Obstructive Sleep Apnea Treatment to Improve Cardiac Rehabilitation
Phase: NA
Conditions: Obstructive Sleep Apnea, Coronary Heart Disease
Sponsor: VA Office of Research and Development

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Obstructive Sleep Apnea Treatment to Improve Cardiac Rehabilitation 
NCT02005445 
Protocol Final Version Date: January 1, 2017 
 
 

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STUDY PROTOCOL 
Obstructive Sleep Apnea Treatment to Improve Cardiac Rehabilitation 
 
Overview 
The proposed study is a randomized, parallel group study comparing three months of 
therapy with continuous positive airway pressure (CPAP) to an educational control for 
patients with comorbid obstructive sleep apnea and coronary heart disease undergoing 
a structured cardiac rehabilitation program.  The study will be conducted over 2 years 
and participants will be recruited from among patients seen at the VA Boston 
Healthcare Systems with a diagnosis of coronary heart disease and referred to the 
Cardiac Rehabilitation Program.   A total of approximately 150 patients will be recruited 
in order to randomize 25 patients to each group (CPAP or Control).  Participation of an 
individual subject will be approximately 1 week for subjects not meeting criteria for 
randomization, and 8-10 weeks for subjects randomized.  Participants will be age 18 
and over, of either gender, have a diagnosis of coronary heart disease, and be referred 
to the Cardiac Rehabilitation Program at the VA Boston Healthcare System.  No 
children or other special classes of individuals will be enrolled. All enrolled subjects will 
be veterans.   
 
(1) RATIONALE 
(a) Statement of the Problem:  
Coronary heart disease is the leading cause of death in the United States and a major 
cause of disability.  Cardiac rehabilitation programs that include an exercise training 
intervention have been shown to reduce cardiac mortality by approximately 25%, with 
improved exercise tolerance and peak oxygen consumption, and a concomitant 
improvement in functional status and quality of life.  Unfortunately, many patients 
entering cardiac rehabilitation programs do not complete them, and the increase in 
exercise capacity among completers is variable.  Although psychosocial factors are 
important predictors of successful cardiac rehabilitation, one common but often 
undiagnosed barrier to successful rehabilitation is the presence of obstructive sleep 
apnea (OSA), which is highly prevalent in patients with coronary heart disease.  
Obstructive sleep apnea is a common condition in adults, associated with recurrent 
airway collapse during sleep resulting in intermittent hypoxemia and sleep 
fragmentation.  Two studies of OSA in patients undergoing cardiac rehabilitation 
suggest prevalence in excess of 50%. While OSA is strongly associated with obesity, 
studies of exercise training in patients with OSA demonstrate a poorer response to 
exercise independent of body habitus.  The sleepiness and fatigue caused by OSA may 
contribute to impaired motivation to exercise, although intermittent hypoxia itself has 
been shown to decrease ventilatory efficiency in healthy adults.  Patients with OSA 
have reduced exercise tolerance compared to obese controls, and treatment of OSA 
with continuous positive airway pressure (CPAP) results in increased peak oxygen 
consumption on symptom-limited exercise testing and an increase in constant load 
exercise time.  These studies suggest that treatment of OSA might substantially 
improve the response to exercise training as part of cardiac rehabilitation, although 

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these were uncontrolled case series in general patients with OSA, not in the setting of 
cardiac rehabilitation. 
 
(b) Hypothesis 
We hypothesize that identification and treatment of obstructive sleep apnea (OSA) in 
patients with comorbid OSA and coronary heart disease undergoing cardiac 
rehabilitation will improve their response to rehabilitation.   
 
(c) Specific Objectives 
The goal of the proposed study is to evaluate the impact of OSA treatment on the 
effectiveness of cardiac rehabilitation.  This goal will be met through a parallel-group, 
randomized, clinical trial in patients with coronary heart disease referred for cardiac 
rehabilitation that screen positive for OSA on home sleep testing.  These patients will be 
randomized to treatment with OSA with CPAP or to an educational control intervention 
for a three month treatment period. 
 
