Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm
Conditions
Brief summary
This phase IIb trial studies how well low-dose carvedilol works in preventing heart failure in cancer survivors exposed to high dose anthracyclines for management of childhood cancer. Patients who received high-dose anthracycline chemotherapy are at a much greater risk for developing heart failure compared to survivors who didn't get any anthracycline chemotherapy. Heart failure happens when the heart muscle has been weakened and can't pump blood as well as it should. Carvedilol may help lower the risk of cardiovascular complications.
Detailed description
PRIMARY OBJECTIVE: I. To determine the impact of a two-year course of low-dose carvedilol on surrogate echocardiographic indices of heart failure (HF) risk, including: Left ventricular (LV) posterior wall thickness-dimension ratio (LV T-D); LV systolic and diastolic function, and afterload; Natriuretic peptides, troponins, and galectin-3. SECONDARY OBJECTIVES: I. To establish safety and tolerability of this two-year course of low-dose carvedilol, assessing both objective measures (hepatic function) and patient reported outcomes. II. To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year carvedilol intervention. EXPLORATORY OBJECTIVE: I. To evaluate the long-term efficacy of carvedilol in preventing cardiomyopathy and/or heart failure in high-risk childhood cancer survivors. OUTLINE: This is a dose-escalation study. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive low-dose carvedilol orally (PO) once daily (QD) or twice daily (BID) for 24 months. ARM II: Patients receive placebo PO QD or BID for 24 months. After completion of study treatment, patients are followed up for 3 years.
Interventions
DRUGCarvedilol
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
Correlative studies
OTHERPharmacological Study
Correlative studies
OTHERPlacebo Administration
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Males and females must weigh \>= 40 Kg * Patient must have had a cancer diagnosis \< 22 years of age, irrespective of current age * Patient must have a lifetime cumulative anthracycline dose of \>= 250 mg/m\^2 DOXOrubicin equivalent without the protection of dexrazoxane (Zinecard) therapy; the anthracycline dose threshold must be met as part of the treatment of a cancer that was diagnosed at \< 22 years of age * Note: Institutional records (e.g., clinic note, treatment summary, chemotherapy roadmap) can be used to document lifetime receipt of anthracycline dose * Patient must have completed cancer treatment \>= 2 years prior to study enrollment
Exclusion criteria
* Receiving treatment for cardiomyopathy or heart failure * Ejection fraction of \< 50% (by radionuclide angiogram or echocardiogram) or shortening fraction of \< 25% (by echocardiogram) * Note: for instances where both are reported, and one is below the threshold, the site will have the option to re-measure it centrally at the core lab * Uncorrected primary obstructive or severe regurgitative valvular disease: * Nondilated (restrictive); or * Hypertrophic cardiomyopathy; or * Significant systemic ventricular outflow obstruction * Sustained or symptomatic ventricular dysrhythmias uncontrolled with drug therapy or implantable device * Significant conduction defects (i.e. second or third degree atrio-ventricular block or sick sinus syndrome) * Bradycardia: heart rate \< 50 beats per minute (BPM) * Use of an investigational drug or beta adrenergic blockers, including metoprolol, sotalol, within 30 days of enrollment * History of drug sensitivity or allergic reaction to alpha or beta-blockers * Low resting systolic blood pressure: \< 90 mmHg * Use of any other blood pressure lowering medication for treatment of hypertension within 30 days of enrollment except calcium channel blockers and diuretics * History or current clinical evidence of moderate-to-severe obstructive pulmonary disease or reactive airway diseases (i.e. asthma) requiring therapy * Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 3 times upper limit of institutional normal * Gastrointestinal, or biliary disorders that could impair absorption, metabolism, or excretion of orally administered medications * Endocrine disorders (such as primary aldosteronism, pheochromocytoma, hyper- or hypothyroidism) not controlled with medication * Uncontrolled diabetes (controlled diabetes per the American Diabetes Association and International Diabetes Center's Glycemic Target Goals is hemoglobin A1C \< 7%) * Anemia (hematocrit \< 28%) * Currently using select CYP2D6 inhibitor or inducer medications * Inability to swallow pills * Female patients who are pregnant are not eligible; women of childbearing potential require a negative pregnancy test prior to starting study drug * Lactating females are not eligible unless they have agreed to not breastfeed their infants * Sexually active female patients of reproductive potential are not eligible unless they agree to use an effective contraceptive method during study and for 2 months after stopping the study drug; abstinence is an acceptable method of birth control * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | Z-score of the ratio of left ventricular (LV) posterior wall dimension of systole to internal LV dimension in diastole, calculated for each subject by subtracting the reference healthy population mean, then dividing by the standard deviation. The Z-score indicates the number of standard deviations away from the mean of the reference population. Negative Z- score indicates worse outcome. The mean is reported by arm at each timepoint with corresponding standard errors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Left Ventricular End-systolic Dimension | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | Thickness of cardiac muscle (in cm) of the left ventricle at the end of systole. