Mitral Regurgitation
Conditions
Keywords
Chronic MR, Volume Overload, Beta-1 receptor blocker, LV remodelling, LV dimensions, LV systolic function, LV diastolic dysfunction, Cardiac MRI
Brief summary
The investigators hypothesize that beta-1 receptor blockade (ß1-RB) attenuates extracellular matrix (ECM) degradation and progressive adverse Left Ventricular (LV) remodeling and failure in the volume overload of mitral regurgitation (MR). Patients without coronary artery disease and moderate MR, as assessed by color/flow Doppler echocardiography, will be randomized to ß1-RB vs. placebo to address the following aims: \*Aim 1: Establish whether ß1-RB attenuates adverse LV remodeling compared to placebo in patients with non-surgical, chronic MR. Using 3-dimensional magnetic resonance imaging (MRI) and tissue tagging, LV function and geometry will be assessed at baseline and every 6 months for up to 2 years. Aim 2: Determine whether indices of inflammation correlate with degree of LV remodeling and whether ß1-RB decrease indices of inflammation and collagen turnover. At the time of MRI, blood samples for collagen breakdown products, matrix metalloproteinase (MMP) activity, and markers of excess production of reactive inflammatory species (RIS) will be obtained and related to changes in LV remodeling defined by serial 3-dimensional MRI and tissue tagging.
Detailed description
In Western society, the most common causes of chronic mitral regurgitation (MR) are ischemic heart disease and myxomatous degeneration of the valve, resulting in prolapse, ruptured chordae or partial flail leaflet. Current indications for surgery are only for patients with severe MR and either notable symptoms or overt Left Ventricular (LV) dysfunction (ejection fraction \< 60%, end-systolic diameter \> 40 mm). Therefore, despite the availability of surgery, most patients with MR of moderate severity are not immediate candidates for surgery, warranting analysis of potential beneficial effects of medical treatment. Chronic therapy with vasodilators reduces LV wall stress and thereby delays the need for valve replacement in aortic regurgitation; however, no such data are currently available in patients with chronic MR using standard vasodilators or agents that block the renin angiotensin system (RAS). In a clinically-relevant dog model of MR, the investigators have shown increased LV ACE and chymase expression, increased LV angiotensin II but, as opposed to pressure overload, there was an absence of fibrosis with net extracellular matrix (ECM) degradation and activation of matrix metalloproteinases (MMPs). However, blockade of the RAS does not improve (and may actually exacerbate) LV remodeling in MR. Interestingly, the investigators and others have shown that ß1-receptor blockade (ß1-RB) is more effective than RAS blockade in attenuating progressive LV remodeling and ECM degradation in MR. Moreover, increased sympathetic drive and inflammation has been identified in patients with chronic MR. ß1-RB reduced plasma markers of inflammation in patients with heart failure and resulted in substantial reverse LV remodeling in patients with heart failure. Taken together, activation of the adrenergic nervous system early in the course of volume overload contributes to increased production of reactive inflammatory species (RIS) and that one mechanism underlying the salutary effects of ß1-blockade may relate to attenuation of myocardial formation of RIS with subsequent beneficial effects on MMP activation and ECM and LV remodeling and function.
Interventions
DRUGmetoprolol succinate (Toprol XL)
Toprol XL 100 mg once a day for 2 years
DRUGPlacebo
Placebo 100 mg once a day for 2 years
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
AstraZeneca
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Patients who have Moderate MR documented by color flow doppler: 1. LV ejection fraction \> 55%; LV end-systolic dimension \< 4.0 cm. 2. Quantifiable by Doppler-Echo equal or more than moderate in severity. 3. Organic disease of the mitral valve demonstrated by echocardiography (not normal valve as in functional or ischemic MR). 4. Isolated MR (no valve disease other than mild tricuspid or pulmonic regurgitation by Doppler-Echocardiography that is often associated with mitral valve prolapse). 5. Asymptomatic (or mildly symptomatic but not considered as candidates for immediate surgery by their attending physician).
