Cardiac stem-cell results highlight need for standardization and collaboration for the field to move forward
Orlando, FL - Three new stem-cell studies presented on the final day of the
American Heart Association 2007 Scientific Sessions—two positive, one negative—offer incremental new insights into how cell therapies might one day be able to help the heart. But after more than a decade of trial and error in countless small, single- or dual-center studies, some experts are calling for more consensus about the biologic fundamentals, what cells to use, how they're delivered, and when they should be used.
"We need randomized, blinded, placebo-controlled trials that are adequately sized," Dr Paul Armstrong (University of Alberta, Edmonton) argued following the presentation of the three trials. "They need to be cooperative, multicenter, and organized by academic research organizations where there are standardized, robust end points for efficacy and safety, with adequate long-term follow-up. Only then will we understand the true architecture of what this phenomenon and exciting area provides as it relates to the promise of helping our patients."
| Results from the US, UK, and Finland |
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Dr Nabil Dib
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The first of the three studies unveiled today was the CAUSMIC study, which may breathe new life into the strategy of catheter-based autologous skeletal-myoblast delivery in patients with ischemic cardiomyopathy. As Dr Nabil Dib showed today, NYHA class and Minnesota Living With Heart Failure Questionnaire scores improved at six and 12 months in the 23 patients who underwent skeletal-muscle-cell delivery as compared with placebo-treated patients. Echocardiograms of left ventricular function also showed significant improvements at six and 12 months in the cell-treated patients. In striking three-dimensional NOGA images, Dib showed that tissue viability appears to be significantly restored in and around the sites of myoblast injection. In contrast to the arrhythmias that stymied skeletal myoblast studies, no "arrhythmia concerns" were seen.
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Dr Gordon Tomaselli
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The FDA has now cleared a phase 2 clinical trial in 165 patients to see whether the findings can be replicated, Dib noted.
Commenting on the CAUSMIC study to heartwire, Dr Gordon Tomaselli (Johns Hopkins University, Baltimore, MD) emphasized that the NOGA mapping results are intriguing, pointing to the fact that there is electrically active tissue of some kind—a hint that some sort of cell differentiation has taken place. "It suggests that there is something going on that's more than just cells that are not muscle cells, secreting something to make things better in that area," Tomaselli said.
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Dr Heikki Huikuri
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The second positive study presented in today's session, dubbed FINCELL, was a double-blind comparison of bone-marrow-derived cells (BMCs) and placebo infusion delivered by intracoronary injection within two to six days after an acute MI, conducted at two centers in Finland. Presenting the results, Dr Heikki Huikuri (University of Oulu, Finland) showed that left ventricular ejection fraction improved significantly over six months (from a mean of 58.8% to 65.9%; p=0.002) in BMC-treated patients, but no such significant improvement was seen in placebo-treated patients. No significant differences were seen between the two groups in terms of arrhymogenesis or restenosis.
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Dr Manuel Galinanes
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The third study, however, presented to the press by Dr Manuel Galinanes and during the main sessions by Dr Keng-Leong Ang (University of Leicester, UK), which also looked at bone-marrow-derived cells, showed no improvement in contractility as measured by echocardiography in scarred akinetic myocardium among patients randomly allocated to intramuscular BMCs, intracoronary BMCs, or no injection
In the press conference, Galinanes acknowledged that his trial was not the first to show a lack of benefit of a stem-cell strategy to treat an older scar. "We are putting the bar here for the BMCs very, very high," he said. "When the scar is old it is very difficult to remove, but we wanted to do that because these are precisely the heart-failure patients who are dying. I think that the study we have done, while negative, is very important, and a step forward to really identifying the best clinical condition and the best stem cell."
-SW
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In a discussion following the trial presentations, experts pointed to a host of other unresolved questions confronting cardiac stem-cell therapy research. One of the early pioneers, Dr Philippe Menasché (HEGP, Paris, France), pointed out that arguments over what cell lines should be used is only one part of a larger problem. "No matter what cell type we are dealing with, as long as we have less than 1% of cells surviving after a few weeks, we cannot hope to trigger clinically meaningful and therapeutic benefits," he said. "If we are not able to improve on our delivery methods and not able to achieve reasonable levels of engraftment and survival, I don't think we're going to be able to really do anything efficient in our patients."
Armstrong came down hard on the need for larger trials and reiterated the need for more consensus within the field, pointing to the recent European task force recommendations that, he said, should form the core of an international consensus statement. "I do believe that this is a time for pause," he said, adding that it is up to institutional review boards to ensure that trials are adequately powered and held to a recognized standard before patients are put potentially at risk.
Others, including the presenters, underscored the need for a better understanding of the fundamental biology. Galinanes, senior author on the negative study, countered that large trials pose a "dilemma."
"How can we design big, huge trials when we still don't know enough about the biology of those cells?" he asked. "Should we instead decide on a smaller-sized trial that is very well designed, asking a very specific question?"
Tomaselli, likewise, proposed: "There needs to be a way to coordinate the things that are done at various locations with slightly different protocols so that we can somehow pool that information and be a bit smarter about the global effects we are seeing, rather than a study here, a study there, that function completely differently and may not be at all comparable," he said.
Dib is a board member of and shareholder in Mytogen Inc, the sponsor of the CAUSMIC trial.
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