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
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 percutaneous coronary intervention (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. This study will evaluate the safety and effectiveness of using adult stem cells for improving heart function in people who have had a recent heart attack and a PCI.
Detailed description
More than 1 million Americans suffer a heart attack each year, resulting in about a 38% mortality rate. 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. The permanent damage to the heart can lead to more severe problems, such as heart failure and irregular heartbeat, making the discovery of treatments to improve heart function after a heart attack important. 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. 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. 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 placing adult stem cells into injured heart muscle for improving heart function in people who have had a recent heart attack and a PCI. Additionally, this study will help determine the best time to insert stem cells after a heart attack. 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 either 3 or 7 days 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 following 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 with successful primary percutaneous coronary intervention (PCI) in an artery at least 2.5 mm in diameter within 24 hours of onset of symptoms. 3. No contraindications to undergoing cell therapy procedure within three to seven days 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 TB 17. Patients with active inflammatory or autoimmune disease on chronic immuno-suppressive 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. |
| 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. |
| Infarct Volume | Measured at Baseline and Month 6 | Infarct volume(mL). Values reported represent the change in infarct volume 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. |
| Clincal and Safety Outcomes | Measured from baseline to six months. | Number of events -death, reinfarction, repeat revascularizations (target and nontarget vessels) hospitalizations for heart failure, ICD placements |
Countries
United States
Participant flow
Recruitment details
Enrollment took place at five Network centers and their associated satellite facilities between July 2008 and November 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 |
|---|---|
| Day 3 Stem Cell Arm Participants will receive active adult stem cell infusion 3 days after percutaneous coronary intervention (PCI). | 43 |
| Day 3 Placebo Arm Participants will receive placebo infusion (5% human serum albumin \[HSA\]) 3 days after PCI. | 24 |
| Day 7 Stem Cell Arm Participants will receive active adult stem cell infusion 7 days after PCI. | 36 |
| Day 7 Placebo Arm Participants will receive placebo infusion (5% HSA) 7 days after PCI. | 17 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | MRI Contraindicated | 1 | 1 | 1 | 0 |
| Overall Study | MRI not performed | 0 | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Day 3 Stem Cell Arm | Day 3 Placebo Arm | Day 7 Stem Cell Arm | Day 7 Placebo Arm | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.6 years STANDARD_DEVIATION 10.8 | 57.0 years STANDARD_DEVIATION 12.4 | 58.2 years STANDARD_DEVIATION 11.3 | 57.0 years STANDARD_DEVIATION 8 | 56.9 years STANDARD_DEVIATION 10.9 |
| Region of Enrollment United States | 43 participants | 24 participants | 36 participants | 17 participants | 120 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 5 Participants | 2 Participants | 15 Participants |
| Sex: Female, Male Male | 38 Participants | 21 Participants | 31 Participants | 15 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 43 | 6 / 24 | 13 / 36 | 6 / 17 |
| serious Total, serious adverse events | 17 / 43 | 6 / 24 | 11 / 36 | 2 / 17 |
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 |
|---|---|---|---|
| Day 3 Stem Cell Arm | Global Left Ventricular Function | 3.5 percentage of ejection fraction | Standard Deviation 11 |
| Day 3 Placebo Arm | Global Left Ventricular Function | 4.4 percentage of ejection fraction | Standard Deviation 10.6 |
| Day 7 Stem Cell Arm | Global Left Ventricular Function | 2.8 percentage of ejection fraction | Standard Deviation 9.7 |
| Day 7 Placebo Arm | Global Left Ventricular Function | 1.7 percentage of ejection fraction | Standard Deviation 8.2 |
p-value: 0.95995% CI: [-4.1, 3.9]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: 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 |
|---|---|---|---|
| Day 3 Stem Cell Arm | Regional Left Ventricular Function (Border Zone Wall Motion) | 3.5 mm | Standard Deviation 9.3 |
| Day 3 Placebo Arm | Regional Left Ventricular Function (Border Zone Wall Motion) | 4.3 mm | Standard Deviation 8.7 |
| Day 7 Stem Cell Arm | Regional Left Ventricular Function (Border Zone Wall Motion) | 4.2 mm | Standard Deviation 8.3 |
| Day 7 Placebo Arm | Regional Left Ventricular Function (Border Zone Wall Motion) | 4.4 mm | Standard Deviation 7.2 |
p-value: 0.77795% CI: [-3.9, 2.9]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. Values reported represent the change in wall motion over time in the infarct zone from baseline to six months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 3 Stem Cell Arm | Regional Left Ventricular Function (Infarct Zone Wall Motion) | 2.1 mm | Standard Deviation 5.9 |
| Day 3 Placebo Arm | Regional Left Ventricular Function (Infarct Zone Wall Motion) | 2.4 mm | Standard Deviation 5.3 |
| Day 7 Stem Cell Arm | Regional Left Ventricular Function (Infarct Zone Wall Motion) | 1.2 mm | Standard Deviation 4.9 |
| Day 7 Placebo Arm | Regional Left Ventricular Function (Infarct Zone Wall Motion) | 2.8 mm | Standard Deviation 4.4 |
p-value: 0.40995% CI: [-3, 1.2]t-test, 2 sided
p-value: 0.0295% CI: [15, 1000]Regression, Linear
Secondary
Clincal and Safety Outcomes
Number of events -death, reinfarction, repeat revascularizations (target and nontarget vessels) hospitalizations for heart failure, ICD placements
Time frame: Measured from baseline to six months.