(2) BACKGROUND AND SIGNIFICANCE 
 
(a) Background 
Coronary heart disease remains the leading cause of death in the United States, and is 
a major cause of disability.  Cardiac rehabilitation programs that include an exercise 
training intervention have been shown to reduce the rate of recurrent myocardial 
infarction by approximately 20% and cardiac mortality by approximately 25% (1).  
Following 3 months of exercise training three times per week, exercise tolerance 
increases by 30-50% and peak oxygen consumption by 15-20%, with a concomitant 
improvement in activities of daily living (2).  The cardioprotective effects of exercise 
training are thought to relate to the salutary effects of shear stress on endothelial 
function, reduced systemic inflammation, reductions in adiposity and blood pressure, 
and improved glucose homeostatsis (1), while improved exercise tolerance and 
functional capacity from aerobic conditioning relate to cardiac, skeletal muscle and 
vascular adaptations (2).  Despite the well documented beneficial effects of cardiac 
rehabilitation on cardiac morbidity and mortality, a minority of eligible patients 
undergoes cardiac rehabilitation, and many patients who do enroll in cardiac 
rehabilitation programs do not complete the program, typically 36 sessions over 12 
weeks (3).  While psychosocial and demographic factors appear to be important 
predictors of referral to and participation in cardiac rehabilitation programs, comorbid 
illnesses are also predictive (4).    
 
Obstructive sleep apnea (OSA) is a common chronic adult illness characterized by 
recurrent collapse of the pharyngeal airway during sleep causing episodes of decreased 
(hypopnea) or absent (apnea) airflow, resulting in intermittent hypoxemia and sleep 
fragmentation. OSA is a highly prevalent condition among US Veterans and is 
associated with excessive daytime sleepiness, diabetes, hypertension, incident 
coronary heart disease and stroke, and increased mortality and health care utilization. 
The general population prevalence of OSA is estimated at 9% of women and 24% of 
men aged 30-60 years (5), with estimates of even higher prevalence in the veteran 

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population (6,7).  Prevalence of OSA is even higher in patients with coronary heart 
disease.  Two studies of OSA prevalence in patients undergoing cardiac rehabilitation 
suggest prevalence in excess of 50% (8, 9).   
 
While these studies did not evaluate the impact of OSA on the effectiveness of cardiac 
rehabilitation, a number of studies have evaluated the impact of OSA on exercise 
tolerance and response to exercise training programs outside the context of coronary 
heart disease.  Patients with OSA have reduced exercise tolerance compared to obese 
controls (10), and a poorer cardiac response to exercise as measured by cardiac output 
and stroke volume as a function of workload (11).  In a one-year study of a diet and 
exercise intervention, OSA was associated with a smaller reduction in cardiovascular 
risk factors, including body mass index, waist circumference, and visceral adiposity, and 
smaller improvements in HDL cholesterol and glucose homeostasis, compared with 
obese controls without OSA (12).  Sleepiness and fatigue, cardinal symptoms of OSA, 
are commonly cited by OSA patients as a reason they are unable to exercise, and may 
be an important mediator of poor response to exercise training; however, intermittent 
hypoxia has itself been shown to decrease ventilatory efficiency in healthy adults (13), 
which might also limit exercise capacity in OSA.  Treatment of OSA with CPAP results 
in improved cardiac response to exercise (11) and increased peak oxygen consumption 
on exercise testing of 1.8 to 3.2 ml/kg/min even in the absence of a structured exercise 
training program (14,15).  Perhaps even more relevant to functional capacity, a 40% 
increase in constant load exercise time was noted after one month of CPAP treatment 
(16).  These studies suggest that OSA may be an unrecognized barrier to effective 
cardiac rehabilitation.   
 
(b) Significance 
Coronary heart disease is a common disease with high morbidity, mortality, and health 
care utilization.  Obstructive sleep apnea (OSA) is highly prevalent in patients with 
coronary heart disease.   The present study will for the time directly evaluates the 
impact of CPAP treatment in patients with comorbid coronary heart disease and OSA 
that undergo cardiac rehabilitation.  If a beneficial effect is confirmed, this could have a 
direct impact on clinical practice, leading to routine screening for and treatment of OSA 
to improve the effectiveness of cardiac rehabilitation.   
 
