Early Identification of Patients With Coexisting Atrial Fibrillation and Obstructive Sleep Apnea
Phase: NA
Conditions: Atrial Fibrillation, Arrhythmia, Stroke, Cardiovascular
Sponsor: University of Miami

Arrhythmia Detection In Obstructive Sleep apnea (ADIOS)  
Original title: “Early Identification of patients with coexisting atrial fibrillation and obstructive sleep 
apnea” 
NCT02743520 
Version Date: 03/21/2019 
 
Principal Investigator: Alberto Ramos, MD, MSPH, FAASM 
Department of Neurology & Stroke Program 
University of Miami Miller School of Medicine 
 
Co-Investigators: Alexandre Abreu, MD  
Division of Pulmonary Medicine 
 
 
  Salim Dib, MD  
 
Department of Neurology 
 
 
  Douglas Wallace, MD  
Department of Neurology 
 
 
  Litsa Lambrakos, MD  
Division of Cardiology 
 
 
 

A. BACKGROUND 
Obstructive sleep apnea (OSA) is characterized by repetitive interruption of ventilation during sleep due 
to collapse of the pharyngeal airway. A diagnosis of OSA is established when a patient has an apnea-
hypopnea index (AHI) >5 and symptoms of excessive daytime sleepiness1. OSA affects an estimated 15 
million adults and is prevalent in a large percentage of patients with hypertension and other forms of 
cardiovascular disease1. Obesity and male sex are recognized risk factors for the presence of sleep-
disordered breathing2. 
OSA is a recognized risk factor for ischemic stroke3, 4. The mechanisms whereby OSA increases the risk of 
stroke are complex, including hypoxia, increased likelihood of arrhythmia and congestive heart failure, 
increased atherosclerosis, and production of inflammatory changes in the blood5. Although OSA is well 
recognized as an independent stroke risk factor, little focus has been devoted to modifying potential 
stroke risk factors in patients with OSA. 
One of the mechanisms whereby OSA can lead to ischemic stroke is via atrial fibrillation (AF). AF is the 
leading cause of cardioembolic stroke and there is an important bidirectional relationship between 
these two conditions6, 7. OSA is present in up to 50% of patients with AF8. Also, when patents with OSA 
are followed longitudinally, up to 15% will develop AF over a five year period9.  
In addition to overt AF, performance of the polysomnogram (PSG) will allow the detection of premature 
atrial contractions (PACs). PACs are a recognized potential predictor for AF10.  
Early detection of AF in patients with OSA is important since oral anticoagulants are extremely effective 
for stroke prevention in patients with nonvalvular AF7. Institution of anticoagulation in the patient 
population with coexistent AF and OSA represents a significant opportunity for primary stroke 
prevention. 
B. METHODS 
The specific goal of this study is to assess the frequency of AF in patients with OSA using a cardiac event 
monitor (www.lifewatch.com). We will specifically target OSA patients with a CHADS2 score of ≥2. 
Patients who are newly diagnosed with OSA (within the last 12 months) based on a PSG at one of our 
participating hospitals will be eligible. Patients with a CHADS2 score of ≥2 will be approached for 
evaluation with a two week cardiac event monitor. The target sample size is 200 patients. The rationale 
for this sample size is provided below. 
Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Diagnosis of OSA within the last 12 months 
2. No previous diagnosis of atrial fibrillation 