Exclusion criteria
1. Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion. 2. Previous myocardial infarction or percutaneous coronary intervention. 3. Hypertrophic cardiomyopathy, congenital or pericardial disease. 4. Aortic valve disease (\> trace aortic regurgitation or mean gradient \> 10 mmHg). 5. Mitral stenosis (mean gradient \>5 mmHg, valve area \< 1.5 cm2). 6. Intolerance or contraindication to Beta1-AR blockade. 7. Renal failure with creatinine \> 2.5 mg/dl. 8. Hypertension requiring medical treatment or renal artery stenosis. 9. Severe comorbidity: liver disease, malignancy, collagen vascular, steroid requirement. 10. Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential). 11. Uncontrolled (rate \> 120/min) or recent (\<4 weeks) atrial fibrillation. 12. Routine, regular use of anti-inflammatory medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular End Diastolic Volume Indexed to Body Surface Area | 5 visits per Participant over 2 years (about every 6 months) | Left Ventricular End Diastolic Volume Indexed to Body Surface Area: As an indicator of heart size, the blood volume of the heart is related to the body size. The end diastolic volume is the blood volume of the heart at the end of filling, just before contraction. The relation of heart blood volume to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium. |
| Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | 5 visits per Participant over 2 years (about every 6 months) | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume As an indicator of heart muscle mass and heart blood volume, the mass indexed to end diastolic volume determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a three-dimensional analysis. The values that are too high or too low indicate a diseased myocardium. |
| Left Ventricular End-Diastolic Radius to Wall Thickness | 5 visits per Participant over 2 years (about every 6 months) | Left Ventricular End-Diastolic Radius to Wall Thickness As an indicator of heart muscle mass and heart volume chamber diameter, the end-diastolic radius indexed to end diastolic wall thickness determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a two-dimensional analysis. The values that are too high or too low indicate a diseased myocardium. |
| Left Ventricular End Systolic Volume Indexed to Body Surface Area | 5 visits per Participant over 2 years (about every 6 months) | Left Ventricular End Systolic Volume Indexed to Body Surface Area As an indicator of heart size, the blood volume of the heart is related to the body size. The end systolic volume is the blood volume of the heart at the end of contraction and is an index of the pump function of the heart. This relation to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium. |
| Left Ventricular Ejection Fraction | 5 visits per Participant over 2 years (about every 6 months) | Left Ventricular Ejection Fraction Is a calculation of heart pump function determined from the volume after complete filling minus the volume after complete contraction divided by the volume after complete filling. A value of 55% or greater is normal. |
| Systolic Longitudinal Strain | 5 visits per Participant over 2 years (about every 6 months) | Systolic Longitudinal Strain. By identifying two points on the heart, the strain is the difference between the distance between these two points at the end of filling of the heart and the end of contraction divided by the length at the end of filling. Thus, the measure is like the ejection fraction, however the strain is more localized to a specified segment in the heart muscle. The higher values indicate a healthy heart. |
| Peak Early Filling Rate: Rate of Change Over Time | 5 visits per Participant over 2 years (about every 6 months) | Peak Early Filling Rate The peak early filling rate of change is calculated from the slope of the volume during the early filling of the heart with respect to time. The higher values indicate a very healthy heart muscle and lower values are indicative of a very stiff muscle. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo | 19 |
| Toprol-XL | 19 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Toprol-XL | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 19 Participants | 35 Participants |
| Age Continuous | 55.9 years STANDARD_DEVIATION 9.2 | 52.6 years STANDARD_DEVIATION 9.3 | 54.2 years STANDARD_DEVIATION 9.3 |
| Region of Enrollment United States | 19 participants | 19 participants | 38 participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 19 | 6 / 19 |
| serious Total, serious adverse events | 7 / 19 | 4 / 19 |
Outcome results
Primary
Left Ventricular Ejection Fraction
