Angina, Chronic Ischemic Heart Disease, Ischemic Cardiomyopathy, Left Ventricular Dysfunction
Conditions
Keywords
Congestive Heart Failure, Regional Wall Motion, Perfusion Defects
Brief summary
Coronary artery disease (CAD) is a common disorder that can lead to heart failure. Not all people with CAD are eligible for today's standard treatments. One new treatment approach uses stem cells-specialized cells capable of developing into other types of cells-to stimulate growth of new blood vessels for the heart. This study will determine the safety and effectiveness of withdrawing stem cells from someone's bone marrow and injecting those cells into the person's heart as a way of treating people with CAD and heart failure.
Detailed description
Coronary artery disease (CAD), a disease in which blood vessels become clogged by a build-up of plaque, is the leading cause of heart failure, a condition in which the heart can no longer pump enough blood to the rest of the body. People with heart failure caused by CAD are said to have ischemic cardiomyopathy. Normal treatment for CAD involves coronary artery bypass grafting (in which a vein from another part of the body is grafted around an artery that has become blocked) or coronary angioplasty and stent placement (in which a blocked artery is opened and a small tube is placed to keep the artery open). However, some people with ischemic cardiomyopathy, such as those with substantial scar tissue on the heart wall or those with a particular heart structure, may not be eligible for these treatments. An alternative treatment being developed is therapeutic angiogenesis, which involves stimulating the growth of new blood vessels. Recent research has shown that withdrawing stem cells from bone marrow and implanting the cells into heart tissue may be an effective way to achieve therapeutic angiogenesis. This study will determine the safety and effectiveness of using stem cells to stimulate new blood vessel growth in the hearts of people with ischemic cardiomyopathy. Participation in this study, including follow-up visits and phone calls, will last 60 months. Participants will first undergo 3 to 4 days of screening procedures that will include a physical examination, multiple lab tests, and a battery of tests on heart health. Next, participants will be randomized to receive either active stem cell injections or placebo injections. The injections and related procedures will be performed in a hospital and last approximately 72 hours. During this time, participants in both groups will first undergo a bone marrow aspiration procedure. Participants receiving active stem cells will also undergo NOGA electromechanical cardiac mapping, which involves inserting a monitoring device through a catheter and into the heart. Injections of stem cells will then be made to 15 damaged sites on the heart through a special catheter. Participants receiving placebo injections will receive 15 injections of an inactive, saline-based solution. After the injection procedures, all participants will undergo two echocardiograms, an electrocardiogram, blood tests, and overnight monitoring in a telemetry unit. After the hospital stay, all participants will attend five study visits that will occur 1 week and 1, 3, 6, and 12 months after the injection procedures. At all study visits, participants will undergo an electrocardiogram, lab tests, and a review of adverse health events. On all but the last study visit, participants will have cardiac markers assessed, and they will wear a 24-hour Holter monitor to track heart activity. At the last three visits, participants will also complete quality of life questionnaires. All participants will then receive four follow-up telephone calls that will occur 2, 3, 4, and 5 years after the injection procedures.
