Oxygen Versus PAP for Treatment of Sleep Apnea in Chronic Heart Failure
Phase: PHASE4
Conditions: Heart Failure, Sleep Apnea Syndromes
Sponsor: VA Office of Research and Development

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STUDY PROTOCOL 
 
Title: Oxygen versus PAP for treatment of sleep apnea in chronic heart failure 
 
Brief title: OPTIMAL-HF 
 
NCT number: NCT01807897    
 
Unique Protocol ID: CLIN-008-12S 
 
Funding source: Department of Veterans Affairs 
 
Protocol date: 8/4/2017 
 
 

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STUDY PROTOCOL 
Oxygen versus PAP for treatment of sleep apnea in chronic heart failure 
 
OVERVIEW 
The proposed study is a randomized, parallel group clinical trial comparing three months of 
therapy with of continuous positive airway pressure (CPAP) or nocturnal supplemental 
oxygen (NSO) to optimized medical therapy for treatment of sleep apnea in patients with 
chronic heart failure. This study will be conducted over 4 years and participants will be 
recruited from among patients seen at the VA Boston and VA Connecticut Healthcare 
Systems for a diagnosis of heart failure.  A total of approximately 500 patients will be 
recruited to undergo portable sleep monitoring in order to randomize 39 patients to each 
active treatment group (CPAP or NSO) and 20 subjects to optimized medical therapy 
alone (HSLE). Participation of an individual subject will be approximately 1 week for 
subjects not meeting criteria for randomization, and 3.5 months for subjects randomized.  
Participants will be age 18 and over, of either sex, and will have chronic heart failure with 
left ventricular ejection fraction <45%. No children or other special classes of individuals 
will be enrolled.  All enrolled subjects will be veterans. 
 
(1) RATIONALE 
(a) Statement of the Problem 
Chronic heart failure (HF) is a highly prevalent disease associated with physical 
disability, extensive health care utilization and high rates of mortality, which have 
persisted despite recent advances in pharmacologic therapy.  The prevalence of HF in 
the US is estimated at 5.7 million individuals, with an annual incidence of 10 per 1000 
population over the age of 65 and a lifetime risk of HF of approximately 20%. Heart 
failure is a major cause of health care utilization, accounting for over 3 million doctor 
visits and over 1.1 million hospitalizations in 2006.  According to the VA Chronic Heart 
Failure Quality Enhancement Research Initiative 2009 Strategic Plan, VA outpatient 
encounters for HF reached 900,000 in FY09 and VA hospitalizations were over 96,000.  
HF is reported to be the most common medical discharge diagnosis for veterans treated 
within the VA system.  Heart failure also carries a high mortality risk, with 1-year mortality 
of approximately 20% and 5-year mortality of 42- 54%, with HF listed as a contributing 
cause of death on 12% of US death certificates in 2005 and as the underlying cause in 
almost 59,000.  Sleep apnea is a common comorbid condition in patients with chronic 
HF.  Multiple studies demonstrate that moderate to severe sleep apnea (AHI >15 per 
hour) is present in 50-60% of patients with chronic HF with reduced left ventricular 
ejection fraction (LVEF), with a slight preponderance of central over obstructive sleep 
apnea.  Moreover, sleep apnea portends a markedly worse prognosis in patients with 
chronic HF, with a 2- to 3-fold increased hazard ratio for mortality in those with either 
central or obstructive sleep apnea.  There are currently three recommended treatments 
for sleep apnea with a prominent central component, but the relative benefits of these 
therapies have never been directly compared. 
(b) Hypotheses 
We hypothesize that the two recommended treatments for sleep apnea with a 

OPTIMAL-HF Protocol   August 4, 2017 
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component of central sleep apnea, continuous positive airway pressure (CPAP) and 
nocturnal supplemental oxygen (NSO), are each superior to medical management 
alone in their effect on LVEF and exercise capacity. 
(c) Specific Objectives 
Our primary goals are to establish the efficacies of continuous positive airway pressure 
(CPAP)) and nocturnal supplemental oxygen (NSO) compared to a control group 
receiving usual care plus healthy lifestyle and sleep education (HLSE).  Because past 
studies were suggestive of a more beneficial effect of CPAP or NSO compared to 
HLSE, we will randomize more subjects to the two experimental treatment groups.  
Specifically, we will allocate patients into CPAP,NSO, or HLSE randomly according to 
a 2:2:1 ratio. This strategy also improves statistical power for the secondary 
comparisons between CPAP and NSO. 
 
 
(2) BACKGROUND AND SIGNIFICANCE 
(a) Background 
Heart failure prevalence, morbidity and mortality.  Chronic heart failure (HF) is a 
highly prevalent disease associated with physical disability, extensive health care 
utilization and high rates of mortality, which have persisted despite recent advances 
in pharmacologic therapy.  The prevalence of HF in the US is estimated at 5.7 million 
individuals, with an annual incidence of 10 per 1000 population over the age of 65 
and a lifetime risk of HF of approximately 20% (1).  Heart failure is a major cause of 
health care utilization, accounting for over 3 million doctor visits and over 1.1 million 
hospitalizations in 2006 (1).  According to the VA Chronic Heart Failure Quality 
Enhancement Research Initiative 2009 Strategic Plan, VA outpatient encounters for 
HF reached 900,000 in FY09 and VA hospitalizations were over 96,000 (2).  HF is 
reported to be the most common medical discharge diagnosis for veterans treated 
within the VA system (3).  Heart failure also carries a high mortality risk, with 1-year 
mortality of approximately 20% and 5-year mortality of 42-54%, with HF listed as a 
contributing cause of death on 12% of US death certificates in 2005 and as the 
underlying cause in almost 59,000 (1). 
Prevalence of sleep apnea in patients with chronic HF.  Sleep apnea is a common 
comorbid condition in patients with chronic HF.  It is characterized by recurrent 
episodes of decreased (hypopnea) or absent (apnea) airflow during sleep, resulting in 
intermittent hypoxemia and sleep fragmentation.  These respiratory events can result 
from either collapse of the upper airway (obstructive sleep apnea) or ventilatory 
control instability (central sleep apnea).  Multiple studies of patients with chronic HF 
with reduced left ventricular ejection fraction (LVEF), selected independent of sleep 
complaints, provide remarkably consistent estimates of the prevalence of sleep 
apnea.  Sleep apnea of at least mild severity (apnea-hypopnea index [AHI], defined 
as the frequency of apneas plus hypopneas per hour of sleep, >5 per hour) is present 
in >70% of patients with chronic HF, while moderate to severe sleep apnea (AHI >15 
per hour) is present in 50-60% (4-10), with a slight preponderance of central over 
obstructive sleep apnea.  In the three largest studies, totaling over 1300 patients, the 
prevalence of moderate to severe central sleep apnea was 28-32% overall (6, 9,10). 

