Hypertension
Conditions
Keywords
Diastolic Function, Nebivolol
Brief summary
The goal of this pilot study is to effectively treat hypertension in subjects with either known or newly diagnosed hypertension and concurrent evidence of diastolic dysfunction. Due to the unique properties of nebivolol, it is hypothesized that there will be improvements in left ventricular (LV) systolic and diastolic function manifesting as increase exercise capacity in this patient population with primarily LV diastolic dysfunction. The present study was performed to determine the effects of nebivolol on blood pressure, exercise tolerance and parameters of left ventricular systolic and diastolic function in a group of hypertensive patients with echocardiographic evidence diastolic dysfunction.
Detailed description
Prior to the initiation of Nebivolol and after 10 weeks of Nebivolol therapy, subjects underwent a resting 2D echocardiogram including routine sampling of mitral valve (MV) inflow and LV tissue Doppler imaging as well as a symptom limited exercise treadmill stress test with echocardiographic imaging. Primary endpoints were 1) changes in systolic blood pressure before and after 10 weeks of treatment and 2) changes in exercise capacity as determined by exercise duration and metabolic equivalent (MET) level before and after treatment. Secondary endpoints were changes in exercise hemodynamics and Doppler echocardiographic parameters of LV systolic and diastolic function and quality of life before and after 10 weeks of nebivolol treatment. Subjects completed an EuroQol (EQ-SD) Quality of Life questionnaire which is a standardized measure of health status developed by the EuroQol group as a simple general measure of health at baseline and at conclusion of the 10 week trial period.
Interventions
DRUGNebivolol
Initial dose of 5 mg titrated (doubling of previous dose) to optimal blood pressure. The dose was titrated by doubling the previous dosage to achieve BP less than or equal to 130/80 mm Hg at 2 weeks and 4 weeks. The mean dose of nebivolol used week 4 through week 10 was 7.8 mg. It should be noted that nebivolol was added to the subject's existing stable antihypertensive regimen which included a mean of 2 other medications.
Sponsors
Forest Laboratories
Mercy Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis (new or established) hypertension, defined by serial measurements \>/= 140/90 * Evidence of diastolic dysfunction on echocardiography measured by tissue Doppler
Exclusion criteria
* Severe bronchospastic disease/ reactive airway disease * Inability to tolerate beta blocker therapy including: \>1st degree atrioventricular (AV) block, symptomatic hypotension, symptomatic bradycardia, * Subjects with physical limitations that would prevent them from participating in an exercise treadmill test * Age \<18 or \>90 years * Those with life expectancy \<1 year * Subjects with class III/IV New York Heart Association (NYHA) heart failure symptoms * Chronic Kidney Disease 3 or greater (CrCl \<30 cc/min) * Subjects with active ischemia or evidence of ischemia on initial stress echocardiography
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resting Systolic BP | 10 Weeks | — |
| Exercise Duration | 10 Weeks | — |
| Metabolic Equivalent (METS) Level | 10 Weeks | METs is a measure of exercise capacity. One MET is defined as 3.5 mL 02 uptake/kg per minute which is the resting oxygen uptake in a sitting position. The Bruce protocol consisted of successive 3 minute stages each of which requires the subject to walk at a faster speed and higher grade of incline. Each stage is assigned a MET level. The achieved exercise capacity in METs has been shown to be predictive in older adult population of survival with higher MET levels associated with improved survival. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Vein Peak Diastolic Velocity | 10 Week | — |
| Diastolic BP | 10 Week | — |
| Peak Stress Systolic BP | 10 Week | — |
| Peak Stress Diastolic BP | 10 Week | — |
| Resting Heart Rate | 10 Week | — |
| Stress Heart Rate | 10 Week | — |
| Resting EF | 10 Weeks | — |
| Stress EF | 10 Week | — |
| Resting Stroke Volume | 10 weeks | — |
| Stress Stroke Volume | 10 week | — |
| Mitral Valve Tissue Doppler Velocity (a') | 10 Week | — |
| Stress Cardiac Output | 10 week | — |
| LV End Diastolic Diameter | 10 week | — |
| LV End Systolic Diameter | 10 week | — |
| LV Mass | 10 week | — |
| Mitral Valve Inflow (E) Velocity | 10 Week | — |
| Mitral Valve Inflow (A) Velocity | 10 Week | — |
| Mitral Valve E/A Ratio | 10 Week | mitral valve doppler E velocity to A velocity |
| Mitral Valve Deceleration Time | 10 Week | — |
| Mitral Valve Tissue Doppler Velocity (e') | 10 Week | — |
| Quality of Life | 10 Weeks | Quality of life was assessed by a visual analogue scale before and after 10 weeks of nebivolol. The subjects self reported assessment of his/her overall health was recorded on a vertical visual analogue scale where 100 is the best imaginable health state and 0 is the worst imaginable health state. |
| Resting Cardiac Output | 10 week | — |
| E/e' Ratio | 10 Week | — |
| Pulmonary Vein Peak Systolic Velocity | 10 Week | — |
Countries
United States
Participant flow
Recruitment details
Recruited from the outpatient office at Mercy St. Louis between January 2010 and August 2012. The inclusion criteria were new or established hypertension as defined by serial BP measurements greater than or equal to 140/90 and evidence of left ventricular (LV) diastolic dysfunction as defined by a routine Doppler within a year of enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Nebivolol Treatment All subjects will begin an initial dosage of 5mg of Nebivolol titrated (doubling of previous dose) to optimal blood pressure below 130/80 at 2 and 4 weeks after treatment initiation.