Interventions
BIOLOGICALAdult stem cells
Single procedure of intramyocardial electromechanical-guided injection of approximately 100 million bone marrow mononucleated cells (BM-MNCs), administered in 15 different injection sites
BIOLOGICALPlacebo
Single procedure of intramyocardial electromechanical-guided needle insertions and injection of 5% human serum albumin and saline in 15 different injection sites
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Cardiovascular Cell Therapy Research Network (CCTRN)
The University of Texas Health Science Center, Houston
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
* Patients \>18 years of age with significant coronary heart disease not amenable to revascularization. * Left ventricular dysfunction (LVEF) less than or equal to 45%, measured by echocardiogram; limiting angina (Class II to IV); and/or congestive heart failure (CHF), NYHA class II to III * Receiving maximal medical therapy, defined as a medical regimen that includes the maximal tolerated dose of at least two antiangina medications, such as beta-blockers, nitrates, or calcium-channel blockers * Presence of a defect, as identified by single photon emission computed tomography (SPECT) isotope protocol, or viability, as identified by NOGA electromechanical cardiac mapping system * Coronary artery disease not well suited to any other type of revascularization procedure in the target region of the ventricle, as determined by a cardiovascular surgeon and interventional cardiologist who are not investigators in the trial * Hemodynamic stability, as defined by systolic blood pressure of at least 80 mm Hg without intravenous pressors or support devices * Females of childbearing potential must be willing to use two forms of birth control for the duration of the study
Exclusion criteria
* Atrial fibrillation or flutter without a pacemaker that guarantees a stable heart rate * Unstable angina * Left ventricular (LV) thrombus, as documented by echocardiography or LV angiography * A vascular anatomy that precludes cardiac catheterization * Severe valvular disease or mechanical aortic valve that precludes safe entry of the catheter into the left ventricle * Pregnant or lactating * Platelet count less than 100,000 per mm3 * White blood cell count less than 2,000 per mm3 * Revascularization within 30 days of consent * Transient ischemic attack or stroke within 60 days of study consent * Implantable cardioverter-defibrillator shock within 30 days of baseline consent, and within 30 days of randomization * Presence of ventricular tachycardia lasting 30 seconds or more on 24-hour Holter monitor or electrocardiogram (ECG) performed during screening period * Bleeding diathesis, defined as an international normalized ratio of at least 2.0 in the absence of warfarin therapy * A history of malignancy in the last 5 years excluding basal cell carcinoma, that has been surgically removed, with proof of surgical clean margins * Has a known history of HIV, has active hepatitis B or active hepatitis C * Any condition requiring immunosuppressive medication * High-risk acute coronary syndrome (ACS) or a myocardial infarction in the month prior to consent * A left ventricular wall thickness of \<8 mm (by echocardiogram) of the infero-lateral wall at the target site for cell injection. * Inability to walk on a treadmill, except for class IV angina patients, who will be evaluated separately * Enrolled in an investigational device or drug study within the previous 30 days * Hepatic dysfunction, as defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal range prior to study entry * Chronic renal insufficiency, defined as a serum creatinine level greater than 2.5 mg/dL or requiring dialysis * Any other condition that in the judgment of the investigator would be a contraindication to enrollment or follow-up
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Maximal Oxygen Consumption (VO2max) | Measured at Baseline and Month 6 | The VO2(max) is assessed using the Naughton treadmill protocol. |
| Change in Left Ventricular End Systolic Volume (LVESV)as Assessed Via Echo | Measured at Baseline and Month 6 | Echocardiographic measurements were performed by an echocardiographic core laboratory. LVESVs were calculated by the modified biplane Simpson method, using myocardial contrast to enhance endocardial definition. To account for patient body surface area, LVESV indices are reported. |
