Cell Therapy Trials Show Mixed Results at AHA 2012

LOS ANGELES, CA—A plethora of trials examining different cell therapy techniques demonstrates the promise and problems inherent in such strategies in patients with myocardial ischemia undergoing coronary revascularization, according to results presented November 6, 2012, at the American Heart Association Scientific Sessions. 

Mesenchymal Cells Safe Regardless of Origin

The POSEIDON trial, led by Joshua M. Hare, MD, of the University of Miami Miller School of Medicine (Miami, FL), found that both allogeneic and autologous mesenchymal stem cells are safe in patients with LV dysfunction due to ischemic cardiomyopathy. Thirty patients were randomized in a 1:1 fashion to therapy with either cell type. Twenty, 100, or 200 million cells (5 patients in each cell type/dose level) were delivered into 10 LV sites.

At 30 days, 1 patient in each group (6.7%) was hospitalized for heart failure. The 1-year incidence of adverse events was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = 0.46). At 1 year, there were no ventricular arrhythmia events observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = 0.10).

Relative to baseline, autologous but not allogeneic cell therapy was associated with an improvement in the 6-minute walk test and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, but neither improved peak exercise oxygen consumption. Allogeneic and autologous cell therapy reduced mean early enhancement defect by -33.21% (95% CI -43.61% to -22.81%; P < 0.001) and sphericity index but did not increase LVEF.

Allogeneic cells reduced LV end-diastolic volumes. Low-dose cell concentrations (20 million cells) produced the greatest reductions in LV volumes and increased LVEF. Allogeneic stem cells did not stimulate substantial donor-specific reactions.

“Transendocardial stem cell injection has a highly satisfactory safety profile whether using allogeneic or autologous mesenchymal stem cells,” Dr. Hare noted. “Coupled with a similar efficacy impact, these data support the ongoing conduct of clinical trials with allogeneic mesenchymal stem cells.”

In addition, treatment with allogeneic stem cells “may be an acceptable alternative to autologous cells, thereby providing a convenience factor,” he concluded. “Cell therapy may not only improve LV structure, but may also improve quality of life and functional capacity.”

Cardiac Stem Cells Show Benefit

Likewise, Roberto Bolli, MD, of the University of Louisville (Louisville, KY), presented successful results of the open-label, single-center SCIPIO (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy) trial studying intracoronary infusion of autologous cardiac stem cells in patients with heart failure after MI. The therapy safely improved left ventricular systolic function and reduced infarct size up to 2 years after infusion.

Patients who had undergone CABG and who had post-infarction LV dysfunction were randomized in a 2:3 fashion to either stem cell treatment or no treatment. Patients in the treatment arm (for this analysis, n = 20; n = 13 for controls) were given autologous cardiac stem cells at a mean of 113 days after surgery.

At 4 months post-infusion, treated patients saw their LVEF increase from 29.0% at baseline to 36.0% (P < 0.001). This was associated with an improvement in regional wall motion score in the infused LV regions (P = 0.012) as well as in all segments (P = 0.003) and improved quality of life by MLHFQ score (P < 0.001). By contrast, control patients saw no improvement in LVEF (29.2% vs. 29.4%) or MLFHQ over the corresponding time interval.

The beneficial effects of cardiac stem cells persisted and became progressively greater at 1 (P < 0.001) and 2 (P = 0.008) years. In the 9 treated patients who underwent MRI, there was a profound reduction in infarct size at 4 months (P < 0.001) that improved at 1 year (P = 0.003). Viable LV tissue also increased in treated patients at 4 months (P = 0.055) and 1 year (P = 0.035). No adverse effects were observed with cardiac stem cell therapy up to 2 years.

Dr. Bolli concluded that the administration of cardiac stem cells in this patient group is “feasible and safe, at least in the short term.” Going forward, “we need to perform larger, multicenter, randomized, blinded studies to confirm these data,” he said. “But the important point is that we can now apply this therapy to almost every patient with heart failure because we can obtain the cells with a percutaneous biopsy, which can be done as an outpatient procedure.”

Novel Hybrid Strategy

For the phase I ALCADIA (AutoLogous human CArdiac-Derived stem cell to treat Ischemic cArdiomyopathy) trial, Naofumi Takehara, MD, PhD, of Kyoto Prefectual University of Medicine (Kyoto, Japan), and colleagues used a unique hybrid strategy to treat 6 patients with ischemic cardiomyopathy following acute MI.

In addition to CABG, Dr. Takehara and colleagues administered autologous cardiac stem cells (5 x 105 cell/kg) via intramyocardial injection combined with sustained release of basic fibroblast growth factor (bFGF; 200 µg) using a biodegradable scaffold. At 6 months, there was a single MACE event, consisting of congestive heart failure. At 24 weeks, LVEF improved on cardiac MRI compared with baseline from roughly 22% to 35% (P = 0.0117). In addition, maximal oxygen consumption improved from roughly 12.5 ml/kg/min to 16.5 ml/kg/min (P = 0.0308). 

There was also partial reverse remodeling, as wall motion score improved by 24 weeks (P = 0.0013) and infarct volume/LV mass decreased from roughly 23% to 20%, though the difference was not significant (P = 0.1742).

“The transplantation of human cardiac-derived stem cells with controlled release of bFGF is safe and feasible for ischemic cardiomyopathy patients,” Dr. Takehara said. “This novel biotherapy may have a potential to restore the injured heart and to achieve functional repair with reconstruction of the post-ischemic environment.”