OPTIMAL-HF Protocol   August 4, 2017 
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There is a clear sex difference, with a prevalence of moderate to severe central sleep 
apnea of 15-26% in women and 31-45% in men (6, 9, 10).  Another important finding 
of these and other studies is that sleep apnea in chronic HF typically lacks the 
daytime sleepiness characteristic of sleep apnea in the general population (4, 7-9, 11, 
12) and central sleep apnea in particular is less strongly associated with obesity (4, 9, 
10). This may explain why as few as 2% of patients with newly diagnosed HF are 
evaluated for the presence of sleep apnea within a year of HF diagnosis (13). 
Impact of sleep apnea on HF incidence and mortality.  At the baseline 
examination of the Sleep Heart Health Study, a multi-center prospective 
epidemiologic study of the cardiovascular consequences of sleep apnea, moderate to 
severe sleep apnea was associated with a 2.4-fold increased odds of prevalent HF 
(14).  While HF-related ventilatory instability may cause sleep apnea, the relation of 
sleep apnea to HF is clearly bidirectional.  We have recently demonstrated that sleep 
apnea is an independent predictor of incident HF: in the Sleep Heart Health Study, 
severe sleep apnea was associated with a 58% increased risk of incident HF over 8 
years of follow-up in middle-aged and older men (15).  In a dog model, it has been 
demonstrated that 1-3 months of exposure to obstructive sleep apnea results in 
sustained daytime hypertension (16), reduced left ventricular ejection fraction and 
eccentric left ventricular hypertrophy (17).  We have demonstrated a similar pattern of 
reduced ejection fraction and eccentric left ventricular hypertrophy associated with 
sleep apnea in 2058 Sleep Heart Health Study participants (18).  Moreover, sleep 
apnea portends a markedly worse prognosis in patients with chronic HF.  In studies of 
sleep apnea and mortality in chronic HF, the adjusted hazard ratio for mortality was 
2.8 in those with obstructive sleep apnea (19) and 2.1 in those with central sleep 
apnea (20), when compared to HF patients without sleep apnea. 
Mechanisms of the effect of sleep apnea on HF.  The adverse effects of sleep 
apnea on cardiac function are multifactorial and have been recently summarized in an 
American Heart Association/American College of Cardiology Scientific Statement (21). 
These include sympathetic nervous system hyperactivity, oxidative stress, reduced 
myocardial oxygen delivery, activation of inflammatory pathways, and (in the case of 
obstructive sleep apnea) increased left ventricular transmural pressure resulting from 
large negative swings in intrathoracic pressure when breathing against an occluded 
glottis. While the relative contributions of these factors is uncertain, it is likely that the 
repetitive cycles of hypoxemia and resaturation that characterize sleep apnea play a 
central role in its impact on chronic HF, contributing to sympathetic activation, systemic 
inflammation and oxidative stress. 
Role of hypoxemia in sleep apnea-related sympathetic activation.  Multiple studies 
over more than two decades demonstrate increased sympathetic activity in patients with 
either obstructive or central sleep apnea, which may contribute to progression of 
myocardial dysfunction by both direct adverse effects on myocardial remodeling and 
through elevation of diurnal and especially nocturnal blood pressure. Hypoxemia 
increases sympathetic nerve activity in humans, and this effect is particularly great in  
the presence of hypercapnia, as occurs in sleep apnea (22).  In sleeping patients with 
HF, muscle sympathetic nerve activity (MSNA) is higher during periods of central sleep 
apnea than during periods of stable breathing (23).  MSNA increases across the 
duration of each central apnea, reaching values 50% above the already elevated 
baseline MSNA in these patients (23). Intermittent hypoxia results in sustained 

OPTIMAL-HF Protocol   August 4, 2017 
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hypertension in rodent models, an effect that is mediated by the sympathetic nervous 
system (24). In canine models of sleep apnea, the acute hypertensive response to 
obstructive apneas is considerably diminished by supplemental oxygen (25), and while 
obstructive apneas result in sustained hypertension, acoustic arousals of a similar 
frequency do not (16). Thus, it appears that hypoxemia is the major stimulus to 
sympathetic activation and consequent hypertension in patients with sleep apnea. 
Hypertension is recognized as a major risk factor for the development of chronic HF 
(26), and sleep apnea is strongly associated with hypertension in both cross-sectional 
(27,28) and longitudinal observational studies (29). Among middle-aged adults 
participating in the Wisconsin Sleep Cohort Study, mild to moderate sleep apnea was 
associated with more than a 2-fold increased risk of incident hypertension over 
approximately 8 years of follow-up, after adjusting for potential confounding factors such 
as body habitus (29). Moreover, while sleep is usually associated with a decrease in 
blood pressure, failure of the blood pressure to fall at night (blood pressure ‘non- 
dipping’) is more common in individuals with sleep apnea (30), and is an important 
predictor of left ventricular hypertrophy (31). In addition to its effects on blood pressure, 
long-term activation of the sympathetic nervous system is known to have direct 
deleterious effects on the failing heart, via vasoconstriction, induction of cardiac 
hypertrophy, increased heart rate and reduced myocardial oxygen delivery (26). 
Role of hypoxemia in sleep apnea-related systemic inflammation and oxidative 
stress.  Inflammatory markers are elevated in patients with chronic HF and may play an 
important role in the progression of disease (32).  Systemic inflammation is also present 
in sleep apnea, and intermittent hypoxemia appears to be central to its pathogenesis. 
Intermittent hypoxia induces the expression of transcription factors including hypoxia- 
inducible factor-1 (HIF-1) and nuclear factor kappa B (NF-kB), which play key roles in 
upregulating expression of inflammatory cytokines including TNF-α and IL-6 (33). 
Induction of NF-kB in heart and aorta has been demonstrated in a mouse model of 
intermittent hypoxemia (34), and elevated monocyte NF-kB activity in human subjects 
with sleep apnea is normalized by treatment of the sleep apnea with continuous positive 
airway pressure (34).  In a rat model of sleep apnea, it has been demonstrated that, 
compared to tracheotomy alone, repetitive upper airway obstruction and repetitive 
hypoxia-resaturation each increase NF-kB expression and markers of endothelial 
dysfunction, while airway obstruction with supplemental oxygen to prevent hypoxemia 
does not (35). Our preliminary data (Section 2.3) indicate that in patients with moderate 
to severe sleep apnea, hypoxemia is much more strongly correlated with inflammatory 
markers than is apnea-hypopnea index.  Oxidative stress also appears to play a role in 
the pathogenesis of HF (36).  Repetitive episodes of hypoxia-resaturation promote the 
production of reactive oxygen species in animal models, and sleep apnea is associated 
with increased systemic markers of oxidative stress and increased production of  
reactive oxygen species by neutrophils and monocytes (37). Inflammation and  
oxidative stress have also been directly demonstrated in vascular endothelial biopsies in 
patients with obstructive sleep apnea and resolves with treatment of the sleep apnea 
(38). 
As both central and obstructive sleep apnea are associated with intermittent hypoxemia, 
these considerations suggest that prevention of nocturnal hypoxemia, even if it does not 
treat sleep apnea per se, might mitigate the adverse effects of sleep apnea on the  
heart. This may be particularly true of central sleep apnea, in which large swings in 
intra-thoracic pressure are not a potential pathophysiologic factor. 