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Left Ventricular End-systolic Volume | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | The amount of blood (in ml) in the heart's left ventricle just after the heart contracts. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Left Ventricular End-diastolic Dimension | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | Thickness of cardiac muscle (in cm) of the left ventricle at the end of diastole. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Left Ventricular End-diastolic Volume | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | The amount of blood (in ml) in the heart's left ventricle just before the heart contracts. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Left Ventricular Mass | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | The weight of the left ventricle adjusted for body surface area (in g/m2). The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Fractional Shortening | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | A measure to assess preload and afterload (in %). The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Ejection Fraction | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | The percentage of blood leaving the heart at the end of diastole. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Peak Early Atrial Divided by Peak Late Atrial Velocities | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | Ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E wave) to peak velocity flow in late diastole caused by atrial contraction (A wave). Number shown for Unit of Measure refers to this ratio. Normal: \>1. Impaired: \<1. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average N-terminal Pro B-type Natriuretic Peptide | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | B-type natriuretic peptide- a biomarker for heart failure (in pg/ml). The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Left Ventricular End-systolic Wall Stress | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | Echocardiographic measure of left ventricular (LV) afterload based on LV pressure (P), volume (V), and wall thickness (T), calculated by the formula (P x V)/T, which equals the number referred to below in the Measure Type. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Cardiac Troponin I | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | Troponin I is a biomarker for myocardial cell injury (in ng/ml). The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Galectin-3 | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | A protein produced by activated macrophages, and a member of a family of β-galactoside-binding lectings and promotes cardiac fibroblast proliferation and collagen synthesis following myocadial injury (in ng/ml). The mean is reported by arm at each timepoint with corresponding standard errors. |
| Proportion of Patients With Reportable Adverse Events as Described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). | From baseline to month 24 since baseline | Patients with toxicities reported via CTEP-AERS and all Grade ≥ 2 adverse events (AEs) that can be attributed probably or definitely to the study drug are considered to have AEs. The proportion of patients with AEs are reported by arm with corresponding 95% confidence intervals. |
| Average Bilirubin | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | A liver function measurement (in mg/dL). The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Aspartate Aminotransferase | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | A liver function measurement (in U/L). Normal range is 14-20 for men, 10-36 for women. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Average Alanine Aminotransferase | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | A liver function measurement (in U/L). Normal range is 8-48 IU/L. The mean is reported by arm at each timepoint with corresponding standard errors. |
| Proportion of Participants With Average Adherence > 90% | Average adherence across 6 months, 12 months, 18 months, 24 months after treatment initiation are calculated. | The number of pills taken out of the total prescribed in a 3-month period, averaged across all study time points. The proportion of participants with average adherence rate \>90% is computed by arm and corresponding 95% confidence intervals are reported. |
| Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Responses at days 14 to 730 were combined | In a questionnaire, patients responded Yes/No to certain symptoms. If answered Yes, they selected slightly, moderately, quite a bit, or extremely regarding how bothersome the symptom was. The proportion of participants responding with any of these three categories was calculated by arm, and corresponding 95% confidence intervals are reported. |
| Average Cardiac N-terminal Pro B-type Natriuretic Peptide | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | N-terminal pro b-type natriuretic peptide- a biomarker for heart failure (in pg/ml). The mean is reported by arm at each timepoint with corresponding standard errors. |
Countries
Australia, Canada, New Zealand, United States
Participant flow
Pre-assignment details
196 pts were enrolled (109 pts enrolled with Childrens Oncology Group (COG) and 87 pts enrolled on a pilot study at City of Hope (COH) 182 of those pts started tx (14 excluded: 6 ineligible and 8 pts started tx). (The (109) enrollment number in the protocol section reflects the number of pts enrolled on the COG portion of the study. Per Section 9.2 of the protocol (pt accrual and expected duration of the trial), 87 pts had already been accrued through a different mechanism the pilot study)
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Carvedilol) Patients receive low-dose carvedilol orally (PO) once daily (QD) or twice daily (BID) for 24 months. | 89 |
| Arm II (Placebo) Patients receive placebo PO QD or BID for 24 months. | 93 |
| Total | 182 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Cardiac Event | 2 | 6 |
| Overall Study | Lost to Follow-up | 5 | 8 |
| Overall Study | Pregnancy | 1 | 1 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Relapse | 1 | 1 |
| Overall Study | Withdrawal by Subject | 20 | 20 |
Baseline characteristics
| Characteristic | Arm I (Carvedilol) | Arm II (Placebo) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 15 Participants | 16 Participants | 31 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 74 Participants | 77 Participants | 151 Participants |
| Age, Continuous | 26.9 years STANDARD_DEVIATION 10.3 | 27.7 years STANDARD_DEVIATION 10.1 | 27.3 years STANDARD_DEVIATION 10.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 22 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants | 69 Participants | 134 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 77 Participants | 82 Participants | 159 Participants |
| Region of Enrollment United States | 89 participants | 93 participants | 182 participants |
| Sex: Female, Male Female | 43 Participants | 48 Participants | 91 Participants |
| Sex: Female, Male Male | 46 Participants | 45 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 89 | 0 / 93 |
| other Total, other adverse events | 2 / 89 | 0 / 93 |
| serious Total, serious adverse events | 0 / 89 | 0 / 93 |
Outcome results
Primary
Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz)
Z-score of the ratio of left ventricular (LV) posterior wall dimension of systole to internal LV dimension in diastole, calculated for each subject by subtracting the reference healthy population mean, then dividing by the standard deviation. The Z-score indicates the number of standard deviations away from the mean of the reference population. Negative Z- score indicates worse outcome. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | 6m | -0.2167 z-score | Standard Error 0.167 |
| Arm I (Carvedilol) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | 18m | -0.2375 z-score | Standard Error 0.21 |
| Arm I (Carvedilol) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | 12m | -0.2416 z-score | Standard Error 0.1721 |
| Arm I (Carvedilol) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | 24m | 0.0213 z-score | Standard Error 0.2353 |
| Arm I (Carvedilol) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | BL | -0.1372 z-score | Standard Error 0.1711 |
| Arm II (Placebo) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | 24m | -0.1834 z-score | Standard Error 0.2145 |
| Arm II (Placebo) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | BL | -0.0893 z-score | Standard Error 0.1917 |
| Arm II (Placebo) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | 6m | 0.3215 z-score | Standard Error 0.154 |
| Arm II (Placebo) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | 12m | -0.2367 z-score | Standard Error 0.1822 |
| Arm II (Placebo) | Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | 18m | -0.1974 z-score | Standard Error 0.1976 |
Comparison: The null hypothesis is that change in LVWT/Dz across time do not vary by arm. Assuming a type I error=0.05, 2-sided test, 15% attrition/year, and correlation range of 0.6-0.8 between measurements, we projected that a sample size of 125/arm would provide 80% power to detect an effect size of 0.23-0.32 for LVWT/Dz at 24m.p-value: 0.1595% CI: [-0.057, 0.383]Generalized Estimating Equation (GEE)
Secondary
Average Alanine Aminotransferase
A liver function measurement (in U/L). Normal range is 8-48 IU/L. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Alanine Aminotransferase | 24m | 29.86 IU/L | Standard Error 3.064 |
| Arm I (Carvedilol) | Average Alanine Aminotransferase | BL | 29.122 IU/L | Standard Error 2.31 |
| Arm I (Carvedilol) | Average Alanine Aminotransferase | 6m | 28.014 IU/L | Standard Error 2.533 |