Left Ventricular Ejection Fraction Is a calculation of heart pump function determined from the volume after complete filling minus the volume after complete contraction divided by the volume after complete filling. A value of 55% or greater is normal.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Left Ventricular Ejection Fraction | Month 3 (n=1,0) | 63.90 percent | — |
| Placebo | Left Ventricular Ejection Fraction | Month 15 (n=3,2) | 44.70 percent | Standard Deviation 16.03 |
| Placebo | Left Ventricular Ejection Fraction | Month 9 (n=1,1) | 41.90 percent | — |
| Placebo | Left Ventricular Ejection Fraction | Month 18 (n=14,18) | 60.95 percent | Standard Deviation 8.23 |
| Placebo | Left Ventricular Ejection Fraction | Month 6 (n=17,19) | 63.80 percent | Standard Deviation 6.15 |
| Placebo | Left Ventricular Ejection Fraction | Month 21 (n=5,0) | 53.79 percent | Standard Deviation 11.2 |
| Placebo | Left Ventricular Ejection Fraction | Month 12 (n=14,15) | 61.70 percent | Standard Deviation 6.87 |
| Placebo | Left Ventricular Ejection Fraction | Month 24 (n=16,18) | 59.95 percent | Standard Deviation 8.27 |
| Placebo | Left Ventricular Ejection Fraction | Month 0 (n=19,19) | 62.62 percent | Standard Deviation 5.25 |
| Toprol XL | Left Ventricular Ejection Fraction | Month 24 (n=16,18) | 63.02 percent | Standard Deviation 6.05 |
| Toprol XL | Left Ventricular Ejection Fraction | Month 0 (n=19,19) | 62.09 percent | Standard Deviation 6.45 |
| Toprol XL | Left Ventricular Ejection Fraction | Month 3 (n=1,0) | NA percent | — |
| Toprol XL | Left Ventricular Ejection Fraction | Month 6 (n=17,19) | 61.29 percent | Standard Deviation 4.66 |
| Toprol XL | Left Ventricular Ejection Fraction | Month 9 (n=1,1) | 54.81 percent | — |
| Toprol XL | Left Ventricular Ejection Fraction | Month 12 (n=14,15) | 62.77 percent | Standard Deviation 6.14 |
| Toprol XL | Left Ventricular Ejection Fraction | Month 15 (n=3,2) | 68.47 percent | Standard Deviation 2.02 |
| Toprol XL | Left Ventricular Ejection Fraction | Month 18 (n=14,18) | 62.05 percent | Standard Deviation 5.68 |
| Toprol XL | Left Ventricular Ejection Fraction | Month 21 (n=5,0) | NA percent | — |
Comparison: The differences in the rate of progression of the outcome measures were the focus of the comparisons over time between the treatment groups. A significant interaction effect between time and treatment group in the mixed model is the measure of treatment effect. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes and the number of Participants for each interval is indicated as (n=x,y)p-value: 0.006Mixed Models Analysis
Primary
Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume
Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume As an indicator of heart muscle mass and heart blood volume, the mass indexed to end diastolic volume determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a three-dimensional analysis. The values that are too high or too low indicate a diseased myocardium.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 3 (n=1,0) | 0.53 g/ml | — |
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 15 (n=3,2) | 0.65 g/ml | Standard Deviation 0.18 |
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 9 (n=1,1) | 0.67 g/ml | — |
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 18 (n=14,18) | 0.65 g/ml | Standard Deviation 0.11 |
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 6 (n=17,19) | 0.62 g/ml | Standard Deviation 0.11 |
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 21 (n=5,0) | 0.61 g/ml | Standard Deviation 0.13 |
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 12 (n=14,15) | 0.65 g/ml | Standard Deviation 0.12 |
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 24 (n=16,18) | 0.64 g/ml | Standard Deviation 0.12 |
| Placebo | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 0 (n=19,19) | 0.61 g/ml | Standard Deviation 0.13 |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 24 (n=16,18) | 0.62 g/ml | Standard Deviation 0.11 |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 0 (n=19,19) | 0.61 g/ml | Standard Deviation 0.12 |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 3 (n=1,0) | NA g/ml | — |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 6 (n=17,19) | 0.6 g/ml | Standard Deviation 0.12 |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 9 (n=1,1) | 0.53 g/ml | — |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 12 (n=14,15) | 0.60 g/ml | Standard Deviation 0.1 |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 15 (n=3,2) | 0.55 g/ml | Standard Deviation 0.05 |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 18 (n=14,18) | 0.59 g/ml | Standard Deviation 0.09 |
| Toprol XL | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Month 21 (n=5,0) | NA g/ml | — |