Nebivolol: Initial dose of 5 mg titrated (doubling of previous dose) to optimal blood pressure. | 53 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ischemia on baseline stress test | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Nebivolol Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 33 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 66 Years STANDARD_DEVIATION 10 |
| BMI | 31 kg/m2 STANDARD_DEVIATION 5 |
| E/e' Ratio | 10.8 Ratio STANDARD_DEVIATION 4.7 |
| Exercise Duration | 385 seconds STANDARD_DEVIATION 174 |
| LV End Diastolic Diameter | 4.7 cm STANDARD_DEVIATION 0.5 |
| LV End Systolic Diameter | 3.0 cm STANDARD_DEVIATION 0.8 |
| LV Mass | 163 grams STANDARD_DEVIATION 52 |
| Metabolic Equivalent | 6.2 Mets STANDARD_DEVIATION 3.1 |
| Mitral Valve Deceleration Time | 229 ms STANDARD_DEVIATION 62 |
| Mitral Valve E/A Ratio | .86 Ratio STANDARD_DEVIATION 0.18 |
| Mitral Valve Inflow (A) Velocity | 91 cm/s STANDARD_DEVIATION 21 |
| Mitral Valve Inflow (E) Velocity | 77 cm/s STANDARD_DEVIATION 24 |
| Mitral Valve Tissue Doppler Velocity (a') | 11.8 cm/s STANDARD_DEVIATION 2.9 |
| Mitral Valve Tissue Doppler Velocity (e') | 7.6 cm/s STANDARD_DEVIATION 1.9 |
| Peak Stress Diastolic BP | 75 mm Hg STANDARD_DEVIATION 15 |
| Peak Stress Systolic BP | 178 mm Hg STANDARD_DEVIATION 23 |
| Pulmonary Vein Peak Diastolic Velocity | 47 cm/s STANDARD_DEVIATION 13 |
| Pulmonary Vein Peak Systolic Velocity | 62 cm/s STANDARD_DEVIATION 13 |
| Quality of Life | 77 units on a scale STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 53 participants |
| Resting Cardiac Output | 3.1 L per minute STANDARD_DEVIATION 1.1 |
| Resting Diastolic BP | 79 mm Hg STANDARD_DEVIATION 11 |
| Resting Ejection Fraction (EF) | 61 Percent of LV end diastolic volume STANDARD_DEVIATION 10 |
| Resting Heart Rate | 69 Beats per Minute STANDARD_DEVIATION 11 |
| Resting Stroke Volume | 46 ml STANDARD_DEVIATION 15 |
| Resting Systolic BP | 145 mm Hg STANDARD_DEVIATION 19 |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 33 Participants |
| Stress Cardiac Output | 5.6 L per minute STANDARD_DEVIATION 2.2 |
| Stress EF | 67 Percent of LV end diastolic volume STANDARD_DEVIATION 10 |
| Stress Heart Rate | 136 Beats per Minute STANDARD_DEVIATION 24 |
| Stress Stroke Volume | 47 ml STANDARD_DEVIATION 13 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 50 |
| serious Total, serious adverse events | 0 / 50 |
Outcome results
Primary
Exercise Duration
Time frame: 10 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Exercise Duration | 419 Seconds | Standard Deviation 180 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Primary
Metabolic Equivalent (METS) Level
METs is a measure of exercise capacity. One MET is defined as 3.5 mL 02 uptake/kg per minute which is the resting oxygen uptake in a sitting position. The Bruce protocol consisted of successive 3 minute stages each of which requires the subject to walk at a faster speed and higher grade of incline. Each stage is assigned a MET level. The achieved exercise capacity in METs has been shown to be predictive in older adult population of survival with higher MET levels associated with improved survival.