(c) Relevance 
Coronary heart disease remains a leading cause of morbidity and mortality among 
veterans treated in the VA Health Care System (17, 18).  Cardiac rehabilitation 
programs that include an exercise training intervention have been shown to reduce 
cardiac mortality by approximately 25% (1), with improved exercise tolerance and peak 
oxygen consumption, and a concomitant improvement in functional status and quality of 
life.   Sleep apnea is a common co-morbid condition in patient with coronary heart 
disease and may be a barrier to effective cardiac rehabilitation.   Determining the impact 
of sleep apnea treatment in patients with comorbid coronary heart disease and OSA, 
who undergo cardiac rehabilitation is therefore of great relevance to Veterans Health.   
 
 

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(3) Work Protocol 
Overview 
The proposed study is a randomized, parallel group study comparing three months of 
therapy with continuous positive airway pressure (CPAP) to an educational control for 
patients with comorbid obstructive sleep apnea and coronary heart disease undergoing 
a structured cardiac rehabilitation program.  The study will be conducted over 2 years 
and participants will be recruited from among patients seen at the VA Boston 
Healthcare Systems with a diagnosis of coronary heart disease and referred to the 
Cardiac Rehabilitation Program.   A total of approximately 150 patients will be recruited 
in order to randomize 25 patients to each group (CPAP or Control).  Participation of an 
individual subject will be approximately 1 week for subjects not meeting criteria for 
randomization, and  8-10 weeks for subjects randomized.  Participants will be age 18 
and over, of either gender, have a diagnosis of coronary heart disease, and be referred 
to the Cardiac Rehabilitation Program at the VA Boston Healthcare System.  No 
children or other special classes of individuals will be enrolled. All enrolled subjects will 
be veterans.   
 
Study procedures will include:  
• Screening Questionnaires (Epworth Sleepiness Scale) 
• Portable Sleep Monitoring  
• Baseline (Randomization) Visit, including: 
o Anthropometry 
o Randomization to treatment with one of the following two treatments: 
▪ Healthy Lifestyle and Sleep Education alone (HLSE) 
▪ HLSE plus CPAP (CPAP) 
• Interim Telephone Contacts  
• Final Study Visit  
o Anthropometry  
o Epworth Sleepiness Scale 
o 7 day actigraphy recording 
 
Inclusion criteria for sleep apnea screening: 
• Age ≥ 18 years 
• Physician diagnosis of ischemic heart disease, with prior myocardial infarction or 
coronary revascularization procedure 
• Referral to the Cardiac Rehabilitation Program 
• Epworth Sleepiness Scale < 18 
• Ability to provide informed consent   
 
For continuing to randomization, the following additional inclusion criterion applies: 
• Moderate to severe obstructive sleep apnea, defined as an apnea-hypopnea 
index ≥ 15 events per hour, with >50% of events being obstructive apneas or 
hypopneas 
 

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Exclusion criteria: 
• Poorly controlled hypertension (>170/>110), poorly controlled diabetes (HbAtc > 
9.0), severe renal failure with estimated glomerular filtration rate <30 ml/min, prior 
stroke with functional impairment or other severe, uncontrolled medical problems 
that may impair ability to participate in the study exams, based on medical history 
and review of medical records 
• Severe daytime sleepiness, defined as Epworth Sleepiness Scale score 18 or 
higher or a report of falling asleep driving during the previous year 
• Awake resting oxyhemoglobin saturation <89% 
• Pregnancy 
• Current use of a positive airway pressure device (including continuous or bi-level 
positive airway 
 
 
Study Design 
The proposed study is a randomized, parallel group study comparing 8 weeks of 
therapy with continuous positive airway pressure (CPAP) to an educational control for 
patients with comorbid obstructive sleep apnea and coronary heart disease undergoing 
a structured cardiac rehabilitation program.  The primary study outcome measure, to be 
made at baseline and at end of the treatment period, is change in walking distance and 
speed as measured by 6 minute walk test, a valid and reproducible measure of 
functional capacity.  The primary analysis will compare the active treatment group to the 
control group.  Secondary outcome measures include measures of functional status and 
health related quality of life, and adherence to cardiac rehabilitation.    
 
Sample Selection 
The target population is veterans with stable coronary heart disease referred for cardiac 
rehabilitation at the VA Boston Healthcare System and comorbid sleep apnea.  Patients 
will be recruited from among those patients enrolled in the VA Boston Healthcare 
System who carry a diagnosis of coronary heart disease and are referred for cardiac 
rehabilitation.  Potential participants will be identified via the computerized patient 
record system, by confirming a diagnosis of coronary heart disease and an active 
referral to the Cardiac Rehabilitation Program.   We propose to recruit approximately 75 
patients per year for home sleep testing, in order to identify 25 per year for inclusion in 
the randomized clinical trial. Given the low participant burden of home sleep testing, and 
the potential health benefit, we believe this is a reasonable recruitment target. 
 
