Heart Failures
Conditions
Brief summary
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.
Interventions
DRUGAcetazolamide
4 mg/kg, once daily before bed, for 7 days
DRUGPlacebo
4 mg/kg, once daily before bed, for 7 days
Sponsors
American Heart Association
National Institutes of Health (NIH)
David Andrew Wellman
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) | 1 week | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ventilatory Chemoreflex Sensitivity, Loop Gain Using Carbon Dioxide Pulses | 1 week | 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. |
| Sympathetic Activity (Urinary Norepinephrine) | 1 week | Urinary norepinephrine levels overnight |
| Left-atrial Volume | 1 week | 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). |
| Brain Natriuretic Peptide (NT-proBNP) | 1 week | Brain natriuretic peptide (NT-proBNP) in morning |
| Pittsburgh Sleep Quality Index | 1 week | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Patients All patients randomized | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout (7 Days) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 13 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 17 / 28 | 6 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 |
Outcome results
Primary
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.
Time frame: 1 week
Population: All participants who were randomized and completed the relevant study arm. Data are for non-REM supine sleep.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetazolamide | The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) | All participants | 26.3 events per hour | Standard Deviation 22.7 |
| Acetazolamide | The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) | Patients with sleep apnea | 32.3 events per hour | Standard Deviation 22.1 |
| Placebo | The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) | All participants | 36.1 events per hour | Standard Deviation 27.8 |
| Placebo | The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) | Patients with sleep apnea | 44.6 events per hour | Standard Deviation 25.3 |
Secondary
Brain Natriuretic Peptide (NT-proBNP)
Brain natriuretic peptide (NT-proBNP) in morning
Time frame: 1 week
Population: All participants who completed the relevant arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Brain Natriuretic Peptide (NT-proBNP) | 919 pg/ml | Standard Deviation 1320 |
| Placebo | Brain Natriuretic Peptide (NT-proBNP) | 932 pg/ml | Standard Deviation 1403 |
Secondary
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).
Time frame: 1 week
Population: echocardiography could not be performed on one study due to rescheduling issues
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Left-atrial Volume | 34.3 mL/m^2 | Standard Deviation 12.1 |
| Placebo | Left-atrial Volume | 40.0 mL/m^2 | Standard Deviation 13.5 |
Secondary
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.
Time frame: 1 week
Population: All participants who participated in the relevant study arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Pittsburgh Sleep Quality Index | 6.7 units on a scale | Standard Deviation 3.6 |
| Placebo | Pittsburgh Sleep Quality Index | 7.5 units on a scale | Standard Deviation 3.8 |
Secondary
Sympathetic Activity (Urinary Norepinephrine)
Urinary norepinephrine levels overnight
Time frame: 1 week
Population: All participants who completed the relevant study arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Sympathetic Activity (Urinary Norepinephrine) | 40.8 ug/g-creatinine | Standard Deviation 23.6 |
| Placebo | Sympathetic Activity (Urinary Norepinephrine) | 35.0 ug/g-creatinine | Standard Deviation 17.3 |
Secondary
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.
Time frame: 1 week
Population: All participants who completed the relevant arm. Morning data are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Ventilatory Chemoreflex Sensitivity, Loop Gain Using Carbon Dioxide Pulses | 0.40 unitless | Standard Deviation 0.16 |
| Placebo | Ventilatory Chemoreflex Sensitivity, Loop Gain Using Carbon Dioxide Pulses | 0.49 unitless | Standard Deviation 0.14 |