Obstructive Sleep Apnea
Conditions
Keywords
Obstructive sleep apnea, CPAP, Propranolol, Metabolism
Brief summary
The primary objective of this study is to test whether a beta blocker, propranolol, lowers the overnight heart rate sleep in obstructive sleep apnea (OSA) during CPAP withdrawal. The secondary objectives are to test whether propranolol influences sleep architecture, morning blood pressure, and vascular function including reactive hyperemia index (RHI) and a marker of arterial stiffness, augmentation index (AIX).
Detailed description
The overnight heart rate is increased in patients with obstructive sleep apnea (OSA), reflecting excessive sympathetic nervous system activity which may lead to long-term adverse cardiovascular consequences. Propranolol is a non-selective beta blocker that is used for a variety of indications including hypertension and anxiety. In this study investigators will administer propranolol or placebo to patients with OSA before sleep. Investigators will examine the effect of drug on nocturnal heart rate, morning blood pressure, and vascular health outcomes
Interventions
Patients will receive Propranolol LA 80 mg PO at 7 PM before sleep (on CPAP withdrawal nights only)
DRUGPlacebo Oral Tablet
Patients will receive Placebo tablet at 7 PM before sleep (on CPAP withdrawal nights only)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* History of OSA (AHI\>20, \>50% events obstructive) * Accustomed to CPAP use, and willing to discontinue CPAP temporarily for the study. * If the participant has already completed Metabolic Impact of Intermittent CPAP (NA\_00086830), they must have exhibited a \>10% increase in nocturnal FFA or glucose during CPAP
Exclusion criteria
* Cardiovascular risks * Decompensated congestive heart failure * Atrial fibrillation, sick sinus syndrome, 2nd or 3rd degree heart block, pacemaker implantation, Wolff-Parkinson-White Syndrome (if not known, will check on a screening EKG) * Uncontrolled hypertension \> 170/110 * History of postural hypotension. * Resting systolic pressure \<90 or heart rate \< 50 on screening visit * Drug interactions - currently taking any of the following drugs. (Subjects on these medications are excluded from participation and will not have the drug in question discontinued for the purposes of participation in the study. ) * Calcium channel blockers that reduce heart rate (diltiazem, verapamil, fendiline, gallopamil) * Sympatholytic drugs: any other beta blocker; clonidine, terazosin or doxazosin; reserpine * Anti-arrhythmic drugs: (e.g. amiodarone, sotalol, digoxin, quinidine, lidocaine, propafenone) * Coumadin (propranolol may prolong INR) * Drugs that Inhibit CYP2D6, CYP1A2, or CYP2C19: amiodarone, ciprofloxacin, cimetidine, delavirdine, fluconazole, fluoxetine, fluvoxamine, imipramine, isoniazid, paroxetine, quinidine, ritonavir, rizatriptan, teniposide, theophylline, tolbutamide, zileuton, zolmitriptan * Drugs that increase hepatic metabolism of propranolol: rifampin, ethanol, phenytoin, and phenobarbital * Neuroleptics/anxiolytics: (thioridazine, chlorpromazine - may increase propranolol level), haloperidol, valium * Illicit drugs such as cocaine or amphetamines. * Other medical conditions * Sleep disorder other than OSA, including: restless leg syndrome, parasomnia, or narcolepsy. * Shift work or circadian rhythm disorder that is expected to prevent good sleep as scheduled in the protocol * Insulin-dependent diabetes mellitus * Myasthenia gravis * Pheochromocytoma * Uncontrolled bronchospastic lung disease such as asthma or chronic obstructive pulmonary disease (COPD) * Current smoking * Chronic renal or liver failure * Known pregnancy, by urine testing in women of child-bearing age; nursing mothers * Known hypersensitivity to any beta blocker * History of falling asleep while driving, near miss * High risk occupation (pilot, commercial driver) Hemoglobin \< 10 g/dL on point of care screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nocturnal Heart Rate (Beats/Min, BPM) | 1 Night (approximately 4 hours post administration for each intervention), from 10:30 PM to 06:30 AM | Average overnight heart rate (10:30 PM to 06:30 AM) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reactive Hyperemia Index (RHI) | The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention) | Reactive Hyperemia Index (RHI) is measured by assessing the change in pulse wave amplitude in the brachial artery before and after a period of occlusion (usually 5 minutes). RHI is unitless as it reflects the ratio of pulse wave amplitude after : before occlusion. A high RHI indicates good endothelial function (values \>1.67) and healthy vascular reactivity, while a low RHI (values \<1.67) suggest endothelial dysfunction, which may be a risk factor for cardiovascular disease. |
| Systolic Blood Pressure (mmHg) | The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention) | Measured in the morning (7 AM) |
| Diastolic Blood Pressure (mmHg) | The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention) | Measured in the morning (7 AM) |
| Augmentation Index (%) | The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention) | The Augmentation Index (AIx) is measured by analyzing the arterial pulse wave, which captures the pressure wave reflections in the arteries. A higher AIx indicates increased arterial stiffness and higher cardiovascular risk, while a lower AIx suggests more compliant, healthier arteries. AIx can theoretically range from negative values to over 100%, although clinical values usually are between -10% and +40%. |
Countries
United States
Participant flow
Recruitment details
Patients with a history of obstructive sleep apnea (OSA) who were accustomed to continuous positive airway pressure (CPAP) use were enrolled from the Johns Hopkins Sleep Disorders Center. Patients with arrhythmias or taking beta blockers were excluded, among other criteria.