Recruitment 
Subjects will be recruited by mailings to patients seen at the VA Boston Healthcare 
System for a diagnosis of coronary heart disease referred to the Cardiac Rehabilitation 
Program.  This recruitment approach will be supplemented, if needed, by direct contact 
during an inpatient hospitalization or at the time of presentation for intake evaluation into 
the Cardiac Rehabilitation Program.  After initial contact, interested participants will 
have initial screening for eligibility. Potentially eligible patients will be invited to a 
screening visit, at which informed consent will be obtained and the patient will be 
instructed in the use of a portable sleep monitoring device. This screening visit may take 

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place on the day of Cardiac Rehabilitation intake evaluation.  Participants who screen 
positive for moderate to severe obstructive sleep apnea will proceed to the baseline visit 
and randomization to treatment.  
 
Initial Screening 
The primary approach to recruitment will be through mailing to all patients with a 
diagnosis of coronary heart disease referred to the Cardiac Rehabilitation Program at 
the VA Boston Healthcare System. All mailings will contain a cover letter explaining the 
purpose of the mailing and containing the key elements of informed consent. The letter 
will contain the Epworth Sleepiness Scale and several additional questions, including 
age and contact information. The Epworth Sleepiness Scale, the most widely used tool 
for self-report assessment of sleepiness, asks the subject to rate the likelihood of falling 
asleep in a number of common situations. It has good internal reliability and test-retest 
reliability. This scale will be used to identify patients with sleepiness so severe that it 
would preclude safe participation in the study (Epworth Sleepiness Scale score ≥18). 
 
A stamped and addressed return envelope will be provided to return the questionnaire. 
A toll-free number will also be provided to allow patients to respond by telephone, 
should they prefer.  All participants responding to the questionnaire by mail or telephone 
will be screened for eligibility, and potentially eligible subjects invited to attend a 
Screening Visit. In addition, the mailing will include an "opt-out" postcard for patients 
who do not wish to be further contacted.  Patients who do not respond to the mailing 
either by responding to the questionnaire or returning an opt-out postcard will be 
contacted by telephone approximately 2 weeks after the mailing and invited to 
participate. 
 
Subjects may also be recruited directly at the time of the Cardiac Rehabilitation 
Program intake evaluation or during inpatient hospitalizations at the West Roxbury VA 
Medical Center by trained research staff.  This will entail study staff pre-screening the 
charts for eligible patients admitted to the inpatient medical services for recent ischemic 
cardiac event, percutaneous coronary intervention, or coronary artery bypass, or 
referred for Cardiac Rehabilitation and scheduled for initial intake evaluation.  These 
patients will be approached by trained research staff during their hospitalization or at 
their Cardiac Rehabilitation intake visit, to describe the study and ask them if they would 
be interested in participating.  Prior to contacting each patient, the primary medical team 
(in the case of inpatients) or Cardiac Rehabilitation staff will be informed of the study 
and potential eligibility of the patient to participate.  The primary medical team or 
Cardiac Rehabilitation staff will request permission from the patient for a member of the 
research staff to discuss participating in the study.  Patients who provide permission for 
the research staff to speak with them will be screened for eligibility, and potentially 
eligible subjects invited to attend a Screening Visit. This will also ensure no disruption in 
the ongoing care and management of the patient. 
 
No personally identifiable data will be retained for patients who do not opt to participate. 
 

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Screening Visit 
At the Screening Visit, written informed consent will be obtained and participants will be 
instructed in the performance of home portable sleep testing.  Participants will also be 
given the Epworth Sleepiness Scale if it has not already been completed in response to 
a recruitment letter. 
 
Informed Consent Procedures 
The informed consent process will be undertaken by investigators and study staff who 
have current training in human subject protections and are credentialed by the VA to 
conduct the informed consent process.  They will explain the study to the potential 
participants and answer any questions that they may have about the protocol.  They will 
make it clear that participating in research is always voluntary and that not participating 
will in no way affect their further evaluation or care.  All participants will be informed that 
they may withdraw their consent at any point throughout the study. Participants will then 
be asked to sign the IRB-approved written consent form. 
 
