Impact of OSA on Outcomes in Acute Coronary Syndrome

Obstructive sleep apnea (OSA) is very common in middle aged adults. Using a polysomnography
(PSG) derived definition, defined as an apnea hypopnea index (AHI) of >5, it occurs in 20-30
% of males and 10-15 % of females in North America. Various large epidemiological studies
have established a close relationship between OSA and cardiovascular disease including
coronary heart disease (CHD), heart failure, atrial fibrillation, and stroke. Potential
mechanisms including endothelial dysfunction/ systemic inflammation, sympathetic activation,
metabolic dysregulation, and mechanical load effects during respiratory events have been
implicated for this relationship. However, in contrast to previous literature, more recent
studies have also explored a cardio protective role of OSA. Repetitive hypoxemic episodes
noted in OSA may lead to myocardial ischemic preconditioning, conferring protection in the
form of a smaller myocardial infarct size, lower rates of cardiac arrhythmias, heart failure,
and thereby, cardiovascular mortality. Animals exposed to intermittent hypoxia prior to
ischemic insult experience significantly reduced infarct sizes when compared to animals not
exposed to intermittent hypoxemia. Whether a similar effect exists in humans is still
unclear. Recent research indicates better coronary collateral flow in OSA compared to control
subjects presenting with acute coronary syndrome (ACS), which potentially could explain a
cardioprotective role. Others have reported variable outcomes of coronary plaque burden and
lesion complexity, restenosis and target vessel revascularization, serological markers such
as troponin T, high sensitivity-C reactive protein (hs-CRP) and N-terminal pro brain
natriuretic peptide (NT-proBNP), and major adverse cardiovascular events (MACE) in OSA vs.
control subjects. Further, some of these early reports were limited by available devices,
technology and methodology of the era. The objective of this study is to examine the
prognostic role of OSA in patients with acute coronary syndrome (ACS). We tested the
hypothesis whether OSA predicts subsequent MACE in patients undergoing percutaneous coronary
intervention.

Methods This is a prospective, single center, observational study of patients presenting with
ACS, including ST segment elevation (STEMI), non-ST segment elevation (NSTEMI) and unstable
angina who undergo coronary revascularization at our tertiary care center. A total of 160
adult patients above age 18 years who meet our inclusion/ exclusion criteria will be
enrolled. The estimated duration for this study is 2017-2018.

Prospective eligible patients who present for treatment for ACS at our institution in the
study period will be approached for recruitment. Exclusion criteria for the study include:
pregnancy, post-cardiac arrest patients, diagnosis of medical conditions associated with
predicted survival of < 6 months, need for tracheostomy and prolonged mechanical ventilation,
prior treatment for sleep disordered breathing and unavailable sleep data (due to death, no
informed consent, uncooperative subject, technical difficulties, miscellaneous).

All subjects or their legally authorized representatives must provide written informed
consent before any study-related procedure can be conducted. All recruited patients will
undergo a level III sleep study within 48 to 72 hours prior to discharge. The patients will
then be separated into OSA (AHI≥15 events/ h) and non-OSA (AHI<15) groups based on AHI.

There will be no financial incentive offered to patients. All recruited patients will be
treated according to Declaration of Helsinki and amendments, World Medical Association
Declaration of Helsinki — Ethical Principles for Medical Research Involving Human Subjects
and standard clinical guidelines.

Study data will be collected and managed using REDCap electronic data capture tools hosted at
MetroHealth Medical Center. REDCap (Research Electronic Data Capture) is a secure, web-based
application designed to support data capture for research studies, providing: 1) an intuitive
interface for validated data entry; 2) audit trails for tracking data manipulation and export
procedures; 3) automated export procedures for seamless data downloads to common statistical
packages; and 4) procedures for importing data from external sources.