3. Able and willing to follow-up as an outpatient 
4. Age 40-85 years 
Exclusion criteria 
1. Life expectancy < 2 years 
2. Dementia or other neurologic condition which would make outpatient follow-up difficult 
3. CHADS score <2 
4. Alcohol or drug abuse which would interfere with outpatient follow-up 
5. Severe CHF (NYHA class 3 or 4) or use of LVAD 
6. Current dialysis treatment or planned treatment within 12 months 
7. Known bleeding disorder or prothrombin time >15 seconds 
8. Mechanical heart valve requiring anticoagulation 
9. Moderate to severe mitral stenosis or regurgitation 
10. Prior clinical diagnosis of ischemic stroke (radiologic infarcts are not excluded) 
11. COPD with oxygen dependence 
12. Pregnant patients or patients that plan to become pregnant within the course of the study*. 
13. Patients with anticipated need for a pacemaker during the course of the study 
*If any patients become pregnant during the course of the study, pregnancy outcomes will not be 
followed 
Treatment Plan and Dosing Regimen  
Patients will be screened for atrial fibrillation with the Lifewatch ACT MCT monitor.  If positive for AF, 
results will be provided to the patient’s primary care physician and outpatient antithrombotic 
medication use in the following six months will be recorded.  The Lifewatch interpretation will be sent 
by FAX to the patient’s primary care physician for patients recruited at the University of Miami Sleep 
Center.  
 Cardiology consultation will be encouraged for patients with newly detected AF. 
Subject Recruitment 
The study coordinator will work with the PI and co-investigators to institute screening procedures for 
eligible subjects at the two sites, also, protected health information will be access prior as well during 

the course of the proposed research. All newly diagnosed OSA patients who meet the study criteria will 
be invited to join the study. In addition, patients with a diagnosis of OSA within the previous 12 months 
will also be asked to participate if they meet all the study criteria. Patients who will be approached for 
participation in the study are already under the care of the sleep physicians who are co-investigators in 
the study. 
Prior to study initiation, an educational presentation will be provided to the Sleep Program personnel 
(including staff physicians, fellows) to review the nature and purpose of the study. The physicians 
involved in the Sleep Program have regular conferences in which the study will be highlighted. The PI 
will work with the study coordinator and co-investigators to review study enrollment on a biweekly 
basis. Any obstacles to enrollment will be addressed by the study staff.  
A summary of the study schedule of events is provided in Appendix one. 
Description of cardiac monitoring device 
The Lifestar ACT MCT monitor is a continuous ECG monitor and arrhythmia detector that is designed for 
self-testing by patients at home and for analysis by medical professionals at a remote Monitoring 
Center. The chest-worn sensor is utilized for the acquisition, recording, and transmission of the ECG 
signal. The device is equipped with four electrodes on a harness and it houses a 3.6V AA battery, a 
Bluetooth transceiver and a buzzer Patients will be monitored over a  2 week of period. 
The ECG signals are transmitted via Bluetooth to a handheld device with a proprietary interactive 
application, arranged to process and transmit the ECG recordings. The handheld device is mobile 
computing device with a display and a touch input such as a cell phone. It has adequate memory and 
processing capability to run the proprietary application. This device is already used for routine clinical 
care at both the University of Miami Hospital and the Miami VA Hospital. A patient quick start guide is 
attached as an appendix. 
Outcome Measures 
After completion of the four week cardiac event monitor, we will record the frequency of abnormalities 
such as:  
1. Frequent premature atrial contractions 
2. Frequent ventricular premature contractions 
3. Definite AF (defined as an irregularly irregular rhythm with absence of p waves) 
4. Longest duration of AF 
5. AF episodes lasting more than six minutes 
Initial interpretation of the cardiac monitor is provided by Lifewatch technicians and the reports will be 
confirmed by the study assigned cardiologist. The Lifewatch technicians receive ECG information only 
and no identifiable information. We will follow patients for six months after the placement of the 
cardiac event monitor. We will document selection of antithrombotic therapy including the following: 

