Hypertension, Severe Obstructive Sleep Apnea (Apnea Hypopnea Index > 30 Events/Hour)
Conditions
Keywords
Hypertension, High Blood Pressure, Sleep Apnea, Obstructive Sleep Apnea, OSA
Brief summary
The purpose of this study is to determine if two medicines (allopurinol and losartan) can influence heart and blood vessel health compared to placebo in patients with sleep apnea who are using continuous positive airway pressure (CPAP).
Detailed description
The specific aims of this research project are: 1) Determine if treatment with losartan, an angiotensin type I receptor (AT1R) antagonist, or allopurinol, a XO inhibitor, normalize chemoreflex control of sympathetic outflow and ventilation and improve local vascular regulation and stiffness; and 2) Determine if these interventions reduce the severity of sleep disordered breathing and lower diurnal blood pressure.
Interventions
DRUGLosartan
Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic. Remain at 50 mg daily for 4 more weeks or removed from study if symptomatic.
DRUGAllopurinol
Allopurinol 300 mg daily for 6 weeks
DRUGPlacebo
Placebo capsule daily for 6 weeks
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males and females between ages of 21 and 65 years * Apnea hypopnea index or respiratory disturbance index greater than or equal to 25 events per hour * Subjects eligible for CPAP or BiPAP therapy * Hypertension by clinical history/diagnosis (may be controlled with non- exclusionary medications) or average blood pressure \> 140/90 mm Hg (using last two measurements in prior 12 months - or 1 prior blood pressure and 1 blood pressure at screening)
Exclusion criteria
* If subject not using CPAP, having AHI \> 60 events/hour or oxygen saturation ≤ 65% during sleep * Presence of clinical CV disease (coronary artery disease, angina, arrhythmias (subjects with sinus arrhythmias will be reviewed by PI for enrollment), stroke, TIA, cor pulmonale, etc.), heart failure, bruits, or diabetes mellitus by clinical diagnosis/history * Presence of pulmonary disease that results in significant hypoxemia (resting SaO2 \< 88%) * Hypertriglyceridemia (triglycerides \>300 mg/dL), diabetes or impaired glucose tolerance (fasting plasma glucose \> 125 mg/dL) * Patients taking angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, potassium-sparing diuretics (without accompanying loop/thiazide diuretic), allopurinol, oxypurinol, febuxostat, amoxicillin, ampicillin, azathioprine or mercaptopurine. * Patients with chronic kidney disease (Serum creatinine \>1.5 mg/dL) or history of significant hyperkalemia (Serum potassium \> 5.2 mEq/L) with ARB therapy * Patients with history of angioedema * Patients with bilateral,modified radical or radical mastectomies * Patients who have a Serum potassium \> 5.0 mEq/L at the screening visit * Female patients who are pregnant (determined by urine pregnancy test) or breastfeeding * Patients with active MRSA or VRE (vancomycin resistant enterococcus) infection * History of adverse reaction to allopurinol,losartan, or zolpidem\*\* * Patients who cannot swallow oral capsules * Patients who are hospitalized or who have been recently hospitalized (last 2 weeks) * Inability to comply with or complete the protocol or other reasons at the discretion of the investigators
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia | baseline and 6 weeks | The primary outcome variable is the change in the individual slope of the MSNA - SaO2 response curve at 6 weeks and baseline between treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cerebrovascular Conductance | baseline and 6 weeks | Assessment measures of cerebral blood flow during basal conditions and during graded hypoxia before and after study drug treatment. Cerebrovascular conductance (CVC) was calculated as velocity-time integral/mean arterial pressure. |
| Forearm Vascular Conductance | baseline and 6 weeks | Assessment measurements of forearm vascular conductance during basal conditions and during graded hypoxia before and after study drug treatment. |
| Change in Minute Ventilation at Normoxia | baseline and 6 weeks | assessed before and after study drug treatment |
| Change in Minute Ventilation During Hypoxia | baseline and 6 weeks | assessed before and after study drug treatment |
| Change in Aortic Pulse Wave Velocity | baseline and 6 weeks | measurement of vascular stiffness assessed before and after study drug treatment |
| Mean Change in PERCENT Vasodilation | baseline and 6 weeks | Flow-mediated vasodilation (FMD) (measurement of vascular endothelial function) assessed before and after study drug treatment |
| Apnea-Hypopnea Index | baseline and 6 weeks | Severity of sleep apnea assessed before and after study drug treatment |
| PERCENT Time Spent Below 88 PERCENT Oxygen Saturation | baseline and 6 weeks | assessed before and after study drug treatment |
| Change in Mean 24-Hour Blood Pressure (Mean Arterial Pressure) | baseline and 6 weeks | Change in mean 24 hour blood pressure (mean arterial pressure) |
| Aortic Augmentation Index | baseline and 6 weeks | assessed before and after study drug treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Losartan Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic and blood pressure within range.
