Heart Failure, Congestive
Conditions
Keywords
Randomized Controlled Trial, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Sympathetic Nervous System, Ventricular Remodeling, Chemokines
Brief summary
The goal of the investigators' study is to further understand the potentially beneficial effects of statin therapy in patients with heart failure. It is hypothesized that statins will 1) increase the heart's pumping ability 2) improve functioning of the sympathetic nervous system and 3) decrease immune activation in heart failure.
Detailed description
Recent evidence suggests that HMG-Coenzyme A (statin) therapy may be associated with improved survival in both ischemic and non-ischemic heart failure (HF). Large, randomized outcome studies of statins in HF are currently underway, but these trials will not address underlying mechanisms. The aim of the study is to investigate statins' potentially beneficial mechanisms of action in HF, focusing on: 1) sympathetic nervous system activation and 2) myocardial remodeling, and 3) immune activation in heart failure. Fifty patients with systolic HF of non-ischemic etiology from a single center will be randomized in a double-blinded fashion to 3 months of atorvastatin 10mg QD (25 subjects) vs matching placebo QD (25 subjects). The following exams will be performed at baseline (pre-treatment) and at end of study (post-treatment): sympathetic microneurography, echocardiography, and peripheral blood chemokine analysis. Sympathetic microneurography at the peroneal nerve will directly quantify changes in sympathetic nerve activity (bursts/minute). Echocardiography (with the addition of MRI in a subset of subjects without pacemakers or implantable defibrillators) will be used to track changes in cardiac structure and function; indices of remodeling will include measurement of left ventricular mass index, left ventricular volume indices, left ventricular ejection fraction, and subendocardial scar quantification (MRI only). Immune activation will be characterized by circulating cytokines and chemokines. Additionally, quantification of established cardiac biomarkers (cardiac troponin, B-type natriuretic peptide, and C-reactive Protein), Holter monitor/heart rate variability studies, and quality of life and global clinical assessment will be performed pre- and post- treatment. Neither sympathetic microneurography nor MRI have been previously utilized to assess statins' effects in humans with HF. The impact of statin therapy on inflammatory chemokine activation in HF also has not been studied. The knowledge gained from our proposed investigations may serve as a basis for understanding how statin therapy has potential to improve clinical outcomes in HF, and may ultimately lead to new therapeutic strategies for HF.
Interventions
DRUGatorvastatin
atorvastatin 10mg PO QD
DRUGplacebo
matched placebo Qd x 3 months
Sponsors
Pfizer
National Heart, Lung, and Blood Institute (NHLBI)
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age≥18 years old * LVEF ≤ 35%, as documented by echocardiography, radionuclide ventriculography, gated SPECT, or contrast ventriculography within past 6 months * Symptomatic HF (NYHA II-IV) or current NYHA I with history of symptomatic HF within the last year * Stable doses of optimal HF medical therapy, unless documented contraindication.
Exclusion criteria
* Ischemic etiology of HF, defined as the presence of at least one of the following four criteria; angiographic evidence of \> 50% lesion in 1 or more of the 3 major epicardial vessels; history of myocardial infarction; history of revascularization procedure; evidence of significant perfusion defect in the setting of ischemic symptoms. * Clinical indication for statin treatment - coronary artery, cerebrovascular, or peripheral vascular disease * Major cardiovascular event or surgical procedure within past 8 weeks * LDL\<70 mg/dL * HF secondary to congenital heart disease or uncorrected valvular disease * Treatment with statin within past 2 months * Pregnancy * Contraindication to statin: moderate liver disease, AST/ALT \> 150 U/ L, known hypersensitivity * Likely to receive heart transplant within 3 months * Known peripheral or autonomic neuropathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| LVEF (Left Ventricular Ejection Fraction) | baseline and three months | Left ventricular ejection fraction was assessed by transthoracic echocardiography according to Simpson's rule (biplane method of disks). |
| Muscle Sympathetic Nerve Activity (by Sympathetic Microneurography) | Baseline and three months | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular End-diastolic Dimension (LVEDD) | Baseline and three months | The end-diastolic dimension of the left ventricle (in mm) was measured with 2D echocardiography performed by experienced technicians using Acuson Sequoia Echocardiography System |
| Cardiac Biomarker Level BNP | Baseline, 3 months | B-type natriuretic peptide, measured pg/mL at baseline and post-treatment |
| High-sensitivity C-reactive Protein (hsCRP) as a Cardiac Biomarker | Baseline, Three months | — |
| Cardiac Troponin I (cTnI) | Baseline, Three months | Participants with cTnI ≥0.04 ng/mL |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Treatment atorvastatin 10mg QD x 3 months | 14 |
| Placebo matched placebo QD x 3 months | 12 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Underwent status II heart transplant | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Active Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 14 Participants | 26 Participants |
| Age, Continuous | 49 years STANDARD_DEVIATION 17 | 47 years STANDARD_DEVIATION 14 | 48 years STANDARD_DEVIATION 15 |
| Region of Enrollment United States | 12 participants | 14 participants | 26 participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 10 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 14 | 0 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 |
Outcome results
Primary
LVEF (Left Ventricular Ejection Fraction)
Left ventricular ejection fraction was assessed by transthoracic echocardiography according to Simpson's rule (biplane method of disks).