OPTIMAL-HF Protocol   August 4, 2017 
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Positive airway pressure treatment of sleep apnea in patients with chronic HF. 
The mainstay of therapy for obstructive sleep apnea for over 25 years has been 
continuous positive airway pressure (CPAP).  The major effect of CPAP is to prevent 
a drop in upper airway pressure during inspiration, thereby preventing airway 
collapse.  CPAP has also been used in the treatment of central sleep apnea. 
Although the mechanism of improvement in central sleep apnea with CPAP is 
uncertain, short-term studies demonstrate that in many chronic HF patients with 
central sleep apnea, CPAP therapy results in fewer central apneas, improved 
nocturnal oxygenation, and improved LVEF (39, 40).  Moreover, while CPAP resulted 
in an 8% increase in mean LVEF in HF patients with central sleep apnea, no 
improvement was seen in HF patients without sleep apnea, suggesting that the 
improvement in LVEF is a result of treating the central sleep apnea, and not a non- 
specific effect of CPAP on chronic HF (40).  A recent meta-analysis of 7 controlled 
CPAP treatment trials for CSA in patients with HF, presented in an American Academy 
of Sleep Medicine (AASM) Practice Parameters paper published this year, estimates 
the meta-analyzed mean effect of CPAP on LVEF to be 6.5% (41).  Although this effect 
is substantial, it should be interpreted with caution. All but one of these studies was a 
small, single-center, unregistered clinical trial, with an average sample size of 20 
subjects, raising concern for possible publication bias. The seventh study, the 
multicenter Canadian Positive Airway Pressure (CANPAP) trial found that, compared 
to usual care, CPAP therapy for central sleep apnea in chronic HF resulted in a much 
smaller mean improvement in LVEF of only 2.2% (42).  Moreover, although CPAP 
improved mean LVEF, there was no difference in transplant-free survival and a trend 
towards increased short-term mortality (42).  Subgroup analyses indicated that those 
participants whose sleep apnea was suppressed by CPAP had a better disease-free 
survival than the usual care group, while those whose sleep apnea was not 
suppressed had a worse outcome (43).  Although the ability to suppress sleep apnea 
with CPAP may simply be a positive prognostic indicator in chronic HF with central 
sleep apnea, the finding that CPAP therapy acutely lowers stroke volume and 
ejection fraction in patients with HF and obstructive sleep apnea (44) suggests a 
plausible explanation for increased short-term mortality in the CPAP-treated group.  
Despite the initial reduction in stroke volume and LVEF, after 4 weeks of chronic 
CPAP therapy both measures increased to above baseline levels (44). 
Until recently, adaptive servo-ventilation (ASV) had emerged as a preferred form of 
positive pressure ventilation for central sleep apnea.  It differs from CPAP in providing 
a higher pressure during inspiration than during expiration but, unlike standard bi- 
level positive airway pressure devices, it monitors respiration and varies the 
inspiratory pressure support level to maintain ventilation above 90% of the preceding 
baseline value.  The AASM Practice Parameters paper includes a meta-analysis 
of 6 ASV treatment trials, and estimates the meta-analyzed mean effect of ASV 
on LVEF to be 6.2% (41). Again, this value should be interpreted with caution, as 
all were small, unregistered clinical trials with a mean sample size of 23.7 
subjects. In three head-to-head comparisons of ASV with CPAP, ASV appears 
more effective than CPAP for treating central sleep apnea in patients with chronic 
HF, with more complete suppression of sleep apnea and greater improvements in 
LVEF (45-47).  In these 3 studies, the increase in LVEF over 3-6 months of treatment 
with ASV was 4.0-9.1%, compared to changes of -2.4- 1.9% for CPAP.  Four other 
uncontrolled studies of ASV treatment for 2 weeks to 12 months in patients with HF 
and central sleep apnea also showed improvements in LVEF of 4.6-7.9% (49-52).  

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Two studies have reported significantly improved exercise capacity following 6 
months of ASV treatment for central sleep apnea, with increases in maximal oxygen 
consumption on cardiopulmonary exercise testing of 1.4-2.7 ml/kg/min (47, 50).  The 
long-term safety and effectiveness of ASV for sleep apnea in chronic HF patients 
was until recently unknown; however, a preliminary report from a randomized clinical 
trial of over 1300 patients with heart failure, LVEF <45%, and predominantly central 
sleep apnea found a significant increase in mortality in the ASV-treated group, from 
7.5% annual mortality in those treated with usual cardiac care, to 10% annually in 
those treated with ASV, and revised labeling of this product as contraindicated in this 
patient population is planned (http://www.resmed.com/us/en/serve-hf.html - accessed 
5/24/2015). 
 
Despite the effectiveness of positive airway pressure for treatment of obstructive sleep 
apnea, many patients find it uncomfortable and are unwilling to use it, with reported 
utilization for >4 hours per night in fewer than two-thirds of patients in most reports, with 
adherence generally worse in asymptomatic or mildly symptomatic patients (51). As 
sleep apnea in HF patients is often asymptomatic, adherence to positive airway pressure 
therapy is likely to be particularly problematic. In the CANPAP trial, even among patients 
completing the study, average nightly use of CPAP after 1 year was only 3.6 hours (42). 
Oxygen as an alternative therapeutic option in sleep apnea. Despite evidence that 
hypoxemia plays a major role in the cardiovascular consequences of sleep apnea, there 
has been little research into the potential benefits of supplemental oxygen to treat this 
condition. Supplemental oxygen delivered by nasal cannula during sleep is very well 
tolerated; our preliminary experience indicates substantially greater adherence to 
nocturnal supplemental oxygen than to CPAP for treatment of sleep apnea in patients 
screened for sleep apnea in a Cardiology clinic (Section 2.7).  In patients with 
obstructive sleep apnea, several studies have demonstrated that supplemental oxygen 
at 1-4 liters per minute delivered by nasal cannula improves hypoxemia but does not 
reduce the AHI. In one study of patients with moderate to severe obstructive sleep 
apnea, oxygen was delivered at 2 lpm in those with a nadir oxyhemoglobin saturation 
below 80% at baseline, and at 1 lpm in those with a higher nadir saturation. This was 
sufficient to increase the mean nadir saturation from 70% to 90%, and reduced the 
frequency of 4% desaturation events by 89% (52).  In another study of patients with 
moderate to severe obstructive sleep apnea, supplemental oxygen at 3 lpm improved 
nocturnal oxyhemoglobin saturation but had no significant impact on other measures of 
sleep quality (53).  In a sample of 46 patients who underwent ambulatory blood 
pressure monitoring, blood pressure was modestly but not significantly reduced in the 
group receiving supplemental oxygen compared to those receiving placebo CPAP, with 
an effect approximately half as large as therapeutic CPAP (54). 
In contrast to its effect in obstructive sleep apnea, supplemental oxygen in patients with 
central sleep apnea not only improves oxygenation, but often leads to a reduction in the 
frequency of apneas and hypopneas, with the reported reduction in AHI typically 40- 
75% (55-59). Two controlled studies have examined the effect of nocturnal 
supplemental oxygen on cardiac function (58, 59). These studies showed 
improvements in LVEF of 5.5-9.7% following 3 to 12 months of treatment, with 
increases in LVEF of only 1.3% among controls in each study.  A third, uncontrolled 
trial was included with these in the AASM Practice Parameters paper meta-analysis, 
which estimated the effect of nocturnal supplemental oxygen on LVEF to be 5.0% (41); 
again, all were small, single-center, unregistered clinical trials, with an average sample 