Comparison: The differences in the rate of progression of the outcome measures were the focus of the comparisons over time between the treatment groups. A significant interaction effect between time and treatment group in the mixed model is the measure of treatment effect. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes and the number of Participants for each interval is indicated as (n=x,y)p-value: 0.1967Mixed Models Analysis
Primary
Left Ventricular End-Diastolic Radius to Wall Thickness
Left Ventricular End-Diastolic Radius to Wall Thickness As an indicator of heart muscle mass and heart volume chamber diameter, the end-diastolic radius indexed to end diastolic wall thickness determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a two-dimensional analysis. The values that are too high or too low indicate a diseased myocardium.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 3 (n=1,0) | 5.02 unitless | — |
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 15 (n=3,2) | 4.61 unitless | Standard Deviation 1.69 |
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 9 (n=1,1) | 4.15 unitless | — |
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 18 (n=14,18) | 4.43 unitless | Standard Deviation 0.69 |
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 0 (n=19,19) | 4.76 unitless | Standard Deviation 0.92 |
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 21 (n=5,0) | 4.72 unitless | Standard Deviation 0.91 |
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 12 (n=14,15) | 4.46 unitless | Standard Deviation 0.64 |
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 24 (n=16,18) | 4.52 unitless | Standard Deviation 0.78 |
| Placebo | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 6 (n=17,19) | 4.51 unitless | Standard Deviation 0.62 |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 24 (n=16,18) | 4.59 unitless | Standard Deviation 0.97 |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 0 (n=19,19) | 4.69 unitless | Standard Deviation 0.92 |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 3 (n=1,0) | NA unitless | — |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 6 (n=17,19) | 4.85 unitless | Standard Deviation 0.92 |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 9 (n=1,1) | 5.74 unitless | — |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 12 (n=14,15) | 4.79 unitless | Standard Deviation 0.95 |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 15 (n=3,2) | 5.02 unitless | Standard Deviation 0.48 |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 18 (n=14,18) | 4.77 unitless | Standard Deviation 0.83 |
| Toprol XL | Left Ventricular End-Diastolic Radius to Wall Thickness | Month 21 (n=5,0) | NA unitless | — |
Comparison: The differences in the rate of progression of the outcome measures were the focus of the comparisons over time between the treatment groups. A significant interaction effect between time and treatment group in the mixed model is the measure of treatment effect. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes and the number of Participants for each interval is indicated as (n=x,y)p-value: 0.55Mixed Models Analysis
Primary
Left Ventricular End Diastolic Volume Indexed to Body Surface Area
Left Ventricular End Diastolic Volume Indexed to Body Surface Area: As an indicator of heart size, the blood volume of the heart is related to the body size. The end diastolic volume is the blood volume of the heart at the end of filling, just before contraction. The relation of heart blood volume to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 3 (n=1,0) | 90.93 ml/m^2 | — |
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 15 (n=3,2) | 82.73 ml/m^2 | Standard Deviation 14.18 |
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 9 (n=1,0) | 70.56 ml/m^2 | — |
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 18 (n=14,18) | 90.16 ml/m^2 | Standard Deviation 21.49 |
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 6 (n=17,19) | 90.84 ml/m^2 | Standard Deviation 16.39 |
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 21 (n=5,0) | 85.75 ml/m^2 | Standard Deviation 15.24 |
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 12 (n=14,15) | 88.99 ml/m^2 | Standard Deviation 16.63 |
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 24 (n=16,18) | 87.31 ml/m^2 | Standard Deviation 20.91 |
