INTRODUCTION
The Timing In Myocardial Infarction Evaluation (TIME)1 trial assessed whether the timing of stem cell delivery affects the recovery of left-ventricular (LV) function following myocardial infarction. Patients with anterior ST-elevation myocardial infarction (STEMI) who were reperfused with primary percutaneous coronary intervention and stenting and had at least moderate LV dysfunction. (left-ventricular ejection fraction [LVEF] ≤ 45%) were randomized (2:1) to 150 million autologous bone marrow mononuclear cells (BMCs) or placebo with intracoronary delivery performed on Day 3 (n=67) or Day 7 (n=53). At 6 months, no benefit of cell therapy was observed compared to placebo following cell delivery on Day 3 or Day 7. We now report outcomes at 1 year; the collection of clinical endpoint and cardiac magnetic resonance imaging (MRI) data was pre-specified but not the analysis plan.
METHODS
TIME was reviewed and approved by each center’s institutional review board with written informed consent collected from all participants. A total of 95 patients (n= 65 BMCs, n= 30 placebo) of the original 112 analyzed at 6 months (n=75 BMCs; n=37 placebo) had analyzable MRI data through 1- year. Reasons for the drop-off between 6-mo and 1-year included implantable cardioverter-defibillator placement (ICD) (3), death (1) loss to follow-up/refused (2), not performed (1) or no-show (10). Follow-up for all patients was completed by November 12, 2012.
The primary analyses were changes in LVEF and regional (infarct and border zone) LV function between baseline and 6 months by cardiac MRI. Primary and secondary outcomes followed to 1 year are listed in Table 1 and safety outcomes in Table 2. Because an effect of timing was not observed, data are presented as the aggregate of the means of Day-3 and Day-7 groups. Differences in the changes in primary and secondary endpoints between therapy groups and trajectories over time were assessed using repeated measures analysis of variance. Worst case imputation (substitute worse value in the cohort for the missing value) was also conducted. All hypothesis testing was 2-tailed. Results < 0.05 were considered statistically significant. Software analyses was performed with SAS for Windows version 9.3.
Table 1.
Baseline, 6-month and 1-year cardiac MRI Results from TIME
| BMC | Placebo | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CI | CI | ||||||||||||
| N | mean | SD | LB | UB | N | mean | SD | LB | UB | P-value* | P-value† | P-value‡ | |
| LVEF | |||||||||||||
| 3 day | 65 | 46.2 | 9.6 | 43.9 | 48.5 | 30 | 46.3 | 8.5 | 43.3 | 49.3 | |||
| 6 month | 65 | 50.1 | 11.8 | 47.2 | 53.0 | 30 | 51.5 | 11.2 | 47.5 | 55.5 | ≤0.001 | 0.20 | |
| 1 year | 65 | 49.5 | 12.3 | 46.5 | 52.5 | 30 | 49.6 | 10.7 | 45.8 | 53.4 | ≤0.001 | 0.30 | |
| Regional Infarct Zone (mm) | |||||||||||||
| 3 day | 65 | 3.8 | 4.9 | 2.6 | 5.0 | 30 | 4.6 | 4.6 | 3.0 | 6.2 | |||
| 6 month | 65 | 5.8 | 6.6 | 4.2 | 7.4 | 30 | 8.1 | 6.4 | 5.8 | 10.4 | ≤0.001 | 0.58 | |
| 1 year | 65 | 6.2 | 5.9 | 4.8 | 7.6 | 30 | 6.4 | 5.8 | 4.3 | 8.5 | ≤0.001 | 0.67 | |
| Regional Border Zone (mm) | |||||||||||||
| 3 day | 65 | 16.4 | 10.2 | 13.9 | 18.9 | 30 | 14.4 | 9.8 | 10.9 | 17.9 | |||
| 6 month | 65 | 20.6 | 11.6 | 17.8 | 23.4 | 30 | 21.1 | 13.4 | 16.3 | 25.9 | ≤0.001 | 0.49 | |
| 1 year | 65 | 21.2 | 12.0 | 18.3 | 24.1 | 30 | 21.2 | 13.2 | 16.5 | 25.9 | ≤0.001 | 0.00 | |
| Infarct Size (g) | |||||||||||||
| 3 day | 63 | 44.7 | 23.1 | 39.0 | 50.4 | 30 | 46.3 | 27.4 | 36.5 | 56.1 | |||
| 6 month | 63 | 30.7 | 15.4 | 26.9 | 34.5 | 30 | 31.7 | 20.2 | 24.5 | 38.9 | ≤0.001 | 0.04 | |
| 1 year | 63 | 28.8 | 15.4 | 25.0 | 32.6 | 30 | 27.7 | 17.2 | 21.5 | 33.9 | ≤0.001 | ≤0.001 | |
| LV Mass (g) | |||||||||||||
| 3 day | 63 | 180.4 | 47.6 | 168.6 | 192.2 | 30 | 177.3 | 46.1 | 160.8 | 193.8 | |||
| 6 month | 63 | 156.8 | 41.0 | 146.7 | 166.9 | 30 | 161.3 | 42.6 | 146.1 | 176.5 | ≤0.001 | 0.00 | |
| 1 year | 63 | 148.9 | 41.8 | 138.6 | 159.2 | 30 | 151 | 44 | 135.3 | 166.7 | ≤0.001 | 0.00 | |
| LVEDVI (ml/m2) | |||||||||||||
| 3 day | 65 | 77.1 | 18.0 | 72.7 | 81.5 | 30 | 70.5 | 17.1 | 64.4 | 76.6 | |||
| 6 month | 65 | 86.7 | 25.0 | 80.6 | 92.8 | 30 | 80.3 | 22.8 | 72.1 | 88.5 | ≤0.001 | 0.14 | |
| 1 year | 65 | 88.7 | 25.0 | 82.6 | 94.8 | 30 | 82.6 | 22.4 | 74.6 | 90.6 | ≤0.001 | ≤0.001 | |
| LVESVI (ml/m2) | |||||||||||||
| 3 day | 65 | 41.9 | 13.5 | 38.6 | 45.2 | 30 | 38 | 11.7 | 33.8 | 42.2 | |||
| 6 month | 65 | 44.7 | 20.3 | 39.8 | 49.6 | 30 | 40 | 17.6 | 33.7 | 46.3 | 0.08 | 0.02 | |
| 1 year | 65 | 46.3 | 21.3 | 41.1 | 51.5 | 30 | 42.9 | 18.4 | 36.3 | 49.5 | 0.00 | 0.02 | |
BMC=bone marrow cells; CI=confidence interval; LB=lower bound; UB=upper bound; LVEF=Left Ventricular Ejection Fraction; LVEDVI=left ventricular end-diastolic volume index; LVESI=left ventricular end-systolic volume index
vs. Day 3
1 year vs. 6 month
change in the mean value from baseline through six months to one year using a repeated measures mixed model
Table 2.
