Left Ventricular Dysfunction
Conditions
Keywords
Acute Myocardial Infarction, Global Left Ventricular Ejection Fraction, Regional Left Ventricular Ejection Fraction, Left Ventricular Mass, Infarct Size, End Systolic Volume, End Diastolic Volume
Brief summary
More than 1 million Americans suffer heart attacks each year. Although current treatments are able to stabilize the condition of the heart, none is able to restore heart function as it was prior to the heart attack. Adult stem cells, which are immature cells that can become many different types of cells, may offer a potential means of reversing or preventing permanent damage caused by a heart attack. Recent studies have shown promise in using adult stem cells from bone marrow to reverse damage to the heart muscle caused by a heart attack, but more research is needed to assess the safety and effectiveness of stem cell use and to discover the best time to administer treatment. This study will evaluate the safety and effectiveness of using adult stem cell infusions 2 to 3 weeks after a heart attack for improving heart function in people who have had a recent heart attack and a common procedure called a percutaneous coronary intervention (PCI).
Detailed description
Heart attacks are a leading cause of death for both men and women in the United States. A heart attack occurs when blood flow to the heart is restricted, commonly due to a blood clot that has formed in one of the coronary arteries. If the clot becomes large enough, blood flow to the heart can be blocked almost completely and the heart muscle in that area can suffer permanent injury or death. Although a PCI can be used to open up the blocked artery and restore blood flow to the heart muscle, there may be a significant amount of heart tissue that has been irreversibly damaged. Recent studies have shown that adult stem cells from bone marrow may be able to improve heart function after a heart attack. These specialized cells may have the ability to promote blood vessel growth, prevent cell death, and transform themselves into a number of tissues, including muscle. After an acute heart attack, a remodeling process is initiated in the heart in an attempt to compensate for damaged areas. Consequently, the condition of the heart muscle several weeks after a heart attack may differ considerably from the heart's condition during the acute setting. For some patients, delaying the delivery of the stem cells until 2 to 3 weeks after a heart attack may be better than initiating treatment during the acute phase. This study will evaluate the safety and effectiveness of placing adult stem cells into injured heart muscle 2 to 3 weeks after a heart attack for improving heart function in people who have had a recent heart attack and a PCI. Participation in this study will last 24 months. All participants will first undergo baseline assessments that will include a medical history, a physical exam, an electrocardiogram (ECG), blood draws, an echocardiogram, and a magnetic resonance imaging (MRI) test. Participants will then be assigned randomly to receive stem cells or placebo between 2 and 3 weeks after their heart attack. The morning of the stem cell or placebo infusion, participants will undergo a blood draw and a bone marrow aspiration procedure of the hip bone to collect the stem cells. Later the same day, either stem cells or placebo will be infused through a catheter and into the damaged area of the heart. For the first 24 hours after the infusion, participants will be asked to wear a small ECG machine called a Holter monitor. Participants will also be asked to record their temperature twice a day for a month after the infusion. Participants will return for follow-up visits at Months 1, 3, 6, 12, and 24 and will repeat many of the baseline assessments.
Interventions
BIOLOGICALAdult stem cells
One time infusion of approximately 150 million total nucleated cells (TNC) in 30 ml of 5% HSA/saline solution
BIOLOGICALPlacebo
One time infusion of 30 ml of HSA (5%)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
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
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients at least 21 years of age. 2. Patients with first acute MI and subsequent successful primary percutaneous coronary intervention (PCI) in an artery at least 2.5 mm in diameter occurring two to three weeks before recruitment. 3. No contraindications to undergoing cell therapy procedure within two to three weeks following AMI and PCI. 4. Hemodynamic stability as defined as no requirement for IABP, inotropic or blood pressure supporting medications. 5. Ejection fraction following reperfusion with PCI \<=45% as assessed by echocardiography. 6. Consent to protocol and agree to comply with all follow-up visits and studies. 7. Women of child bearing potential willing to use an active form of birth control.
