Idiopathic Dilated Cardiomyopathy
Conditions
Keywords
ejection fraction, beta-blocker, carvedilol, metoprolol, myocardial gene expression, human heart, ventricular remodeling, wall stress, adrenergic signaling, myosin heavy chain
Brief summary
The primary goal of the study is to measure in the intact human heart, the alterations in gene expression over time that are associated with reverse remodeling in response to β-blockade. The second goal is to investigate the signaling mechanisms which in turn are responsible for these changes in gene expression, and the third goal is to determine the relationship between intrinsic systolic dysfunction and remodeling of the left ventricle. This will be accomplished by measuring ventricular size, function, and gene expression in myocardial tissue samples obtained by percutaneous biopsy prior to initiation of β-blockade and at 3 and 12 months after start of therapy. The specific Aims and Hypotheses to be tested are: 1. Aim: Determine the changes in gene expression associated with changes in intrinsic systolic function and with functional decompensation in the intact, failing human heart. a. Hypothesis: Changes in the expression of select genes precede or accompany changes in left ventricular systolic function in humans with idiopathic dilated cardiomyopathy (IDC). 2. Aim: Identify signaling mechanisms responsible for alterations in expression of key genes involved in mediation of ventricular hypertrophy or contractile dysfunction. a. Hypothesis: Myocardial-failure-associated regulation of select messenger ribonucleic acids and proteins are related to left ventricular wall stress and neurohormonal signaling. 3. Aim: In the relationship between contractile dysfunction and dilatation/remodeling, determine the relationship between contractile dysfunction and structural remodeling. b. Hypothesis: the contractile dysfunction is primary and structural remodeling secondary.
Interventions
DRUGCarvedilol
DRUGMetoprolol succinate
DRUGMetoprolol succinate + doxazosin
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
GlaxoSmithKline
AstraZeneca
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Idiopathic dilated cardiomyopathy with New York Heart Association Class II-IV symptoms * No evidence of coronary artery disease by angiography within 2 years of randomization * If female, patient is (a) surgically sterile or (b) practices an accepted method of birth control and has negative serum pregnancy test * Patient has been on other conventional cardiac heart failure(CHF) therapy at least 3 weeks prior to baseline assessments (includes angiotensin converting enzyme inhibitors, digoxin, diuretics, and/or vasodilators) * Patient has left ventricular ejection fraction \< 40% by radionuclide ventriculography within 60 days of randomization * Patient must demonstrate mental and physical ability and willingness to follow all study-specific instructions * Patient must voluntarily sign Institutional Review Board (IRB)-approved informed consent form prior to any study-specific procedure
Exclusion criteria
* Patient has heart failure due to or associated with uncorrected primary valvular disease, uncorrected thyroid disease, obstructive/hypertrophic cardiomyopathy, pericardial disease, amyloidosis, active myocarditis, or malfunctioning artificial heart valve. * Patient is actively on heart transplant list or anticipated to be within 6 months of randomization * Patient is receiving any of the following medicines: 1. Calcium channel blockers 2. Theophylline 3. Tricyclic antidepressants 4. Monoamine oxidase inhibitors 5. β-agonists 6. β-adrenergic blocking agent (oral) 7. Any investigational cardiovascular medication or involvement in another investigational trial 8. Flecainide, encainide, propafenone, sotalol, disopyramide, or amiodarone * Patient has a contraindication to β-blockade (eg asthma) * Patient has another life-threatening disease with life expectancy \< 2 years due to other illness * Patient has active hepatic, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease which may adversely affect the safety and efficacy of the study drug or life span of the patient * Unstable decompensated heart failure (evidence of hypoperfusion, acute pulmonary edema, or hypotension with SBP \< 80 mm Hg) * Patient is actively abusing ethanol or illicit drugs within 3 months of randomization * Patient has an automatic implantable cardiac defibrillator that has fired within 3 months of randomization * Patient has an asymptomatic waking, resting heart rate \< 50 bpm or symptomatic bradycardia \< 60 bpm. * Patient has uncontrolled insulin-dependent diabetes mellitus with a history of frequent hypoglycemia episodes * Patient has a high degree atrioventricular block (Mobitz Type II or complete heart block) * Patient is unable to tolerate magnetic resonance imaging procedures * Patient has demonstrated non-compliance with previous medical regimens
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months | 12 months | The primary clinical outcome will be LVEF response at 12 months defined as an improvement in LVEF of ≥ 8% at 12 months or if not available, ≥5% at 3 months in the absence of an adverse clinical outcome. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in LVEF at 3 Months | 3 months | A secondary outcome will be LVEF response at 3 months, defined as an improvement of ≥ 5% Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. |
| Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device. | 18 months | Clinical status at 18 months will be assessed at time of study completion, specifically for the composite outcome of all-cause mortality, need for heart transplant, or need for ventricular assist device. Outcomes are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Myocardial Gene Expression at 3 Months | 3 months | Changes in myocardial mRNA expression at 3 months compared to baseline using targeted quantitative polymerase chain reaction and genome wide microarray assays. Due to the large number of results genes interrogated (\ 20,000 genes), these results will instead be uploaded to the Gene Expression Omnibus. |
| Change in Myocardial microRNA Expression at 12 Months | 12 months | Changes in myocardial microRNA expression at 12 months compared to baseline using an Affymetrix microRNA microarray assay. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. |
| Change in Myocardial Gene Expression at 12 Months | 12 months | Changes in myocardial mRNA expression at 12 months compared to baseline using targeted quantitative polymerase chain reaction and Affymetrix genome-wide microarray assays. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. |
| Change in Myocardial microRNA Expression at 3 Months | 3 months | Changes in myocardial microRNA expression at 3 months compared to baseline using an Affymetrix microRNA microarray assay. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited between 9/1/2000 and 3/1/2008 from outpatient general cardiology and heart failure specialty clinics at the University of Colorado Hospital and University of Utah Health Sciences Center.
