Sleep Apnea in TIA/Stroke: Reducing Cardiovascular Risk With Positive Airway Pressure

Study Overview
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Brief Summary
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The goal of this study is to develop a novel study design to safely and ethically conduct a long-term randomized controlled trial among patients at high risk for both sleep apnea and cardiovascular events that will examine whether effective positive airway pressure(PAP) therapy reduces cardiovascular risk. Patients with transient ischemic attack(TIA) or stroke have a high prevalence of sleep apnea(60-80%), and they are at high risk of cardiovascular events(myocardial infarction, congestive heart failure, recurrent stroke, and cardiovascular death)in the first year post event, despite current prevent strategies. Therefore, the treatment of sleep apnea may represent a novel therapeutic target to reduce cardiovascular outcomes in this high risk population.

Detailed Description
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The proposed study is a randomized controlled trial among patients with transient ischemic attack (TIA) and minor stroke, comparing strategies for the diagnosis and treatment of sleep apnea with usual care over 6-12 months at 2 sites (Yale University School of Medicine and Indiana University School of Medicine). Patients with TIA and minor stroke will be randomly assigned to either usual care or a diagnosis and treatment approach that includes ambulatory polysomnography and initiation of autotitrating CPAP for sleep apnea in a 1:2 (control:intervention) randomization scheme. Intervention patients with sleep apnea will receive either a standard CPAP treatment intervention or an enhanced protocol designed to increase long-term CPAP adherence. The primary outcomes will include: (a) the impact of CPAP on pathophysiologic markers in the following domains of cardiovascular risk: inflammation (CRP, Il-6), heightened sympathetic activity/parasympathetic withdrawal (plasma catecholamines and heart rate variability (HRV)), insulin resistance (HOMA-IR, HbA1C), endothelial injury (flow mediated vasodilation), and atherosclerosis (carotid intima-media thickness); and (b) long-term (6-12 month) CPAP adherence.

Official Title
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Sleep Apnea in TIA/Stroke: Reducing Cardiovascular Risk With Positive Airway Pressure

Conditions
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Transient Ischemic Attack, Stroke

Intervention / Treatment
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* Device: Standard CPAP Intervention
* Behavioral: Enhanced CPAP Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years and older TIA or ischemic stroke within 1 week of neurological symptom onset brain imaging within 24 hours Exclusion Criteria: known to have sleep apnea suspected sleep disorder other than sleep apnea hospice patients or patients receiving comfort only measures patients unable to use a nasal or face mask patients who require mechanical ventilation Non English language patients inability to provide informed consent active suicidal ideation live outside the recruitment area provider does not allow researcher to contact patient