Exclusion criteria
Patients will be excluded from the study if they meet any of the following conditions: 1. History of sustained ventricular arrhythmias not related to their AMI (evidenced by previous holter monitoring and/or medication history for sustained ventricular arrhythmias in patient's medical chart). 2. Require CABG or PCI due to the presence of residual coronary stenosis \>70% luminal obstruction in the non-infarct related vessel (Additional PCI of non-culprit vessels may be performed prior to enrollment). 3. History of any malignancy within the past five years excluding non-melanoma skin cancer or cervical cancer in-situ. 4. History of chronic anemia (hemoglobin (Hb) \<9.0 mg/dl). 5. History of thrombocytosis (platelets \>500k). 6. History of thrombocytopenia in the absence of recent evidence that platelet counts are normal 7. Known history of elevated INR (PT) or PTT. 8. Life expectancy less than one year. 9. History of untreated alcohol or drug abuse. 10. Currently enrolled in another Investigational drug or device trial 11. Previous CABG. 12. Previous MI resulting in LV dysfunction (LVEF \<55%) 13. History of stroke or transient ischemic attack (TIA) within the past six months. 14. History of severe valvular heart disease (aortic valve area \<1.0 cm2 or \>3+ mitral regurgitation). 15. Pregnancy or breast feeding 16. Subjects with a known history of HIV, or has active hepatitis B, active hepatitis C, or active tuberculosis (TB) 17. Patients with active inflammatory or autoimmune disease on chronic immunosuppressive therapy. 18. Contraindications to cMRI. 19. Previous radiation to the pelvis with white blood cell count (WBC) and platelet counts below hospital specific normal values. 20. Women child bearing potential not willing to practice an active form of birth control. 21. Chronic liver disease that might interfere with survival or treatment with cell therapy. 22. Chronic renal insufficiency as defined by a creatinine ≥2.0 mg/dL or requires chronic dialysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Left Ventricular Function | Measured at Baseline and Month 6 | Left ventricular ejection fraction (global) as assessed via cardiac MRI. Values reported represent the change in Global EF from baseline to six months. |
| Regional Left Ventricular Function (Infarct Zone Wall Motion) | Measured at Baseline and Month 6 | One of two calculated values of regional left ventricular function as assessed via cardiac MRI. The infarct zone is defined as the cMRI segments with the largest 2 signal intensity enhancement measures with gadolinium (using a 17-segment model).Values reported represent the change in wall motion over time in the infarct zone from baseline to six months. |
| Regional Left Ventricular Function (Border Zone Wall Motion) | Measured at Baseline and Month 6 | Two of two calculated values of regional left ventricular function assessed via cardiac MRI. The border zone is defined as those regions adjacent to the infarct zone in which the cMRI signal intensity enhancement were in the 10%-75% range. Values reported represent the change in wall motion over time in the border zone of the infarct from baseline to six months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| End Systolic Volume Index | Measured at Baseline and Month 6 | Left ventricular end systolic volume index. Values reported represent the change in LV end systolic volume index from baseline to six months. |
| Combined Endpoint | Measured at Baseline and Month 6 | Combined endpoint: first of death, reinfarction, repeat revascularization, and hospitalization for heart failure. This is measured as the number of events by treatment group over the 6 month follow up period. |
| Infarct Volume | Measured at Baseline and Month 6 | Infarct volume(mL). Values reported represent the change in infarct volume from baseline to six months. |
| Left Ventricular Mass | Measured at Baseline and Month 6 | Left ventricular mass (LV mass. Values reported represent the change in LV mass from baseline to six months.) |
| End Diastolic Volume Index | Measured at Baseline and Month 6 | Left ventricular end diastolic volume index. Values reported represent the change in LV end diastolic index 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 July 8, 2008 and February 28, 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 |
|---|---|
| Stem Cell Arm Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI). | 58 |
| Placebo Arm Participants will receive placebo infusion (5% human serum albumin \[HSA\]) 2 to 3 weeks after a PCI. | 29 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | New stenosis identified | 1 | 0 |
| Overall Study | Unable to collect MRI | 1 | 2 |
Baseline characteristics
| Characteristic | Stem Cell Arm | Placebo Arm | Total |
|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 11 | 54.6 years STANDARD_DEVIATION 11 | 57 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 58 participants | 29 participants | 87 participants |
| Sex: Female, Male Female | 12 Participants | 3 Participants | 15 Participants |
| Sex: Female, Male Male | 46 Participants | 26 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 58 | 14 / 29 |
| serious Total, serious adverse events | 8 / 58 | 14 / 29 |
Outcome results
Primary
Global Left Ventricular Function
Left ventricular ejection fraction (global) as assessed via cardiac MRI. Values reported represent the change in Global EF from baseline to six months.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and 6 month MRI images available are included.~Values reported represent the change in Global EF from baseline to six months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stem Cell Arm | Global Left Ventricular Function | 0.5 percentage of ejection fraction | Standard Deviation 8.2 |
| Placebo Arm | Global Left Ventricular Function | 3.6 percentage of ejection fraction | Standard Deviation 9.3 |
Comparison: Comparison of change in global LVEF in the active group minus change in global LVEF in the control group. 80 percent power based on BOOST resultsp-value: <0.0595% CI: [-7.05, 0.95]t-test, 2 sided
Primary
Regional Left Ventricular Function (Border Zone Wall Motion)
Two of two calculated values of regional left ventricular function assessed via cardiac MRI. The border zone is defined as those regions adjacent to the infarct zone in which the cMRI signal intensity enhancement were in the 10%-75% range. Values reported represent the change in wall motion over time in the border zone of the infarct from baseline to six months.
