Clinical trial NCT02576587: Influence of Sleep Apnea on Risk of Atrial Fibrillation
Official title: Elucidation of the Influence of Sleep Apnea on Risk of Atrial Fibrillation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Sleep Apnea
Atrial Fibrillation
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2015-10-15
Enrollment: 317
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The Elucidation of the Influence of Sleep Apnea on Risk of Atrial Fibrillation study.

The study involves a case control design to investigate the extent to which there is an independent relationship of sleep disordered breathing (SDB) and paroxysmal atrial fibrillation (PAF). Cases will be defined as clinically identified patients with PAF and controls as those without AF. In order to rigorously address important biologic confounding influences, the cases and controls will be individually matched based upon age, gender, race, and body mass index. Those participants with both PAF and SDB (Apnea Hypopnea Index, AHI\>=15) will be asked to return for a follow up exam after 3 months of SDB treatment in the Clinical Research Unit (CRU) for collection of the same measures collected at the baseline exam to observe for any significant changes with the purpose of collecting effect size data to inform future clinical trials.

The total duration of the study is 4 years. The duration for any individual participant is up to from one to 13 weeks months, including a 3-month treatment period for those with moderate to severe SDB, i.e. AHI\>15.

Detailed description: Sleep-disordered breathing (SDB) is common in patients with cardiovascular disease and its attendant hypoxemia and autonomic dysfunction create a milieu that is likely to enhance AF propensity. Thus, SDB may represent a novel target for AF prevention and treatment strategies. Although our prior cross-sectional work has shown a 2-4 fold higher odds of AF related to SDB, these and other reports have not included cardiac structural data or autonomic/biochemical measures, and have addressed only arrhythmic events occurring during an overnight sleep study. In this proposal, we will examine paroxysmal AF (PAF), an early stage risk factor for persistent AF, and relevant to this proposal because it occurs prior to extensive cardiac electrical remodeling/fibrosis.

OUTLINE OF STUDY VISITS Baseline Visit (SA 1 and 2). After informed consent, eligible participants will be scheduled to arrive for an overnight visit in the CRU. During the evening, participants will undergo questionnaire administration, blood pressure measurements, and anthropometry. They will be provided dinner and undergo polysomnography (PSG). In the morning, participants will undergo fasting venipuncture, overnight urine collection, ECHO, 6 minute walk test, vascular measures and blood pressure measurements. For those with PAF (cases), hook-up for continuous ECG monitoring will be performed along with education regarding how to handle the device and bathing instructions, etc. All measurements in the DCRU/CRU will be performed blinded to PAF status. The only unblinded staff will be a dedicated research assistant who will perform the ECG monitoring hook-up. Blinded staff will collect and process data and perform data entry. After the baseline visit, participants with PAF (n=150) will undergo hook-up of the ECG monitor and an activity monitor at the baseline visit to wear for a 7-21 day period.

Follow-Up Visit (SA3). Those with SDB (AHI\>=15) without evidence of central apnea (central apnea index\>5) or Cheyne Stokes Respirations via baseline visit PSG and who have PAF will undergo the following. A 5-7 day home-based auto-titration (APAP, Respironics Autopap System One with humidifier) to identify the optimal positive airway pressure (PAP) setting will be performed (with settings 4-20cm H2O). At the end of the 5-7 day titration, the goal will be to identify the pressure that results in an AHI\<5 events/hour (optimally). The research assistant will re-set the device to deliver this optimal fixed pressure identified by the PI through the secure wireless web-site. An overnight DCRUCRU visit will be scheduled after 3 months of wearing CPAP during which the same measures performed at the baseline visit will be collected.

STUDY PROCEDURES 2-DIMENSIONAL DOPPLER ECHOCARDIOGRAPHY. Parasternal, apical and subcostal 2-D views and apical 3D views will be obtained with transducer orientation and gain settings adjusted to optimally define endocardial surface of each cardiac chamber.

