Study of Cardiovascular Disease and Obstructive Sleep Apnea

Study Overview
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Brief Summary
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The purpose of this study is to determine if two medicines (allopurinol and losartan) can influence heart and blood vessel health compared to placebo in patients with sleep apnea who are using continuous positive airway pressure (CPAP).

Detailed Description
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The specific aims of this research project are: 1) Determine if treatment with losartan, an angiotensin type I receptor (AT1R) antagonist, or allopurinol, a XO inhibitor, normalize chemoreflex control of sympathetic outflow and ventilation and improve local vascular regulation and stiffness; and 2) Determine if these interventions reduce the severity of sleep disordered breathing and lower diurnal blood pressure.

Official Title
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Pharmacologic Interventions for Cardiovascular Disease in Obstructive Sleep Apnea

Conditions
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Severe Obstructive Sleep Apnea (Apnea Hypopnea Index > 30 Events/Hour), Hypertension

Intervention / Treatment
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* Drug: Losartan
* Drug: Allopurinol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females between ages of 21 and 65 years Apnea hypopnea index or respiratory disturbance index greater than or equal to 25 events per hour Subjects eligible for CPAP or BiPAP therapy Hypertension by clinical history/diagnosis (may be controlled with non- exclusionary medications) or average blood pressure > 140/90 mm Hg (using last two measurements in prior 12 months - or 1 prior blood pressure and 1 blood pressure at screening) Exclusion Criteria: If subject not using CPAP, having AHI > 60 events/hour or oxygen saturation ≤ 65% during sleep Presence of clinical CV disease (coronary artery disease, angina, arrhythmias (subjects with sinus arrhythmias will be reviewed by PI for enrollment), stroke, TIA, cor pulmonale, etc.), heart failure, bruits, or diabetes mellitus by clinical diagnosis/history Presence of pulmonary disease that results in significant hypoxemia (resting SaO2 < 88%) Hypertriglyceridemia (triglycerides >300 mg/dL), diabetes or impaired glucose tolerance (fasting plasma glucose > 125 mg/dL) Patients taking angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, potassium-sparing diuretics (without accompanying loop/thiazide diuretic), allopurinol, oxypurinol, febuxostat, amoxicillin, ampicillin, azathioprine or mercaptopurine. Patients with chronic kidney disease (Serum creatinine >1.5 mg/dL) or history of significant hyperkalemia (Serum potassium > 5.2 mEq/L) with ARB therapy Patients with history of angioedema Patients with bilateral,modified radical or radical mastectomies Patients who have a Serum potassium > 5.0 mEq/L at the screening visit Female patients who are pregnant (determined by urine pregnancy test) or breastfeeding Patients with active MRSA or VRE (vancomycin resistant enterococcus) infection History of adverse reaction to allopurinol,losartan, or zolpidem** Patients who cannot swallow oral capsules Patients who are hospitalized or who have been recently hospitalized (last 2 weeks) Inability to comply with or complete the protocol or other reasons at the discretion of the investigators

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Losartan<br>Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic and blood pressure within range. | Drug: Losartan<br>* Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic. Remain at 50 mg daily for 4 more weeks or removed from study if symptomatic.<br>|
| Active Comparator: Allopurinol<br>Allopurinol 300 mg daily for 6 weeks | Drug: Allopurinol<br>* Allopurinol 300 mg daily for 6 weeks<br>|
| Placebo Comparator: Placebo<br>Placebo capsule daily for 6 weeks | Drug: Placebo<br>* Placebo capsule daily for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia | The primary outcome variable is the change in the individual slope of the MSNA - SaO2 response curve at 6 weeks and baseline between treatment groups. | baseline and 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Aortic Pulse Wave Velocity | measurement of vascular stiffness assessed before and after study drug treatment | baseline and 6 weeks | 
| Cerebrovascular Conductance | Assessment measures of cerebral blood flow during basal conditions and during graded hypoxia before and after study drug treatment. Cerebrovascular conductance (CVC) was calculated as velocity-time integral/mean arterial pressure. | baseline and 6 weeks | 
| Forearm Vascular Conductance | Assessment measurements of forearm vascular conductance during basal conditions and during graded hypoxia before and after study drug treatment. | baseline and 6 weeks | 
| Change in Minute Ventilation at Normoxia | assessed before and after study drug treatment | baseline and 6 weeks | 
| Change in Minute Ventilation During Hypoxia | assessed before and after study drug treatment | baseline and 6 weeks | 
| Aortic Augmentation Index | assessed before and after study drug treatment | baseline and 6 weeks | 
| Mean Change in PERCENT Vasodilation | Flow-mediated vasodilation (FMD) (measurement of vascular endothelial function) assessed before and after study drug treatment | baseline and 6 weeks | 
| Apnea-Hypopnea Index | Severity of sleep apnea assessed before and after study drug treatment | baseline and 6 weeks | 
| PERCENT Time Spent Below 88 PERCENT Oxygen Saturation | assessed before and after study drug treatment | baseline and 6 weeks | 
| Change in Mean 24-Hour Blood Pressure (Mean Arterial Pressure) | Change in mean 24 hour blood pressure (mean arterial pressure) | baseline and 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, High Blood Pressure, Sleep Apnea, Obstructive Sleep Apnea, OSA