| Arm I (Carvedilol) | Average Alanine Aminotransferase | 12m | 30.148 IU/L | Standard Error 2.985 |
| Arm I (Carvedilol) | Average Alanine Aminotransferase | 18m | 27.196 IU/L | Standard Error 2.645 |
| Arm II (Placebo) | Average Alanine Aminotransferase | 18m | 30.536 IU/L | Standard Error 3.567 |
| Arm II (Placebo) | Average Alanine Aminotransferase | 12m | 31.155 IU/L | Standard Error 2.742 |
| Arm II (Placebo) | Average Alanine Aminotransferase | BL | 30.467 IU/L | Standard Error 1.948 |
| Arm II (Placebo) | Average Alanine Aminotransferase | 24m | 29.245 IU/L | Standard Error 2.626 |
| Arm II (Placebo) | Average Alanine Aminotransferase | 6m | 32.158 IU/L | Standard Error 2.516 |
Comparison: The null hypothesis is that change in Average Alanine aminotransferase across time-points described above does not differ by treatment arm, tested using a longitudinal GEE analysis of Average Alanine aminotransferase with a treatment by time interaction.p-value: 0.7295% CI: [-5.595, 8.091]Generalized Estimating Equation (GEE)
Secondary
Average Aspartate Aminotransferase
A liver function measurement (in U/L). Normal range is 14-20 for men, 10-36 for women. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Aspartate Aminotransferase | 6m | 24.068 IU/L | Standard Error 1.293 |
| Arm I (Carvedilol) | Average Aspartate Aminotransferase | 18m | 24.375 IU/L | Standard Error 1.637 |
| Arm I (Carvedilol) | Average Aspartate Aminotransferase | 12m | 25.426 IU/L | Standard Error 1.423 |
| Arm I (Carvedilol) | Average Aspartate Aminotransferase | 24m | 24.561 IU/L | Standard Error 1.488 |
| Arm I (Carvedilol) | Average Aspartate Aminotransferase | BL | 26.608 IU/L | Standard Error 1.726 |
| Arm II (Placebo) | Average Aspartate Aminotransferase | 24m | 27.038 IU/L | Standard Error 1.509 |
| Arm II (Placebo) | Average Aspartate Aminotransferase | BL | 25.773 IU/L | Standard Error 1.089 |
| Arm II (Placebo) | Average Aspartate Aminotransferase | 6m | 26.342 IU/L | Standard Error 1.252 |
| Arm II (Placebo) | Average Aspartate Aminotransferase | 12m | 27.014 IU/L | Standard Error 1.432 |
| Arm II (Placebo) | Average Aspartate Aminotransferase | 18m | 28.411 IU/L | Standard Error 2.665 |
p-value: 0.9795% CI: [-4.877, 4.685]Generalized Estimating Equation (GEE)
Secondary
Average Bilirubin
A liver function measurement (in mg/dL). The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Bilirubin | 6m | 0.5973 mg/dL | Standard Error 0.0453 |
| Arm I (Carvedilol) | Average Bilirubin | 18m | 0.593 mg/dL | Standard Error 0.0665 |
| Arm I (Carvedilol) | Average Bilirubin | 12m | 0.563 mg/dL | Standard Error 0.0487 |
| Arm I (Carvedilol) | Average Bilirubin | 24m | 0.5561 mg/dL | Standard Error 0.0436 |
| Arm I (Carvedilol) | Average Bilirubin | BL | 0.5634 mg/dL | Standard Error 0.0428 |
| Arm II (Placebo) | Average Bilirubin | 24m | 0.5449 mg/dL | Standard Error 0.0354 |
| Arm II (Placebo) | Average Bilirubin | BL | 0.4989 mg/dL | Standard Error 0.0272 |
| Arm II (Placebo) | Average Bilirubin | 6m | 0.4942 mg/dL | Standard Error 0.0262 |
| Arm II (Placebo) | Average Bilirubin | 12m | 0.4969 mg/dL | Standard Error 0.0302 |
| Arm II (Placebo) | Average Bilirubin | 18m | 0.507 mg/dL | Standard Error 0.04 |
p-value: 0.8295% CI: [-0.18, 0.229]Generalized Estimating Equation (GEE)
Secondary
Average Cardiac N-terminal Pro B-type Natriuretic Peptide
N-terminal pro b-type natriuretic peptide- a biomarker for heart failure (in pg/ml). The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | 6m | 90.7536 pg/mL | Standard Error 11.7877 |
| Arm I (Carvedilol) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | 18m | 99.4912 pg/mL | Standard Error 15.7275 |
| Arm I (Carvedilol) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | 12m | 87.7167 pg/mL | Standard Error 13.38 |
| Arm I (Carvedilol) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | 24m | 101.8333 pg/mL | Standard Error 14.2521 |
| Arm I (Carvedilol) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | BL | 85.6301 pg/mL | Standard Error 13.3731 |
| Arm II (Placebo) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | 24m | 107.8490 pg/mL | Standard Error 26.6515 |
| Arm II (Placebo) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | BL | 115.7222 pg/mL | Standard Error 22.243 |
| Arm II (Placebo) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | 6m | 128.9565 pg/mL | Standard Error 23.736 |
| Arm II (Placebo) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | 12m | 115.6364 pg/mL | Standard Error 26.823 |
| Arm II (Placebo) | Average Cardiac N-terminal Pro B-type Natriuretic Peptide | 18m | 93.2105 pg/mL | Standard Error 18.5618 |
p-value: 0.5595% CI: [-11.608, 21.835]Generalized Estimating Equation (GEE)
Secondary
Average Cardiac Troponin I
Troponin I is a biomarker for myocardial cell injury (in ng/ml). The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Cardiac Troponin I | 6m | 0.00265 ng/mL | Standard Error 0.001 |
| Arm I (Carvedilol) | Average Cardiac Troponin I | 18m | 0.00737 ng/mL | Standard Error 0.0017 |
| Arm I (Carvedilol) | Average Cardiac Troponin I | BL | 0.00446 ng/mL | Standard Error 0.0024 |
| Arm I (Carvedilol) | Average Cardiac Troponin I | 24m | 0.01111 ng/mL | Standard Error 0.002 |
