Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00300599 |
| Other study ID # |
Resp/hui/2006/001 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 2006 |
| Est. completion date |
August 6, 2019 |
Study information
| Verified date |
July 2022 |
| Source |
Chinese University of Hong Kong |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Sleep-disordered breathing (SDB) briefly means cessation of breathing during sleep at least 5
times per hour. Sleep-disordered breathing affects 9 to 24% of the middle-aged and overall 4%
of the middle-aged males suffers from Obstructive sleep apnea syndrome (OSAS) i.e. SDB with
associated daytime sleepiness. Several major epidemiological studies have shown that SDB is
not only an independent risk factor for systemic hypertension but it is also associated with
cardiovascular complications such as heart failure, stroke, and sudden death.
The mechanisms for the linkage between Sleep-disordered breathing and cardiovascular diseases
are not fully determined but surges in sympathetic nerve activity are seen at the end of each
apneic episode accompanied by large rises in systemic arterial blood pressure (BP). The
increased levels of muscle sympathetic nerve activity are diminished by nasal continuous
positive airway pressure (CPAP) therapy. Numerous studies have found a hypercoagulable state
in terms of increased clotting factor and platelet activities, and impaired fibrinolysis in
coronary artery disease, ischaemic stroke, and sleep-disordered breathing. Common carotid
artery intima-media thickness (IMT) has been shown to correlate with traditional vascular
risk factors and may predict the likelihood of acute coronary events and stroke. Recently,
carotid artery intima-media thickness has been shown to have positive correlations with the
severity of sleep disordered breathing.
Despite robust evidence showing improvement of symptoms, cognitive function and quality of
life in patients with obstructive sleep apnea treated with nasal continuous positive airway
pressure, there are conflicting short-term data whether continuous positive airway pressure
can reduce blood pressure in patients with obstructive sleep apnea. This randomized
controlled study aims to assess the long-term effects of nasal continuous positive airway
pressure on 1) 24 hr systemic blood pressure; 2) Coagulation state; and 3) Carotid artery
intimal media thickness.
Description:
Subjects and Methods: We propose to carry out a prospective, randomized controlled study on
100 consecutive patients newly diagnosed with obstructive sleep apnea syndrome, as defined by
overnight sleep study showing Apnea- hypopnoea index (AHI) >or=5 per hour of sleep plus
Epworth sleepiness scale (ESS) ≥10.1 The patients will be recruited from the Respiratory
Clinic, Prince of Wales Hospital (PWH), Shatin.
Sleep assessment: Overnight diagnostic polysomnography(PSG) [Healthdyne Alice 4, USA] will be
performed at Prince of Wales Hospital, Hong Kong for every subject on the first night
recording electroencephalogram, electro-oculogram, submental electromyogram, bilateral
anterior tibial electromyogram, electrocardiogram, chest and abdominal wall movement by
inductance plethysmography, airflow measured by a nasal pressure transducer [PTAF2, Pro-Tech,
Woodinville, WA, USA]and supplemented by oronasal airflow thermister, and finger pulse
oximetry as in our previous studies.2,3 Sleep stages will be scored according to standard
criteria by Rechtshaffen and Kales.4 Apnoea is defined as cessation of airflow for > 10
seconds and hypopnea as a reduction of airflow of > 50% for > 10 seconds plus an oxygen
desaturation of > 3% or an arousal.
Ambulatory Blood Pressure Monitoring (ABPM):
All patients with obstructive sleep apnea syndrome will be fitted with the Ultralite
Ambulatory Blood Pressure Monitoring (Spacelabs Medical, Redmond, WA) via an arm cuff as
out-patients during normal activities and monitored for 48 hrs prior to commencement of
continuous positive airway pressure or conservative treatment. The patients' arm
circumference will be measured at the biceps level and an appropriate sized arm cuff will be
applied. The machine will be programmed for cuff inflation measurement every 30 minutes for
48 hrs and can only be removed for bathing. Patients will be asked to abstain from
caffeine-containing products during this time but to continue their normal daily activities.
Patients will record the time they retire to bed and the subsequent time of waking in order
to identify the sleep period. Data gathered before 6pm on the second evening will be
discarded to allow for acclimatization and the analysis will be performed with the second 24
hr of data (6pm to 6am).5 Data will be manually checked for artifact by our respiratory
fellow, who will be blinded to the treatment status of the patient. Ambulatory Blood Pressure
Monitoring will be repeated for all patients with significant OSAS at 3, 6, and 12 months of
the study.
Conservative treatment 6 months followed by continuous positive airway pressure 6 months vs
Concurrent continuous positive airway pressure+ Conservative treatment for 12 months:
Following confirmation of significant obstructive sleep apnea syndrome from the overnight
sleep study with Apnoea hyponea index ≥ 5/hr and Epworth Sleepiness Scale ≥10 and completion
of baseline Ambulatory Blood Pressure Monitoring, each patient will be interviewed by the
physician on duty and randomized by computer into either Group 1) Conservative treatment for
the first 6 months followed by therapeutic Continuous positive airway pressure for the next 6
months or Group 2) Conservative treatment plus therapeutic Continuous positive airway
pressure for 12 months. As sleepiness is the main indication for Continuous positive airway
pressure treatment, we have decided that a randomized placebo controlled design is not
feasible for this long-term study. The research nurse responsible for randomization of
patients to different treatment arms will not participate in outcome assessments, which will
be conducted by a different team of nurses who are not aware of the randomization status of
the patients.6,7 Group 1: After confirmation of significant obstructive sleep apnea syndrome,
the patients will be informed about the nature of their disease and the need to start
treatment. They are encouraged to a) avoid sleep deprivation by having sufficient hours of
sleep every night; b) sleep in lateral positions; c) avoid sedatives and alcohol consumption;
and d) lose weight by following a home diet prescribed by a dietitian.8 The patients will be
reviewed at the respiratory clinic at 1, 3 and 6 months to re-assess their sleepiness & body
mass index. Ambulatory blood pressure monitoring will be repeated at 3, 6, and 12 months. On
completion of the conservative treatment and evaluation including ambulatory blood pressure
monitoring at 6 months, patients in group 1 will be started on therapeutic continuous
positive airway pressure treatment, as outlined under group 2, after an overnight continuous
positive airway pressure titration study.