1. Novel oral anticoagulant (NOAC) 
2. Warfarin 
3. Antiplatelet therapy 
4. No antithrombotic therapy 
After all patients have completed the six month follow-up period, we will record the following: 
1. Frequency of undetected AF 
2. AF frequency according to baseline CHADS2 score 
3. Rate of utilization of anticoagulants in patients with AF 
4. Rate of utilization of antiplatelet therapy in patients with AF 
5. Predictors of AF based on baseline variables (age, sex, history of CHF, BMI, etc.) 
If we find that >5% of patients with OSA and CHADS2 score of ≥2 have undetected AF, then this would 
support a larger multi-center study of screening OSA patients for AF and identifying predictors of AF in 
this population.  
Risk/benefit considerations 
No benefit can be guaranteed to study participants. However, if they do have early detection of AF, they 
can be placed on appropriate antithrombotic treatment to prevent stroke, which is a potential benefit.  
There are no major risks with the device. Some patients may have skin irritation and special “sensitive 
skin” leads are available for these patients. There is no restriction with the use of the device with 
pacemakers or other implanted devices since only surface recordings are made. 
C. SAMPLE SIZE CONSIDERATIONS 
The frequency of AF in the general population is likely to be <1%. Our hypothesis is that 5% of OSA 
patients screened with a four week monitor will have AF. 
If p = the percent of patients with sleep apnea who have afib, then the z-test will assess the following 
hypotheses: 
H0:  p <= 1%  
H1: p > 1% 
If the true value of p is 5%, then a study with 200 patients has power = 97%. That is, the probability is 
0.97 that the null hypothesis (H0) will be rejected at a significance level of 5% in favor of the alternate 
hypothesis (H1).  
The sample size needed for 80% power is 59 patients. The higher sample size is justified since the point 
estimate of AF frequency will be more precise with the larger sample size. Further, analysis of the 
predictors of AF according to baseline variables will be more fruitful with a larger sample size. 
 

D. Performance sites 
Patients with OSA will be identified and recruited for the study at The University of Miami Sleep Center, 
which is accredited by the American Academy of Sleep Medicine.(http://uhealthsystem.com/sleep-
center). The UM Sleep Center has an eight bed sleep lab and performs over 1000 sleep studies per year 
and diagnoses over 500 patients per year with OSA. There is ample volume of clinical patients for study 
recruitment.  
E. Study Procedures and Timeline 
See Table 1 
F. Data Management Plan 
The Department of Neurology at the University of Miami Miller School of Medicine has a full time 
statistician and has served as the clinical coordinating center for previous multi-center trials. The 
research infrastructure is excellent. The Neurology Department participates in two major NIH-sponsored 
clinical trial consortia, the NeuroNext Initiative and the Stroke Trials Network (StrokeNet). 
With regard to data collection and adequacy, data will be obtained directly from the study participants 
via office visits or through phone follow-up, and thus we feel that the data source for those elements 
will be quite accurate. The electronic medical record (EMR) at the two facilities will be another source 
for obtaining information on any medical encounters for cardiac issues such as atrial fibrillation. 
Electronic case report forms will be created for data collection in the study. 
Although all measures will be undertaken to prevent missing data, it is likely that there will be some 
missing data elements due to patients who drop out of the study. Due to the relatively short duration of 
study participation and the patient stipend being offered, we expect a dropout rate of <2%.  To handle 
missing data, we will first examine the characteristics of those who are missing outcome data compared 
to those who are not, as well as those who were lost-to-follow-up and those who were not, to 
determine whether there are differences in important characteristics between the groups (e.g. age, 
race). To deal with missing data in the outcome, we will employ methodology such as the use of 
multiple imputation. 
G. Drug Supply Request 
None  
H. Adverse Events  
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS 
1.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 

An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and unintended 
sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.  
Adverse reaction (ADR) 
An adverse reaction is defined as a response to a medicinal product which is noxious and unintended. 
Response in this context means that a causal relationship between a medical product and an adverse 
event is at least a reasonable possibility. Adverse reactions may arise from use of the product within or 
outside the terms of the marketing authorization or from occupational exposure. Conditions of use 
outside the marketing authorization include off-label use, overdose, misuse, abuse and medication 
errors. 
Serious adverse event 
A serious adverse event is defined as any AE which 
- 
results in death,  
- 
is life-threatening,  
- 
requires in-patient hospitalization, or 
- 
prolongation of existing hospitalization,  
- 
results in persistent or significant disability or incapacity, or  
- 
is a congenital anomaly/birth defect  
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time 
of the reaction; it does not refer to a reaction that hypothetically might have caused death if more 
severe. 
Medical and scientific judgement should be exercised in deciding whether other situations should be 
considered serious reactions, such as important medical events that might not be immediately life 
threatening or result in death or hospitalization, but might jeopardize the patient or might require 
intervention to prevent one of the other outcomes listed above. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization or development of dependency or abuse. Any suspected 
transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction. 
 