| Placebo | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 0 (n=19,19) | 91.66 ml/m^2 | Standard Deviation 16.48 |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 24 (n=16,18) | 95.16 ml/m^2 | Standard Deviation 23.94 |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 0 (n=19,19) | 95.74 ml/m^2 | Standard Deviation 19.89 |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 3 (n=1,0) | NA ml/m^2 | — |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 6 (n=17,19) | 95.24 ml/m^2 | Standard Deviation 18.52 |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 9 (n=1,0) | NA ml/m^2 | — |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 12 (n=14,15) | 95.71 ml/m^2 | Standard Deviation 20.59 |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 15 (n=3,2) | 98.16 ml/m^2 | Standard Deviation 2.89 |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 18 (n=14,18) | 97.6 ml/m^2 | Standard Deviation 19.82 |
| Toprol XL | Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Month 21 (n=5,0) | NA ml/m^2 | — |
Comparison: The differences in the rate of progression of the outcome measures were the focus of the comparisons over time between the treatment groups. A significant interaction effect between time and treatment group in the mixed model is the measure of treatment effect. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes and the number of Participants for each interval is indicated as (n=x,y)p-value: 0.4568Mixed Models Analysis
Primary
Left Ventricular End Systolic Volume Indexed to Body Surface Area
Left Ventricular End Systolic Volume Indexed to Body Surface Area As an indicator of heart size, the blood volume of the heart is related to the body size. The end systolic volume is the blood volume of the heart at the end of contraction and is an index of the pump function of the heart. This relation to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 3 (n=1,0) | 32.83 ml/m^2 | — |
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 15 (n=3,2) | 47.25 ml/m^2 | Standard Deviation 21.32 |
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 9 (n=1,0) | 40.99 ml/m^2 | — |
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 18 (n=14,18) | 34.99 ml/m^2 | Standard Deviation 10.08 |
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 6 (n=17,19) | 32.53 ml/m^2 | Standard Deviation 6.15 |
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 21 (n=5,0) | 39.97 ml/m^2 | Standard Deviation 13.22 |
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 12 (n=14,15) | 33.70 ml/m^2 | Standard Deviation 7.62 |
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 24 (n=16,18) | 34.47 ml/m^2 | Standard Deviation 8.72 |
| Placebo | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 0 (n=19,19) | 34.01 ml/m^2 | Standard Deviation 6.86 |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 24 (n=16,18) | 35.13 ml/m^2 | Standard Deviation 10.47 |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 0 (n=19,19) | 35.98 ml/m^2 | Standard Deviation 8.12 |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 3 (n=1,0) | NA ml/m^2 | — |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 6 (n=17,19) | 36.53 ml/m^2 | Standard Deviation 6.76 |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 9 (n=1,0) | NA ml/m^2 | — |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 12 (n=14,15) | 35.89 ml/m^2 | Standard Deviation 10.52 |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 15 (n=3,2) | 30.97 ml/m^2 | Standard Deviation 2.9 |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 18 (n=14,18) | 36.72 ml/m^2 | Standard Deviation 8.04 |
| Toprol XL | Left Ventricular End Systolic Volume Indexed to Body Surface Area | Month 21 (n=5,0) | NA ml/m^2 | — |
Comparison: The differences in the rate of progression of the outcome measures were the focus of the comparisons over time between the treatment groups. A significant interaction effect between time and treatment group in the mixed model is the measure of treatment effect. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes and the number of Participants for each interval is indicated as (n=x,y)p-value: 0.21Mixed Models Analysis
Primary
Peak Early Filling Rate: Rate of Change Over Time
Peak Early Filling Rate The peak early filling rate of change is calculated from the slope of the volume during the early filling of the heart with respect to time. The higher values indicate a very healthy heart muscle and lower values are indicative of a very stiff muscle.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 3 (n=1,0) | 2.58 EDV/sec | — |
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 9 (n=1,0) | 1.56 EDV/sec | — |
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 0 (n=19,19) | 2.27 EDV/sec | Standard Deviation 0.61 |
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 12 (n=14,15) | 2.26 EDV/sec | Standard Deviation 0.52 |
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 6 (n=17,19) | 2.38 EDV/sec | Standard Deviation 0.53 |
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 15 (n=3,2) | 1.83 EDV/sec | Standard Deviation 1.56 |