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size of only 26.7.  Two studies have reported that nocturnal oxygen improves exercise 
capacity, with increases in maximal oxygen consumption on cardiopulmonary exercise 
testing of 2.3-5 ml/kg/min (55, 58).  Little is known regarding the effect of oxygen 
treatment for sleep apnea on long-term cardiovascular risk. 
(b) Significance 
HF is a common disease with high morbidity, mortality and health care utilization.  
Sleep apnea is highly prevalent in patients with chronic HF and is associated with a 
doubling of mortality risk, although it is commonly asymptomatic and usually goes 
undiagnosed. There are currently three approved therapies for sleep apnea in patients 
with HF, although as noted above ASV will soon be contraindicated in this patient 
population. The present study will for the first time directly compare the two remaining 
treatments, evaluating their effects on ventricular function, exercise capacity, and other 
markers of risk for progression of HF. This study will also lay the foundation for a long-
term study comparing the effects on morbidity and mortality of these therapies for 
treatment of sleep apnea in patients with chronic HF. 
 
(c) Relevance to Veterans Health 
Heart failure is reported to be the most common medical discharge diagnosis for 
veterans treated within the VA system (3).  Heart failure also carries a high mortality 
risk, with 1-year mortality of approximately 20% and 5-year mortality of 42-54%. 
Sleep apnea is a common co-morbid condition associated with increased HF 
mortality.  Identifying the optimal treatment regimen for sleep apnea in patients with 
HF is therefore of great relevance to Veterans health. 
 
(3) Work Proposed 
Overview 
The proposed study is a randomized, parallel group clinical trial comparing three 
months of therapy with continuous positive airway pressure (CPAP) or nocturnal 
supplemental oxygen (NSO) to optimized medical therapy for treatment of sleep apnea 
in patients with chronic heart failure. This study will be conducted over 4 years and 
participants will be recruited from among patients seen at the VA Boston and VA 
Connecticut Healthcare Systems for a diagnosis of heart failure. A total of 
approximately 500 patients will be recruited to undergo portable sleep monitoring in 
order to randomize 39 patients to each active treatment group (CPAP or NSO) and 20 
subjects to optimized medical therapy alone.  Participation of an individual subject will 
be approximately 1 week for subjects not meeting criteria for randomization, and 3.5 
months for subjects randomized. Participants will be age 18 and over, of either 
gender, and will have chronic heart failure with left ventricular ejection fraction ≤45%. 
No children or other special classes of individuals will be enrolled. All enrolled subjects 
will be veterans. 
 
Study procedures will include: 
• 
Screening Questionnaires 
• 
Portable Sleep Monitoring 
• 
Baseline (Randomization) Visit, including: 
o Resting Blood Pressure and Pulse 
o Blood draw 
o Anthropometry 
o Heart Failure and Quality of Life Health Questionnaires 

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o 24 Hour Blood Pressure 
o Echocardiogram 
o Cardiopulmonary Testing 
• 
Randomization to treatment with one of the following three treatments: 
o Healthy Lifestyle and Sleep Education alone (HLSE) 
o HLSE plus PAP (HLSE-P) 
o HLSE plus nighttime supplemental oxygen (HLSE-O) 
• 
Titration Visit for patients randomized to HLSE-P 
• 
Interim Telephone Contacts 
• 
Final Study Visit with repeat of Baseline Visit procedures 
 
Inclusion criteria for sleep apnea screening: 
• 
Age ≥18 years 
• 
Physician diagnosis of chronic HF, American Heart Association Stage C-D 
• 
LVEF ≤45% 
• 
No change in active cardiac medications for 4 weeks prior to randomization 
• 
Ability to provide informed consent 
 
For continuing to randomization, the following additional inclusion criterion applies: 
• 
Moderate to severe sleep apnea with a prominent central component, defined as 
an apnea-hypopnea index ≥15 events per hour, with a central apnea-hypopnea 
index >5 events per hour 
• 
LVEF ≤45% indicated at baseline echo test. 
 
Exclusion criteria: 
• 
Hospitalization for acute decompensated HF within previous 30 days 
o 
The patient may be screened for inclusion in the study and 
administered an HST at this time, but will not be eligible to complete a 
baseline visit until the 30 day window has passed 
• 
Hospitalization for myocardial infarction or cardiac surgery within previous 30 
days 
o 
The patient may be screened for inclusion in the study and 
administered an HST at this time, but will not be eligible to complete a 
baseline visit until the 30 day window has passed 
• 
Presence of a left ventricular assist device 
• 
History of heart transplantation 
• 
Poorly controlled hypertension (>175/>110), OR severe renal failure requiring 
dialysis, OR prior stroke with functional impairment OR other severe, or 
uncontrolled medical problems that may impair ability to participate in study exams 
based on medical history and review of medical records.  
• 
Severe chronic primary insomnia, with reported usual sleep duration <4 hours 
• 
Severe daytime sleepiness, defined as Epworth Sleepiness Scale score ≥18 or 
report of falling asleep driving during the previous year, unless determined by a 
study physician to be at low risk for motor vehicle accident 
• 
Awake resting oxyhemoglobin saturation <89% 
• 
Pregnancy 
• 
Smoking by subject or other person in the subject’s bedroom, or other open 
flame in bedroom 

OPTIMAL-HF Protocol   August 4, 2017 
Page10 
 
• 
Current use of a positive airway pressure device (including continuous or bi- 
level positive airway pressure or adaptive servo-ventilation) or supplemental 
oxygen therapy 
 
 
Study Design 
The proposed study is a randomized, parallel group study comparing three months of 
therapy with optimized medical therapy plus continuous positive airway pressure 
(CPAP) or nocturnal supplemental oxygen (NSO), respectively, to optimized medical 
therapy alone for patients with comorbid sleep apnea and chronic HF with reduced 
ejection fraction. The primary study outcomes are: (1) left ventricular ejection fraction 
(LVEF) measured by echocardiography, which is identified by the American College of 
Cardiology and American Heart Association as the single most useful test in the 
evaluation of patients with HF (26) and which has been shown in several studies to 
increase significantly over 4 to 12 weeks of therapy with CPAP or NSO in patients with 
heart failure and central sleep apnea (41), and (2) peak oxygen consumption on 
cardiopulmonary exercise testing (peak VO2), a valid and reproducible measure of 
functional capacity that has also been reported to increase following ASV or NSO (47, 
50, 58, 59). The primary analysis will compare each of the active treatment arms to the 
optimized care control group.  
 