Pre-assignment details
24 participants signed a consent form. 1 subject was lost to follow up after consent, leaving 23 participants who were randomized to placebo first (n=11) or propranolol first (n=12).
Participants by arm
| Arm | Count |
|---|---|
| Placebo First, Then Propranolol This is a crossover study comparing placebo to propranolol taken before sleep prior to CPAP withdrawal. This arm received placebo during the first intervention and propranolol during the second intervention. | 11 |
| Propranolol First, Then Placebo This is a crossover study comparing placebo to propranolol taken before sleep prior to CPAP withdrawal. This arm received propranolol during the first intervention and placebo during the second intervention. | 12 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (1 Night) | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Propranolol First, Then Placebo | Total | Placebo First, Then Propranolol |
|---|---|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 13 | 51 years STANDARD_DEVIATION 11 | 51 years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 21 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 12 Participants | 6 Participants |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 15 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 0 / 21 | 0 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 |
Outcome results
Primary
Nocturnal Heart Rate (Beats/Min, BPM)
Average overnight heart rate (10:30 PM to 06:30 AM)
Time frame: 1 Night (approximately 4 hours post administration for each intervention), from 10:30 PM to 06:30 AM
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Oral Tablet | Nocturnal Heart Rate (Beats/Min, BPM) | 64.1 BPM | Standard Deviation 5.1 |
| Propranolol Oral Tablet | Nocturnal Heart Rate (Beats/Min, BPM) | 60.2 BPM | Standard Deviation 4.4 |
Secondary
Augmentation Index (%)
The Augmentation Index (AIx) is measured by analyzing the arterial pulse wave, which captures the pressure wave reflections in the arteries. A higher AIx indicates increased arterial stiffness and higher cardiovascular risk, while a lower AIx suggests more compliant, healthier arteries. AIx can theoretically range from negative values to over 100%, although clinical values usually are between -10% and +40%.
Time frame: The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Oral Tablet | Augmentation Index (%) | 14 Percentage of arterial pulse pressure | Standard Deviation 19 |
| Propranolol Oral Tablet | Augmentation Index (%) | 21 Percentage of arterial pulse pressure | Standard Deviation 18 |
Secondary
Diastolic Blood Pressure (mmHg)
Measured in the morning (7 AM)
Time frame: The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Oral Tablet | Diastolic Blood Pressure (mmHg) | 80 mmHg | Standard Deviation 9 |
| Propranolol Oral Tablet | Diastolic Blood Pressure (mmHg) | 76 mmHg | Standard Deviation 11 |
Secondary
Reactive Hyperemia Index (RHI)
Reactive Hyperemia Index (RHI) is measured by assessing the change in pulse wave amplitude in the brachial artery before and after a period of occlusion (usually 5 minutes). RHI is unitless as it reflects the ratio of pulse wave amplitude after : before occlusion. A high RHI indicates good endothelial function (values \>1.67) and healthy vascular reactivity, while a low RHI (values \<1.67) suggest endothelial dysfunction, which may be a risk factor for cardiovascular disease.
Time frame: The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Oral Tablet | Reactive Hyperemia Index (RHI) | 2.04 Ratio | Standard Deviation 0.55 |
| Propranolol Oral Tablet | Reactive Hyperemia Index (RHI) | 2.11 Ratio | Standard Deviation 0.49 |
Secondary
Systolic Blood Pressure (mmHg)
Measured in the morning (7 AM)
Time frame: The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Oral Tablet | Systolic Blood Pressure (mmHg) | 131 mmHg | Standard Deviation 14 |
| Propranolol Oral Tablet | Systolic Blood Pressure (mmHg) | 125 mmHg | Standard Deviation 15 |