Losartan: Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic. Remain at 50 mg daily for 4 more weeks or removed from study if symptomatic. | 28 |
| Allopurinol Allopurinol 300 mg daily for 6 weeks
Allopurinol: Allopurinol 300 mg daily for 6 weeks | 30 |
| Placebo Placebo capsule daily for 6 weeks
Placebo: Placebo capsule daily for 6 weeks | 28 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 2 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Losartan | Total | Placebo | Allopurinol |
|---|---|---|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 12 | 49 years STANDARD_DEVIATION 10 | 47 years STANDARD_DEVIATION 9 | 49 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 78 Participants | 24 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 27 Participants | 79 Participants | 24 Participants | 28 Participants |
| Region of Enrollment United States | 28 participants | 86 participants | 28 participants | 30 participants |
| Sex: Female, Male Female | 15 Participants | 34 Participants | 9 Participants | 10 Participants |
| Sex: Female, Male Male | 13 Participants | 52 Participants | 19 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 30 | 0 / 28 |
| other Total, other adverse events | 0 / 29 | 0 / 30 | 0 / 28 |
| serious Total, serious adverse events | 0 / 29 | 0 / 30 | 0 / 28 |
Outcome results
Primary
Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia
The primary outcome variable is the change in the individual slope of the MSNA - SaO2 response curve at 6 weeks and baseline between treatment groups.
Time frame: baseline and 6 weeks
Population: Data is for fewer subjects than were randomized to treatment because a useable nerve signal was not obtained on all participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia | Baseline | -0.54 bursts/minute*%SaO2 | Standard Deviation 0.29 |
| Losartan | Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia | Following 6 weeks of therapy | -0.69 bursts/minute*%SaO2 | Standard Deviation 0.5 |
| Allopurinol | Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia | Baseline | -0.84 bursts/minute*%SaO2 | Standard Deviation 0.47 |
| Allopurinol | Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia | Following 6 weeks of therapy | -0.66 bursts/minute*%SaO2 | Standard Deviation 0.38 |
| Placebo | Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia | Baseline | -0.71 bursts/minute*%SaO2 | Standard Deviation 0.43 |
| Placebo | Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia | Following 6 weeks of therapy | -0.61 bursts/minute*%SaO2 | Standard Deviation 0.4 |
Secondary
Aortic Augmentation Index
assessed before and after study drug treatment
Time frame: baseline and 6 weeks
Population: The number of participants differ between outcome measures due to difficulty in obtaining a viable signal for one outcome vs another and based on scheduling to prioritize the primary outcome measure.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Losartan | Aortic Augmentation Index | baseline | 17.3 PERCENT of the pulse pressure |
| Losartan | Aortic Augmentation Index | following six weeks of therapy | 16.1 PERCENT of the pulse pressure |
| Allopurinol | Aortic Augmentation Index | baseline | 18.8 PERCENT of the pulse pressure |
| Allopurinol | Aortic Augmentation Index | following six weeks of therapy | 16.7 PERCENT of the pulse pressure |
| Placebo | Aortic Augmentation Index | baseline | 21.5 PERCENT of the pulse pressure |
| Placebo | Aortic Augmentation Index | following six weeks of therapy | 22.5 PERCENT of the pulse pressure |
Secondary
Apnea-Hypopnea Index
Severity of sleep apnea assessed before and after study drug treatment
Time frame: baseline and 6 weeks
Population: The number of participants differ between primary and secondary outcome variables due to occasional inability to obtain a viable signal for the variable and due to scheduling difficulties and prioritizing the primary outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Losartan | Apnea-Hypopnea Index | baseline | 46 events/hour |
| Losartan | Apnea-Hypopnea Index | after six weeks of treatment | 44 events/hour |
| Allopurinol | Apnea-Hypopnea Index | baseline | 33 events/hour |
| Allopurinol | Apnea-Hypopnea Index | after six weeks of treatment | 45 events/hour |
| Placebo | Apnea-Hypopnea Index | baseline | 35 events/hour |
| Placebo | Apnea-Hypopnea Index | after six weeks of treatment | 26 events/hour |
Secondary
Cerebrovascular Conductance
Assessment measures of cerebral blood flow during basal conditions and during graded hypoxia before and after study drug treatment. Cerebrovascular conductance (CVC) was calculated as velocity-time integral/mean arterial pressure.