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Intervention group<br>This group gets unattended sleep study, auto titrating CPAP, and standard CPAP support. | Device: Standard CPAP Intervention<br> <br> |
| Active Comparator: Enhanced CPAP intervention<br>This group gets an unattended sleep study, autotitrating CPAP, and enhanced CPAP support. | Behavioral: Enhanced CPAP Intervention<br> <br> |
| No Intervention: Usual Care<br>This group usual care after TIA/stroke and a sleep study at the end of the study. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HOMA IR Change From Baseline | The homeostasis model assessment-estimated insulin resistance (HOMA-IR). HOMA IR change is one of the measures used to assess cardiovascular risk. HOMA-IR Index (measured by calculating - fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5.). The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline and up to 12 months | 
| CRP Change From Baseline | C-reactive protein (CRP) is a blood test marker for inflammation in the body. CRP is produced in the liver and its level is measured by testing the blood. CRP is classified as an acute phase reactant, which means that its levels will rise in response to inflammation. CRP is one of the measures used to assess cardiovascular risk. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline and up to 12 months | 
| IL-6 Change From Baseline | IL-6 is a type of protein known as a cytokine, produced by cells of the immune system in response to an infection. IL-6 test results measure the amount of IL-6 circulating in the blood and are used as one sign of systemic inflammation. Il-6 is one of the measures used to assess cardiovascular risk. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline and up to 12 months | 
| Catecholamine Change From Baseline | Catecholamine testing measures the amounts of catecholamines which are a group of similar substances/hormones released into the blood in response to physical or emotional stress. The primary catecholamines are dopamine, epinephrine (adrenaline), and norepinephrine. Catecholamine is one of the measures used to assess cardiovascular risk. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline and up to 12 months | 
| Heart Rate Variability Change From Baseline | Heart rate variability (HRV) is the constant variation in milliseconds between heartbeats. HRV is one of the measures used to assess cardiovascular risk. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline and up to 12 months | 
| 24-H Systolic Blood Pressure Mean Change From Baseline | 24-H Systolic Blood Pressure is one of the measures used to assess cardiovascular risk- this was assessed multiple times and averaged across a in 24 hour time period. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline and up to 12 months | 
| Flow-mediated Vasodilation Mean Change From Baseline | Flow-mediated vasodilation is performed when the brachial artery diameter is measured (in mm) during three conditions; baseline (after at least 10 min supine rest), during reactive hyperaemia (induced by inflation to 250 mmHg and then deflation of a sphygmomanometer cuff around the forearm) and finally after the administration of sublingual nitroglycerin. A linear array, high resolution ultrasound transducer is used to provide B-mode images of the target vessel, proximal to the forearm cuff. Flow-mediated vasodilation is one of the measures used to assess cardiovascular risk and the mean of the change in the multiple measurements was used at each time point. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| Carotid Intima-Medial Thickness Mean Change From Baseline | Carotid Intima-Medial Thickness are measurements of the mean values of Intima-media thickness (IMT) of carotid arteries. Caroid Intima-Medial Thickness mean change is one of the measures used to assess cardiovascular risk. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| CPAP Adherence Rates Change From Baseline | CPAP adherence rates were calculated as hours of CPAP use per night. The change from baseline up until the final measurement (up to 12 months) was assessed. The Respironics M-series (now System One, Phillips Respironics, North Ryde, Australia) produced a record of the patient adherence (hours of use per night) throughout the duration of the follow up period. | Baseline to up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HOMA IR Change From Baseline With CPAP Use | The homeostasis model assessment-estimated insulin resistance (HOMA-IR). HOMA IR change is one of the measures used to assess cardiovascular risk. HOMA-IR Index (measured by calculating - fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5.) To determine if CPAP use had an impact on cardiovascular risk, these measures were compared among CPAP usage groups. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| CRP Change From Baseline With CPAP Use | C-reactive protein (CRP) is a blood test marker for inflammation in the body. CRP is produced in the liver and its level is measured by testing the blood. CRP is classified as an acute phase reactant, which means that its levels will rise in response to inflammation. CRP is one of the measures used to assess cardiovascular risk. To determine if CPAP use had an impact on cardiovascular risk, these measures were compared among CPAP usage groups. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| IL-6 Change From Baseline With CPAP Use | IL-6 is a type of protein known as a cytokine, produced by cells of the immune system in response to an infection. IL-6 test results measure the amount of IL-6 circulating in the blood and are used as one sign of systemic inflammation. IL-6 is one of the measures used to assess cardiovascular risk. To determine if CPAP use had an impact on cardiovascular risk, these measures were compared among CPAP usage groups. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| Catecholamine Change From Baseline With CPAP Use | Catecholamine testing measures the amounts of catecholamines which are a group of similar substances/hormones released into the blood in response to physical or emotional stress. The primary catecholamines are dopamine, epinephrine (adrenaline), and norepinephrine. Catecholamines change is one of the measures used to assess cardiovascular risk. To determine if CPAP use had an impact on cardiovascular risk, these measures were compared among CPAP usage groups. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| Heart Rate Variability Change From Baseline With CPAP Use | Heart rate variability (HRV) is the constant variation in milliseconds between heartbeats. HRV is one of the measures used to assess cardiovascular risk. To determine if CPAP use had an impact on cardiovascular risk, these measures were compared among CPAP usage groups. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| 24-H Mean Systolic Blood Pressure Change From Baseline With CPAP Use | 24-H Mean Systolic Blood Pressure change is one of the measures used to assess cardiovascular risk- this was assessed multiple times and averaged across a in 24 hour time period. To determine if CPAP use had an impact on cardiovascular risk, these measures were compared among CPAP usage groups. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| Flow-mediated Vasodilation Mean Change From Baseline With CPAP Use | Flow-mediated vasodilation is performed when the brachial artery diameter is measured (in mm) during three conditions; baseline (after at least 10 min supine rest), during reactive hyperaemia (induced by inflation to 250 mmHg and then deflation of a sphygmomanometer cuff around the forearm) and finally after the administration of sublingual nitroglycerin. A linear array, high resolution ultrasound transducer is used to provide B-mode images of the target vessel, proximal to the forearm cuff. Flow-mediated vasodilation is one of the measures used to assess cardiovascular risk and the mean of the change in the multiple measurements was used at each time point. To determine if CPAP use had an impact on cardiovascular risk, these measures were compared among CPAP usage groups. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 
| Carotid Intima-Medial Thickness Change From Baseline With CPAP Use Change | Carotid Intima-Medial Thickness are measurements of the mean values of Intima-media thickness (IMT) of carotid arteries. Caroid Intima-Medial Thickness change is one of the measures used to assess cardiovascular risk. To determine if CPAP use had an impact on cardiovascular risk, these measures were compared among CPAP usage groups. The change from baseline up until the final measurement (up to 12 months) was assessed. The carotid intimal thickness measurement was obtained by averaging the distance between the lumen-intima interface and the media-adventitia interface obtained from 5 contiguous sites 1 mm apart. | Baseline to up to 12 months | 
| Medication-adjusted 24-H SBP Change From Baseline | Change in medication-adjusted 24-hour SBP, which is calculated as [mean 24-hour SBP in mmHg] + [patient's DDD × (8.0 mmHg), was assessed between CPAP adherence groups. The change from baseline up until the final measurement (up to 12 months) was assessed. | Baseline to up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep Apnea, CPAP adherence, behavioral adherence, stroke