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High-dose autologous cell therapy may benefit patients with LV dysfunction after STEMI
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CHICAGO — New data from the phase 2 PreSERVE-AMI study suggest a dose-dependent benefit of autologous CD34+ cell therapy for patients with left ventricular dysfunction after STEMI.
Previous research has demonstrated that infusion of cell therapy in this patient population was associated with a modest improvement in LV ejection fraction, reductions in infarct size and end-systolic volume, and a trend toward reduction in major adverse cardiac events, especially if given at least 5 days after STEMI and if containing a high number of CD34+ cells, Arshed A. Quyyumi, MD, FRCP, from Emory University School of Medicine, said at the American Heart Association Scientific Sessions. A phase 1 study showed evidence of safety and feasibility and suggested a threshold dose of 10 million CD34+ cells, Quyyumi said.
Arshed A. Quyyumi*
PreSERVE-AMI was a phase 2, randomized, double blind, placebo-controlled trial of patients with LV dysfunction after STEMI. Patients were assigned NBS10, a formulation of autologous CD34+ cells known to enhance and preserve functional CXCR4 expression, or matching cell-diluent placebo, administered 6 to 11 days after stent placement.
Although there is a lot of current research on potential CV benefits of bone-marrow or cardiac cell therapy, PreSERVE-AMI differs in two key respects, Douglas W. Losordo, MD, chief medical officer of NeoStem Inc., the trial’s sponsor, and adjunct professor of medicine at Northwestern University Feinberg School of Medicine and clinical professor of medicine at New York University School of Medicine, told Cardiology Today.
“One, rather than taking the entire bone marrow mononuclear cell population, we have looked at the science and made a determination that the CD34+ cell represents one of the key, if not the key, active ingredients in the bone marrow cell population that exercises this effect of tissue repair,” said Losordo, a member of the Cardiology Today Editorial Board and an investigator for PreSERVE-AMI. “The second … is the evidence that has been generated relating to the dose of cells to an observed effect, whether it’s ventricular function or safety events.”
Douglas W. Losordo
In total, 190 patients were randomly assigned, but some dropped out of the study due to death, withdrawal of consent, screen failure or cell product not meeting release criteria. Quyyumi reported data from an intention-to-treat population of all 161 patients who received infusions.
The primary endpoints were major adverse cardiac events up to 3 years, serious adverse events up to 3 years and change in myocardial perfusion at 6 months. The secondary endpoint was 6-month change in LVEF.
There was no difference between the groups in serious adverse events during the harvest procedure (P=.42) or the infusion procedure (P=.9), and overall rates were low, Quyyumi said.
During a median follow-up of 1 year, the groups also did not differ in the rate of adverse events (P=.89) or serious adverse events (P=.97). However, patients who received higher doses of autologous CD34+ cells had a lower rate of serious adverse events compared with patients who received lower doses or placebo, he said.
Three patients in the placebo group died compared with none in the CD34+ cell treatment group (P=.04). Although the rate of total major adverse cardiac events was similar between the groups (P=.66), patients who received higher doses of cells were less likely to experience major adverse cardiac events vs. placebo (P=.002 and P=.017, respectively).
Both groups showed a reduction in Resting Total Severity Score, a measure of myocardial perfusion, but “the differences between the two did not reach statistical significance,” according to Quyyumi. Patients showed an average LVEF improvement of 4% to 5%; there was no difference between the groups, but those receiving at least 20 million cells had better LVEF improvement than the placebo group (10.2% vs. 4.9%; P<.05), he said.
“Intracoronary administration of high-dose autologous CD34+ cells appears to be safe and well tolerated, is associated with a statistically significant reduction in mortality, and although there was no overall difference in [serious adverse event] rate, there was a trend toward a dose-dependent reduction in [serious adverse events], with a similar trend in [major adverse cardiac events] rates,” Quyyumi said.
The study showed enough evidence to warrant further research, Losordo said. “What you want answered from a phase 2 study is does it warrant going forward,” he said. “Everybody at NeoStem has spent a lot of time thinking about that question, and our assessment of the data is, yes, it does warrant moving forward. We’ll continue to follow [PreSERVE-AMI participants] for 3 years and continue to analyze data along the way to give us clearer direction in terms of what the design of the next-phase study would look like.” – by Erik Swain
For more information:
Quyyumi AA. CS.02: Off the Beaten Pathologies. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.
Disclosure: The study was funded by NeoStem Inc. Quyyumi reports serving on an advisory board for NeoStem Inc. Losordo is an employee of NeoStem Inc.
* Photo by Jack Kearse, Emory University
Perspective
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Carl J. Pepine, MD
PreSERVE-AMI represents the first cell-therapy trial to show a reduction in mortality with administration of CD34+ cells. A unique aspect of this trial is that the investigators used high-dose CD34+ cells. In addition, patients enrolled in this trial had among the lowest baseline ejection fractions of the cell-therapy trials. The investigators did link the CD34+ cell number with a number of the outcomes. We previously published that using mobilized CD34+ cells in patients with refractory angina markedly reduced angina frequency and had a strong trend (P=.058) toward reduction in death or MI at 1 year (Losordo DW. Circ Res. 2011;109:428-436). It seems like this study too is zeroing in on something important for the CD34+ cells in ischemic heart disease. I would like to see more trials on this. All of these data are starting to fit together as important and the PreSERVE-AMI results will rejuvenate the cell therapy field.
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