Predicting Successful Sleep Apnea Treatment With Acetazolamide in Heart Failure Patients

Study Overview
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Brief Summary
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The ultimate goal is to improve our understanding of the pathophysiology and resistance to effective treatment of sleep disordered breathing in patients with heart failure, with a focus on selecting patients that will benefit specifically from acetazolamide treatment. The study addresses three primary hypotheses: 1) Acetazolamide treatment will reduce the apnea-hypopnea index and improve markers of heart-failure severity in heart-failure patients with sleep apnea. 2) Acetazolamide will provide the greatest improvement in patients with the most severe ventilatory control instability (strongest chemoreflex response to carbon dioxide; highest loop gain). 3) Acetazolamide will act primarily via stabilizing ventilatory control (reducing loop gain), rather than via improvement to upper airway anatomy, pulmonary congestion, and cardiac function.

Official Title
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Physiological Study to Predict Successful Sleep Apnea Treatment With Acetazolamide in Heart Failure Patients

Conditions
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Heart Failures

Intervention / Treatment
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* Drug: Acetazolamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Heart failure patients) Left ventricular ejection fraction (EF) <50%, or heart failure with preserved EF Age 18-89 Exclusion Criteria: severe obstructive respiratory disease unstable heart failure status recent use of positive airway pressure therapy current use of opioids, benzodiazepines severe kidney disease severe anemia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acetazolamide<br> | Drug: Acetazolamide<br>* 4 mg/kg, once daily before bed, for 7 days<br>* Other names: Diamox;|
| Placebo Comparator: Sugar pill<br> | Drug: Placebo<br>* 4 mg/kg, once daily before bed, for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) | The frequency of apneas and hypopneas (apnea-hypopnea index) was assessed. The primary measure was the value for non-REM supine sleep. A higher value indicates more severe sleep apnea. A value above 15 indicates the presence of moderate-to-severe sleep apnea. | 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilatory Chemoreflex Sensitivity, Loop Gain Using Carbon Dioxide Pulses | Chemoreflex loop gain was assessed according to Sands SA et al AJRCCM 2017 Jan 15;195(2):237-246. Loop gain is a unitless ratio measure that describes the magnitude of the increase in ventilation that occurs in response to a prior reduction in ventilation (disturbance) and has units of L/min per L/min. A larger value indicates a more sensitive and unstable control system predisposing to oscillatory breathing. Loop gain was measured on the time scale of 1 min (i.e. response to a 1 cycle/min sinusoidal disturbance, referred to as LG1). The procedure involved brief administration of 7% carbon dioxide in air for 0.5 min (pulses); tests were repeated every 3 min for 30 min while measuring ventilation and carbon dioxide levels at the nose with patients awake and supine. measured using 0.5 min pulses of carbon dioxide. | 1 week | 
| Sympathetic Activity (Urinary Norepinephrine) | Urinary norepinephrine levels overnight | 1 week | 
| Left-atrial Volume | Left-atrial volume index, echocardiography, bi-plane method. Lower values were considered a favorable outcome. We considered values ≤28 mL/m^2 to indicate normal left atrial volume. Values indicating graded left atrial enlargement were described as follows: mild (29-33 mL/m^2), moderate (34-39 mL/m^2), severe (≥40 mL/m^2). | 1 week | 
| Brain Natriuretic Peptide (NT-proBNP) | Brain natriuretic peptide (NT-proBNP) in morning | 1 week | 
| Pittsburgh Sleep Quality Index | Pittsburgh Sleep Quality Index is a measure of self-reported sleep quality containing 19 questions that make up 7 component scores that are added to provide a total score. Total scores range from 0-21 (units on a scale) with higher scores representing reduced sleep quality. A score of 5 or more is interpreted as reduced sleep quality. The total score is reported. | 1 week |