Cardiomyopathy, Congestive Heart Failure
Conditions
Keywords
Heart failure, Natriuretic peptides, B-type natriuretic peptide, Kidney, Nesiritide, Natrecor, CHF
Brief summary
The purpose of this study is to determine the effects of subcutaneous injection of Human BNP (nesiritide), a hormone produced by the heart, on the pumping ability of the heart, kidney function, and hormonal function in persons with heart failure.
Detailed description
The cardiac hormone brain natriuretic peptide (BNP) plays an important role in the pathophysiology of congestive heart failure (CHF). Studies have established that BNP mediates natriuresis, renin and aldosterone (RAAS) inhibition, vasodilation and lusitropism. Acute cardiac hormone replacement with intravenous infusion of BNP has been shown to possess potent vasodilating actions in humans with acute decompensated CHF resulting in improvement of clinical symptoms. Natrecor (nesiritide) a sterile, purified preparation of human BNP is approved by the FDA for intravenous administration in the treatment of patients with acute decompensated congestive heart failure. However, chronic cardiac hormone replacement with BNP as therapeutic strategy in CHF has been limited by the need to administer BNP intravenously. The objective of this study is to define the cardiorenal and humoral actions of short term (eight weeks) chronic cardiac hormone replacement with subcutaneous (SQ) BNP in human NYHA class II-III CHF. Systolic and diastolic function, left ventricular remodeling as assessed by its volume, renal function, neurohumoral profiling and exercise capacity will be assessed prior to and after eight weeks of treatment.
Interventions
DRUGB-type Natriuretic Peptide (BNP)
BNP hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.
OTHERPlacebo
Placebo self-administered subcutaneously twice daily for 8 weeks.
Sponsors
American Heart Association
Scios, Inc.
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Research Resources (NCRR)
Horng Chen
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
1. Age \> 18 years 2. Resting left ventricular ejection fraction (LVEF) of 35% or less (determined within 48 months of recruitment by echocardiography, multiple gate acquisition scan (MUGA) or left ventriculogram.) 3. New York Heart Association (NYHA) Class I (with previous symptoms of heart failure), Class II and III 4. Female subjects not menopausal or surgically sterilized will need to have a negative pregnancy test the day before the study day and be on contraception.
Exclusion criteria
1. Myocardial infarction (MI) within 3 months of screening. 2. Unstable angina within 14 days of screening, or any evidence of myocardial ischemia. 3. Valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis. 4. Sustained ventricular tachycardia (VT) or ventricular fibrillation (V-fib) within 14 days of screening. 5. Second or third degree atrioventricular (AV) block without a permanent cardiac pacemaker. 6. Cerebrovascular accident (CVA) within 3 months of screening, or other evidence of significantly compromised central nervous system (CNS) perfusion. 7. Serum creatinine of \>3.0 mg/dL. 8. Serum sodium of \<125 milliequivalents per decaLiter (mEq/dL) or \> 160 mEq/dL. 9. Serum potassium of \< 3.5 mEq/dL or \> 5.2 mEq/dL. 10. Serum digoxin level of \> 2.0 ng/ml. 11. Systolic pressure of \<85 mmHg immediately prior to the first injection of study drug/placebo. 12. LVEF \> 35% by within 24 months of screening. 13. Unable to self-administer subcutaneous injection twice a day. 14. Diagnosed with AIDS or known positive HIV titer. 