Etiology of Sleep Apnea-related Hyperaldosteronism - BP Treatment

Study Overview
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Brief Summary
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Hypertension affects an estimated 60-70 million Americans, predisposing them to potentially life threatening cardiovascular complications. Resistant hypertension, defined as uncontrolled blood pressure on 3 or more different antihypertensive agents, is common, affecting 15-20% of the entire hypertensive population or an estimated 12-14 million Americans. Although associated with obesity, increasing age, black race, and chronic kidney disease, mechanisms of treatment resistance remain obscure. The investigators' laboratory identified primary aldosteronism (PA) as a common cause of treatment resistance with a prevalence of 20% among subjects with resistant hypertension. This is clinically important because recognition of PA can lead to effective treatment with use of aldosterone blockers. Obstructive sleep apnea (OSA) is strongly associated with and predicts development of hypertension as demonstrated in landmark cohort studies including the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study. The investigators' laboratory has confirmed OSA to be extremely common in subjects with resistant hypertension, with a prevalence of approximately 85%. Recognizing that PA and OSA are exceptionally common in subjects with resistant hypertension, the investigators hypothesized that the 2 may be causally related. In testing this hypothesis, the investigators recently reported that plasma aldosterone levels are positively correlated with OSA severity in subjects with resistant hypertension but not in normotensive control subjects. This observation suggests that there is an important mechanistic interaction between untreated OSA and aldosterone excess in subjects with resistant hypertension. While the investigators' original hypothesis was that OSA stimulates aldosterone release, the investigators recognize that the opposite may also be true; that is, aldosterone excess in subjects with resistant hypertension worsens OSA. Distinguishing between these two possibilities has potentially far-reaching clinical implications. If the former hypothesis is true, effective treatment of OSA would be expected to suppress aldosterone release in subjects with resistant hypertension, thereby reversing the underlying cause of their treatment resistance. If the latter hypothesis is true, use of mineralocorticoid receptor antagonists would be expected to reduce OSA severity in subjects with resistant hypertension, thereby enhancing treatment of OSA. Either scenario would represent a new treatment approach for a highly prevalent and serious medical problem.

Official Title
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Randomized Controlled Trial of Spironolactone Versus Standard of Care Blood Pressure Treatment on the Severity of Obstructive Sleep Apnea in Patients With Resistant Hypertension

Conditions
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Obstructive Sleep Apnea, Resistant Hypertension, Hyperaldosteronism

Intervention / Treatment
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* Drug: Spironolactone
* Drug: BP medication uptitration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Resistant hypertension defined as office BP that is uncontrolled with 3 or more antihypertensive medications Moderate-severe OSA defined as AHI ≥15 events/hr Self-reported adherence >80% with prescribed antihypertensive medications. Exclusion Criteria: Ongoing use of a potassium sparing diuretic History of congestive heart failure (ejection fraction of <40%) Chronic kidney disease (creatinine clearance <60 ml/min) History of cardiovascular disease (stroke, TIA, myocardial infarction, or revascularization procedure) Known or suspected history of secondary cause of hypertension other than primary aldosteronism Severe nocturnal hypoxemia (O2 desaturation nadir <60%) White coat hypertension defined as office BP >140/90 mm Hg and ambulatory daytime BP <135/85 mm Hg Central sleep apnea (defined as 5% or more of the apneas as central apneas) and/or the presence of any Cheyne-Stokes breathing Subjects working shift work or having other known circadian rhythm disorders such that their sleep-wake schedule is altered Excessive daytime sleepiness as indicated by an Epworth score of >10 Pregnant Women

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 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: Spironolactone<br>Spironolactone 25 mg administered following baseline measurements and uptitrated to 50 mg if BP > 140/90 mm Hg throughout the 3 month study. | Drug: Spironolactone<br> <br> |
| Sham Comparator: Standard of care BP treatment<br>Antihypertensive medication added and/or uptitrated to keep BP < 140/90 mm Hg throughout the study. | Drug: BP medication uptitration<br>* antihypertensive medication added or uptitrated following standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Obstructive Sleep Apnea | 3 month change in apnea-hypopnea index assessed by diagnostic, full-night polysomnography. AHI values are typically categorized as 5-15/hr = mild; 15-30/hr = moderate; and > 30/h = severe. | baseline and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperaldosteronism, spironolactone, blood pressure, resistant, sleep apnea, hypertension, aldosterone