Hypertension
Conditions
Brief summary
Patients who have obstructive sleep apnea (OSA) frequently stop breathing while they sleep. They often develop high blood pressure. We are not sure what drug is best to treat the high blood pressure. This study will give the patients nebivolol or hydrochlorothiazide (HCTZ) for 6 weeks after 2 weeks of placebo. The blood pressure response will be evaluated by 24 hour monitoring.
Detailed description
This is a blinded crossover study measuring the antihypertensive efficacy of nebivolol vs HCTZ in up to 34 subjects. Subjects with an apnea-hypopnea index (AHI) \> 10 and hypertension can enter the study. Hypertension is defined as a systolic blood pressure (SBP) \> 140 or a diastolic blood pressure (DBP) \> 90 on the average of three seated blood pressure measurements or a history of medical therapy for hypertension. Subjects who have tried and abandoned continuous positive airway pressure (CPAP) therapy for sleep apnea are eligible for this study. All others will be advised that CPAP is preferred treatment for sleep apnea and are eligible only if they decline CPAP or use it for too short a time at night to be effective. Then patients will have their antihypertensive drugs tapered off and receive single blind placebo for two weeks. After that, all subjects receive nebivolol or HCTZ for six weeks with a full evaluation at that time. Subjects are crossed over to HCTZ 12.5 mg for 2 weeks followed by HCTZ 25 mg for 4 more weeks. Nebivolol 5 mg will be taken daily at bedtime for 2 weeks and then as a dose of 10 mg for the remaining 4 weeks. Subjects will receive a telephone call at the time of increased dosage as a reminder. Blood, urine and 24-hour blood pressure measurements, hemodynamic measurements, questionnaires and drug accountability are measured in the same manner toward at the the end of placebo and each drug treatment. The entire study will take 14 weeks, although each study period may be lengthened by one week if necessary for the convenience of the subject's personal schedule. Patients will provide blood pressure readings from their home monitor or in clinic and will not have the dose increased if they have systolic blood pressure below 105 mm Hg or side effects suggesting that an increased dose might worsen side effects At the end of each treatment period, subjects will undergo noninvasive hemodynamic testing. Ultrasound will be used to measure aortic diameter and blood velocity in the ascending aorta in order to better estimate cardiac output. Then, finger plethysmography will be used to acquire beat-to-beat finger blood pressure and pulse rate. Beat-to-beat derived hemodynamic variables will be calculated by a model flow algorithm (e.g. brachial artery flow, stroke volume, cardiac output, ejection time, blood pressure rate of change, peripheral resistance). Applanation tonometry will be used to obtain pulse wave velocity and central arterial pressure. ECG will be recorded with standard ECG leads to determine heart rate variability in both time and frequency domains. Spontaneous baroreflex will be determined from beat-to-beat changes in blood pressure and pulse pressure interval. Forearm reactive hyperemia will be used to quantify endothelial dysfunction during 4 minutes of post-ischemic change. Subjects will then complete an Epworth Sleepiness Scale questionnaire (ESS) and a Functional Outcomes of Sleep Questionnaire (FOSQ) to find whether they are drowsy in the daytime and if they feel that they are compromised by not having adequate rest. Any adverse event will be recorded. They are asked about any concurrent medication over the prior period, including prescription medication, over the counter medication, and caffeine intake. Medication compliance is evaluated by pill count. Those who fail to return their pill bottle are requested to bring it in. Finally, a 24-hour ambulatory blood pressure monitor (ABPM) will be attached to automatically collect blood pressure and heart rate values every 15 minutes during the wake period and every 30 minutes during the sleep period.
Interventions
DRUGNebivolol
Nebivolol 5mg then nebivolol 10 mg
DRUGHydrochlorothiazide
Hydrochlorothiazide 12.5 mg then hydrochlorothiazide 25 mg
Sponsors
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients ranging from 20 - 80 years * Body mass index (BMI) of 20-38 to include the typical obese OSA patients * Hypertension with blood pressures \> 140/90 but less than 180/105 mmHg. * Apnea-hypopnea index above 10
Exclusion criteria
* Receiving sleep medicines (including heavy alcohol use) or drugs with adverse interactions with study medication. * Women who have premenstrual syndrome, or those who are pregnant or capable of pregnancy and unwilling to use effective non-hormonal contraception * Shift workers or have symptoms of narcolepsy, restless legs syndrome or insomnia, in order to minimize confounding effects of other sleep disorders * Have apneas which are primarily central * Have sleep fragmentation caused by syndromes such as chronic pain or movement disorders * Have diseases such as asthma or chronic obstructive pulmonary disease that compromises respiration. * Have known coronary or cerebral vascular disease, history of arrhythmias, cardiomyopathy, history of psychosis, current alcohol or drug abuse. * Have any contraindications to any study materials, such as heart block. * Have secondary hypertension * Have creatinine levels above 2.5 mg %, more than 1+ proteinuria by dipstick, hematuria or electrolyte disorders.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | At the end of 2 weeks of placebo therapy, at the end of 6 weeks of Nebivolol therapy and at the end of 6 weeks of hydrochlorothiazide therapy. | 24-h Systolic Blood Pressure is the average of all 24-h Ambulatory Systolic Blood Pressure recordings. The Wake Period Systolic Blood Pressure is the average of all Systolic Blood Pressures recorded every 15 minutes during the wake period. The Sleep Period Systolic Blood pressure is the average of all Systolic Blood Pressures recorded every 30 minutes during the sleep period. 24-h Diastolic Blood Pressure is the average of all 24-h Ambulatory Diastolic Blood Pressure recordings. The Wake Period Diastolic Blood Pressure is the average of all Diastolic Blood Pressures recorded every 15 minutes during the wake period. The Sleep Period Diastolic Blood pressure is the average of all Diastolic Blood Pressures recorded every 30 minutes during the sleep period. |