Sample selection 
The target population is veterans with American Heart Association Stage C or D chronic 
HF with reduced ejection fraction and comorbid sleep apnea.  Patients will be recruited 
from among those patients enrolled in the VA Boston or VA Connecticut Healthcare 
Systems who carry a diagnosis of chronic HF.  Potential participants will be identified 
via the computerized patient record system, by searching on the diagnosis of HF using 
diagnostic codes 428.0-428.9.  Medical records will be screened to confirm the 
diagnosis of HF and document reduced LVEF by echocardiogram, nuclear gated blood 
pool scan, or ventriculogram. 
Recruitment 
Subjects will be recruited by mailings to patients seen for a diagnosis of heart failure at 
any time within 3 years of the start of this study, as well as through the inpatient 
cardiology service. This recruitment approach will be supplemented, if needed, by 
direct contact in clinic.  After initial contact, interested participants will have initial 
screening for eligibility. Potentially eligible patients will be invited to complete 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.  Participants who screen 
positive for moderate to severe sleep apnea with a prominent central component 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 heart failure, identified through the computerized medical record or via the 
Xcelera echocardiogram database.  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 

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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). 
Low sleepiness scores will not preclude participation, as sleep apnea is often 
asymptomatic in HF patients. 
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. 
Should response to the mailed questionnaires be inadequate we will pursue direct face- 
to-face recruitment from various Cardiology Clinics at the VA by trained research staff. 
This will entail study staff pre-screening the charts of patients visiting the clinic that day 
and approaching them after their visit to describe the study and ask them if they would 
be interested in participating.  Prior to contacting each patient, the cardiologist from 
each collaborating cardiology clinic will review the rosters of potentially eligible patients 
and will indicate his/her assent to contact each patient.  If needed, study staff will post 
recruitment flyers for the study in heavy traffic areas around the hospital as well as in 
the Cardiology clinics.  No personally identifiable data will be retained for patients who 
do not opt to participate. 
Additionally, study staff will recruit patients from the in-patient Cardiology service, with 
the assent of the Cardiology team. Study staff will pre-screen charts prior to 
approaching patients face-to-face. However, patients screened through the in-patient 
Cardiology service will not be have a baseline visit scheduled until they have been 
without a major cardiac incident for 30 days, as approved by the IRB. 
Screening visit 
At the Screening Visit, written informed consent will be obtained, adherence to 
treatment guidelines for chronic HF will be assessed, and participants will be instructed 
in the performance of home portable sleep monitoring. 
Informed Consent Procedures. The informed consent process will be undertaken by 
investigators and study staff who have current training in human subjects 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. 
Assessment of adherence to heart failure treatment guidelines 
At the screening visit, adherence to current medical treatment guidelines for heart 
failure will be assessed using a standardized checklist based on the 2009 American 
College of Cardiology/ American Heart Association Guideline Update for Evaluation and 
Management of Chronic Heart Failure in the Adult (33), and reviewed by a study 

OPTIMAL-HF Protocol   August 4, 2017 
Page12 
 
physician to ensure adherence to these guidelines. Particular attention will be paid to 
the use of angiotensin converting enzyme inhibitor (or angiotensin receptor blocker) and 
beta blocker in all patients unless contraindicated. Where adherence to these 
recommendations is not met, the treating physician will be contacted by a study 
physician to discuss the rationale for current therapeutic choices and, if appropriate, the 
patient will be referred to the Heart Failure Clinic for optimization of care prior to the 
baseline visit. 
Portable Sleep Monitoring 
At the Screening Visit, after written informed consent is obtained, subjects will be 
instructed in the use of the Embletta Gold portable monitor (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 (60): 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 (NONIN OEM board). 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 a trained staff member. 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 local computers, reviewed by the Research 
Coordinator, and saved to a secure drive for review by a trained research 
polysomnography technician based at the VA Connecticut, who will score the studies 
and grade them for quality.  Studies will be scored following AASM guidelines for 
standard hypopnea and apnea definitions based on respiratory effort, flow sensors and 
oximetry (60).  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 sleep apnea with a prominent central component 
(AHI >15, with central AHI >5) on portable sleep monitoring will proceed to the baseline 
study visit.  Participants will be instructed to arrive between 7 and 9 AM on the day of 
the baseline visit, and asked to eat only a light breakfast on the day of the visit.  The 
visit will begin with a blood draw, after which participants will proceed with the 
remaining baseline measurements and be instructed in use of the ambulatory blood 
pressure monitor. 
These baseline measures will be followed by randomization to one of the three 

OPTIMAL-HF Protocol   August 4, 2017 
Page13 
 
treatment arms and training in the assigned intervention. The entire baseline visit is 
expected to take approximately 4 hours. 
Fasting venipuncture and assays.  Phlebotomy will be performed using standard 
techniques by trained staff following a written protocol, for withdrawal of 20 cc of blood. 
The phlebotomist will draw two 10 ml EDTA plasma tubes for this protocol. Pre-labeled, 
bar coded tubes will be used for specimen tracking.  After venipuncture, the blood tubes 
will be incubated at room temperature for 30 minutes before being spun in a centrifuge, 
aliquoted and frozen. Samples will be placed into an at least -20◦C ± 10◦C freezer within 
90 minutes from venipuncture time. The samples will be transferred into the final freezer 
(-80◦C) within 24 hours. 
Serum PIIINP will be measured in Dr. Jacob’s laboratory using a commercially available 
radioimmunoassay (UniQ PIIINP RIA, Orion Diagnostica). This is a quantitative 
radioimmunoassay of intact aminoterminal propeptide of type III procollagen in human 
serum, which will be used to detect changes in connective tissue metabolism. Plasma 
NT-proBNP will also be measured in Dr. Jacob’s lab, using a commercially available 
ELISA kit (Alpco Diagnostics, Salem, NH). Serum isoprostanes will be measured in Dr. 
Jacob’s laboratory using a commercially available ELISA (Cayman Chemical, Ann 
Arbor, MI). TNFα and IL-6 will also be measuredin Dr. Jacob’s laboratory , using a 
commercially available ELISA (R & D Systems Inc., Minneapolis, MN) for TNFα and an 
Access Chemluminescent Immunoassay (Beckman Coulter, Fullerton, CA) for IL-6. 
Hs-CRP will be measured in the clinical laboratory at the VA Boston Healthcare 
System. 
Echocardiogram. Standard transthoracic 2-dimensional and Doppler 
echocardiography will be performed using a Philips IE33 cardiac ultrasound (Philips 
Healthcare, Andover, MA) to estimate cardiac dimensions, mass, and systolic and 
diastolic function.  All images will be captured in 3-beat loops for patients in sinus 
rhythm, 5-beat loops for those in atrial fibrillation.  M-mode measurements of LV 
dimensions will be performed and analyzed according to the American Society of 
Echocardiography recommendations (61).  LVEF will be measured using the modified 
Simpson’s method.  The interventricular septum thickness (IVST), posterior LV wall 
thickness (LVPWT), and left ventricular internal diastolic diameter (LVIDD) will be 
measured at end-diastole, and left ventricular mass calculated as 
0.8*(1.04*[(LVIDD+IVST+LVPWT)3–(LVIDD)3]+0.6). We will determine standard 
measures of diastolic function including E and A wave velocities, deceleration time, 
and pulmonary venous flow velocities, as well as utilize tissue Doppler imaging to 
detect abnormalities of diastolic function. Pulmonary artery systolic pressure will also 
be estimated utilizing Doppler measurements. For individuals with unclear images, or 
who have required contrast in the past, contrast will be used.  
Cardiopulmonary Exercise Testing. Treadmill exercise testing in association with air- 
gas-exchange, generally considered to be an optimal gauge of functional capacity, will 
be supervised by Dr. Daniel Forman (co-investigator), who has used this technique 
extensively in both clinical and clinical-research applications.  All patients will be 
assessed by a cardiologist for clinical stability immediately before the exercise 
stimulus. An intravenous catheter will be placed in advance of the procedure per 
routine as a routine safety precaution.  A motor-driven treadmill will be used and 
exercise will follow a modified Balke protocol. A bicycle ergometer will be used for 
those participants who are unable to walk on a treadmill but are capable of bicycle 
exercise (e.g., due to balance problems). A lightweight disposable pneumotach 