Portable Sleep Monitoring 
At the Screening Visit, after written informed consent is obtained, subjects will be 
instructed in the use of the portable sleep apnea monitor (Embletta Gold or Embletta 
MPR, Embla Systems, Inc., Broomfield, CO).  This battery-operated device can store 
data at 200 Hz, with 125 MB of storage capacity allowing storage of data from up to 24 
hours of recording.  The device contains the critical sensors which are recommended by 
the American Academy of Sleep Medicine (AASM) as validated sensors for measuring 
sleep apnea (19,20): airflow via a nasal cannula/pressure transducer system and 
oronasal thermocouple; respiratory effort via thoracic and abdominal inductance 
plethysmography; and oxyhemoglobin saturation via finger pulse oximetry.  In addition, 
signals are captured for body position and a 3-lead ECG. 
 
Subjects will be taught how to self-apply the sensors in their own homes.  Application of 
sensors will be demonstrated by the Home Sleep Testing Coordinator.  Subjects will be 
asked to demonstrate their understanding of sensor placement and will be provided with 
simple pictorial and written instructions.  Subjects will be asked to apply the sensors 
before bedtime and remove them upon awakening.  A 24-hour phone service will be 
available to provide assistance should questions arise once the participant is home.  
Patients are instructed to depress the event marker button 3 times in succession at the 
time of lights off, and again upon arising in the morning.  They are also asked to 
complete a simple sleep diary, indicating bed time, rise time, and any long periods of 
wakefulness during the night of the study.  When units are returned to the clinic site (by 
mail or direct drop-off), the data will be downloaded to a VA server for scoring by the 
Home Sleep Testing Coordinator or other polysomnography technician and review by 
Dr. Gottlieb. 
 
Studies will be scored following AASM guidelines for standard hypopnea and apnea 
definitions based on respiratory effort, flow sensors and oximetry (20).  Apneas will be 
identified based on absence of airflow for at least 10 seconds, and scored as 
obstructive if there is continued respiratory effort during the event and as central if there 

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is no respiratory effort during the event.  Identification of hypopneas will require: (1) a 
fall in peak signal excursion of ≥ 30% from the pre-event baseline, using nasal pressure 
as the preferred sensor; (2) an event duration of at least 10 seconds; and (3) an 
associated ≥ 3% fall in oxyhemoglobin saturation from the pre-event baseline.  Studies 
that do not meet minimal quality grades (4 hours of scorable record) will be repeated. 
 
Patients who have had a recent sleep study demonstrating the presence of sleep apnea 
meeting criteria for inclusion in this study, but not yet treated, may proceed to 
randomization without repeating the portable sleep study. 
 
Baseline (randomization) visit 
Participants with at least moderate obstructive sleep apnea (AHI >15, with >50% 
obstructive events) on home sleep testing will proceed to the baseline study visit.  The 
entire baseline visit is expected to take approximately 15 minutes. 
 
Anthropometry 
• Height and weight 
• Waist, hip, and neck circumference 
 
Cardiac Rehab Assessment Measures 
Information from the participant’s initial assessment for Cardiac Rehabilitation will be 
pulled from the Cardiac Rehabilitation exercise evaluation note in CPRS.  Measures of 
particular interest include strength, balance, and range of motion assessments as well 
as results from the 6 min walk test. Participants’ responses to World Health 
Organization Disability Assessment Scale II (WHODAS II) (21) will also be recorded. 
 
Randomization 
After completing the baseline visit, participants will be randomly assigned in a 1:1 ratio 
to one of two treatment groups: Healthy Lifestyle and Sleep Education alone (HLSE) or 
HLSE plus Continuous Positive Airway Pressure (CPAP).  A SAS program will be used 
to generate a list of randomization assignments, which will be placed into a data table in 
a Microsoft SQL Server 2008 database to serve as a lookup table.  When a new 
participant record is created in the database, a trigger is fired on the SQL Server 
randomization data table that picks the next assignment, updates the lookup table with 
the Study ID randomized and the date and time of randomization.  Due to the nature of 
the treatments, blinding of subjects to treatment arm is not possible.  The Home Sleep 
Testing Coordinator or other polysomnography technician will be unblinded to group 
assignment and will administer and troubleshoot the CPAP intervention.  The research 
assistant, research coordinator, exercise physiology staff and physicians overseeing the 
study will be blind to treatment assignment. 
 