Group 2: Patients in the therapeutic continuous positive airway pressure arm will be given a
short trial of continuous positive airway pressure therapy with the Autoset (Resmed, Sydney,
Australia) device for approximately 30 minutes for acclimatization in the afternoon. Each
patient will be given a basic CPAP education programme by our respiratory nurse supplemented
by education brochure.2 Attended continuous positive airway pressure titration will be
performed with the Autoset auto-titrating device on the second night of the polysomonograph
study. All patients will be prescribed the Horizon LT 8001 continuous positive airway
pressure device (De Vilbiss, Somerset, PA, USA) with a time counter recording machine run
time. The continuous positive airway pressure pressure for each patient will be set at the
minimum pressure needed to abolish snoring, obstructive respiratory events and airflow
limitation for 95% of the night as determined by the overnight Autoset continuous positive
airway pressure titration study. 2,3 The patients will be followed up at the Respiratory
clinic at 1, 3, 6, and 12 months and the objective continuous positive airway pressure
compliance will be measured from the time counter. All patients in each arm will be followed
up at the Respiratory clinic regularly and the objective continuous positive airway pressure
usage will be measured from the time counter.
Other outcome assessment:
Prior to commencement of conservative treatment or nasal continuous positive airway pressure
, all patients have to go through several measurements. These include assessment of
subjective sleepiness with the Epworth sleepiness scale (ESS),9 quality of life with the
Calgary Sleep Apnoea Quality of Life Index (SAQLI), 10 hemostatic assays (DD, TAT,
fibrinogen, vWF:ag),11 and evaluation of carotid artery initimal media thickness.12-14 The
ESS is a questionnaire specific to symptoms of daytime sleepiness and the patients are asked
to score the likelihood of falling asleep in eight different situations with different levels
of stimulation, adding up to a total score of 0 to 24.9 The Calgary Sleep Apnea Quality of
Life Index (SAQLI) has 35 questions organized into four domains: daily functioning, social
interactions, emotional functioning and symptoms with a fifth domain, treatment-related
symptoms, to record the possible negative impacts of treatment. It contains items shown to be
important to patients with sleep apnea and is designed as a measure of outcome in clinical
trials in sleep apnea.10 The early version of the Calgary Sleep Apnea Quality of Life Index
(SAQLI) was applied previously to our study on Chinese obstructive sleep aonoea patients on
continuous positive airway pressure 2 but an updated version will be applied to this study.15
Carotid artery intimal media thickness will be assessed with B-mode Doppler according to a
standardized scanning protocol for the right and left carotid arteries using images of the
far wall of the distal 10 mm of the common carotid arteries as described by Woo et al
previously.12-14 Carotid scans will be analyzed with a computerized edge-detection system
that have previously been described and validated.12,16 Two end-diastolic frames are
selected, digitized, and analyzed for mean intimal media thickness, and the average reading
from these 2 frames is calculated for both right and left carotid arteries. The carotid scan
operator is blinded to the identity of studied subjects and stage of the study.
Hemostatic assays: After resting for 20 min in the sitting position, blood is obtained
following the polysomongraphy recording through an indwelling 22-gauge venous forearm cannula
that has been inserted the night before to minimize hemostatic activation due to emotions
related to an impending venepuncture.11 The first 2 ml of blood will be discarded and another
15 ml of blood will be drawn into sterile ethylenediamine-tetra acetic acid (EDTA)-
containing tubes (Becton Dickinson Vacutainer Systems; Franklin Lakes, New Jersey, USA).
Plasma samples are obtained by centrifugation in plastic tubes at -80C until further
processing. Plasma TAT and DD levels are measured by ELIZA as per the manufacturers
instructions (Enzyme Research Laboratories Inc., South Bend, Indiana, USA and Diagnostica
Stago, Asnieres, France). Plasma fibrinogen levels (g/l) are determined using a commercially
available assay (Thrombo-S, Dade Behring, Germany). Plasma levels of vWF:ag are measured
following a previously described ELISA 17 using commercial antibodies (DAKO Corp.,
Carpinteria, California, USA) and substrate (Bio-Rad Laboratories, Hercules, California,
USA).
Primary outcome of interest: Changes in mean systemic blood pressure between group 1 and
group 2 at 6 months.
Secondary outcome of interest: Changes in systolic and diastolic blood pressure between the 2
groups at 6 & 12 months; serial changes of carotid intimal media thickness between the two
treatment groups over 12 months; serial changes in hemostatic assays (TAT, DD, fibrinogen,
vWF:ag) between the two groups at 1 month and 6 months after treatment; Continuous positive
airway pressure compliance at 6, and 12 months; Epworth Sleepiness Scale (ESS) and the
Calgary Sleep Apnea Quality of Life Index (SAQLI) at 1, 3, 6, and 12 months.