OPTIMAL-HF Protocol   August 4, 2017 
Page14 
 
device will be positioned in the participant’s mouth during the exercise  VO2 peak, 
VO2 at anaerobic threshold and VE/VCO2 will be measured using a metabolic cart. 
During exercise, electrocardiogram waveforms and hemodynamics (maximum heart 
rate and blood pressure) will be monitored.  Patients will exercise to their symptomatic 
limits, with encouragement to achieve a respiratory exchange ratio >1.0 (consistent 
with high physiological workload). However, if there are any signs of medical 
instability, the cardiologist will end the test before the symptomatic endpoint is 
achieved. In any instances of submaximal workload, analysis would focus on VO2 at 
anaerobic threshold, VE/VCO2 and other indices that do not depend on peak exercise 
performance. 
Questionnaires 
• 
Medical Outcomes Study SF36 Health-related Quality of Life Questionnaire. 
Each subject will complete the SF36 at their baseline and 3 month follow-up 
appointment. This questionnaire is a multi-purpose, short-form health survey that 
is widely used in research to estimate specific disease burden and to compare 
disease-specific benchmarks with general population norms. The questionnaire 
consists of 36 questions and provides an 8-scale profile of functional health and 
well-being scores (62). 
• 
Kansas City Cardiomyopathy Questionnaire. Each subject will complete this 
questionnaire at their baseline and 3 month follow-up appointment. This 
questionnaire is widely used to evaluate quality of life in heart failure patients. It 
consists of 23 items which assess the level of impact of physical symptoms in 
this population such as shortness of breath, fatigue, peripheral edema, and 
difficulty sleeping.  It also assesses the impact of psychological symptoms like 
anxiety and depression, as well as social functioning (63). 
• 
CHAMPS Physical activity questionnaire for older adults (64). Each subject will 
compete this questionnaire at their baseline and 3 month follow-up 
appointment. This questionnaire is used to assess physical activity in our 
population. 
• 
Health Questionnaire. Each subject will complete this questionnaire at their 
baseline and 3 month follow-up appointment. This questionnaire is used to 
collect data about medical history, and general but important health indicators, 
e.g., alcohol use, sleep quality, and restless leg symptoms. 
 
Ambulatory Blood Pressure Monitoring.  Participants will be instructed in the use of an 
Ambulatory Blood Pressure monitor. The device consists of a blood pressure cuff that 
is connected by rubber tubing to a small pressure monitoring device that weighs only 9 
oz and fits easily in a shirt pocket. The device will be programmed to measure BP at 20 
minute intervals during the day and 30 minute intervals at night (11 PM to 7 AM) for the 
subsequent 24 hours. A pre-paid addressed box will be provided for mail return of the 
device. 
Randomization.  After completing testing at the baseline visit, and being instructed in 
the use of the ambulatory blood pressure monitor, participants will be randomly assigned 
in a 1:2:2 ratio to one of three treatment groups: Healthy Lifestyle and Sleep Education 
alone (HLSE); HLSE plus Continuous Positive Airway Pressure (CPAP); or HLSE plus 
nocturnal supplemental oxygen (NSO).  Randomization will be performed using 
permuted blocks, stratified by recruitment site. A SAS program will be used to generate 
two separate lists of randomization assignments for the two strata. These lists will be 

OPTIMAL-HF Protocol   August 4, 2017 
Page15 
 
placed into a single 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 looks up the corresponding stratum 
using predominant sleep apnea type, picks the next assignment from that stratum, 
updates the lookup table with the Study ID randomized and the date/time of 
randomization.  Due to the nature of the treatments, blinding of subjects to treatment 
arm is not possible. The ultrasonographers and physicians overseeing and scoring the 
echocardiograms and cardiopulmonary exercise tests will be blind to treatment 
assignment. 
 
Treatment 
Healthy Lifestyle and Sleep Education (HLSE Group) 
Research Staff 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 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 
(26), and avoidance of smoking, excessive alcohol consumption, and use of illicit drugs. 
The importance of adherence to prescribed medical regimens will also be emphasized. 
The slides and written materials will be provided to participants at the baseline visit and 
reviewed at the one-week telephone contact.  All participants will have had clinical 
management reviewed by a study physician to ensure adherence to current HF 
treatment guidelines, as described above. 
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). The CPAP device to be employed in this study is the 
AutoSet Med S9 (Resmed, San Diego, CA). Participants will be educated on the use of the 
CPAP device, 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 scheduled for CPAP titration in 
the Sleep Laboratory of the VA Boston or VA Connecticut Healthcare System. All 
technicians in both Sleep Laboratories are Registered Polysomnography Technicians 
who are credentialed for human subjects research and have experience in the 
administration and titration of CPAP. CPAP titration will be performed overnight on a 
single night in the Sleep Laboratory.  Participants will undergo polysomnography with a 
typical montage according to current American Academy of Sleep Medicine 
recommendations, including electroencephalogram, electro-oculogram, chin 
electromyogram, respiratory inductance plethysmography, finger pulse oximetry, leg 
electromyogram, and electrocardiogram. Airflow and mask pressure will be monitored 
and recorded from the CPAP device.  Participants will be habituated to the preferred 
mask prior to study initiation. The CPAP device will be set to deliver pressure starting at 
4 cm H2O pressure. The CPAP pressure will be increased in increments of 1 cm H2O, 
at intervals of no less than 10 minutes, in order to eliminate both obstructive and central 
apneas, with a maximum CPAP pressure of 20 cm H2O. 
The Research Coordinator will maintain contact with participants by telephone during 