Treatment  
Healthy Lifestyle and Sleep Education (HLSE Group)  
The Research Coordinator at each site will provide counseling on sleep hygiene and 
general heart healthy lifestyle using a slide show developed for this purpose. The 
presentation will suggest non-pharmacologic approaches to improve the regularity and 

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duration of sleep, aiming for 7-8 hours of sleep per night. General lifestyle advice 
relevant to sleep apnea will also be provided, including a recommendation for weight 
loss and regular exercise as tolerated, per American College of Cardiology/American 
Heart Association guidelines, and avoidance of smoking, excessive alcohol 
consumption, and use of illicit drugs. The importance of adherence to prescribed 
medical regimens will also be emphasized. 
 
Healthy Lifestyle and Sleep Education plus CPAP (CPAP Group)  
In addition to HLSE, this intervention includes sleep apnea treatment with continuous 
positive airway pressure (CPAP). Participants will be educated on the use of the CPAP 
device by the Home Sleep Testing Coordinator or other polysomnography technician, 
targeting self-efficacy and cognitions related to CPAP.  Participants will have an 
opportunity to try various mask interfaces in order to optimize fit.  Verbal and written 
directions on the use of these materials will be provided, with instructions reinforced at 
interim telephone follow-up calls. 
 
Participants randomized to the CPAP Group will then be given an auto-titrating CPAP 
device with pressure range initially set at 4-20 cm H20 pressure.  The CPAP device is 
capable of wireless transmission of utilization and efficacy data.  At the end of the first 
week of CPAP use, the utilization data will be reviewed by the Home Sleep Testing 
Coordinator, who will judge their acceptability based on usage for at least 4 hours/night 
for at least 5 nights and absence of excessive mask leak.  At this time, the pressure 
profile will be reviewed and the 90th percentile pressure (i.e., the pressure that is 
exceeded only 10% of the time) will be identified and the CPAP device wirelessly reset 
to a pressure range of this 90th percentile pressure ± 3 cm H20.  The Coordinator will 
review utilization data again at weeks 2, 4 and 6.  If adherence does not meet the above 
target, the Coordinator will call the participant to discuss ways to overcome barriers to 
adherence.  This approach has been used successfully for evaluating CPAP utilization 
in the recently completed HeartBEAT Study. 
 
Interim telephone contact  
Following initiation of therapy, study staff will make telephone contact with each 
participant at weeks 2, 4 and 6 to identify any early problems with treatment adherence 
and to ascertain any adverse events.  In particular, sleepiness will be re-assessed using 
the Epworth Sleepiness Scale and Dr. Gottlieb will contact any patient whose Epworth 
Sleepiness Scale score is ≥16 or who provides a response of 2 or 3 on the item 
regarding drowsy driving. 
 
Final study visit  
After 8 weeks of intervention, participants will return for a final study visit, at which time 
all procedures performed at the baseline visit will be repeated, including  anthropometry 
and the Epworth Sleepiness Scale..  Measurements taken at the end of participation in 
the Cardiac Rehabilitation program, including 6 minute walk test results and responses 
to the WHODAS II questionnaire, will also be recorded.   
 

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Participants will also be asked to wear an Actigraph GT3X monitor for a period of 7 days 
(except when swimming or bathing).  This will be used to assess the level of activity 
performed by the participant at home following completion of the Cardiac Rehabilitation 
program.   
 
Following completion of study procedures, each participant will be encouraged to accept 
referral to a sleep specialist within the VA to discuss treatment of sleep apnea. 
 
Statistical analysis 
Baseline data will be summarized using standard descriptive statistics for demographic 
and baseline clinical characteristics by treatment group.  Based on our experience with 
the HeartBEAT Study, the rate of dropouts during the course of the three-month trial is 
expected to be low and we do not expect dropouts to be differential with respect to 
treatment group assignment.  The main analysis will include all subjects completing the 
follow-up examination.  For the purposes of a sensitivity analysis, a result of “no 
change” will be imputed for all dropouts, and compared to the main analysis. 
 