Population: All randomized patients were followed for clinical outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Day 3 Stem Cell Arm | Clincal and Safety Outcomes | 10 events |
| Day 3 Placebo Arm | Clincal and Safety Outcomes | 9 events |
| Day 7 Stem Cell Arm | Clincal and Safety Outcomes | 6 events |
| Day 7 Placebo Arm | Clincal and Safety Outcomes | 1 events |
Comparison: Clinical and Safety Outcomes including death, reinfarction, repeat revascularization, hospitalization for heart failure and ICD placement. The relative incidences of events are compared between the active and placebo groups.However the paucity of events precluded a reliable time to event analysis.p-value: 0.9395% CI: [0.42, 2.23]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 |
|---|---|---|---|
| Day 3 Stem Cell Arm | End Diastolic Volume Index | 11.4 mL/m2 | Standard Deviation 18.5 |
| Day 3 Placebo Arm | End Diastolic Volume Index | 11.7 mL/m2 | Standard Deviation 19.8 |
| Day 7 Stem Cell Arm | End Diastolic Volume Index | 13.3 mL/m2 | Standard Deviation 19.5 |
| Day 7 Placebo Arm | End Diastolic Volume Index | 9.7 mL/m2 | Standard Deviation 16 |
Comparison: Day 3 Stem Cell Arm and Day 7 Stem Cell Arm were combined and compared to the combination of Day 3 Placebo and Day 7 Placebo arms.p-value: 0.83195% CI: [-6.6, 8.2]Regression, Linear
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 |
|---|---|---|---|
| Day 3 Stem Cell Arm | End Systolic Volume Index | 4.1 mL/m2 | Standard Deviation 15 |
| Day 3 Placebo Arm | End Systolic Volume Index | 4.1 mL/m2 | Standard Deviation 16.5 |
| Day 7 Stem Cell Arm | End Systolic Volume Index | 6.2 mL/m2 | Standard Deviation 17.4 |
| Day 7 Placebo Arm | End Systolic Volume Index | 4.6 mL/m2 | Standard Deviation 12.8 |
Comparison: Day 3 Stem Cell Arm and Day 7 Stem Cell Arm were combined and compared to the combination of Day 3 Placebo and Day 7 Placebo arms.p-value: 0.81795% CI: [-5.5, 7]Regression, Linear
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 |
|---|---|---|---|
| Day 3 Stem Cell Arm | Infarct Volume | -9.7 mL | Standard Deviation 18.4 |
| Day 3 Placebo Arm | Infarct Volume | -7.7 mL | Standard Deviation 23.4 |
| Day 7 Stem Cell Arm | Infarct Volume | -13.6 mL | Standard Deviation 18.8 |
| Day 7 Placebo Arm | Infarct Volume | -5.3 mL | Standard Deviation 29.3 |
Comparison: Day 3 Stem Cell Arm and Day 7 Stem Cell Arm were combined and compared to the combination of Day 3 Placebo and Day 7 Placebo arms.p-value: 0.27295% CI: [-13.7, 3.67]Regression, Linear
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 |
|---|---|---|---|
| Day 3 Stem Cell Arm | Left Ventricular Mass | -20.4 g | Standard Deviation 22.8 |
| Day 3 Placebo Arm | Left Ventricular Mass | -13.2 g | Standard Deviation 30.6 |
| Day 7 Stem Cell Arm | Left Ventricular Mass | -16.3 g | Standard Deviation 16.7 |
| Day 7 Placebo Arm | Left Ventricular Mass | -20.7 g | Standard Deviation 26.9 |
Comparison: Day 3 Stem Cell Arm and Day 7 Stem Cell Arm were combined and compared to the combination of Day 3 Placebo and Day 7 Placebo arms.p-value: 0.58595% CI: [-12.2, 6.9]Regression, Linear