1.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND REPORTING 

INSTITUTION/Investigator will be responsible for reporting AEs which occur during the conduct of the 
Study to the competent regulatory authorities, accredited Institutional Review Boards and/or 
Independent Ethics Committee(s) (“IRB/IEC(s)”) in accordance with the applicable laws and regulations.  
1.3 
 
ADVERSE EVENT REPORTING TO BOEHRINGER-INGELHEIM (BI) 
Dabigatran is not part of the protocol but the following section is added at the request of the sponsor 
in case patients receive dabigatran. 
 
INSTITUTION shall report  
(i) 
all ADRs, serious and non-serious 
(ii) 
all fatal AEs 
(iii) 
pregnancies in female subjects and partners of male subjects 
which are associated with dabigatran by fax the BI Unique Entry Point (Fax : 1-203-837-4329) using BI 
NIS SAE report form in following timelines. 
All Serious ADRs and AEs with fatal outcome shall be forwarded immediately (within twenty four (24) 
hours or next business day whichever is shorter). 
All non-serious ADRs shall be forwarded within seven (7) days 
The investigator carefully assesses whether an AE constitutes an ADR using the information below.  
Causal relationship of adverse event 
The definition of an adverse reaction implies at least a reasonable possibility of a causal relationship 
between a suspected medicinal product and an adverse event. An adverse reaction, in contrast to an 
adverse event, is characterized by the fact that a causal relationship between a medicinal product and 
an occurrence is suspected.   
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors 
such as concomitant medication, concomitant diseases and relevant history.  
Reporting of related Adverse Events associated with any other BI drug 
The investigator is encouraged to report all adverse events related to any BI drug other dabigatran than 
the  according to the local regulatory requirements for spontaneous AE reporting at the investigator’s 
discretion by using the locally established routes and AE report forms.  
 
I. Regulatory Considerations 

1. Institutional Review Board (IRB)  
 
Written informed consent will be obtained from study participants at each of the two 
performance sites. All study personnel will be trained in Good Clinical Practices (GCP) and fulfill other 
requirements of the University of Miami and Miami VA Hospital Research Committees. 
2. Subject confidentiality 
 
In order to maintain participant confidentiality, any records that leave the center will be 
identified only by the Study Identification number (SID). All records will be kept in a locked file cabinet. 
All computer entry will be done using SIDs only. Clinical information will not be released without the 
written permission of the participant. The patient contact information and restricted clinical information 
will be maintained by the study coordinator in a password-protected file on a laptop computer which 
will be kept in a locked office (CRB 1362).   
3. Study Registration 
The study will be registered at www.clinicaltrials.gov prior to initiation. 
4. Study Modification/Discontinuation 
The study may be discontinued at any time by the sponsor as per the contract. 
J. Future Directions 
In order to have the greatest impact on stroke prevention, it is important to have AF patients on the 
most effective antithrombotic medication7. Furthermore, it is important to have the anticoagulant 
medication started before a stroke to avoid permanent neurologic injury. Screening high risk patients for 
AF is one method to identify AF patients prior to the development of a disabling stroke.  
We feel that the group of patients with OSA represents an excellent target population for AF screening 
due to their high frequency of multiple stroke risk factors (hypertension, diabetes mellitus, obesity, etc.). 
If we are able to establish that the frequency of AF in this population is at least 5%, then a larger study 
can be justified. Screening of OSA patients would also be a novel method for early identification of 
individual patients at elevated risk for ischemic stroke. Future studies could also investigate genetic 
polymorphisms which are associated with an increased propensity for AF11, 12. By combining genetic 
predisposition with environmental factors and conventional risk factors, an “AF prediction” score could 
be developed for patients with OSA and other conditions such as congestive heart failure. 
 