15. Other acute or chronic medical conditions or laboratory abnormality, which may increase the risks, associated with study participation or may interfere with interpretation of the data. 16. Received an investigational drug within 1 month prior to dosing. 17. Unable to undergo cardiac magnetic resonance imaging (MRI). Contraindications to MRI include pacemaker or defibrillator, pregnant women, atrial fibrillation or other arrhythmia, cerebral aneurysm clips, or severe claustrophobia. 18. In the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reasons. 19. Patient in atrial fibrillation or who have a pacemaker or implantable cardioverter defibrillator (ICD) 20. Hemoglobin \< 10g/dl. 21. Patients with an allergy to iodine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Left Ventricular (LV) Volume Index at 8 Weeks | Baseline and 8 weeks | LV volume was measured for systolic volume and diastolic volume using a cardiac Magnetic Resonance Imaging (MRI) scan. All cardiac MRI images were reviewed by an independent cardiologist in a blinded fashion. |
| Change in Left Ventricular (LV) Mass Index at 8 Weeks | Baseline and 8 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Renal Function as Measured by Glomerular Filtration Rate (GFR) at 8 Weeks | Baseline and 8 weeks | Kidney function was measured by GFR determined by iothalamate clearance. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m\^2 of body-surface area. A lower GFR means the kidney is not filtering normally. |
| Change in Heart Rate at 8 Weeks | Baseline and 8 weeks | Heart rate was measured when MRI was performed |
| Change in Left Ventricular (LV) Filling Pressure at 8 Weeks | Baseline and 8 weeks | Filling pressure determined by ratio of E/e' \[Echocardiograph Doppler mitral inflow velocity (E) to mitral annulus tissue Doppler velocity (e') ratio\] |
| Change in Left Ventricular Ejection Fraction at 8 Weeks | Baseline and 8 weeks | Left Ventricle Ejection Fraction (LVEF)is a clinical parameter used by cardiologists to describe how well the heart is pumping. LVEF is a measure of the amount of blood pumped out of the lower chamber (ventricle) of the heart during a heartbeat, measured by Magnetic Resonance Imaging (MRI). |
| Change in Blood Pressure at 8 Weeks | Baseline and 8 weeks | Blood pressure was measured during the MRI |
| Change in Plasma Renin Activity at 8 Weeks | Baseline and 8 weeks | Plasma renin is synthesized within circulation or at tissue sites, causing vasoconstriction or vasodilation. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from May 2003 to May 2008 at the Mayo Clinic in Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| B-type Natriuretic Peptide (BNP) BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg. | 24 |
| Placebo Placebo self-administered subcutaneously twice daily for 8 weeks. | 21 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | B-type Natriuretic Peptide (BNP) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 10 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 22 Participants |
| Age Continuous | 66 years STANDARD_DEVIATION 10 | 65 years STANDARD_DEVIATION 11 | 66 years STANDARD_DEVIATION 11 |
| Blood pressure Diastolic blood pressure | 72 mmHg STANDARD_DEVIATION 11 | 72 mmHg STANDARD_DEVIATION 14 | 72 mmHg STANDARD_DEVIATION 12 |
| Blood pressure Systolic blood pressure | 131 mmHg STANDARD_DEVIATION 18 | 127 mmHg STANDARD_DEVIATION 17 | 129 mmHg STANDARD_DEVIATION 17 |
| Concomitant Medication(s) ACE I inhib, Angio II receptor blocker or nitrates | 23 participants | 20 participants | 43 participants |