| Arm I (Carvedilol) | Average Cardiac Troponin I | 12m | 0.00467 ng/mL | Standard Error 0.0014 |
| Arm II (Placebo) | Average Cardiac Troponin I | 24m | 0.01132 ng/mL | Standard Error 0.002 |
| Arm II (Placebo) | Average Cardiac Troponin I | 12m | 0.00742 ng/mL | Standard Error 0.0034 |
| Arm II (Placebo) | Average Cardiac Troponin I | BL | 0.0011 ng/mL | Standard Error 0.0008 |
| Arm II (Placebo) | Average Cardiac Troponin I | 18m | 0.00684 ng/mL | Standard Error 0.0017 |
| Arm II (Placebo) | Average Cardiac Troponin I | 6m | 0.00174 ng/mL | Standard Error 0.0009 |
p-value: 0.5195% CI: [-0.004, 0.002]Generalized Estimating Equation (GEE)
Secondary
Average Ejection Fraction
The percentage of blood leaving the heart at the end of diastole. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Ejection Fraction | 6m | 58.16 Percent | Standard Error 0.59 |
| Arm I (Carvedilol) | Average Ejection Fraction | 18m | 57.35 Percent | Standard Error 0.69 |
| Arm I (Carvedilol) | Average Ejection Fraction | 12m | 58.07 Percent | Standard Error 0.62 |
| Arm I (Carvedilol) | Average Ejection Fraction | 24 | 58.16 Percent | Standard Error 0.79 |
| Arm I (Carvedilol) | Average Ejection Fraction | BL | 57.6 Percent | Standard Error 0.69 |
| Arm II (Placebo) | Average Ejection Fraction | 24 | 57.5 Percent | Standard Error 0.62 |
| Arm II (Placebo) | Average Ejection Fraction | BL | 57.42 Percent | Standard Error 0.58 |
| Arm II (Placebo) | Average Ejection Fraction | 6m | 56.84 Percent | Standard Error 0.6 |
| Arm II (Placebo) | Average Ejection Fraction | 12m | 56.61 Percent | Standard Error 0.7 |
| Arm II (Placebo) | Average Ejection Fraction | 18m | 57.6 Percent | Standard Error 0.71 |
Comparison: The null hypothesis is that change in LVEF across time do not vary by arm. Assuming a type I error=0.05, 2-sided test, 15% attrition/year, and correlation range of 1.2-1.6 between measurements, we projected that a sample size of 125/arm would provide 80% power to detect an effect size of 0.23-0.32 for LVEF at 24m.p-value: 0.4995% CI: [-0.472, 0.991]Generalized Estimating Equation (GEE)
Secondary
Average Fractional Shortening
A measure to assess preload and afterload (in %). The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Fractional Shortening | 12m | 29.6121 percent | Standard Error 0.483 |
| Arm I (Carvedilol) | Average Fractional Shortening | 18m | 27.8219 percent | Standard Error 0.4951 |
| Arm I (Carvedilol) | Average Fractional Shortening | 6m | 28.5409 percent | Standard Error 0.4738 |
| Arm I (Carvedilol) | Average Fractional Shortening | 24 | 28.0302 percent | Standard Error 0.5073 |
| Arm I (Carvedilol) | Average Fractional Shortening | BL | 28.5362 percent | Standard Error 0.4549 |
| Arm II (Placebo) | Average Fractional Shortening | 24 | 28.5953 percent | Standard Error 0.5901 |
| Arm II (Placebo) | Average Fractional Shortening | BL | 28.4339 percent | Standard Error 0.4764 |
| Arm II (Placebo) | Average Fractional Shortening | 6m | 27.6866 percent | Standard Error 0.5799 |
| Arm II (Placebo) | Average Fractional Shortening | 18m | 27.8891 percent | Standard Error 0.596 |
| Arm II (Placebo) | Average Fractional Shortening | 12m | 28.1085 percent | Standard Error 0.4918 |
p-value: 0.8495% CI: [-0.652, 0.532]Generalized Estimating Equation (GEE)
Secondary
Average Galectin-3
A protein produced by activated macrophages, and a member of a family of β-galactoside-binding lectings and promotes cardiac fibroblast proliferation and collagen synthesis following myocadial injury (in ng/ml). The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Galectin-3 | 6m | 4.3252 ng/mL | Standard Error 0.2519 |
| Arm I (Carvedilol) | Average Galectin-3 | 18m | 3.4548 ng/mL | Standard Error 0.2482 |
| Arm I (Carvedilol) | Average Galectin-3 | 12m | 3.7345 ng/mL | Standard Error 0.234 |
| Arm I (Carvedilol) | Average Galectin-3 | 24m | 3.8073 ng/mL | Standard Error 0.3099 |
| Arm I (Carvedilol) | Average Galectin-3 | BL | 4.4464 ng/mL | Standard Error 0.2625 |
| Arm II (Placebo) | Average Galectin-3 | 24m | 4.0791 ng/mL | Standard Error 0.2853 |
| Arm II (Placebo) | Average Galectin-3 | BL | 5.2538 ng/mL | Standard Error 0.6531 |
| Arm II (Placebo) | Average Galectin-3 | 6m | 4.3735 ng/mL | Standard Error 0.2746 |
| Arm II (Placebo) | Average Galectin-3 | 12m | 4.3415 ng/mL | Standard Error 0.327 |
| Arm II (Placebo) | Average Galectin-3 | 18m | 4.0214 ng/mL | Standard Error 0.2506 |
p-value: 0.9295% CI: [-0.468, 0.424]Generalized Estimating Equation (GEE)
Secondary
Average Left Ventricular End-diastolic Dimension
Thickness of cardiac muscle (in cm) of the left ventricle at the end of diastole. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Dimension | 6m | 4.6035 cm | Standard Error 0.0431 |
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Dimension | 18m | 4.6032 cm | Standard Error 0.0568 |
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Dimension | 12m | 4.636 cm | Standard Error 0.0556 |
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Dimension | 24 | 4.5147 cm | Standard Error 0.0614 |