| Change in Reversible Defect Size | Measured at Baseline and Month 6 | Adenosine myocardial perfusion (SPECT) tests were collected at baseline and 6 months to identify change in ischemic (reversible) defects. SPECT imaging was performed at rest and after adenosine infusion over 4 minutes. To enhance the detection of viability on resting images, sublingual nitroglycerin was administered 15 minutes before injecting technetium Tc 99m sestamibi for the resting image. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Improvement in CCS Classification (Angina Pectoris) | Measured at Baseline and Month 6 | Clinical improvement in Canadian Cardiovascular Society (CCS) functional classification of angina pectoris. The CCS scale ranges from Class I (best)able to conduct ordinary daily activity without causing angina to Class IV (worst) Inability to perform any physical activity without discomfort; anginal symptoms may be present at rest. Patients receive a rating of 1-4 for their anginal symptoms. Results reflect the mean change in the total score over time. |
| Clinical Improvement in NYHA Classification | Measured at Baseline and Month 6 | Clinical improvement in New York Heart Association (NYHA) classification. The NYHA scale ranges from 1 (best)Mild- no limitation of physical activity due to heart failure to 4 (worst) Severe-Unable to carry out any physical activity without discomfort due to heart failure. Patients receive a rating of 1-4 for their heart failure symptoms. Results reflect the mean change in the total score over time. |
| Number of Participants With a Decrease in Anti-anginal Medication | Measured at Baseline and Month 6 | Number of participants with a decrease in anti-anginal medication (nitrates needed weekly) |
| Exercise Time and Level | Measured at Baseline and Month 6 | Exercise time and level as assessed via six minute walk test. (change in number of feet walked) |
| Regional Wall Motion by MRI (in Eligible Patients) | Measured at Baseline and Month 6 | Regional wall motion as measured by cardiac MRI (in patients who are not contraindicated) |
| LV Diastolic Dimension | Measured at Baseline and Month 6 | Left ventricular (LV) diastolic dimension as assessed by contrast echocardiography |
| Incidence of a Major Adverse Cardiac Event | Measured at Baseline and Month 6 | Incidence of major adverse cardiac events (new MI, rehospitalization for PCI in coronary artery territories that were treated, death, or rehospitalization for acute coronary syndrome and for congestive heart failure). (Incidence rate) |
| Reduction in Fixed Perfusion Defect(s)Via SPECT | Measured at Baseline and Month 6 | Fixed total defect is the stress total defect minus the reversible component. |
| Serum BNP Levels in Patients With CHF | Measured at Baseline and Month 6 | Serum b-type natriuretic peptide (BNP) levels in patients with congestive heart failure (CHF). A minority number of patients had pro-BNP collected versus regular BNP; these numbers are reported in the analysis population description. |
| Regional Blood Flow Improvement by MRI (in Eligible Patients) | Measured at Baseline and Month 6 | Regional blood flow improvement as measured by cardiac MRI (in patients who are not contraindicated) |
| Regional Wall Motion by Echocardiography | Measured at Baseline and Month 6 | Movement of the left ventricular wall measured in mm from baseline to six months. |
Countries
United States
Participant flow
Recruitment details
Enrollment took place at five Network centers and their associated satellite facilities between April 29, 2009 and April 18, 2011. The main centers are located in Ohio, Texas, Florida, Minnesota, and Tennessee. Study brochures, patient informational DVDs, and clinical trials.gov were among the tools used for recruitment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Injections Participants will receive placebo injections. | 31 |
| Active Stem Cell Injections Participants will receive active stem cell injections. | 61 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Injections | Active Stem Cell Injections | Total |
|---|---|---|---|
| Age, Continuous | 62.32 years STANDARD_DEVIATION 8.25 | 63.95 years STANDARD_DEVIATION 10.9 | 63.4 years STANDARD_DEVIATION 10.1 |
| Region of Enrollment United States | 31 participants | 61 participants | 92 participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 10 Participants |
| Sex: Female, Male Male | 29 Participants | 53 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 31 | 19 / 61 |
| serious Total, serious adverse events | 6 / 31 | 9 / 61 |
Outcome results
Primary
Change in Left Ventricular End Systolic Volume (LVESV)as Assessed Via Echo
Echocardiographic measurements were performed by an echocardiographic core laboratory. LVESVs were calculated by the modified biplane Simpson method, using myocardial contrast to enhance endocardial definition. To account for patient body surface area, LVESV indices are reported.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month LVESV data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | Change in Left Ventricular End Systolic Volume (LVESV)as Assessed Via Echo | 0 mL/m2 | Standard Deviation 10.8 |