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 21 (n=5,0) | 1.73 EDV/sec | Standard Deviation 0.99 |
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 24 (n=16,18) | 2.17 EDV/sec | Standard Deviation 0.6 |
| Placebo | Peak Early Filling Rate: Rate of Change Over Time | Month 18 (n=14,18) | 1.95 EDV/sec | Standard Deviation 0.63 |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 24 (n=16,18) | 2.25 EDV/sec | Standard Deviation 0.63 |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 15 (n=3,2) | 2.28 EDV/sec | Standard Deviation 0.47 |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 0 (n=19,19) | 2.12 EDV/sec | Standard Deviation 0.57 |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 3 (n=1,0) | NA EDV/sec | — |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 6 (n=17,19) | 2.08 EDV/sec | Standard Deviation 0.55 |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 18 (n=14,18) | 2.26 EDV/sec | Standard Deviation 0.56 |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 9 (n=1,0) | NA EDV/sec | — |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 12 (n=14,15) | 2.24 EDV/sec | Standard Deviation 0.46 |
| Toprol XL | Peak Early Filling Rate: Rate of Change Over Time | Month 21 (n=5,0) | NA EDV/sec | — |
Comparison: The differences in the rate of progression of the outcome measures were the focus of the comparisons over time between the treatment groups. A significant interaction effect between time and treatment group in the mixed model is the measure of treatment effect. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes and the number of Participants for each interval is indicated as (n=x,y)p-value: 0.001Mixed Models Analysis
Primary
Systolic Longitudinal Strain
Systolic Longitudinal Strain. By identifying two points on the heart, the strain is the difference between the distance between these two points at the end of filling of the heart and the end of contraction divided by the length at the end of filling. Thus, the measure is like the ejection fraction, however the strain is more localized to a specified segment in the heart muscle. The higher values indicate a healthy heart.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Systolic Longitudinal Strain | Month 3 (n=1,0) | 115.07 percent/%Systolic interval | — |
| Placebo | Systolic Longitudinal Strain | Month 15 (n=3,2) | 52.95 percent/%Systolic interval | Standard Deviation 20.87 |
| Placebo | Systolic Longitudinal Strain | Month 9 (n=1,0) | 37.2 percent/%Systolic interval | — |
| Placebo | Systolic Longitudinal Strain | Month 18 (n=14,18) | 88.11 percent/%Systolic interval | Standard Deviation 34.96 |
| Placebo | Systolic Longitudinal Strain | Month 6 (n=17,19) | 45.90 percent/%Systolic interval | Standard Deviation 34.56 |
| Placebo | Systolic Longitudinal Strain | Month 21 (n=5,0) | 67.53 percent/%Systolic interval | Standard Deviation 26.81 |
| Placebo | Systolic Longitudinal Strain | Month 12 (n=14,15) | 87.85 percent/%Systolic interval | Standard Deviation 26.07 |
| Placebo | Systolic Longitudinal Strain | Month 24 (n=16,18) | 79.94 percent/%Systolic interval | Standard Deviation 24.24 |
| Placebo | Systolic Longitudinal Strain | Month 0 (n=19,19) | 87.94 percent/%Systolic interval | Standard Deviation 27.44 |
| Toprol XL | Systolic Longitudinal Strain | Month 24 (n=16,18) | 85.18 percent/%Systolic interval | Standard Deviation 32.2 |
| Toprol XL | Systolic Longitudinal Strain | Month 0 (n=19,19) | 82.55 percent/%Systolic interval | Standard Deviation 29.31 |
| Toprol XL | Systolic Longitudinal Strain | Month 3 (n=1,0) | NA percent/%Systolic interval | — |
| Toprol XL | Systolic Longitudinal Strain | Month 6 (n=17,19) | 78.68 percent/%Systolic interval | Standard Deviation 22.97 |
| Toprol XL | Systolic Longitudinal Strain | Month 9 (n=1,0) | NA percent/%Systolic interval | — |
| Toprol XL | Systolic Longitudinal Strain | Month 12 (n=14,15) | 80.04 percent/%Systolic interval | Standard Deviation 20.58 |
| Toprol XL | Systolic Longitudinal Strain | Month 15 (n=3,2) | 88.34 percent/%Systolic interval | Standard Deviation 6.7 |
| Toprol XL | Systolic Longitudinal Strain | Month 18 (n=14,18) | 79.29 percent/%Systolic interval | Standard Deviation 22.14 |
| Toprol XL | Systolic Longitudinal Strain | Month 21 (n=5,0) | NA percent/%Systolic interval | — |
Comparison: The differences in the rate of progression of the outcome measures were the focus of the comparisons over time between the treatment groups. A significant interaction effect between time and treatment group in the mixed model is the measure of treatment effect. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes and the number of Participants for each interval is indicated as (n=x,y)p-value: 0.16Mixed Models Analysis