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Dimension | BL | 4.5836 cm | Standard Error 0.0501 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Dimension | 24 | 4.5976 cm | Standard Error 0.067 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Dimension | BL | 4.5269 cm | Standard Error 0.0565 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Dimension | 6m | 4.565 cm | Standard Error 0.0463 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Dimension | 12m | 4.5884 cm | Standard Error 0.0768 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Dimension | 18m | 4.5462 cm | Standard Error 0.0663 |
p-value: 0.0195% CI: [-141, -0.024]Generalized Estimating Equation (GEE)
Secondary
Average Left Ventricular End-diastolic Volume
The amount of blood (in ml) in the heart's left ventricle just before the heart contracts. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Volume | 6m | 99.3216 ml | Standard Error 2.9788 |
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Volume | 18m | 101.174 ml | Standard Error 3.5977 |
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Volume | 12m | 102.378 ml | Standard Error 2.975 |
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Volume | 24m | 100.659 ml | Standard Error 4.0356 |
| Arm I (Carvedilol) | Average Left Ventricular End-diastolic Volume | BL | 99.7507 ml | Standard Error 3.0157 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Volume | 24m | 98.9602 ml | Standard Error 4.6469 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Volume | BL | 93.3155 ml | Standard Error 3.0337 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Volume | 6m | 95.7434 ml | Standard Error 3.2631 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Volume | 12m | 96.5002 ml | Standard Error 3.3889 |
| Arm II (Placebo) | Average Left Ventricular End-diastolic Volume | 18m | 99.4656 ml | Standard Error 4.0815 |
p-value: 0.3695% CI: [-7.499, 2.704]Generalized Estimating Equation (GEE)
Secondary
Average Left Ventricular End-systolic Dimension
Thickness of cardiac muscle (in cm) of the left ventricle at the end of systole. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Dimension | 6m | 3.2901 centimeter | Standard Error 0.0382 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Dimension | 18m | 3.32 centimeter | Standard Error 0.0436 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Dimension | 12m | 3.262 centimeter | Standard Error 0.043 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Dimension | 24m | 3.2441 centimeter | Standard Error 0.0435 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Dimension | BL | 03.2765 centimeter | Standard Error 0.043 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Dimension | 24m | 3.286 centimeter | Standard Error 0.0607 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Dimension | BL | 3.2396 centimeter | Standard Error 0.0459 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Dimension | 6m | 3.3023 centimeter | Standard Error 0.0442 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Dimension | 12m | 3.2964 centimeter | Standard Error 0.0571 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Dimension | 18m | 3.2798 centimeter | Standard Error 0.0579 |
p-value: 0.0595% CI: [-0.09, 0.001]Generalized Estimating Equation (GEE)
Secondary
Average Left Ventricular End-systolic Volume
The amount of blood (in ml) in the heart's left ventricle just after the heart contracts. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Volume | 6m | 41.6128 ml | Standard Error 1.4041 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Volume | 18m | 43.1453 ml | Standard Error 1.605 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Volume | 12m | 42.8437 ml | Standard Error 1.3498 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Volume | 24m | 42.0086 ml | Standard Error 1.7268 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Volume | BL | 42.2193 ml | Standard Error 1.3907 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Volume | 24m | 42.442 ml | Standard Error 2.3661 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Volume | BL | 39.7354 ml | Standard Error 1.3633 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Volume | 6m | 41.3839 ml | Standard Error 1.5337 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Volume | 12m | 41.8113 ml | Standard Error 1.6275 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Volume | 18m | 42.5634 ml | Standard Error 2.1281 |
p-value: 0.1795% CI: [-5.34, 0.951]Generalized Estimating Equation (GEE)
Secondary
Average Left Ventricular End-systolic Wall Stress
Echocardiographic measure of left ventricular (LV) afterload based on LV pressure (P), volume (V), and wall thickness (T), calculated by the formula (P x V)/T, which equals the number referred to below in the Measure Type. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Wall Stress | 6m | 90.3088 g/cm^2 | Standard Error 2.0577 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Wall Stress | 18m | 93.9267 g/cm^2 | Standard Error 2.4333 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Wall Stress | 12m | 88.984 g/cm^2 | Standard Error 2.0069 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Wall Stress | 24m | 89.2513 g/cm^2 | Standard Error 2.4341 |