The analysis for the primary outcome measure will consist of a one-factor analysis of 
variance comparing the mean changes from baseline in six minute walk distance.  The 
primary analysis is a simple analysis of variance, with data transformation or adoption of 
rank-based inference if approximate normality is not present.   A p value <0.05 will be 
considered statistically significant.  While the randomization should achieve 
approximate balance on potentially confounding conditions, analysis of covariance 
models that employ adjustments for age, sex, sleep apnea severity, comorbid illness, 
smoking and alcohol use will be fit to potentially improve the efficiency of the treatment 
effect estimates.  Should a significant difference between treatment and comparator be 
identified, further exploratory analyses will assess the relation of adherence to CPAP 
therapy to change in outcome measures.  
 
Each of the secondary outcome measures is continuous; therefore, analysis of these 
variables will be treated in a similar fashion to the analysis of the primary study 
endpoints. 
 
Sample size and power 
Our primary goal is to determine the impact of identification and treatment of obstructive 
sleep apnea in patients with coronary heart disease undergoing cardiac rehabilitation.  
Patients will be allocated into the two groups, HLSE or HLSE plus CPAP, randomly 
according to a 1:1 ratio.   
 
There are no published data on the effect of CPAP therapy on 6-minute walk distance in 
patients with coronary heart disease; however, in a recent report from a general sample 
of patients with OSA, treatment with CPAP was associated with a mean 114 m 
improvement in 6-minute walk distance after 4 weeks, compared to a control group not 
treated with CPAP (22),  This is well above the minimal clinically important difference of 
23 m in 6-minute walk distance reported for patients with stable coronary heart disease 
(23).  The standard deviation in 6-minute walk distance in patients with stable coronary 

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heart disease has been estimated at 104 m (24), similar to the 90 m estimated for 
healthy adults (25).  Assuming a modest correlation of 0.4 between repeated measures 
of the 6-minute walk test, the sample size of 25 subjects in each group will have 80% 
power to detect a difference between groups of 57 m in 6-minute walk distance, half of 
the difference reported for the effect of OSA treatment (22).   
 
Human Subjects  
Potential Risks 
The study procedures do not place the subjects at risk of harm or discomfort greater 
than those encountered in routine medical care.  Portable sleep monitoring may lead to 
minor sleep disturbance and some subjects may experience mild skin irritation from the 
sensors or electrodes used.  The administration of questionnaires may be stressful, 
although none ask sensitive information.   
 
The study treatment is generally considered quite safe.  CPAP is a FDA-approved 
therapy for the treatment of sleep apnea. The use can be associated with a number of 
minor side effects, including nasal congestion, runny nose, dry nose or mouth, skin 
irritation from the mask or headgear, aerophagia or discomfort from the mask or air 
pressure. Rarely, sinus problems may get worse while using CPAP and mild nose 
bleeds may occur.  These side effects will be minimized by using a humidifier built into 
the device and by using the most appropriate pressure. 
 
It is possible that patients randomized to HLSE alone may not effectively be treated for 
their sleep apnea for the 8 weeks of the study.  Untreated sleep apnea may place 
subjects at increased risk of motor vehicle and other accidents; however, in a study of 
1105 patients with sleep apnea randomly assigned to CPAP or sham CPAP for 6 
months (the Apnea Positive Pressure Long-term Efficacy Study), we had no episodes of 
motor vehicle accidents due to sleepiness using safety education and monitoring 
procedures similar to those of present study. 
 
Protection against risks  
All study personnel will be fully trained and credentialed in Human Subjects Protections.  
All research data will be collected on standardized research forms with de-identified ID 
numbers, without personal identifiers.  Any data collected from medical records will be 
entered onto case report forms with only study ID numbers, excluding personal 
identifiers.  Only study personnel will have access to research data, which is kept either 
in locked cabinets, in password-protected computers in locked offices, or on secure 
password-protected drives located behind the VA firewall.  Research staff members that 
are no longer involved during the course of the study will have their access terminated.  
All personal data will be stored separately from de-identified research data, and will be 
stored in password-protected files behind the VA firewall or in locked cabinets within the 
VA.  Records will be destroyed in accordance with the VA Record retention schedule. 
 
