A Cardiosleep Research Program on Obstructive Sleep Apnea, Blood Pressure Control and Maladaptive Myocardial Remodeling

Study Overview
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Brief Summary
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The objective of this proposal is to evaluate whether mandibular advancement device (MAD) is non-inferior to continuous positive airway pressure (CPAP) in the treatment of obstructive sleep apnea (OSA) and blood pressure reduction. OSA and hypertension are highly prevalent disorders with profound impacts on health. Apart from improving quality of-life, an effective OSA treatment could improve cardiovascular risk partly through blood pressure reduction, particularly in patients with high cardiovascular risk in whom blood pressure control is often suboptimal. Although CPAP is useful, the high non-acceptance and non-adherence preclude its widespread use. East Asians have a restrictive craniofacial phenotype that predisposes them to OSA and the associated cardiovascular stress. CPAP, while considered the first-line therapy for OSA, has failed to improve cardiovascular outcomes in randomized trials till date because it is poorly tolerated. MADs are oral appliances that correct the restrictive craniofacial phenotype present in East Asians by protruding the lower jaw to reduce upper airway collapsibility. MADs are better tolerated than CPAP, and this may be an important determinant of the overall effectiveness in treating OSA, and thus ameliorating the downstream adverse health outcomes. We hypothesize that MADs are non-inferior to CPAP in treating OSA and reducing cardiovascular risk by blood pressure reduction in East Asians. We will recruit East Asian subjects with hypertension and high cardiovascular risk for polysomnography. Patients diagnosed with OSA (n=220) will be randomized to MAD or CPAP groups in a 1:1 ratio for a treatment duration of 6 months. The primary endpoint is the 24-hour mean blood pressure as determined by ambulatory monitoring. The secondary endpoints include sleep-time systolic BP, target blood pressure, cardiovascular biomarkers, and myocardial remodeling. Association between OSA and silent paroxysmal atrial fibrillation will also be determined. If MADs are shown to be effective, the next step is to evaluate our novel device- drug-eluting MAD that the team is developing.

Official Title
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A Cardiosleep Research Program on Obstructive Sleep Apnea, Blood Pressure Control and Maladaptive Myocardial Remodeling

Conditions
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Hypertension,Essential, Obstructive Sleep Apnea

Intervention / Treatment
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* Device: Mandibular Advancement Device
* Device: Continuous Positive Airway Pressure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of at least 40 years Chinese (based on the Identity Card or other Identity Document if the subject is a non-Singapore citizen or permanent resident) Physician diagnosed essential hypertension, on at least 1 medication for BP control High cardiovascular risk, as defined by one or more of the following: (a) diabetes mellitus, (b) stroke, (c) significant coronary artery disease (at least one stenosis of >50% diameter in at least one major epicardial artery), (d) chronic kidney disease, excluding polycystic kidney disease, with an estimated glomerular filtration rate of <60 ml/min/1.73m2, or (e) age of 75 years or older. Exclusion Criteria: Known OSA on treatment Cheyne-Stokes breathing or predominantly central sleep apnea (>50%) Known secondary hypertension: from renal (renal artery stenosis, chronic renal failure); endocrine (aldosterone excess, pheochromocytoma, cushing's syndrome, hyperthyroidism) or cardiac causes (aortic coarctation) Contraindications to CMR: implantable devices, cerebral aneurysm clips, cochlear implants, renal impairment (GRF <30ml/min/1.73m2), claustrophobia and pregnant women Contraindications to MAD: <6 to 10 teeth in each arch, inability to advance the mandible and open the jaw widely, pre-existing temporomandibular joint problems, severe bruxism Limited life expectancy (< 1 year) Hypertensive crisis, acute coronary syndromes or acute heart failure in the past 30 days Known AF (not suitable for CMR and affects remodelling analysis)

Ages Eligible for Study
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Minimum Age: 40 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CPAP<br>Continuous Positive Airway Pressure | Device: Continuous Positive Airway Pressure<br>* Continuous positive airway pressure (CPAP) is a form of positive airway pressure ventilator, which applies mild air pressure on a continuous basis to keep the airways continuously open in people with OSA<br>|
| Experimental: MAD<br>Mandibular Advancement Device | Device: Mandibular Advancement Device<br>* Mandibular advancement device (MAD) has been a novel method in the management of snoring and OSA. For mild to moderate sleep apnea, MADs have been a boon. A guideline published by American Academy of Sleep Medicine stated that MAD was indicated as first-line therapy for mild OSA and a second-line therapy for moderate to severe OSA<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour mean BP (24MBP) | Difference in 24-hour mean BP (24MBP) between the patients in the MAD and CPAP groups as determined by 24-hour ambulatory BP monitoring. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour systolic BP (24SBP) | Difference in 24-hour systolic BP (24SBP) between the patients in the MAD and CPAP groups as determined by 24-hour ambulatory BP monitoring. | 6 months and 12 months | 
| 24-hour pulse pressure (24PP) | Difference in 24-hour pulse pressure (24PP) between the patients in the MAD and CPAP groups as determined by 24-hour ambulatory BP monitoring. | 6 months and 12 months | 
| Nocturnal dipping | Difference in prevalence of nocturnal dipping between the patients in the MAD and CPAP groups as determined by 24-hour ambulatory BP monitoring. | 6 months and 12 months | 
| Ectopic beat | Difference in prevalence of ectopic beats between the patients in the MAD and CPAP groups as determined by continuous ECG monitoring | 12 months | 
| Myocardial remodeling | Difference in LV and LA dimensions between the patients in the MAD and CPAP groups as determined by cardiac MRI | 12 months | 
| Epworth Sleepiness Scale (ESS) score | Difference in change in ESS score between the MAD and CPAP groups | 6 months and 12 months | 
| Sleep Apnea Quality of Life Index (SAQLI) | Difference in change in SAQLI score between the MAD and CPAP groups | 6 months and 12 months | 
| Functional Outcome of Sleep Questionnaire (FOSQ) | Difference in change in SAQLI score between the MAD and CPAP groups | 6 months and 12 months | 
| 36-Item Short Form Health Survey (SF-36) | Difference in change in SF-36 score between the MAD and CPAP groups | 6 months and 12 months | 
| EuroQol 5Q (EQ5D) | Difference in change in EQ5D score between the MAD and CPAP groups | 6 months and 12 months | 
| Daytime systolic BP | Difference in change in daytime systolic BP between the patients in the MAD and CPAP | 6 months and 12 months | 
| Nighttime systolic BP | Difference in change in nighttime systolic BP between the patients in the MAD and CPAP | 6 months and 12 months | 
| Percentage of patient with 24-hour systolic BP<130 mmHg | Difference in percentage of patients with 24-hour systolic BP<130 mmHg in the MAD and CPAP groups | 6 months and 12 months | 
| Percentage of patient with 24-hour systolic BP<120 mmHg | Difference in percentage of patients with 24-hour systolic BP<120 mmHg in the MAD and CPAP groups | 6 months and 12 months | 
| NT-proBNP | Change in the plasma level of NT-proBNP from baseline to 6-month follow-up | 6 months and 12 months | 
| High sensitivity troponin | Change in the plasma level of high sensitivity troponin from baseline to 6-month follow-up | 6 months and 12 months | 
| High sensitive C-reactive protein | Change in the plasma level of high sensitive C-reactive protein from baseline to 6-month follow-up | 6 months and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sleep, remodeling, blood pressure, trial