Hypertension
Conditions
Keywords
hypertension, prevention, endothelial function
Brief summary
This is a randomized, double-blind, placebo-controlled study comparing the efficacy of nebivolol and atenolol at improving small artery elasticity and reducing cardiovascular disease risk in subjects with early vascular disease. Approximately 75 subjects with borderline/elevated blood pressures and impaired endothelial function, as measured by arterial elasticity scores, will be recruited and assigned to treatment groups using a block randomization scheme. Patients will be randomly allocated to nebivolol, atenolol or placebo, and then followed for 9 months.
Detailed description
The Rasmussen Disease Score (RDS) test panel is the chosen methodology for this study. The 10 parameters of the RDS were selected because of their ability to quantify early structural and functional abnormalities in the vasculature and left ventricle which appear long before cardiovascular disease is present. The RDS tests include: large and small artery elasticity (measured by pulse contour analysis), resting blood pressure, mild treadmill exercise test, carotid IMT, left ventricle mass, ECG, retinal vasculature evaluation, as well as quantification of serum NT-proBNP, and microalbuminuria. Quantitative results from these tests are converted into categorical classifications based on values stratified by age and gender when appropriate. The categorical data is scored as follows: normal = 0 points, borderline = 1 point, abnormal = 2 points. Point values from all parameters are summed to create the RDS, with values ranging from 0-20. Scores of 0-2 are classified as normal, 3-5 as early disease, and 6+ as advanced disease. Previous research has shown that the RDS is a powerful predictor of future cardiovascular events. The small artery elasticity (C2) parameter is of particular interest as it is responsive to changes in NO levels and is an effective and reliable predictor of future hypertension and other cardiovascular events. Changes in C2 will serve as the primary outcome of this study. Similar studies using anti-hypertensive or lipid-lowering interventions have found significant improvements in C2 values. Brachial artery flow-mediated dilation (FMD) measurements will also be measured as an index of endothelial function, although this method appears to be less sensitive to functional changes related to NO bioavailability than C2. Utilizing both FMD and C2 will allow comparison with previous studies and take advantage of a large sample size to further examine the relative sensitivity of each method for reliably measuring endothelial dysfunction. The duration of intervention for this study is 9 months which is the minimum time to adequately detect improvement in left ventricle (LV) mass values. LV mass measurements are a critical component of a comprehensive assessment of cardiovascular health and have improved within this temporal window as a result of anti-hypertensive intervention.
Interventions
DRUGNebivolol
5 mg daily or 10 mg daily
DRUGatenolol
25 mg daily or 50 mg daily
DRUGplacebo
one tablet daily
Sponsors
Forest Laboratories
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* borderline blood pressure (120-145/80-90 mm Hg); * borderline or abnormal small artery elasticity (C2) as measured by pulse contour analysis; * treatment-naive for all blood pressure medications including diuretics for at least 30 days prior to baseline visit; * able to walk on a treadmill for 3 minutes; * female patients with reproductive potential must use an approved contraceptive method if appropriate (for example, intrauterine device \[IUD\], birth control pills, or barrier device during and for 1 month after the last dose of study drug; * voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
Exclusion criteria
* history of intolerance to beta-blockers or clear contraindications to their use; current pharmaceutical treatment of blood pressure; * known history of cardiovascular disease (myocardial infarction, coronary artery bypass graft, unstable angina, uncontrolled arrhythmias, stroke, etc.); * known history of diabetes; known history of hepatic, renal or gastrointestinal disorder; * known history of any illness that may cause additional risk (as determined by study investigator); * pregnant or lactating women \[when used during pregnancy, beta-blockers may cause fetal harm\]; * participation in a concomitant clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Small Artery Elasticity | baseline, 9 months | Change in small artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Large Artery Elasticity | baseline, 9 months | Change in large artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation. |
| Change in Systolic Blood Pressure | baseline, 9 months | Change in systolic blood pressure as measured by sphygmomanometer from baseline to 9 months after intervention initiation. |
| Change in Diastolic Blood Pressure | baseline, 9 months | Change in diastolic blood pressure as measured by sphygmomanometer from baseline to 9 months after intervention initiation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nebivolol 5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur.
Nebivolol: 5 mg daily or 10 mg daily | 20 |
| Atenolol 25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur.
atenolol: 25 mg daily or 50 mg daily | 18 |
| Placebo Continue for 1 month; dose titration to high dose placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur.
placebo: one tablet daily | 22 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 1 |
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 2 |
| Overall Study | Study Medication Sensitivity | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 2 | 1 |
Baseline characteristics
| Characteristic | Atenolol | Placebo | Nebivolol | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 6 Participants | 2 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 16 Participants | 18 Participants | 50 Participants |
| Age, Continuous | 50.8 years STANDARD_DEVIATION 14 | 54 years STANDARD_DEVIATION 9 | 47.1 years STANDARD_DEVIATION 14.5 | 50.7 years STANDARD_DEVIATION 13.2 |
| Region of Enrollment United States | 18 participants | 22 participants | 20 participants | 60 participants |
| Sex: Female, Male Female | 4 Participants | 13 Participants | 9 Participants | 26 Participants |
| Sex: Female, Male Male | 14 Participants | 9 Participants | 11 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 1 / 18 | 1 / 22 |
| other Total, other adverse events | 6 / 20 | 4 / 18 | 7 / 22 |
| serious Total, serious adverse events | 0 / 20 | 0 / 18 | 0 / 22 |
Outcome results
Primary
Change in Small Artery Elasticity
Change in small artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation.
Time frame: baseline, 9 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Change in Small Artery Elasticity | 2.4 (ml/mmHg × 100) | Standard Deviation 2.1 |
| Atenolol | Change in Small Artery Elasticity | 1.0 (ml/mmHg × 100) | Standard Deviation 2.1 |
| Placebo | Change in Small Artery Elasticity | 0.4 (ml/mmHg × 100) | Standard Deviation 1.7 |
Secondary
Change in Diastolic Blood Pressure
Change in diastolic blood pressure as measured by sphygmomanometer from baseline to 9 months after intervention initiation.
Time frame: baseline, 9 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Change in Diastolic Blood Pressure | -8.5 mmHg | Standard Deviation 10.1 |
| Atenolol | Change in Diastolic Blood Pressure | -8.5 mmHg | Standard Deviation 8.9 |
| Placebo | Change in Diastolic Blood Pressure | -2.9 mmHg | Standard Deviation 6.7 |
Secondary
Change in Large Artery Elasticity
Change in large artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation.
Time frame: baseline, 9 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Change in Large Artery Elasticity | 3.2 (ml/mmHg × 10) | Standard Deviation 5.4 |
| Atenolol | Change in Large Artery Elasticity | 2.9 (ml/mmHg × 10) | Standard Deviation 3.4 |
| Placebo | Change in Large Artery Elasticity | 0.2 (ml/mmHg × 10) | Standard Deviation 2.6 |
Secondary
Change in Systolic Blood Pressure
Change in systolic blood pressure as measured by sphygmomanometer from baseline to 9 months after intervention initiation.
Time frame: baseline, 9 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Change in Systolic Blood Pressure | -9 mmHg | Standard Deviation 12.9 |
| Atenolol | Change in Systolic Blood Pressure | -13 mmHg | Standard Deviation 10.6 |
| Placebo | Change in Systolic Blood Pressure | -3.2 mmHg | Standard Deviation 12.4 |