabetes and cardiovascular disease.
2013
https://dx.doi.org/10.5694/mja13.10579
Embase
The Sleep Apnea cardiovascular Endpoints (SAVE) trial: Rationale, ethics, design, and progress.
2015
https://dx.doi.org/10.5665/sleep.4902
Embase
In CVD with moderate-to-severe obstructive sleep apnea, adding CPAP to usual care did not reduce major CV events.
2016
https://dx.doi.org/10.7326/ACPJC-2016-165-10-059
Embase
SAVE me from CPAP.
2016
https://dx.doi.org/10.5664/jcsm.6366
Embase
CPAP increases physical activity in obstructive sleep apnea with cardiovascular disease.
2021
https://dx.doi.org/10.5664/JCSM.8792
N.B. These documents automatically identified may not have been verified by the study sponsor.
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