Time frame: Measured at Baseline and Month 6
Population: Five patients were excluded from analysis due to incomplete signal intensity enhancement data (1) or lack of a signal intensity enhancement signal in the border zone (4).~Values reported represent the change in wall motion over time in the border zone of the infarct from baseline to six months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stem Cell Arm | Regional Left Ventricular Function (Border Zone Wall Motion) | 0.5 mm | Standard Deviation 7.2 |
| Placebo Arm | Regional Left Ventricular Function (Border Zone Wall Motion) | 3.2 mm | Standard Deviation 6.3 |
Comparison: Comparison of change in border zone wall motion in the active group minus change in global LVEF in the control group. 80 percent power based on BOOST resultsp-value: <0.0595% CI: [-6, 0.8]t-test, 2 sided
Primary
Regional Left Ventricular Function (Infarct Zone Wall Motion)
One of two calculated values of regional left ventricular function as assessed via cardiac MRI. The infarct zone is defined as the cMRI segments with the largest 2 signal intensity enhancement measures with gadolinium (using a 17-segment model).Values reported represent the change in wall motion over time in the infarct zone from baseline to six months.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and 6 month MRI images available are included. One patient was excluded from the analysis due to incomplete signal intensity enhancement data.~Values reported represent the change in wall motion over time in the infarct zone from baseline to six months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stem Cell Arm | Regional Left Ventricular Function (Infarct Zone Wall Motion) | 0.3 mm | Standard Deviation 4.3 |
| Placebo Arm | Regional Left Ventricular Function (Infarct Zone Wall Motion) | 1.0 mm | Standard Deviation 4.5 |
Comparison: Comparison of change in infarct zone wall motion in the active group minus change in global LVEF in the control group. 80 percent power based on BOOST resultsp-value: <0.0595% CI: [-2.8, 1.3]t-test, 2 sided
Secondary
Combined Endpoint
Combined endpoint: first of death, reinfarction, repeat revascularization, and hospitalization for heart failure. This is measured as the number of events by treatment group over the 6 month follow up period.
Time frame: Measured at Baseline and Month 6
Population: All randomized patients were followed for clinical outcomes. However the paucity of events precluded a reliable time to event analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stem Cell Arm | Combined Endpoint | 3 events |
| Placebo Arm | Combined Endpoint | 4 events |
Comparison: comparison of the proportion of events in patients in the active group to those in patients in the control groupp-value: <0.0595% CI: [0.08, 1.17]Fisher Exact
Secondary
End Diastolic Volume Index
Left ventricular end diastolic volume index. Values reported represent the change in LV end diastolic index from baseline to six months.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and 6 month MRI images available are included.~Values reported represent the change in LV end diastolic index from baseline to six months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stem Cell Arm | End Diastolic Volume Index | 3.4 mL/m2 | Standard Deviation 23.4 |
| Placebo Arm | End Diastolic Volume Index | 2.7 mL/m2 | Standard Deviation 18.1 |
Comparison: Comparison of change in the active group minus change in global LVEF in the control group.p-value: <0.0595% CI: [-9.5, 10.9]t-test, 2 sided
Secondary
End Systolic Volume Index
Left ventricular end systolic volume index. Values reported represent the change in LV end systolic volume index from baseline to six months.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and 6 month MRI images available are included.~Values reported represent the change in LV end systolic volume index from baseline to six months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stem Cell Arm | End Systolic Volume Index | 0.2 mL/m2 | Standard Deviation 14 |
| Placebo Arm | End Systolic Volume Index | -2.3 mL/m2 | Standard Deviation 14.7 |
Comparison: Comparison of change in the active group minus change in the control group.p-value: <0.0595% CI: [-4.1, 9.2]t-test, 2 sided
Secondary
Infarct Volume
Infarct volume(mL). Values reported represent the change in infarct volume from baseline to six months.
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and 6 month MRI images available are included.~Values reported represent the change in infarct volume from baseline to six months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stem Cell Arm | Infarct Volume | -3.5 mL | Standard Deviation 19 |
| Placebo Arm | Infarct Volume | -2.0 mL | Standard Deviation 14.4 |
Comparison: Comparison of change in the active group minus change in the control group.p-value: <0.0595% CI: [-9.9, 6.9]t-test, 2 sided
Secondary
Left Ventricular Mass
Left ventricular mass (LV mass. Values reported represent the change in LV mass from baseline to six months.)
Time frame: Measured at Baseline and Month 6
Population: Only participants with both baseline and 6 month MRI images available are included.~Values reported represent the change in LV mass from baseline to six months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stem Cell Arm | Left Ventricular Mass | -12.0 g | Standard Deviation 18.1 |
| Placebo Arm | Left Ventricular Mass | -10.8 g | Standard Deviation 15.2 |
Comparison: Comparison of change in the active group minus change in global LVEF in the control group.p-value: <0.0595% CI: [-9.3, 6.8]t-test, 2 sided