| Concomitant Medication(s) Antiarrhythmics | 5 participants | 0 participants | 5 participants |
| Concomitant Medication(s) Beta blocker | 23 participants | 20 participants | 43 participants |
| Concomitant Medication(s) Coumadin | 3 participants | 1 participants | 4 participants |
| Concomitant Medication(s) Digoxin | 8 participants | 9 participants | 17 participants |
| Concomitant Medication(s) Diuretic (loop) | 18 participants | 15 participants | 33 participants |
| Concomitant Medication(s) Diuretic (potassium sparing) | 5 participants | 4 participants | 9 participants |
| Concomitant Medication(s) Diuretic (thiazide) | 4 participants | 3 participants | 7 participants |
| Concomitant Medication(s) Diuretic (Thiazide) | 4 participants | 3 participants | 7 participants |
| Glomerular Filtration Rate | 73 ml/min/1.73 m^2 STANDARD_DEVIATION 22 | 77 ml/min/1.73 m^2 STANDARD_DEVIATION 21 | 75 ml/min/1.73 m^2 STANDARD_DEVIATION 22 |
| Heart Rate | 65 beats per minute STANDARD_DEVIATION 13 | 68 beats per minute STANDARD_DEVIATION 12 | 67 beats per minute STANDARD_DEVIATION 13 |
| History or concomitant medical conditions History of arrythmia | 5 participants | 4 participants | 9 participants |
| History or concomitant medical conditions History of chronic obstructive pulmonary disease | 3 participants | 1 participants | 4 participants |
| History or concomitant medical conditions History of Coronary Artery Disease | 11 participants | 11 participants | 22 participants |
| History or concomitant medical conditions History of diabetes | 11 participants | 7 participants | 18 participants |
| History or concomitant medical conditions History of high cholesterol | 15 participants | 17 participants | 32 participants |
| History or concomitant medical conditions History of hypertension | 10 participants | 17 participants | 27 participants |
| History or concomitant medical conditions History of peripheral vascular diseases | 2 participants | 1 participants | 3 participants |
| History or concomitant medical conditions History of smoking | 10 participants | 8 participants | 18 participants |
| Left Ventricle Ejection Fraction (Echo) | 32 Percentage STANDARD_DEVIATION 9 | 31 Percentage STANDARD_DEVIATION 7 | 31 Percentage STANDARD_DEVIATION 8 |
| New York Heart Association (NYHA) CHF Classification NYHA CHF Class II | 13 participants | 10 participants | 23 participants |
| New York Heart Association (NYHA) CHF Classification NYHA CHF Class III | 2 participants | 1 participants | 3 participants |
| Plasma BNP | 51 picograms/milliliter | 63 picograms/milliliter | 53 picograms/milliliter |
| Region of Enrollment United States | 24 participants | 21 participants | 45 participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 20 Participants | 13 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 24 | 17 / 21 |
| serious Total, serious adverse events | 3 / 24 | 1 / 21 |
Outcome results
Primary
Change in Left Ventricular (LV) Mass Index at 8 Weeks
Time frame: Baseline and 8 weeks
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| B-type Natriuretic Peptide (BNP) | Change in Left Ventricular (LV) Mass Index at 8 Weeks | -4.4 mg/m^2 | Standard Deviation 9.8 |
| Placebo | Change in Left Ventricular (LV) Mass Index at 8 Weeks | 6.2 mg/m^2 | Standard Deviation 12.9 |
p-value: 0.006Chi-squared
Primary
Change in Left Ventricular (LV) Volume Index at 8 Weeks
LV volume was measured for systolic volume and diastolic volume using a cardiac Magnetic Resonance Imaging (MRI) scan. All cardiac MRI images were reviewed by an independent cardiologist in a blinded fashion.