Time frame: baseline and 6 weeks
Population: Since this was a secondary outcome measure, not all participants were able to undergo this procedure since scheduling did not always allow with scheduling for primary outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Cerebrovascular Conductance | baseline | 0.32 cm/sec/mmHg | Standard Deviation 0.13 |
| Losartan | Cerebrovascular Conductance | After six weeks treatment | 0.36 cm/sec/mmHg | Standard Deviation 0.14 |
| Allopurinol | Cerebrovascular Conductance | baseline | 0.27 cm/sec/mmHg | Standard Deviation 0.97 |
| Allopurinol | Cerebrovascular Conductance | After six weeks treatment | 0.31 cm/sec/mmHg | Standard Deviation 0.12 |
| Placebo | Cerebrovascular Conductance | baseline | 0.33 cm/sec/mmHg | Standard Deviation 0.11 |
| Placebo | Cerebrovascular Conductance | After six weeks treatment | 0.34 cm/sec/mmHg | Standard Deviation 0.12 |
Secondary
Change in Aortic Pulse Wave Velocity
measurement of vascular stiffness assessed before and after study drug treatment
Time frame: baseline and 6 weeks
Population: Since this was a secondary outcome measure, not all participants were able to undergo this procedure since scheduling did not always allow with scheduling for primary outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Losartan | Change in Aortic Pulse Wave Velocity | -0.6 m/s |
| Allopurinol | Change in Aortic Pulse Wave Velocity | -0.03 m/s |
| Placebo | Change in Aortic Pulse Wave Velocity | 0.2 m/s |
Secondary
Change in Mean 24-Hour Blood Pressure (Mean Arterial Pressure)
Change in mean 24 hour blood pressure (mean arterial pressure)
Time frame: baseline and 6 weeks
Population: The number of participants differ between primary and secondary outcome variables due to occasional inability to obtain a viable signal for the variable and due to scheduling difficulties and prioritizing the primary outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Losartan | Change in Mean 24-Hour Blood Pressure (Mean Arterial Pressure) | -4.73 mm Hg |
| Allopurinol | Change in Mean 24-Hour Blood Pressure (Mean Arterial Pressure) | -2.58 mm Hg |
| Placebo | Change in Mean 24-Hour Blood Pressure (Mean Arterial Pressure) | 1.02 mm Hg |
Secondary
Change in Minute Ventilation at Normoxia
assessed before and after study drug treatment
Time frame: baseline and 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Change in Minute Ventilation at Normoxia | baseline - normoxia in L/min | 8.9 normoxia - L/min | Standard Deviation 1.7 |
| Losartan | Change in Minute Ventilation at Normoxia | six weeks - normoxia in L/min | 8.9 normoxia - L/min | Standard Deviation 2.1 |
| Allopurinol | Change in Minute Ventilation at Normoxia | baseline - normoxia in L/min | 9.3 normoxia - L/min | Standard Deviation 2.1 |
| Allopurinol | Change in Minute Ventilation at Normoxia | six weeks - normoxia in L/min | 9.8 normoxia - L/min | Standard Deviation 2.6 |
| Placebo | Change in Minute Ventilation at Normoxia | baseline - normoxia in L/min | 9.3 normoxia - L/min | Standard Deviation 2.1 |
| Placebo | Change in Minute Ventilation at Normoxia | six weeks - normoxia in L/min | 8.8 normoxia - L/min | Standard Deviation 1.9 |
Secondary
Change in Minute Ventilation During Hypoxia
assessed before and after study drug treatment
Time frame: baseline and 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Change in Minute Ventilation During Hypoxia | hypoxia - baseline in L/min*PERCENTSaO2 | -0.41 hypoxia - L/min*%SaO2 | Standard Deviation 0.28 |
| Losartan | Change in Minute Ventilation During Hypoxia | hypoxia - after six weeks treatment in L/min*%SaO2 | -0.37 hypoxia - L/min*%SaO2 | Standard Deviation 0.25 |
| Allopurinol | Change in Minute Ventilation During Hypoxia | hypoxia - baseline in L/min*PERCENTSaO2 | -0.53 hypoxia - L/min*%SaO2 | Standard Deviation 0.41 |
| Allopurinol | Change in Minute Ventilation During Hypoxia | hypoxia - after six weeks treatment in L/min*%SaO2 | -0.43 hypoxia - L/min*%SaO2 | Standard Deviation 0.37 |
| Placebo | Change in Minute Ventilation During Hypoxia | hypoxia - baseline in L/min*PERCENTSaO2 | -0.44 hypoxia - L/min*%SaO2 | Standard Deviation 0.29 |
| Placebo | Change in Minute Ventilation During Hypoxia | hypoxia - after six weeks treatment in L/min*%SaO2 | -0.48 hypoxia - L/min*%SaO2 | Standard Deviation 0.32 |
Secondary
Forearm Vascular Conductance
Assessment measurements of forearm vascular conductance during basal conditions and during graded hypoxia before and after study drug treatment.