Time frame: 10 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Metabolic Equivalent (METS) Level | 6.7 METS | Standard Deviation 3.2 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Primary
Resting Systolic BP
Time frame: 10 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Resting Systolic BP | 135 mm Hg | Standard Deviation 17 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of treatment. Each subject served as his/her own control.p-value: <0.05t-test, 2 sided
Secondary
Diastolic BP
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Diastolic BP | 76 mm Hg | Standard Deviation 9 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.078t-test, 2 sided
Secondary
E/e' Ratio
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | E/e' Ratio | 10.5 Ratio | Standard Deviation 4.4 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.561t-test, 2 sided
Secondary
LV End Diastolic Diameter
Time frame: 10 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | LV End Diastolic Diameter | 4.8 cm | Standard Deviation 0.6 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.47t-test, 2 sided
Secondary
LV End Systolic Diameter
Time frame: 10 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | LV End Systolic Diameter | 3.1 cm | Standard Deviation 0.7 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.55t-test, 2 sided
Secondary
LV Mass
Time frame: 10 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | LV Mass | 167 grams | Standard Deviation 47 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.64t-test, 2 sided
Secondary
Mitral Valve Deceleration Time
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Mitral Valve Deceleration Time | 227 ms | Standard Deviation 55 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.925t-test, 2 sided
Secondary
Mitral Valve E/A Ratio
mitral valve doppler E velocity to A velocity
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Mitral Valve E/A Ratio | 0.97 Ratio | Standard Deviation 0.31 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Secondary
Mitral Valve Inflow (A) Velocity
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Mitral Valve Inflow (A) Velocity | 90 cm/s | Standard Deviation 23 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.526t-test, 2 sided
Secondary
Mitral Valve Inflow (E) Velocity
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Mitral Valve Inflow (E) Velocity | 85 cm/s | Standard Deviation 21 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Secondary
Mitral Valve Tissue Doppler Velocity (a')
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Mitral Valve Tissue Doppler Velocity (a') | 11.5 cm/s | Standard Deviation 2.9 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.458t-test, 2 sided
Secondary
Mitral Valve Tissue Doppler Velocity (e')
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Mitral Valve Tissue Doppler Velocity (e') | 8.7 cm/s | Standard Deviation 2.6 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Secondary
Peak Stress Diastolic BP
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Peak Stress Diastolic BP | 68 mm Hg | Standard Deviation 17 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Secondary
Peak Stress Systolic BP
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Peak Stress Systolic BP | 171 mm Hg | Standard Deviation 26 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.186t-test, 2 sided
Secondary
Pulmonary Vein Peak Diastolic Velocity
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Pulmonary Vein Peak Diastolic Velocity | 51 cm/s | Standard Deviation 16 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.129t-test, 2 sided
Secondary
Pulmonary Vein Peak Systolic Velocity
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Pulmonary Vein Peak Systolic Velocity | 63 cm/s | Standard Deviation 10 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.734t-test, 2 sided
Secondary
Quality of Life
Quality of life was assessed by a visual analogue scale before and after 10 weeks of nebivolol. The subjects self reported assessment of his/her overall health was recorded on a vertical visual analogue scale where 100 is the best imaginable health state and 0 is the worst imaginable health state.
Time frame: 10 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Quality of Life | 78 units on a scale | Standard Deviation 15 |
Secondary
Resting Cardiac Output
Time frame: 10 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Resting Cardiac Output | 3.0 L per minute | Standard Deviation 0.9 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.64t-test, 2 sided
Secondary
Resting EF
Time frame: 10 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Resting EF | 63 Percent of LV end diastolic volume | Standard Deviation 9 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Secondary
Resting Heart Rate
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Resting Heart Rate | 65 Beats per Minute | Standard Deviation 9 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Secondary
Resting Stroke Volume
Time frame: 10 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Resting Stroke Volume | 48 ml | Standard Deviation 14 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.85t-test, 2 sided
Secondary
Stress Cardiac Output
Time frame: 10 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Stress Cardiac Output | 5.3 L per minute | Standard Deviation 1.7 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.49t-test, 2 sided
Secondary
Stress EF
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Stress EF | 72 Percent of LV end diastolic volume | Standard Deviation 10 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: <0.05t-test, 2 sided
Secondary
Stress Heart Rate
Time frame: 10 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Stress Heart Rate | 118 Beats per Minute | Standard Deviation 24 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.06t-test, 2 sided
Secondary
Stress Stroke Volume
Time frame: 10 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol Treatment | Stress Stroke Volume | 51 ml | Standard Deviation 16 |
Comparison: Nebivolol treatment group refers to 50 patients that completed 10 weeks of open label nebivolol treatment. Results were compared using paired T-tests in a pre - post study design before and after 10 weeks of his/her treatment. Each subject served as own control.p-value: =0.4t-test, 2 sided