OPTIMAL-HF Protocol   August 4, 2017 
Page16 
 
the first 7 days of CPAP treatment to assist with any troubleshooting. The CPAP device 
is capable of wireless transmission of utilization and efficacy data. At the end of the first 
week of CPAP use, and again at weeks 2, 4 and 8 (in advance of each scheduled 
interim telephone contact), the utilization data will be reviewed by the Research 
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.  If adherence does not meet 
these targets, the Research Coordinator will discuss with the participant in an attempt to 
overcome barriers to adherence. 
Healthy Lifestyle and Sleep Education plus Nocturnal Supplemental Oxygen (NSO 
Group) 
In addition to HLSE, this intervention includes nightly treatment with nocturnal 
supplemental oxygen (NSO).  Oxygen therapy will be initiated at 2 lpm via nasal 
cannula, with routine clinical follow-up using overnight oximetry to assess adequacy of 
this flow rate.  If needed, oxygen will be increased in 1 lpm increments as needed to (1) 
maintain baseline saturation >90%, and (2) to reduce the frequency of 3% 
oxyhemoglobin desaturation events to <5 per hour (independent of baseline saturation 
level).  As oxygen at 2 lpm via nasal cannula has been shown to reduce the number of 
4% desaturations during sleep in patients with sleep apnea by 89%, we anticipate that 
most participants will be adequately treated at 2-4 lpm. Oxygen is provided by a 
stationery oxygen concentrator.  Adherence with oxygen use is measured by hours of 
machine use over the intervention period. 
 
Interim telephone contact 
Following initiation of therapy, study staff will make telephone contact with each 
participant at weeks 1, 2, 4 and 8 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 or Dr. Yaggi 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. At week one the Healthy Lifestyle 
Education will be presented to each group over the phone in conjunction with education 
materials set home with patient at baseline visit. 
 
Final study visit 
After 12 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 phlebotomy, 
echocardiography, cardiopulmonary exercise testing, and questionnaire administration. 
Participants will be asked to complete, while wearing the assigned therapy24-hour 
ambulatory blood pressure monitoring. 
 
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 
This study is a randomized clinical trial with three parallel treatment groups, designed to 
compare the active treatment groups (CPAP and NSO) to the optimal medical 
management comparator (HLSE).  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 

OPTIMAL-HF Protocol   August 4, 2017 
Page17 
 
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 drop- outs, and 
compared to the main analysis. 
The analysis for each of the primary outcome measures (LVEF and peak VO2) will 
consist of a one-factor analysis of variance comparing the mean changes from baseline 
in LVEF (or VO2). As we postulate similar benefits from CPAP and NSO, we will specify 
two contrasts: CPAP vs. HLSE and NSO vs. HLSE as our primary analyses.  In a 
secondary analysis, we will also compare the effects of CPAP to NSO for the purpose of 
hypothesis generation for subsequent larger studies. This analysis is a simple analysis 
of variance, with data transformation or adoption of rank-based inference if approximate 
normality is not present. While the randomization should achieve approximate balance 
on potentially confounding conditions, analysis of covariance models that employ 
adjustments for recruitment site, 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 therapy to 
change in outcome measures. 
In order to compare the effectiveness of the assigned interventions in controlling sleep 
apnea over the course of the study, an additional exploratory analysis will compare the 
change in AHI, change in time in periodic breathing, and change in time at SpO2 <90% 
between the baseline and final portable sleep monitoring studies. This analysis will 
utilize a one-factor analysis of variance.  Further exploratory analyses will assess the 
relation of effectiveness of control of sleep apnea to changes in the primary outcome 
measures. 
This study provides an opportunity to evaluate multiple intermediate measures that 
might shed light on the mechanism of benefit of CPAP or NSO. These analyses are 
considered exploratory in nature.  As each of the secondary outcome measures is 
continuous, analysis of these variables will be treated in a similar fashion to the analysis 
of the primary study endpoints.  For analysis of blood pressure, the 24-hour mean blood 
pressure and the ratio of mean nighttime to mean daytime blood pressure will also be 
analyzed. 
Mean hours of use of therapy over the 3-month intervention period between CPAP and 
NSO groups will be compared using a one-factor analysis of variance, with appropriate 
modification as needed for deviation from normality.  The number of adverse events and 
serious adverse events in each per study arm will be tabulated and categorized 
according to their severity, expectedness and relationship to the study intervention. 
 
Sample size and power 
Our primary goals are to establish the efficacies of CPAP and NSO compared to HLSE. 
Because past studies were suggestive of a more beneficial effect of CPAP or NSO 
compared to HLSE, we propose to randomize more subjects to the two experimental 
treatment groups. That is, we propose to allocate patients into CPAP, NSO or HLSE 
randomly according to a 2:2:1 ratio. This strategy also improves statistical power for the 
secondary comparisons between CPAP and NSO. 
The sample size for this study was chosen to provide adequate power to detect a 
significant difference in LVEF between each treatment group and the control group (Aim 

OPTIMAL-HF Protocol   August 4, 2017 
Page18 
 
1). We have used effect estimates based on the meta-analyzed mean effect sizes for 
CPAP and NSO included in the AASM Practice Parameters paper (41) of 6.4%, and 
5.0% for CPAP and NSO, respectively, and an estimated SD of change in LVEF of 4.8% 
based on previous reports of the effect of either ASV, CPAP or NSO (40, 42, 45-47) on 
LVEF in patients with sleep apnea. We use the Bonferroni method to account for 2 main 
comparisons and perform the test comparing each treatment to control at a 2.5% 
significance level. Using a two-sided two-sample t-test, an evaluable sample size of 34 
in the NSO (or CPAP) group and 17 in the HLSE group will achieve 90% power to detect 
a difference of 5.0% with a significance level of 2.5% assuming a standard deviation of 
4.8% in each group, and 98% power to detect a difference in LVEF of 6.4%; there will be 
80% power to detect a difference as small as 4.4% between either active treatment 
group and the HLSE group. 
Changes in peak V02 (Aim 2) will be compared in a similar fashion as changes in LVEF. 
An evaluable sample size of 34 in CPAP or NSO group and 17 in HLSE group will have 
80% power to detect a difference of 0.92 standard deviations with a significance level of 
2.5% using a two-sided two-sample t-test. Only one study of treatment of central sleep 
apnea in HF reports the SD of change in peak VO2, which was 2.5 ml/kg/min (58). The 
reported change in peak VO2 with treatment of central sleep apnea with NSO was 1.4-5 
ml/kg/min, with a median of 2.5 ml/kg/min (47, 50, 55, 58). The power for this Aim 
therefore appears adequate. 
For the exploratory comparison of CPAP and NSO, the sample sizes of 34 evaluable 
subjects per group will provide 80% power to detect a difference of 3.3% in change in 
LVEF, assuming a SD of change of 4.8% and a two-sided significance level of 5%. 
As comparisons for secondary outcomes (Aim 4) are exploratory in nature, they will be 
performed at 5% significance level without multiple comparison adjustment. For 
comparisons in a continuous outcome between each treatment group and the control 
group, an evaluable sample size of 34 in CPAP or NSO group and 17 in HLSE group 
achieve 80% power to detect a difference of 0.84 standard deviations with a 
significance level of 5% using a two-sided two-sample t-test. 
The proposed sample size of 39 in each active treatment group and 20 in the HLSE 
group includes a 15% increase over the needed number of evaluable subjects, to allow 
for expected rates on non-completion of the protocol. 
 