Time frame: baseline and 6 weeks
Population: Participants were not able to conduct all procedures due to scheduling and on occasion, difficulty obtaining a signal. Prioritization of primary outcome measure was the goal.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Forearm Vascular Conductance | baseline | 0.41 ml/min^-1 dL^-1 mmHg^-1 | Standard Deviation 0.21 |
| Losartan | Forearm Vascular Conductance | After 6 weeks of treatment | 0.42 ml/min^-1 dL^-1 mmHg^-1 | Standard Deviation 0.17 |
| Allopurinol | Forearm Vascular Conductance | baseline | 0.43 ml/min^-1 dL^-1 mmHg^-1 | Standard Deviation 0.2 |
| Allopurinol | Forearm Vascular Conductance | After 6 weeks of treatment | 0.55 ml/min^-1 dL^-1 mmHg^-1 | Standard Deviation 0.31 |
| Placebo | Forearm Vascular Conductance | baseline | 0.49 ml/min^-1 dL^-1 mmHg^-1 | Standard Deviation 0.31 |
| Placebo | Forearm Vascular Conductance | After 6 weeks of treatment | 0.51 ml/min^-1 dL^-1 mmHg^-1 | Standard Deviation 0.29 |
Secondary
Mean Change in PERCENT Vasodilation
Flow-mediated vasodilation (FMD) (measurement of vascular endothelial function) assessed before and after study drug treatment
Time frame: baseline and 6 weeks
Population: The number of participants differ between primary and secondary outcome variables due to occasional inability to obtain a viable signal for the variable and due to scheduling difficulties and prioritizing the primary outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Losartan | Mean Change in PERCENT Vasodilation | 1.38 % change in Max relative FMD |
| Allopurinol | Mean Change in PERCENT Vasodilation | 0.18 % change in Max relative FMD |
| Placebo | Mean Change in PERCENT Vasodilation | -1.06 % change in Max relative FMD |
Secondary
PERCENT Time Spent Below 88 PERCENT Oxygen Saturation
assessed before and after study drug treatment
Time frame: baseline and 6 weeks
Population: The number of participants differ between primary and secondary outcome variables due to occasional inability to obtain a viable signal for the variable and due to scheduling difficulties and prioritizing the primary outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Losartan | PERCENT Time Spent Below 88 PERCENT Oxygen Saturation | baseline | 10 percentage of total sleep time |
| Losartan | PERCENT Time Spent Below 88 PERCENT Oxygen Saturation | following six weeks of therapy | 12 percentage of total sleep time |
| Allopurinol | PERCENT Time Spent Below 88 PERCENT Oxygen Saturation | baseline | 5 percentage of total sleep time |
| Allopurinol | PERCENT Time Spent Below 88 PERCENT Oxygen Saturation | following six weeks of therapy | 8 percentage of total sleep time |
| Placebo | PERCENT Time Spent Below 88 PERCENT Oxygen Saturation | baseline | 5 percentage of total sleep time |
| Placebo | PERCENT Time Spent Below 88 PERCENT Oxygen Saturation | following six weeks of therapy | 3 percentage of total sleep time |