Mixed Start to Planned MARVEL Trial of Post-MI Autologous Skeletal-Myoblast Therapy

September 23, 2009

September 23, 2009 (Boston, Massachusetts) — Early results from a placebo-controlled trial suggest, as have earlier studies, that percutaneous skeletal-myoblast cell therapy (MyoCell, Bioheart) can improve functional capacity in patients with post-MI myocardial scarring, but apparently at a price. The pilot phase of a trial called MARVEL that randomized 20 patients to receive the autologous cells at two dosage levels or to placebo also mirrored earlier studies in its suggestion that the therapy may be proarrhythmic.

There were also signs that amiodarone, started early in the procedure, can lower the risk of serious arrhythmias in patients getting the cell therapy, observed Dr Thomas J Povsic (Duke University, Durham, NC) when reporting the analysis at the Heart Failure Society of America 2009 Scientific Meeting.

Described as the first double-blind, placebo-controlled study of the cell therapy delivered percutaneously, MARVEL randomized its initial patients to receive autologous myoblasts by intramyocardial injection at doses containing 400 or 800 million cells or to a sham procedure. The cells had been cultured from skeletal-muscle tissue obtained by biopsy several weeks earlier.

Enrollment required patients to have nonischemic left ventricular scarring after an MI occurring at least 12 weeks previously, an LVEF <35%, and heart failure of NYHA class 2–4 despite optimal medications. They could not have had sustained VT, acute coronary syndromes, or PCI within the past three months.

We're not just looking at an increase in ejection fraction, although we're interested in that. What we really need to know is what's happening to regional function, infarct size, and tissue perfusion.

By six months, cell-therapy patients had shown steady increases in six-minute-walk distance, the primary efficacy end point, for a total advance of 96 meters and 86 meters in the low- and high-dose groups, respectively, Povsic said. Although the gains weren't significant in these few patients, none were seen in the control group. Quality-of-life scores "improved dramatically" in all three patient groups.

There were seven instances of sustained VT in six cell-therapy patients (three patients in each dosage group) during the follow-up and one episode in one control patient.

Amiodarone had been given at the discretion of treating physicians. Of the 14 cell-therapy recipients, VT occurred in four of the seven who hadn't received prophylactic amiodarone, and there were no VT episodes once all seven were put on the drug; it developed in two of the three patients who either started or stopped amiodarone at implantation; and it never occurred in the three patients who were put on the antiarrhythmic at the time of biopsy--which, Povsic noted, had allowed three weeks of amiodarone loading before the cell injections.

As the invited commenter after the MARVEL presentation, Dr Joshua M Hare (University of Miami, FL) said, "The big problem that's plaguing the use of skeletal myoblasts, as opposed to other cell sources, is this continued signal we've seen, in just about every skeletal-myoblast trial, of a potential for proarrhythmic effects." Here it was nonsignificant, he said, but "the numerical increases are a concern," and it hasn't been observed with other forms of cell therapy, such as those based on bone-marrow–derived cells.

Hare also proposed that, in future investigations, the results of the treatment be evaluated with "sophisticated imaging."

"We're not just looking at an increase in ejection fraction, although we're interested in that. What we really need to know is what's happening to regional function, infarct size, and tissue perfusion--are we really achieving reverse remodeling with the cell-based therapeutic? Imaging modalities such as cardiac MRI and multidetector CT offer that in a way that echocardiography and nuclear imaging don't."

Although MARVEL had been envisioned as a 390-patient trial, the results of the pilot phase have caused the investigators to change course, Povsic said; the plan now is randomization of 60 patients to each group. Based on the current analysis, he said, that size should be sufficient to show a "clinically meaningful" minimum 30-m increase in six-minute-walk distance with cell therapy.

MARVEL is sponsored by Bioheart. Povsic reports no conflicts of interest. Hare reports holding stock in Kardia and receiving research support from Biocardia and Osiris.