Reasons for stopping assigned treatment 
As there is clinical equipoise with respect to the long-term benefits of treatment of sleep 
apnea in chronic HF, and the duration of the intervention is short at 3 months, there is no 
plan to discontinue assigned treatment due to therapeutic failure related to cardiac 
disease.  However, as treatment of sleep apnea may be expected to improve sleepiness, 
any participant who develops unsafe levels of sleepiness that in the opinion of the PI 
place him or her at increased risk of motor vehicle accidents or other safety risks, will be 
treated for their sleep apnea off protocol. While serious adverse effects of either CPAP 
or supplemental oxygen are not anticipated, should any serious adverse events occur 
that in the opinion of the PI are treatment related, the treatment will be discontinued.   
 
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. The vein puncture for blood drawing is 

OPTIMAL-HF Protocol   August 4, 2017 
Page19 
 
associated with temporary pain at the time of needle insertion and may result in bruising 
at the needle insertion site. Rarely, fainting occurs with a blood draw. Portable sleep 
monitoring and ambulatory blood pressure monitoring may lead to minor sleep 
disturbance and some subjects may experience mild skin irritation from the sensors or 
electrodes used. Use of the blood pressure cuff may cause mild discomfort as the cuff 
is inflated. When the blood pressure cuff is worn for 24 hours, there may be some 
soreness in the arm. The administration of questionnaires may be stressful, although 
none ask sensitive information. The echocardiogram may cause transient discomfort as 
the 
ultrasound 
probe 
is 
pressed 
against 
the 
chest 
and 
upper 
abdomen. 
Cardiopulmonary exercise testing may cause shortness of breath, fatigue, muscle 
discomfort, and very rarely (<1:1,000) may be associated with heart attack or death. The 
intravenous (IV) catheter that will be placed for the exercise has a small chance of 
causing bruising or infection. Standard precautions will be followed in cleaning and 
sterilizing the area.  If contrast is needed for the echocardiogram, there is a small chance 
of allergic reaction. There is a rare chance (1:10,000) that patients may be allergic to the 
microscopic bubble contrast (lipid shell and gas), thus allergies will be confirmed via 
patient medical charts and verbally with the patient prior to the injection of the contrast 
agent.  Special efforts will be taken to reduce risks by watching each subject for 30 
minutes after the echo contrast agent.   
 
The study treatments are generally considered quite safe. CPAP  is an FDA-approved 
therapy for the treatment of sleep apnea. Its 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. Polysomnography will be performed for the purpose of CPAP 
titration in patients randomized to this therapy. This procedure is inconvenient, as it 
requires an overnight stay in the Sleep Laboratory, but poses no major risks. There 
may be some discomfort from placement of the sensors on the scalp and face, and 
wearing the sensors may cause sleep disruption. Occasionally there is discomfort or 
redness at the site of sensor placement.  Rarely (<1:100) the skin irritation may require 
treatment with a topical steroid. Supplemental oxygen delivered through the nose may 
be associated with minor side effects such as discomfort from the nasal prongs, 
dry nose, nasal stuffiness, mild nose bleeds or skin irritation. The use of a saline 
nasal spray can help prevent dryness and nosebleeds. Although oxygen at the levels 
prescribed in this study is not known to be harmful, oxygen can increase the risk of 
fire. It is possible that patients randomized to optimized medical care alone or with NSO 
may not be effectively treated for their sleep apnea for the 3 months 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 

OPTIMAL-HF Protocol   August 4, 2017 
Page20 
 
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 or at the Center for Clinical 
Investigation at Brigham & Women’s Hospital.  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. Blood and specimens will 
be stored using de-identified bar codes at the VA Boston and shipped to Dr Jacob’s 
laboratory, the VA Boston clinical lab for testing. Once the assays have been run on the 
samples, any leftovers will be destroyed. 
Risks from cardiopulmonary exercise testing will be minimized by close physician 
supervision of testing, which will be performed by trained technicians in the 
Cardiopulmonary Exercise Laboratories at the VA Boston and VA Connecticut HCS 
sites, with emergency equipment readily available. Although patients will be 
encouraged to exercise to their symptomatic limits, if there are any signs of medical 
instability, the cardiologist will end the test before the symptomatic endpoint is 
achieved. 
 
Phlebotomy will be performed by trained phlebotomists. 
 
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 
and air leaks.  Subjects will be contacted at weeks 1, 2, 4 and 8 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.  Participants 
randomized to NSO will be counseled on risks of fire from use of oxygen near open 
flames, including cigarettes. 
 
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 
or oxygen may experience direct benefit related to treatment of underlying  sleep 
apnea. There are also potentially important benefits to others, if the study identifies a 
well-tolerated alternative to positive pressure ventilation to reduce cardiac risk in the 
many patients with chronic heart failure and sleep apnea. As the risks to 
individual participants are small, and the potential benefit large, the risks of participation 
in the study are justified. 
 
Importance of the knowledge to be gained 
The societal benefits to the study include the generation of pivotal data for designing a 
definitive study that will for the first time address the relative effectiveness of alternative 
approaches to treatment of a very common comorbid illness (sleep apnea) in patients 
with heart failure. The approaches proposed may significantly reduce the costs and 
burden of current diagnostic and treatment approaches and improve access to 
treatment for a high risk population. The study may also provide important insights into 
the mechanism of the adverse cardiac effects of intermittent hypoxemia and sleep 
apnea, thereby stimulating research into additional novel therapies. 
 

OPTIMAL-HF Protocol   August 4, 2017 
Page21 
 
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Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, 
Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, 
Nichol G, O'Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, 
Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, Hong Y. Heart 
disease and stroke statistics--2009 update: a report from the American Heart Association 
Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:480-6. 
PMID: 19171871. 
2. Heidenreich PA. Department of Veterans Affairs Quality Enhancement Research 
Initiative (QUERI) Chronic Heart Failure Strategic Plan, December 2009 
(http://www.queri.research.va.gov/about/strategic_plans/chf.pdf accessed on March 5, 
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