Time frame: Baseline and 8 weeks
Population: Per protocol population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-type Natriuretic Peptide (BNP) | Change in Left Ventricular (LV) Volume Index at 8 Weeks | End-systolic LV volume index | -5.2 ml/m^2 | Standard Deviation 13 |
| B-type Natriuretic Peptide (BNP) | Change in Left Ventricular (LV) Volume Index at 8 Weeks | End-diastolic LV volume index | -10.0 ml/m^2 | Standard Deviation 15.4 |
| Placebo | Change in Left Ventricular (LV) Volume Index at 8 Weeks | End-systolic LV volume index | 5.8 ml/m^2 | Standard Deviation 9.6 |
| Placebo | Change in Left Ventricular (LV) Volume Index at 8 Weeks | End-diastolic LV volume index | 6.1 ml/m^2 | Standard Deviation 12.4 |
Comparison: Change in end systolic LV volume index compared between two groupsp-value: 0.004Chi-squared
Comparison: Change in LV end diastolic volume was compared between two groupsp-value: 0.001Chi-squared
Secondary
Change in Blood Pressure at 8 Weeks
Blood pressure was measured during the MRI
Time frame: Baseline and 8 weeks
Population: Per protocol population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-type Natriuretic Peptide (BNP) | Change in Blood Pressure at 8 Weeks | Change in systolic blood pressure | -4.9 mmHg | Standard Deviation 22.2 |
| B-type Natriuretic Peptide (BNP) | Change in Blood Pressure at 8 Weeks | Change in diastolic blood pressure | -2.4 mmHg | Standard Deviation 8.5 |
| Placebo | Change in Blood Pressure at 8 Weeks | Change in systolic blood pressure | 4.5 mmHg | Standard Deviation 17.7 |
| Placebo | Change in Blood Pressure at 8 Weeks | Change in diastolic blood pressure | 0.9 mmHg | Standard Deviation 12.1 |
Secondary
Change in Heart Rate at 8 Weeks
Heart rate was measured when MRI was performed
Time frame: Baseline and 8 weeks
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| B-type Natriuretic Peptide (BNP) | Change in Heart Rate at 8 Weeks | -1.6 beats per minute | Standard Deviation 8.3 |
| Placebo | Change in Heart Rate at 8 Weeks | -0.9 beats per minute | Standard Deviation 7.2 |
Secondary
Change in Left Ventricular Ejection Fraction at 8 Weeks
Left Ventricle Ejection Fraction (LVEF)is a clinical parameter used by cardiologists to describe how well the heart is pumping. LVEF is a measure of the amount of blood pumped out of the lower chamber (ventricle) of the heart during a heartbeat, measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline and 8 weeks
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| B-type Natriuretic Peptide (BNP) | Change in Left Ventricular Ejection Fraction at 8 Weeks | 0.0 percentage | Standard Deviation 7.5 |
| Placebo | Change in Left Ventricular Ejection Fraction at 8 Weeks | -1.1 percentage | Standard Deviation 4.2 |
Secondary
Change in Left Ventricular (LV) Filling Pressure at 8 Weeks
Filling pressure determined by ratio of E/e' \[Echocardiograph Doppler mitral inflow velocity (E) to mitral annulus tissue Doppler velocity (e') ratio\]
Time frame: Baseline and 8 weeks
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| B-type Natriuretic Peptide (BNP) | Change in Left Ventricular (LV) Filling Pressure at 8 Weeks | -2.3 E/e' | Standard Deviation 2.5 |
| Placebo | Change in Left Ventricular (LV) Filling Pressure at 8 Weeks | 1.1 E/e' | Standard Deviation 3.1 |
p-value: 0.001Chi-squared
Secondary
Change in Plasma Renin Activity at 8 Weeks
Plasma renin is synthesized within circulation or at tissue sites, causing vasoconstriction or vasodilation.
Time frame: Baseline and 8 weeks
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| B-type Natriuretic Peptide (BNP) | Change in Plasma Renin Activity at 8 Weeks | -3.5 nanograms per milliliter per hour | Standard Deviation 7.1 |
| Placebo | Change in Plasma Renin Activity at 8 Weeks | 2.3 nanograms per milliliter per hour | Standard Deviation 4.8 |
Secondary
Change in Renal Function as Measured by Glomerular Filtration Rate (GFR) at 8 Weeks
Kidney function was measured by GFR determined by iothalamate clearance. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m\^2 of body-surface area. A lower GFR means the kidney is not filtering normally.
Time frame: Baseline and 8 weeks
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| B-type Natriuretic Peptide (BNP) | Change in Renal Function as Measured by Glomerular Filtration Rate (GFR) at 8 Weeks | 6.9 ml/min/1.73 m^2 of body-surface area | Standard Deviation 14.2 |
| Placebo | Change in Renal Function as Measured by Glomerular Filtration Rate (GFR) at 8 Weeks | -2.8 ml/min/1.73 m^2 of body-surface area | Standard Deviation 24.8 |
p-value: 0.14Chi-squared