Pre-assignment details
65 patients met screening criteria and provided consent. Exclusions included personal preference (4), administrative reasons such as relocation (2), normalization of LVEF prior to assignment (2), and lack of central venous access (1).
Participants by arm
| Arm | Count |
|---|---|
| Non-failing Control Patients with normal ejection fraction who underwent a single myocardial biopsy and received no β-blocker therapy | 4 |
| Metoprolol Succinate Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months
Metoprolol succinate | 19 |
| Metoprolol Succinate + Doxazosin Idiopathic dilated cardiomyopathy patients who were randomized to receive metoprolol succinate and doxazosin mesylate titrated to goals of 200 mg (metoprolol succinate) and 8 mg (doxazosin mesylate) by mouth daily for 18 months
Metoprolol succinate + doxazosin | 16 |
| Carvedilol Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months
Carvedilol | 17 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative withdrawal | 0 | 1 | 0 | 1 |
| Overall Study | Insufficient biopsy tissue | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Non-failing Control | Metoprolol Succinate | Metoprolol Succinate + Doxazosin | Carvedilol | Total |
|---|---|---|---|---|---|
| Age, Continuous | 41.0 years STANDARD_DEVIATION 17.1 | 45.9 years STANDARD_DEVIATION 13.6 | 46.0 years STANDARD_DEVIATION 7.5 | 44.9 years STANDARD_DEVIATION 15.1 | 45.3 years STANDARD_DEVIATION 12.8 |
| LV ejection fraction | 58.8 % STANDARD_DEVIATION 7.4 | 22.5 % STANDARD_DEVIATION 7.1 | 28.5 % STANDARD_DEVIATION 8.7 | 28.6 % STANDARD_DEVIATION 8.7 | 28.6 % STANDARD_DEVIATION 11.9 |
| Race/Ethnicity, Customized African Ancestry | 0 participants | 1 participants | 4 participants | 0 participants | 5 participants |
| Race/Ethnicity, Customized European Ancestry | 4 participants | 15 participants | 9 participants | 13 participants | 41 participants |
| Race/Ethnicity, Customized Hispanic | 0 participants | 2 participants | 1 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 2 participants | 0 participants | 3 participants |
| Region of Enrollment United States | 4 participants | 19 participants | 16 participants | 17 participants | 56 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 6 Participants | 5 Participants | 16 Participants |
| Sex: Female, Male Male | 3 Participants | 15 Participants | 10 Participants | 12 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 17 | 0 / 14 | 0 / 16 |
| serious Total, serious adverse events | 0 / 17 | 0 / 14 | 0 / 16 |
Outcome results
Primary
Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months
The primary clinical outcome will be LVEF response at 12 months defined as an improvement in LVEF of ≥ 8% at 12 months or if not available, ≥5% at 3 months in the absence of an adverse clinical outcome. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure.
Time frame: 12 months
Population: Idiopathic dilated cardiomyopathy patients naive to beta-blocker therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metoprolol Succinate | Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months | 12 LVEF responders |
| Metoprolol Succinate + Doxazosin | Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months | 10 LVEF responders |
| Carvedilol | Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months | 9 LVEF responders |
Comparison: The null hypothesis is that there is no difference in rate of LVEF improvement according to treatment group.p-value: 0.685Fisher Exact
Secondary
Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device.
Clinical status at 18 months will be assessed at time of study completion, specifically for the composite outcome of all-cause mortality, need for heart transplant, or need for ventricular assist device. Outcomes are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure.
Time frame: 18 months
Population: Idiopathic dilated cardiomyopathy patients randomized to different beta-blocker strategies. Data does not include non-failing controls, as these patients only underwent baseline evaluation with no treatment or follow-up, given that they did not have heart failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metoprolol Succinate | Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device. | 1 participants |
| Metoprolol Succinate + Doxazosin | Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device. | 0 participants |
| Carvedilol | Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device. | 0 participants |
Secondary
Improvement in LVEF at 3 Months
A secondary outcome will be LVEF response at 3 months, defined as an improvement of ≥ 5% Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure.
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metoprolol Succinate | Improvement in LVEF at 3 Months | 16 LVEF responders |
| Metoprolol Succinate + Doxazosin | Improvement in LVEF at 3 Months | 10 LVEF responders |
| Carvedilol | Improvement in LVEF at 3 Months | 10 LVEF responders |
Comparison: The null hypothesis is that there is no difference in rate of LVEF improvement according to treatment group.p-value: 0.071Fisher Exact
Other Pre-specified
Change in Myocardial Gene Expression at 12 Months
Changes in myocardial mRNA expression at 12 months compared to baseline using targeted quantitative polymerase chain reaction and Affymetrix genome-wide microarray assays. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure.
Time frame: 12 months
Other Pre-specified
Change in Myocardial Gene Expression at 3 Months
Changes in myocardial mRNA expression at 3 months compared to baseline using targeted quantitative polymerase chain reaction and genome wide microarray assays. Due to the large number of results genes interrogated (\ 20,000 genes), these results will instead be uploaded to the Gene Expression Omnibus.
Time frame: 3 months
Other Pre-specified
Change in Myocardial microRNA Expression at 12 Months
Changes in myocardial microRNA expression at 12 months compared to baseline using an Affymetrix microRNA microarray assay. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure.
Time frame: 12 months
Other Pre-specified
Change in Myocardial microRNA Expression at 3 Months
Changes in myocardial microRNA expression at 3 months compared to baseline using an Affymetrix microRNA microarray assay. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure.
Time frame: 3 months