Participant flow
Pre-assignment details
41 of 405 participants were randomized. Of those not randomized, 364 did not meet inclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| Placebo, Then Nebivolol, Then Hydrochlorothiazide The participants first received Placebo for 2 weeks. They then received nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks. They then received hydrochlorothyazide 12.5 mg for 2 weeks followed by hydrochlorothyazide 25 mg for 4 weeks. | 21 |
| Placebo, Then Hydrochlorothiazide, Then Nebivolol The participants first received Placebo for 2 weeks. They then received hydrochlorothyazide 12.5 mg for 2 weeks followed by hydrochlorothyazide 25 mg for 4 weeks. They then received nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks. | 20 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (6 Weeks). | Withdrawal by Subject | 3 | 4 |
| Second Intervention (6 Weeks). | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Placebo, Then Hydrochlorothiazide, Then Nebivolol | Placebo, Then Nebivolol, Then Hydrochlorothiazide |
|---|---|---|---|
| 24-h Ambulatory Diastolic Blood Pressure 24-h diastolic blood pressure | 82 mmHg STANDARD_DEVIATION 10 | 79 mmHg STANDARD_DEVIATION 11 | 86 mmHg STANDARD_DEVIATION 11 |
| 24-h Ambulatory Diastolic Blood Pressure Sleep diastolic blood pressure | 76 mmHg STANDARD_DEVIATION 10 | 74 mmHg STANDARD_DEVIATION 10 | 78 mmHg STANDARD_DEVIATION 11 |
| 24-h Ambulatory Diastolic Blood Pressure Wake diastolic blood pressure | 86 mmHg STANDARD_DEVIATION 10 | 83 mmHg STANDARD_DEVIATION 10 | 89 mmHg STANDARD_DEVIATION 11 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants | 19 Participants | 18 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 11 | 54 years STANDARD_DEVIATION 11 | 50 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 41 participants | 20 participants | 21 participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 35 Participants | 18 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 20 |
| other Total, other adverse events | 0 / 21 | 0 / 20 |
| serious Total, serious adverse events | 0 / 21 | 0 / 20 |
Outcome results
Primary
24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure
24-h Systolic Blood Pressure is the average of all 24-h Ambulatory Systolic Blood Pressure recordings. The Wake Period Systolic Blood Pressure is the average of all Systolic Blood Pressures recorded every 15 minutes during the wake period. The Sleep Period Systolic Blood pressure is the average of all Systolic Blood Pressures recorded every 30 minutes during the sleep period. 24-h Diastolic Blood Pressure is the average of all 24-h Ambulatory Diastolic Blood Pressure recordings. The Wake Period Diastolic Blood Pressure is the average of all Diastolic Blood Pressures recorded every 15 minutes during the wake period. The Sleep Period Diastolic Blood pressure is the average of all Diastolic Blood Pressures recorded every 30 minutes during the sleep period.
Time frame: At the end of 2 weeks of placebo therapy, at the end of 6 weeks of Nebivolol therapy and at the end of 6 weeks of hydrochlorothiazide therapy.
Population: The overall Number of Analyzed Participants for primary outcome (27) differs from the Overall Number of Placebo (baseline) Participants (41) because 14 participants were excluded from the analysis due to either low quality of acquired data or due to missing data. Data Analysis was performed for the same 27 participants and for the each test period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | 24-h systolic blood pressure | 137 mmHg | Standard Error 3.1 |
| Placebo | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | 24-h diastolic blood pressure | 82 mmHg | Standard Error 1.9 |
| Placebo | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Wake systolic blood pressure | 141 mmHg | Standard Error 3.1 |
| Placebo | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Wake diastolic blood pressure | 86 mmHg | Standard Error 1.9 |
| Placebo | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Sleep systolic blood pressure | 129 mmHg | Standard Error 3.2 |
| Placebo | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Sleep diastolic blood pressure | 76 mmHg | Standard Error 2 |
| Nebivolol | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Sleep diastolic blood pressure | 71 mmHg | Standard Error 2.02 |
| Nebivolol | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | 24-h systolic blood pressure | 130 mmHg | Standard Error 2.5 |
| Nebivolol | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Wake diastolic blood pressure | 81 mmHg | Standard Error 1.7 |
| Nebivolol | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Sleep systolic blood pressure | 123 mmHg | Standard Error 2.9 |
| Nebivolol | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | 24-h diastolic blood pressure | 77 mmHg | Standard Error 1.6 |
| Nebivolol | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Wake systolic blood pressure | 135 mmHg | Standard Error 2.5 |
| Hydrochlorothiazide | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | 24-h diastolic blood pressure | 80 mmHg | Standard Error 1.9 |
| Hydrochlorothiazide | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Wake systolic blood pressure | 138 mmHg | Standard Error 3.1 |
| Hydrochlorothiazide | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Sleep diastolic blood pressure | 75 mmHg | Standard Error 2.15 |
| Hydrochlorothiazide | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Wake diastolic blood pressure | 85 mmHg | Standard Error 2.1 |
| Hydrochlorothiazide | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | 24-h systolic blood pressure | 133 mmHg | Standard Error 2.9 |
| Hydrochlorothiazide | 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure | Sleep systolic blood pressure | 127 mmHg | Standard Error 3 |