Time frame: baseline and three months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Treatment | LVEF (Left Ventricular Ejection Fraction) | Baseline LVEF | 24 percent ejection fraction | Standard Error 6 |
| Active Treatment | LVEF (Left Ventricular Ejection Fraction) | 3 month LVEF | 25 percent ejection fraction | Standard Error 6 |
| Placebo | LVEF (Left Ventricular Ejection Fraction) | Baseline LVEF | 28 percent ejection fraction | Standard Error 7 |
| Placebo | LVEF (Left Ventricular Ejection Fraction) | 3 month LVEF | 24 percent ejection fraction | Standard Error 7 |
p-value: 0.025paired t test
Primary
Muscle Sympathetic Nerve Activity (by Sympathetic Microneurography)
Time frame: Baseline and three months
Population: Eighteen subjects had baseline and final sympathetic microneurographic tracings that were technically adequate for analysis. Reasons for inadequate microneurographic tracing were: 1) inability of investigators to locate sympathetic nerve on baseline or final study; or 2) inability of patient to tolerate discomfort of the procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Treatment | Muscle Sympathetic Nerve Activity (by Sympathetic Microneurography) | Baseline | 43 bursts per minute | Standard Error 3 |
| Active Treatment | Muscle Sympathetic Nerve Activity (by Sympathetic Microneurography) | Three months | 36 bursts per minute | Standard Error 5 |
| Placebo | Muscle Sympathetic Nerve Activity (by Sympathetic Microneurography) | Baseline | 39 bursts per minute | Standard Error 3 |
| Placebo | Muscle Sympathetic Nerve Activity (by Sympathetic Microneurography) | Three months | 38 bursts per minute | Standard Error 3 |
Secondary
Cardiac Biomarker Level BNP
B-type natriuretic peptide, measured pg/mL at baseline and post-treatment
Time frame: Baseline, 3 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Active Treatment | Cardiac Biomarker Level BNP | Baseline | 175 pg/mL |
| Active Treatment | Cardiac Biomarker Level BNP | Three Months | 107 pg/mL |
| Placebo | Cardiac Biomarker Level BNP | Baseline | 66 pg/mL |
| Placebo | Cardiac Biomarker Level BNP | Three Months | 67 pg/mL |
Secondary
Cardiac Troponin I (cTnI)
Participants with cTnI ≥0.04 ng/mL
Time frame: Baseline, Three months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Treatment | Cardiac Troponin I (cTnI) | Baseline | 8 percent of participants |
| Active Treatment | Cardiac Troponin I (cTnI) | Three Months | 0 percent of participants |
| Placebo | Cardiac Troponin I (cTnI) | Baseline | 21 percent of participants |
| Placebo | Cardiac Troponin I (cTnI) | Three Months | 15 percent of participants |
Secondary
High-sensitivity C-reactive Protein (hsCRP) as a Cardiac Biomarker
Time frame: Baseline, Three months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Active Treatment | High-sensitivity C-reactive Protein (hsCRP) as a Cardiac Biomarker | Baseline | 1.6 mg/L |
| Active Treatment | High-sensitivity C-reactive Protein (hsCRP) as a Cardiac Biomarker | Three months | 1.9 mg/L |
| Placebo | High-sensitivity C-reactive Protein (hsCRP) as a Cardiac Biomarker | Baseline | 1.9 mg/L |
| Placebo | High-sensitivity C-reactive Protein (hsCRP) as a Cardiac Biomarker | Three months | 3.4 mg/L |
Secondary
Left Ventricular End-diastolic Dimension (LVEDD)
The end-diastolic dimension of the left ventricle (in mm) was measured with 2D echocardiography performed by experienced technicians using Acuson Sequoia Echocardiography System
Time frame: Baseline and three months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Treatment | Left Ventricular End-diastolic Dimension (LVEDD) | Baseline LVEDD | 65 Millimeters (mm) | Standard Error 12 |
| Active Treatment | Left Ventricular End-diastolic Dimension (LVEDD) | Three months LVEDD | 25 Millimeters (mm) | Standard Error 6 |
| Placebo | Left Ventricular End-diastolic Dimension (LVEDD) | Baseline LVEDD | 28 Millimeters (mm) | Standard Error 7 |
| Placebo | Left Ventricular End-diastolic Dimension (LVEDD) | Three months LVEDD | 24 Millimeters (mm) | Standard Error 7 |