Study Endpoints Baseline patient information will be collected prospectively at presentation
for the index hospitalization for acute MI including: demographic information, cardiovascular
risk factors, medical conditions, current medications, and relevant laboratory test values.
The primary end point of this study were in-hospital, 30 day major adverse cardiac events
(MACE), defined as a composite endpoint of cardiovascular death, non-fatal MI, stroke and the
need for unplanned repeat revascularization. Secondary endpoints include 6 month major
adverse cardiac events (MACE), individual MACE cardiovascular death, non-fatal MI, stroke,
need for unplanned repeat revascularization, ST segment resolution (STR), heart failure
requiring hospitalization, and all-cause mortality.

Percutaneous Coronary Intervention Primary PCI will be performed according to the standard
clinical practice. There are no restrictions to the usage of pharmacologic and device
strategies during PCI. PCI is defined as any intervention to a major epicardial coronary
artery with a significant stenosis based on ≥70%-diameter narrowing on visual estimation
(≥50% for left main) and/or fulfilling physiological criteria for revascularization (i.e.,
fractional flow reserve ≤0.80, intravascular ultrasound-IVUS). Angiographic findings
including TIMI flow and ST resolution will be obtained as standard of care by the cardiology
team.

Echocardiography Comprehensive Transthoracic 2D and Doppler echocardiography using
commercially available echocardiography machines will be obtained during hospitalization.
Standard parasternal, apical, and subcostal views will be obtained with the subject in a left
lateral recumbent position. Images were stored digitally and on VHS videotape, which were
subsequently analyzed. All measurements will be made according to American Society of
Echocardiography Guidelines.

Overnight Sleep Study All sleep studies will be conducted using a Resmed ApneaLink Air
standardized level III portable diagnostic device (ResMed Corporation, Poway, California).
Although limited by its inability to identify sleep stages and lack of an objective
measurement of sleep duration, this device has been validated for use against in-laboratory
polysomnography with sensitivity and specificity around 91% and 95% at an AHI value of ≥15/
hour, respectively. Outputs recorded from the portable diagnostic device include nasal
airflow (nasal pressure transducer), thoraco-abdominal movements (inductive respiratory
band), arterial oxygen saturation (pulse oximetry), and snoring episodes (derived from the
integrated pressure transducer). All studies will be manually scored and analyzed by a
certified sleep physician. To ensure the accuracy and consistency of scorings, a second sleep
physician will audit the studies.

The primary measure of the sleep study will be the AHI, quantified as the total number of
apneas and hypopneas per hour of sleep. The respiratory event scoring will be performed
according to the American Academy of Sleep Medicine guidelines.

Standardized Obstructive Sleep Apnea Questionnaire Administration During hospitalization for
acute MI, recruited patients will be administered the STOP-BANG Questionnaire, Berlin
Questionnaire (BQ) and Epworth Sleepiness Scale (ESS) by face-to-face interviews by an
investigator.

Referral to Sleep Clinic All patients diagnosed with OSA during this study will be referred
to the Sleep Clinic at MetroHealth Medical Center for further evaluation and treatment.
Relevant sleep study data will be made available to patients and clinicians.

Follow up Patient data will be collected at 30-days and 6 months to record outcomes.

Sample- Size Calculation According to previous study, 23.5% of patients with OSA, based on an
AHI ≥10 are expected to have adverse MACE after undergoing PCI for ACS, whereas only 5.3%
non-OSA patients experienced these events. Based on 85% power and a significance level of 5%,
the required sample size is 130 (OSA, n=65; non-OSA, n=65). Given that an estimated 20% of
the sleep studies may not be successful (due to premature device removal by the patients or
technical errors), a minimum of 162 recruited patients is needed. The projected sample size
of 160 participants will provide sufficient power to test the primary hypothesis.

Inclusion Criteria:

Patients presenting with:

- Acute coronary syndrome, including:

- ST segment elevation (STEMI)

- non-ST segment elevation (NSTEMI)

- unstable angina

- Who undergo coronary revascularization at our tertiary care center .

Exclusion Criteria:

- Pregnancy

- Post-cardiac arrest patients

- Diagnosis of medical conditions associated with predicted survival of < 6 months

- Need for tracheostomy and prolonged mechanical ventilation

- Prior treatment for sleep disordered breathing and unavailable sleep data