| Arm I (Carvedilol) | Average Left Ventricular End-systolic Wall Stress | BL | 93.2892 g/cm^2 | Standard Error 2.222 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Wall Stress | 24m | 94.0647 g/cm^2 | Standard Error 3.6562 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Wall Stress | BL | 90.6135 g/cm^2 | Standard Error 2.9775 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Wall Stress | 6m | 96.8356 g/cm^2 | Standard Error 2.9025 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Wall Stress | 12m | 96.0616 g/cm^2 | Standard Error 3.0406 |
| Arm II (Placebo) | Average Left Ventricular End-systolic Wall Stress | 18m | 91.6458 g/cm^2 | Standard Error 3.1257 |
p-value: 0.0395% CI: [-7.105, -0.424]Generalized Estimating Equation (GEE)
Secondary
Average Left Ventricular Mass
The weight of the left ventricle adjusted for body surface area (in g/m2). The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Left Ventricular Mass | 12m | 60.2116 g/m^2 | Standard Error 1.6786 |
| Arm I (Carvedilol) | Average Left Ventricular Mass | 6m | 58.2839 g/m^2 | Standard Error 1.3859 |
| Arm I (Carvedilol) | Average Left Ventricular Mass | 18m | 57.7053 g/m^2 | Standard Error 1.6667 |
| Arm I (Carvedilol) | Average Left Ventricular Mass | 24m | 58.3315 g/m^2 | Standard Error 1.6478 |
| Arm I (Carvedilol) | Average Left Ventricular Mass | BL | 57.4862 g/m^2 | Standard Error 1.2135 |
| Arm II (Placebo) | Average Left Ventricular Mass | 24m | 59.1026 g/m^2 | Standard Error 1.8092 |
| Arm II (Placebo) | Average Left Ventricular Mass | BL | 57.9322 g/m^2 | Standard Error 1.5767 |
| Arm II (Placebo) | Average Left Ventricular Mass | 6m | 57.0924 g/m^2 | Standard Error 1.29 |
| Arm II (Placebo) | Average Left Ventricular Mass | 12m | 59.4508 g/m^2 | Standard Error 1.4995 |
| Arm II (Placebo) | Average Left Ventricular Mass | 18m | 59.1793 g/m^2 | Standard Error 1.6168 |
p-value: 0.5995% CI: [-1.134, 1.999]Generalized Estimating Equation (GEE)
Secondary
Average N-terminal Pro B-type Natriuretic Peptide
B-type natriuretic peptide- a biomarker for heart failure (in pg/ml). The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average N-terminal Pro B-type Natriuretic Peptide | 6m | 31.8406 pg/mL | Standard Error 3.3339 |
| Arm I (Carvedilol) | Average N-terminal Pro B-type Natriuretic Peptide | 18m | 35.807 pg/mL | Standard Error 3.7939 |
| Arm I (Carvedilol) | Average N-terminal Pro B-type Natriuretic Peptide | 12m | 26.8203 pg/mL | Standard Error 3.4625 |
| Arm I (Carvedilol) | Average N-terminal Pro B-type Natriuretic Peptide | 24m | 34.625 pg/mL | Standard Error 3.0875 |
| Arm I (Carvedilol) | Average N-terminal Pro B-type Natriuretic Peptide | BL | 27.3836 pg/mL | Standard Error 2.0697 |
| Arm II (Placebo) | Average N-terminal Pro B-type Natriuretic Peptide | 24m | 33.3774 pg/mL | Standard Error 3.6481 |
| Arm II (Placebo) | Average N-terminal Pro B-type Natriuretic Peptide | BL | 31.4324 pg/mL | Standard Error 3.424 |
| Arm II (Placebo) | Average N-terminal Pro B-type Natriuretic Peptide | 6m | 34.1857 pg/mL | Standard Error 3.4737 |
| Arm II (Placebo) | Average N-terminal Pro B-type Natriuretic Peptide | 12m | 33.2941 pg/mL | Standard Error 4.095 |
| Arm II (Placebo) | Average N-terminal Pro B-type Natriuretic Peptide | 18m | 32.2807 pg/mL | Standard Error 4.0405 |
p-value: 0.2495% CI: [-1.387, 5.63]Generalized Estimating Equation (GEE)
Secondary
Average Peak Early Atrial Divided by Peak Late Atrial Velocities
Ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E wave) to peak velocity flow in late diastole caused by atrial contraction (A wave). Number shown for Unit of Measure refers to this ratio. Normal: \>1. Impaired: \<1. The mean is reported by arm at each timepoint with corresponding standard errors.
Time frame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Carvedilol) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | 6m | 1.642 ratio | Standard Error 0.048 |
| Arm I (Carvedilol) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | 18m | 1.732 ratio | Standard Error 0.063 |
| Arm I (Carvedilol) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | 12m | 1.723 ratio | Standard Error 0.065 |
| Arm I (Carvedilol) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | 24m | 1.603 ratio | Standard Error 0.063 |
| Arm I (Carvedilol) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | BL | 1.728 ratio | Standard Error 0.067 |
| Arm II (Placebo) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | 24m | 1.64 ratio | Standard Error 0.074 |
| Arm II (Placebo) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | BL | 1.732 ratio | Standard Error 0.071 |
| Arm II (Placebo) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | 6m | 1.769 ratio | Standard Error 0.069 |
| Arm II (Placebo) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | 12m | 1.722 ratio | Standard Error 0.079 |
| Arm II (Placebo) | Average Peak Early Atrial Divided by Peak Late Atrial Velocities | 18m | 1.732 ratio | Standard Error 0.081 |
p-value: 0.8295% CI: [-0.065, 0.082]Generalized Estimating Equation (GEE)
Secondary
Proportion of Participants With Average Adherence > 90%
The number of pills taken out of the total prescribed in a 3-month period, averaged across all study time points. The proportion of participants with average adherence rate \>90% is computed by arm and corresponding 95% confidence intervals are reported.
