Intracoronary delivery of bone marrow mononuclear cells to the infarct zone of patients who have undergone percutaneous coronary intervention following an ST-segment elevation myocardial infarction did not improve left ventricular function at 6 months in the TIME trial.
The trial was designed to examine the difference in effect of infusing the bone marrow mononuclear cells (BMCs) into the infarct-related artery at 7 days after PCI and at 3 days, Dr. Jay H. Traverse reported at the annual scientific sessions of the American Heart Association.
Dr. Jay H. Traverse
Unfortunately, neither of these approaches were any better than placebo infusion at improving the recovery of left ventricular function, improving left ventricular volume, or reducing infarct size at 6 months’ follow-up in this double-blind Timing in Myocardial Infarction Evaluation (TIME) clinical trial, said Dr. Traverse, of the Minneapolis Heart Institute at Abbott Northwestern Hospital.
"However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI [acute myocardial infarction]," Dr. Traverse and his associates said in an article published online simultaneously with his presentation (JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726]).
Recent research indicates that the timing of BMC infusion after PCI due to ST-segment elevation myocardial infarction (STEMI) might be critical. In the days following STEMI, there are significant temporal changes in the release of cytokines and growth factors "that may support stem-cell homing and angiogenesis, leading to improved cell survival and engraftment," they noted.
"Conversely, reactive oxygen species and inflammatory cytokines ... released by [damaged] myocardium and circulating inflammatory cells may adversely affect the bone marrow and stem cell function and/or survival." This could in turn impair the quality and potency of BMCs harvested from the patient.
The results of one large study indicated that stem cells harvested 5-7 days after an acute MI performed better than those harvested earlier, but "this important variable has never been evaluated in a prospective trial that randomly selects the day of cell delivery," the researchers said.
The TIME trial was designed to do so.
A total of 132 high-risk patients were enrolled during a 3-year period after they had experienced STEMI, shown a left ventricular ejection fraction (LVEF) of 45% or less, and were slated for PCI with stenting. These subjects were randomly assigned to have stem cell therapy on either day 3 or day 7 after PCI; they underwent bone marrow aspiration on the day of the procedure, and their BMCs were isolated and stored.
After some of these patients were excluded or withdrawn from the study, the remaining 120 patients underwent a second randomization to receive either the autologous BMCs (79 patients) or placebo infusions (41 patients).
The primary end points of TIME were changes in global and regional left ventricular function on MRI scanning at 6 months post PCI. There were no significant differences in these outcomes between subjects who received stem-cell therapy 3 days after PCI and those who received it 7 days after PCI, the investigators reported.
There also were no significant differences among the study groups in secondary outcomes such as reduction in infarct volume or change in ventricular volumes.
However, there also were no significant differences in any outcomes between subjects who received active BMCs and those who received placebo infusions. This may indicate that, contrary to previous findings, BMCs do not improve left ventricular function when administered in the immediate post-STEMI setting.
But it also is possible that "the phenotype and functionality of the BMC product in this population may be an issue," and that allogeneic BMCs procured from younger, healthier donors may have a better regenerative capacity, Dr. Traverse and his colleagues said.
It was encouraging that despite their high risk, these study subjects had few clinical events during follow-up. One death occurred (due to subarachnoid hemorrhage) before stem-cell therapy was administered. Eleven patients required repeat revascularization, and 6 received implantable cardioverter-defibrillators (ICDs). There were no significant differences among the study groups in the rates of these adverse events.
This study was funded by the National Heart, Lung, and Blood Institute. Dr. Traverse reported no financial conflicts of interest, but his associates reported numerous ties to industry sources.