Clinical/Safety Outcomes, Baseline – 1 year
| BMC* (n=79) |
Placebo* (n=41) |
|||
|---|---|---|---|---|
| Patients with events | 18 | 9 | ||
| Deaths | 1 | |||
| Reinfarctions† | 2 | 3 | ||
| Repeat Revascularizations‡ | 9 | 6 | ||
| Target Vessel | 4 | 4 | ||
| Non-Target Vessel | 5 | 2 | ||
| Hospitalization Heart Failure | 4 | 1 | ||
| ICD Placements€ | 4 | 5 | ||
| Stroke | 2 | 2 | ||
| Total | 22 | 17 | ||
| CIR | 0.228 | 0.220 | ||
N=number of patients randomized; BMC=bone marrow cells; ICD=implantable cardiac defibrillator
=2 new infarctions (1 BMC, 1 placebo)
=4 new repeat revascularizations (2 BMC, 2 placebo)
=3 new ICD (1 BMC, 2 placebo)
RESULTS
LVEF increased from Day-3 to 6-mo in both the BMC (46.2 [(95% CI, 43.9–48.5]) to 50.1 [(95% CI, 47.2–53.0]) %) and placebo groups (46.3 [(95% CI, 43.3–49.3] to 51.5 [(95% CI, 47.5–55.5]) (p < 0.01) but did not improve further between 6-mo and 1-year in either group (BMC = 49.5 [(95% CI, 46.5–52.5)%; Placebo = 49.6 [95% CI, 45.8–53.4]%). Regional LV function increased in infarct and border zones between Day-3 and 6-mo in both groups with no further increase between 6-mo and 1-year (Table 1). There were no differences at any time-point between the BMC and placebo groups. Between Day 3 and 1-year, there were increases in LV volumes in both the BMC and placebo groups, with no significant differences between groups (Table 1). The results were unchanged in the worst-case imputation analysis.
Infarct size decreased in the BMC and placebo groups between Day-3 and 6 months with a smaller reduction between 6-mo and 1-year. The reduction in infarct size was accompanied by a similar significant reduction in LV mass through 1-year (Table 1). There were no differences in the reduction in infarct size and LV mass between the BMC and placebo group at any time-points.
There were 2 more repeat infarctions, and 4 repeat-revascularizations and 3 ICD placements (Table 2).
CONCLUSION
The administration of BMCs following moderate to large anterior STEMIs, was not associated with improved recovery of global and regional LV function at 1-year, irrespective of cell delivery at 3 or 7 days post-PCI. The recovery of LV function following STEMI appeared complete by 6-months as no additional improvement in LV function was observed in either group between 6-months and 1-year. Our results do not support the administration of BMCs following myocardial infarction. However, because we were unable to obtain 1-year MRIs on all subjects, the precision of our estimates of change in LV function is reduced.
Acknowledgements
Jay H Traverse had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.
Funding/Support: Funding for this trial was provided by the National Heart, Lung and Blood Institute under cooperative agreement 5 UO1 HL087318-04. Support for cell processing (Sepax) was provided by Biosafe SA Inc. (Switzerland) Angioplasty catheters were provided by Boston Scientific Corporation (Natick, MA). None of these entities had any role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation of this manuscript. The NHLBI reviewed and approved the manuscript.
Dr Henry reported serving as a consultant for Capricor and Johnson and Johnson (BDS) and receiving grant support from Capricor and OSIRIS. Dr Pepine reported receiving funding for writing assistance, medicines, equipment or administrative support from the NHLBI and Biosafe. Dr. Ellis reported receiving travel support from Abbott Vascular and Boston Scientific. Dr Willerson reported receiving funding from the NHLBI for participation in review activities.
We acknowledge all the contributions by the Investigators of the Cardiovascular Cell Therapy Research Network (CCTRN) and the leadership and vision of the late Dr. Sonia Skarlatos.
Footnotes
Presented at the 2013 Scientific Sessions of the American Heart Association, November 18, 2013, Dallas TX.
Conflict of Interest Disclosure: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
REFERENCES
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