Time frame: Average adherence across 6 months, 12 months, 18 months, 24 months after treatment initiation are calculated.
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Carvedilol) | Proportion of Participants With Average Adherence > 90% | 0.483 proportion of participants |
| Arm II (Placebo) | Proportion of Participants With Average Adherence > 90% | 0.517 proportion of participants |
Secondary
Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point.
In a questionnaire, patients responded Yes/No to certain symptoms. If answered Yes, they selected slightly, moderately, quite a bit, or extremely regarding how bothersome the symptom was. The proportion of participants responding with any of these three categories was calculated by arm, and corresponding 95% confidence intervals are reported.
Time frame: Responses at days 14 to 730 were combined
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Heart racing or skipping beats | 0.08 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Sensation that I have to urinate much of the time | 0.0667 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Insomnia | 0.1733 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Discoloration of urine (i.e., bloody) | 0 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling nervous | 0.1467 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Decreased libido | 0.0667 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Difficulty concentrating | 0.1067 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Unusually heavy menstrual flows (N/A if postmenopausal or male) | 0.2 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Dizziness and/or lightheadedness | 0.16 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Skin rash | 0.0933 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Interrupted sleep | 0.2 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Itchy skin | 0.1467 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling downhearted, sad, and/or tearful | 0.2 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Dry Mouth | 0.0667 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Diarrhea | 0.0533 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Easy bruising | 0.0133 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Mood swings | 0.12 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Nosebleeds | 0.0667 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Tendency to take naps | 0.12 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Sunburn easily | 0.0933 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling shaky or having tremors | 0.0533 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Weight gain | 0.0533 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling unusually tired | 0.2267 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Fluid retention | 0.0267 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Falling asleep at inappropriate times | 0.0267 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Swollen feet | 0 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Decreased bodily movement | 0.0133 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Increased sweating | 0.0933 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Ringing in the ears | 0.0533 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling weak in parts of your body | 0.0933 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Dizziness upon standing (from sitting or lying down) | 0.1467 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Shortness of breath or wheezing | 0.0933 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Difficulty breathing | 0.0267 Proportion of patients |
| Arm I (Carvedilol) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Chest pain or heaviness | 0.08 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Unusually heavy menstrual flows (N/A if postmenopausal or male) | 0.111 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling downhearted, sad, and/or tearful | 0.1184 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling unusually tired | 0.2237 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Heart racing or skipping beats | 0.0395 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling shaky or having tremors | 0.0789 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Decreased bodily movement | 0.0395 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling nervous | 0.1711 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Mood swings | 0.0921 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Dizziness and/or lightheadedness | 0.1316 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Dizziness upon standing (from sitting or lying down) | 0.1579 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Insomnia | 0.1711 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Difficulty concentrating | 0.1316 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Interrupted sleep | 0.2105 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Diarrhea | 0.1316 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Tendency to take naps | 0.1053 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Falling asleep at inappropriate times | 0.0395 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Ringing in the ears | 0.0921 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Difficulty breathing | 0 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Sensation that I have to urinate much of the time | 0.0789 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Discoloration of urine (i.e., bloody) | 0.0395 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Decreased libido | 0.0526 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Chest pain or heaviness | 0.0921 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Skin rash | 0.0789 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Itchy skin | 0.1447 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Dry Mouth | 0.1711 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Easy bruising | 0.0921 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Nosebleeds | 0.0526 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Sunburn easily | 0.0526 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Weight gain | 0.0789 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Fluid retention | 0.0395 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Swollen feet | 0.0921 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Increased sweating | 0.0789 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Feeling weak in parts of your body | 0.1316 Proportion of patients |
| Arm II (Placebo) | Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point. | Shortness of breath or wheezing | 0.0395 Proportion of patients |
Secondary
Proportion of Patients With Reportable Adverse Events as Described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
Patients with toxicities reported via CTEP-AERS and all Grade ≥ 2 adverse events (AEs) that can be attributed probably or definitely to the study drug are considered to have AEs. The proportion of patients with AEs are reported by arm with corresponding 95% confidence intervals.
Time frame: From baseline to month 24 since baseline
Population: We excluded 31 participants who did not have a second time point assessment of echocardiography, resulting in 151 analyzable participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Carvedilol) | Proportion of Patients With Reportable Adverse Events as Described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). | 0.0267 Proportion of patients with AE |
| Arm II (Placebo) | Proportion of Patients With Reportable Adverse Events as Described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). | 0 Proportion of patients with AE |