It’s Not So Much in the Timing

Two studies compared early vs. late cell therapy administration, with neither strategy achieving any benefits. For the TIME trial, Jay H. Traverse, MD, of the Minneapolis Heart Institute (Minneapolis, MN), and colleagues gave autologous bone marrow stem cells (150 x 106 cells) or placebo via intracoronary infusion to 120 patients with a first anterior MI treated by primary PCI with stenting. The patients were divided into two groups, each of which received therapy either 3 or 7 days after MI.

According to the results, which were simultaneously published online in the Journal of the American Medical Association, the change in LVEF from baseline to 6 months was no different with bone marrow stem cells (45.2% to 48.3%) than placebo (45.5% to 47.8%; P = 0.96). In addition, there were no changes in global LV function in patients treated at day 3 (-0.9%; P = 0.76) or day 7 (1.1%; P = 0.70). 

The timing of treatment had no effect on regional LV functional recovery, and major adverse events were rare among all treatment groups.

Dr. Traverse noted that in a subanalysis, younger patients at day 7 randomized to bone marrow stem cells showed improvement in LVEF compared with placebo. Nevertheless, “among patients with STEMI treated with primary PCI, the administration of intracoronary bone marrow stem cells at either 3 days or 7 days after the event had no significant effect,” he concluded.

No Benefit Early or Late

For the SWISS-AMI trial, Daniel Sürder, MD, of Fondazione Cardiocentro Ticino (Lugano Switzerland), and colleagues randomized 192 STEMI patients receiving primary PCI to 1 of 3 groups:

  • Bone marrow stem cell intracoronary infusion 5 to 7 days post MI (early group)
  • Intracoronary infusion 3 to 4 weeks post MI (late group)
  • Control

From baseline to 4 months, there was no change in LVEF in any of the 3 groups (table 1).

Table 1. Change in Median LVEF

 

Baseline

4 Months

P Value

Control

40.0%

39.6%

0.74

Early Infusion

36.5%

37.9%

0.12

Late Infusion

36.3%

37.4%

0.45


The primary endpoint of change in LVEF at 4 months vs. baseline was not different between controls (-0.4%) and patients treated in the early group (1.8%; P = 0.18 vs. controls) or late group (0.8%; P = 0.45 vs. controls). 

The only difference was an improvement in LV end diastolic volume at 4 months in the late group vs. controls (P = 0.03). All other secondary endpoints including LVESV, scar size, and myocardial thickness were similar in each group.

The only predictor of cell therapy treatment efficacy was time from onset of pain to reperfusion within 4.5 hours in both the early group (P = 0.028 for interaction) and the late group (P = 0.003 for interaction).

Clinical events were low and similar in all 3 groups.

“Intracoronary infusion of bone marrow mononuclear cells, either 5 to 7 days or 3 to 4 weeks after primary PCI for STEMI did not improve LV function as assessed by cardiac MRI at 4 months compared with controls,” Dr. Sürder said.

Commenting on the studies, Philippe Menasche, MD, of Hôpital Européen Georges Pompidou (Paris, France), said, “We now have a bunch of cells, so it’s very difficult to sort out which one is going to be the ‘winner’ if there is a winner.” What will be important going forward is to separate the settings of acute infarction and ischemic heart failure, he continued, and to figure out whether “we should simply rely on the paracrine effects of the cells . . . or whether we should go a little bit further by trying to reconstruct a new myocardium by the grafted cells.”



Sources:

1. Hare JM, Fishman JE, Gerstenblith G, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: The POSEIDON randomized trial. JAMA:Epub ahead of print.

2. Bolli R. Effect of cardiac stem cells in patients with ischemic cardiomyopathy: Interim results of the SCIPIO trial up to 2 years after therapy. Presented at: American Heart Association Scientific Sessions; November 6, 2012; Los Angeles, CA.

3. Takehara N. The ALCADIA (autologous human cardiac-derived stem cell to treat ischemic cardiomyopathy) trial. Presented at: American Heart Association Scientific Sessions; November 6, 2012; Los Angeles, CA.

4. Traverse JH, Henry TD, Pepine CJ, et al. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: The TIME randomized trial. JAMA:Epub ahead of print.

5. Sürder D. Intracoronary infusion of BM-MNC early or late after AMI: 4 months results of the SWISS-AMI trial. Presented at: American Heart Association Scientific Sessions; November 6, 2012; Los Angeles, CA.

 

Disclosures:

  • POSEIDON was funded by the National Heart, Lung, and Blood Institute.
  • The TIME trial was funded by a grant from the National Heart, Lung, and Blood Institute.
  • Drs. Bolli, Takehara, Traverse, and Sürder report no relevant conflicts of interest.
  • Dr. Hare reports having a patent for cardiac cell-based therapy, receiving research support from and being a board member of Biocardia, having equity interest in Vestion Inc, and serving as a consultant for Kardia.
  • Dr. Menasche reports serving as a consultant for Regado Biosciences.

 

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Cell Therapy Trials Show Mixed Results at AHA 2012

LOS ANGELES, CA—A plethora of trials examining different cell therapy techniques demonstrates the promise and problems inherent in such strategies in patients with myocardial ischemia undergoing coronary revascularization, according to results presented November 6, 2012, at the American Heart Association

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