POLYSOMNOGRAPHY (PSG). Procedure for PSG: Research PSG will be performed using the Compumedics E-series system (Abbottsford, AU) which will include 3 cortical encephalograms, bilateral electro-oculograms, a bipolar submental electromyogram, thoracic and abdominal respiratory inductance plethysmography, airflow (by nasal-oral thermocouple and nasal cannula pressure recording), oximetry (using highly sensitive finger pulse oximeter, sampling frequency 25Hz), electrocardiogram (ECG) at 250Hz (used to derive HRV measures of autonomic function); body position (mercury switch sensor), bilateral leg movements. EEGs are recorded at 125Hz. 3) 7-21 Day CONTINUOUS ECG MONITORING.

Procedure: A 3-lead (2 channel), wireless, lightweight ECG monitoring device will be used to collect the ECG data over a 7-21 day period in those with PAF after the baseline and follow-up CRU visits.

ACTIVITY MONITORING. Procedure: An accelerometer (GT3X+, Actigraph Co., Ft Walton Bch, Fl) will be used for 7-21 days, coincident with the time of continuous ECG monitoring.

FASTING VENIPUNCTURE (52cc). Procedure: Phlebotomy will be performed the morning of the baseline and follow-up visits using standard techniques by trained research staff following written procedures. 6) DNA collection. Blood will be collected to extract RNA, which will be stored to test future hypotheses regarding genetic determinants of treatment response.

OVERNIGHT URINE. Procedure: Overnight urine collection will be performed. ANTHROPOMETRY. Height (inches, cm), neck circumference (cm), waist circumference (cm), hip circumference (cm) will be obtained. Skinfolds are measured with calibrated metal calipers from 7 sites (chest, calf, thigh, calf, subscapular, midaxillary, suprailiac, abdominal).

RESTING BLOOD PRESSURE (BP). BP will be measured after the participant has been sitting quietly for at least 5 minutes following standardized guidelines using a calibrated sphygmomanometer. Measurements will be repeated three times and recorded.

QUESTIONNAIRES. The following will be collected: a) The Berlin Sleep Questionnaire, b) Epworth Sleepiness Scale, c) The Sleep Habits and Medical Condition Questionnaire d) The Medical Outcomes Survey-SF 36 (MOS-SF) e) Patient Health Questionnaire-9 (PHQ-9) f) Daily ECG/Activity Log g) Atrial Fibrillation Effect on Quality-of-life, a 20-item questionnaire that assesses the impact of atrial fibrillation on quality of life.

6 Minute Walk Test. Baseline oxygen saturation and heart rate will be recorded. If oxygen saturation \>90%, then proceed with protocol. Using the BORG Scale record rate the symptoms of breathlessness and leg fatigue after a 6 minute walk at usual pace.

Arterial Applanation Tonometry: Radial artery measurements will be performed after sphygmomanometric pressure is obtained with use of an applanation tonometry probe with a minimum of two consecutive measurements to obtain pulse wave analysis results. For pulse wave velocity, lead II ECG will be performed along with cardotid and femoral applanation tomometry.

Eligibility criteria: Inclusion Criteria:

Inclusion Criteria for Cases:

PAF defined by recurrent episodes of AF, which self-terminate within a 7-day period (based upon AHA consensus statement 77)

Age 18-80 years

Individuals able to participate in \> 2 overnight/daytime sleep and physiologic assessments over a 3 month period.

Inclusion Criteria for Controls:

Age 18 to 80 years

Individuals in normal sinus rhythm (NSR) with no current AF or history of AF

Individuals able to participate in an overnight/daytime sleep and physiologic assessment.