K. Publication Plan 
Our study team is multidisciplinary, including representatives from neurology, cardiology, and 
pulmonary/sleep medicine. It is likely that this study will be of interest to multiple audiences. Therefore, 
we would like to target abstract presentations for meetings such as the American College of Cardiology 
conference, American Academy of Neurology conference, and the meeting of the Associated 
Professional Sleep Societies. 
Journals targeted for publication include the Journal of the American College of Cardiology (JACC), 
Neurology, and Sleep. 
 

REFERENCES 
1. 
Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, et al. Sleep apnea and 
cardiovascular disease: An american heart association/american college of cardiology 
foundation scientific statement from the american heart association council for high blood 
pressure research professional education committee, council on clinical cardiology, stroke 
council, and council on cardiovascular nursing in collaboration with the national heart, lung, and 
blood institute national center on sleep disorders research (national institutes of health). 
Circulation. 2008;118:1080-1111 
2. 
Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered 
breathing among middle-aged adults. New England Journal of Medicine. 1993;328:1230-1235 
3. 
Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guidelines for the 
primary prevention of stroke: A guideline for healthcare professionals from the american heart 
association/american stroke association. Stroke; a journal of cerebral circulation. 2011;42:517-
584 
4. 
Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as 
a risk factor for stroke and death. New England Journal of Medicine. 2005;353:2034-2041 
5. 
Wallace DM, Ramos AR, Rundek T. Sleep disorders and stroke. International journal of stroke : 
official journal of the International Stroke Society. 2012;7:231-242 
6. 
Wilcox I, Semsarian C. Obstructive sleep apnea: A respiratory syndrome with protean 
cardiovascular manifestations. Journal of the American College of Cardiology. 2009;54:1810-
1812 
7. 
Culebras A, Messe SR, Chaturvedi S, Kase CS, Gronseth G. Summary of evidence-based guideline 
update: Prevention of stroke in nonvalvular atrial fibrillation: Report of the guideline 

development subcommittee of the american academy of neurology. Neurology. 2014;82:716-
724 
8. 
Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proceedings of the American 
Thoracic Society. 2008;5:136-143 
9. 
Gami AS, Hodge DO, Herges RM, Olson EJ, Nykodym J, Kara T, et al. Obstructive sleep apnea, 
obesity, and the risk of incident atrial fibrillation. Journal of the American College of Cardiology. 
2007;49:565-571 
10. 
Gladstone DJ, Dorian P, Spring M, Panzov V, Mamdani M, Healey JS, et al. Atrial premature beats 
predict atrial fibrillation in cryptogenic stroke: Results from the embrace trial. Stroke; a journal 
of cerebral circulation. 2015;46:936-941 
11. 
Mohanty S, Santangeli P, Bai R, Di Biase L, Mohanty P, Pump A, et al. Variant rs2200733 on 
chromosome 4q25 confers increased risk of atrial fibrillation: Evidence from a meta-analysis. 
Journal of cardiovascular electrophysiology. 2013;24:155-161 
12. 
Smith JG, Almgren P, Engstrom G, Hedblad B, Platonov PG, Newton-Cheh C, et al. Genetic 
polymorphisms for estimating risk of atrial fibrillation: A literature-based meta-analysis. Journal 
of internal medicine. 2012;272:573-582 
 
 

APPENDIX ONE 
Visit schedule and tasks for completion 
Time 
Tasks for completion 
Baseline evaluation 
• 
CHADS score calculation* 
• 
Obtain informed consent 
• 
Arrange cardiac monitor for patient 
• 
Explain plan for outpatient follow-up 
• 
Complete baseline data collection form 
• 
Heart monitor will be placed 
1week 
• 
Contact subject to verify that they are 
wearing the cardiac monitor.  
• 
Ask subject about any adverse events. 
• 
Remind subject to return the heart monitor 
(in person or via USPS or UPS) 
• 
Schedule 6-month phone call follow-up. This 
phone call will serve as the study close-out 
visit. 
6 months 
Contact subject for study close-out visit