| Active Stem Cell Injections | Change in Left Ventricular End Systolic Volume (LVESV)as Assessed Via Echo | -0.9 mL/m2 | Standard Deviation 11.6 |
Comparison: Change in the difference of end systolic volume over time.p-value: 0.85695% CI: [-10.05, 12.07]t-test, 2 sided
Primary
Change in Maximal Oxygen Consumption (VO2max)
The VO2(max) is assessed using the Naughton treadmill protocol.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and 6 month VO2max data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | Change in Maximal Oxygen Consumption (VO2max) | -0.6 mL/kg/min | Standard Deviation 3.2 |
| Active Stem Cell Injections | Change in Maximal Oxygen Consumption (VO2max) | 0.4 mL/kg/min | Standard Deviation 2.8 |
Comparison: Compare the change in the cell group to the change in the placebo group.p-value: 0.16995% CI: [-0.42, 2.34]t-test, 2 sided
Primary
Change in Reversible Defect Size
Adenosine myocardial perfusion (SPECT) tests were collected at baseline and 6 months to identify change in ischemic (reversible) defects. SPECT imaging was performed at rest and after adenosine infusion over 4 minutes. To enhance the detection of viability on resting images, sublingual nitroglycerin was administered 15 minutes before injecting technetium Tc 99m sestamibi for the resting image.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month reversible defect data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | Change in Reversible Defect Size | -2.7 percentage of reversible defect | Standard Deviation 18.2 |
| Active Stem Cell Injections | Change in Reversible Defect Size | -3.9 percentage of reversible defect | Standard Deviation 25.4 |
Comparison: Change in percent of the defect that is reversiblep-value: 0.83595% CI: [-12.5, 10.1]t-test, 2 sided
Secondary
Clinical Improvement in CCS Classification (Angina Pectoris)
Clinical improvement in Canadian Cardiovascular Society (CCS) functional classification of angina pectoris. The CCS scale ranges from Class I (best)able to conduct ordinary daily activity without causing angina to Class IV (worst) Inability to perform any physical activity without discomfort; anginal symptoms may be present at rest. Patients receive a rating of 1-4 for their anginal symptoms. Results reflect the mean change in the total score over time.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month CCS data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | Clinical Improvement in CCS Classification (Angina Pectoris) | -0.3 units on a scale | Standard Deviation 0.7 |
| Active Stem Cell Injections | Clinical Improvement in CCS Classification (Angina Pectoris) | -0.5 units on a scale | Standard Deviation 0.8 |
Comparison: Change in average improvement in Canadian Class Score over time between the two groups.p-value: 0.22795% CI: [-0.66, 0.16]t-test, 2 sided
Secondary
Clinical Improvement in NYHA Classification
Clinical improvement in New York Heart Association (NYHA) classification. The NYHA scale ranges from 1 (best)Mild- no limitation of physical activity due to heart failure to 4 (worst) Severe-Unable to carry out any physical activity without discomfort due to heart failure. Patients receive a rating of 1-4 for their heart failure symptoms. Results reflect the mean change in the total score over time.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month NYHA class data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | Clinical Improvement in NYHA Classification | -0.1 units on a scale | Standard Deviation 0.7 |
| Active Stem Cell Injections | Clinical Improvement in NYHA Classification | -0.3 units on a scale | Standard Deviation 0.9 |
Comparison: Difference in the change in NYHA score between the two groupsp-value: 0.36195% CI: [-0.56, 0.21]t-test, 2 sided
Secondary
Exercise Time and Level
Exercise time and level as assessed via six minute walk test. (change in number of feet walked)
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month 6 minute walk data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | Exercise Time and Level | 80 feet | Standard Deviation 415 |
| Active Stem Cell Injections | Exercise Time and Level | 184 feet | Standard Deviation 407 |
Comparison: Change in six minute walk distancep-value: 0.30295% CI: [-95, 303]t-test, 2 sided
Secondary
Incidence of a Major Adverse Cardiac Event
Incidence of major adverse cardiac events (new MI, rehospitalization for PCI in coronary artery territories that were treated, death, or rehospitalization for acute coronary syndrome and for congestive heart failure). (Incidence rate)