Exclusion Criteria:

Exclusion Criteria for Cases:

PAF with rapid or uncontrolled rate (\>120bpm)

Post-operative PAF

History of cardiac ablation or successful electro-cardioversion for PAF (ablation for other arrhythmias such as AVNRT and if PAF persists after cardioversion is acceptable )

Valvular stenosis, prosthesis or significant valvular insufficiency \[i.e. those with moderate or greater severity of aortic stenosis (aortic valve area \<1.5 cm2), mitral regurgitation which is moderate or more severe in degree (\>20% regurgitant fraction) or moderate or greater severity mitral stenosis (mitral valve area \<1.5 cm2)\]

Atrial septal defect

Infiltrative/restrictive cardiomyopathy

Sick sinus syndrome

Previously diagnosed SDB on specific SDB treatments (CPAP, oral appliances)

Severe chronic insomnia

Circadian rhythm disorder (e.g. shift work sleep disorder, delayed or advanced sleep phase syndrome)

Insufficient sleep syndrome defined by reported sleep duration \< 4 hrs

Supplemental oxygen use

Unstable medical conditions (e.g., new onset or changing angina, a myocardial infarction or congestive heart failure exacerbation documented within the previous 3 months, systolic heart failure (Left Ventricular Ejection Fraction \< 35%), high grade cardiac dysrhythmia/heart block, stroke with functional limitations, uncontrolled hypertension (BP\>170/110), abdominal aneurysm \>5.5 cm or \>1 cm growth/year, uncontrolled diabetes mellitus (HbA1c\>9.0), pulmonary hypertension, non-skin cancer diagnosis or treatment within the previous year, end stage renal and hepatic failure, immunodeficiencies (HIV, HCV), uncontrolled hypo- or hyperthyroidism)

Psychiatric disorders which are inadequately treated

Compromised competence

Alcohol abuse (currently drinks \>5 alcoholic drinks/day)

Pregnancy

Inability to provide informed consent

Illicit drug use over last 6 months

Rate controlling anti-arrhythmic medication (Classes I-III and V) with no further clinical occurrence of PAF

Has a Pacemaker or Implantable cardioverter-defibrillator.

Rationale for criteria: The goal of this study is to include those patients with PAF that is not secondary to the post-operative period or valvular disease and without ablation as these processes would result in alteration of atrial physiology and preclude assessment of independent SDB effects on AF which is independent of these conditions. Patients with sleep disorders will be excluded as sleep disorders may influence arrhythmogenesis. Those on treatment for SDB will be excluded because treatment would preclude assessment of SDB pathophysiologic effects on atrial arrhythmogenesis. Those with unstable medical conditions or rapid or uncontrolled heart rate will be excluded due to safety reasons.

Note: Exclusion criteria for positive airway pressure (PAP) intervention: Central Apnea Index\>5 noted on baseline examination sleep study or evidence of Cheyne Stokes Respirations/periodic breathing (cyclical crescendo and decrescendo change in breathing amplitude).

Exclusion Criteria for Controls:

Current or history of AF, otherwise the same exclusion criteria listed for cases.

Primary outcomes:
measure: Number of Participants With Paroxymal Atrial Fibrillation (PAF)
timeFrame: Baseline
Secondary outcomes:
measure: Echocardiography Measures- Left Atrial Volume
timeFrame: Baseline and 12 week follow up
measure: Echocardiographic Measures- LA Volume Index
timeFrame: Baseline and 12 week follow up
measure: Echocardiographic Measures- LA Systolic Strain by A4C View
timeFrame: Baseline and 12 week follow up
measure: Echocardiographic Measures- LA Systolic Strain by A2C View
timeFrame: Baseline and 12 week follow up
measure: Vascular Measures- Pulse Wave Velocity
timeFrame: Baseline and 12 week follow up
measure: Vascular Measures- Augmentation Index
timeFrame: Baseline and 12 week follow up
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: Reena Mehra, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: May AM, Wang L, Kwon DH, Van Wagoner DR, Chung MK, Dalton JE, Mehra R. Sleep apnea screening instrument evaluation and novel model development and validation in the paroxysmal atrial fibrillation population. Int J Cardiol Heart Vasc. 2020 Sep 4;31:100624. doi: 10.1016/j.ijcha.2020.100624. eCollection 2020 Dec.