 
All CPAP devices will be equipped with heated humidifiers to minimize drying, and 
attention will be paid at set-up to identifying a best-fit mask to minimize mask discomfort 

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and air leaks.  Subjects will be contacted at weeks 2, 4 and 6 to identify any early 
problems with treatment and to ascertain any adverse events, in particular the onset of 
dangerous levels of sleepiness.  Participants will be extensively counseled at the 
baseline visit on safety measures related to excessive sleepiness. 
 
Potential Benefits of the proposed Research to Human Subjects and Others 
There are a number of potential benefits to participants. All participants who undergo 
sleep apnea screening will be provided information on the results of their sleep studies, 
which may be useful in further health management. Participants randomized to CPAP 
may experience direct benefit related to treatment of underlying obstructive sleep 
apnea. There are also potentially important benefits to others, if the study confirms 
improved response to cardiac rehabilitation in those treated with CPAP. 
 
Importance of the knowledge to be gained 
The societal benefits to the study include an understanding of the extent to which 
treatment of obstructive sleep apnea, a highly prevalent comorbid condition in patients 
with coronary heart disease, will improve response to cardiac rehabilitation. If an 
improvement is demonstrated, this should lead to a change in practice patterns for the 
millions of adults who are enrolled in cardiac rehabilitation programs, with routing 
screening for and treatment of sleep apnea at the initiation of cardiac rehabilitation. 
 
Data Safety and Monitoring 
As described above, frequent contact will be maintained with participants throughout 
their participation in this study, with contact at 2, 4 and 6 weeks after randomization to 
ascertain sleepiness, hospitalizations, illnesses or other adverse events.  The PI and 
staff will meet on a weekly basis to review study progress and adverse events.  The PI 
will, on a weekly basis, review all data collected to assure that no physiological findings 
warrant immediate intervention.  If so, the participant will be contacted and advised of 
the findings and offered assistance with appropriate referrals.  Data from the 
Cardiopulmonary Exercise Testing procedures will be reviewed by a cardiologist-
investigator and any unusual or adverse findings will be communicated to the 
participant’s primary care physician or Cardiologist. Adverse events (classified by 
severity and unexpected/expected) will be defined and reported to the IRB in 
accordance with the rules regulating each severity class (expected vs unexpected, 
serious vs. other, related vs. unrelated).  No Data and Safety Monitoring Board is 
envisioned. 
 
Resources  
Research Space  
This study will be conducted at the Boston VA hospitals.  The clinical resources of the 
VA Boston Healthcare System for recruitment of patients with coronary heart disease 
undergoing cardiac rehabilitation are large and growing.  Almost 1000 patients per year 
are treated at the VA Boston HCS with diagnoses for which cardiac rehabilitation would 
be indicated. Currently, 180 patients per year are being enrolled in cardiac 
rehabilitation, and this number is expected to increase as additional staff has recently 
been added to meet the demand for cardiac rehabilitation services. 

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The Cardiopulmonary Exercise Laboratory is located in the Clinical Studies Unit of the 
Jamaica Plain campus of the VA Boston Healthcare System, sharing the 11C wing with 
the Cardio/Pulmonary Rehabilitation Exercise Suite.  Dr. Gottlieb has office space on 
the same floor, and  research staff offices are one floor above in the Clinical Studies 
Unit. The close proximity of these research and clinical facilities will facilitate 
coordination of this research project with the cardiac rehabilitation program.   
 
Other Research Resources 
In addition to these patient resources, there is a rich academic and intellectual 
environment at the VA Boston HCS, with close collaborations developed over the past 3 
years between Dr. Gottlieb and members of the Cardiology section, including Dr. 
Forman.  Dr. Gottlieb has collaborated with the chief of Cardiology, Dr. Deepak Bhatt, 
on the NHLBI-funded HeartBEAT Study. Drs. Gottlieb and Forman, along with Dr. Bhatt, 
Dr. Joseph (head of the Heart Failure Program), and Dr. Aragam (head of the 
Echocardiography Lab) have recently received Merit Review funding to initiate a study 
of sleep apnea treatment in patients with chronic heart failure.  Dr. Forman has an 
interest in the relation of sleep to quality of life and functional status in heart failure, and 
has developed a state-of-the-art cardiopulmonary exercise program for both clinical and 
research purposes. These expanding collaborations and shared interests provide an 
excellent environment for the successful conduct of the proposed research. 
 
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