Time frame: Measured at Baseline and Month 6
Population: Incidence of major adverse cardiac events between baseline and 6 months. (Incidence rate)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Injections | Incidence of a Major Adverse Cardiac Event | 4 events |
| Active Stem Cell Injections | Incidence of a Major Adverse Cardiac Event | 5 events |
Comparison: The difference in the incidence of major adverse cardiac events between the two groups over time. (Incidence rate)p-value: 0.4795% CI: [-0.133, 0.039]t-test, 2 sided
Secondary
LV Diastolic Dimension
Left ventricular (LV) diastolic dimension as assessed by contrast echocardiography
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month LV diastolic data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | LV Diastolic Dimension | -8.5 mL | Standard Deviation 34 |
| Active Stem Cell Injections | LV Diastolic Dimension | 0.9 mL | Standard Deviation 30 |
Comparison: Change in the difference of end diastolic volume between the two groups over time.p-value: 0.19895% CI: [-5.03, 23.93]t-test, 2 sided
Secondary
Number of Participants With a Decrease in Anti-anginal Medication
Number of participants with a decrease in anti-anginal medication (nitrates needed weekly)
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month anti-anginal medication data available are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Injections | Number of Participants With a Decrease in Anti-anginal Medication | 0 participants |
| Active Stem Cell Injections | Number of Participants With a Decrease in Anti-anginal Medication | 2 participants |
Comparison: Difference in the change in anti-anginal meds across groupsp-value: 0.2895% CI: [-0.01, 0.09]Chi-squared
Secondary
Reduction in Fixed Perfusion Defect(s)Via SPECT
Fixed total defect is the stress total defect minus the reversible component.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month fixed defect data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | Reduction in Fixed Perfusion Defect(s)Via SPECT | 1.9 percentage of defect that is fixed | Standard Deviation 7.7 |
| Active Stem Cell Injections | Reduction in Fixed Perfusion Defect(s)Via SPECT | 1.2 percentage of defect that is fixed | Standard Deviation 8.7 |
Comparison: Difference in the change between the two groupsp-value: 0.795% CI: [-4.78, 3.36]t-test, 2 sided
Secondary
Regional Blood Flow Improvement by MRI (in Eligible Patients)
Regional blood flow improvement as measured by cardiac MRI (in patients who are not contraindicated)
Time frame: Measured at Baseline and Month 6
Population: The small number of patients without contraindications for MRI (n=17) precluded performing informative analysis on the MRI data.
Secondary
Regional Wall Motion by Echocardiography
Movement of the left ventricular wall measured in mm from baseline to six months.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month wall motion data available are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injections | Regional Wall Motion by Echocardiography | 0 mm | Standard Deviation 0.4 |
| Active Stem Cell Injections | Regional Wall Motion by Echocardiography | 0 mm | Standard Deviation 0.5 |
Comparison: Difference in the change between the two groupsp-value: 0.47195% CI: [-0.3, 0.14]t-test, 2 sided
Secondary
Regional Wall Motion by MRI (in Eligible Patients)
Regional wall motion as measured by cardiac MRI (in patients who are not contraindicated)
Time frame: Measured at Baseline and Month 6
Population: The small number of patients without contraindications for MRI (n=17) precluded performing informative analysis on the MRI data.
Secondary
Serum BNP Levels in Patients With CHF
Serum b-type natriuretic peptide (BNP) levels in patients with congestive heart failure (CHF). A minority number of patients had pro-BNP collected versus regular BNP; these numbers are reported in the analysis population description.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and six month BNP data available are included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Injections | Serum BNP Levels in Patients With CHF | BNP | 63 IUs | Standard Deviation 249 |
| Placebo Injections | Serum BNP Levels in Patients With CHF | pro-BNP | 234 IUs | Standard Deviation 1636 |
| Active Stem Cell Injections | Serum BNP Levels in Patients With CHF | BNP | 28 IUs | Standard Deviation 117 |
| Active Stem Cell Injections | Serum BNP Levels in Patients With CHF | pro-BNP | 497 IUs | Standard Deviation 1637 |
Comparison: Difference in the change in BNP(reg) between cell and placebo groupp-value: 0.5595% CI: [-150, 80]t-test, 2 sided