CHICAGO – After rattling around in early-stage clinical studies for more than a decade, stem cell therapy for heart failure may have finally gained the efficacy evidence to send it to the next level: large-scale, phase III trials.
Patients with ischemic cardiomyopathy and severe heart failure showed a statistically significant 37% relative reduction in their combined rate of death and cardiovascular hospitalization during 1 year of follow-up after autologous stem cell injections to their left ventricular myocardium in a multicenter, fully blinded control, phase II trial with 109 North American patients.
The treatment used a technique in commercial development by Vericel that selectively expands ex vivo bone marrow cells taken from the heart failure patient. Clinicians inject 0.4 mL aliquots of the expanded cells – enriched for mesenchymal stem cells and M2 macrophages – via a transcatheter approach into the left ventricular myocardium using 12-17 injections per patient. The bone marrow preparation during ex vivo expansion is called ixmyelocel-T.
This treatment now needs testing in more patients, Dr. Timothy D. Henry said at the annual meeting of the American College of Cardiology. “We need a new generation of cell trials in larger studies with completely double-blind, placebo controls using a more uniform preparation of cells,” said Dr. Henry.
“To the best of our knowledge, ixCELL-DCM is the largest randomized, double-blind clinical trial to date for cell therapy use in congestive heart failure,” said Dr. Henry and his associates in their report. The concept of stem cell therapy to replace damaged myocardium “has been very attractive, but most clinical trials to date have been small and unblinded, and used unselected bone marrow cells,” explained Dr. Henry, director of cardiology at the Cedars-Sinai Heart Institute in Los Angeles.
The ixCELL-DCM study ran at 31 sites in the United States and Canada. About 90% of patients had New York Heart Association class III disease, the average left ventricular ejection fraction was about 25%, patients on average would cover about 310 m during a 6-minute walk test, and the average serum level of NT-ProBNP was about 1,900 pg/L. Patients in the control arm all underwent the same bone marrow retrieval and transcatheter injection into the left ventricle, but the injections only contained carrier material without active cells.
The primary endpoint of death or a cardiovascular event, primarily hospitalization, occurred at a rate of 110 events per 100 patient years during 1-year follow-up of 51 patients in the sham-treatment group. In the active-treatment arm, the endpoint occurred at a rate of 70 events per 100 patient years among 58 patients. The difference was primarily driven by a 3% death rate with cell therapy, compared with a 14% rate in the controls, and a 38% hospitalization rate, compared with a 47% rate among controls.
The study results appeared online concurrent with Dr. Henry’s report (Lancet. 2016 Apr 5. doi: 10.1016/S0140-673630137-4).
The results showed no significant differences between the active and sham groups for changes in left ventricular size, ejection fraction, and 6-minute walk distance.
“This trial was designed to look at events. It is not a cause for concern that we did not see effects on heart function,” Dr. Henry said. The current results were also generally consistent with results from two earlier, controlled, phase II studies with a total of 61 patients (Circ Res. 2014 Sep 26;115:730-7).
In the safety analysis, done in 114 patients, the rates of all adverse events and major adverse cardiovascular events were similar in the two arms. The rate of serious adverse events was significantly reduced in the patients treated with expanded bone marrow cells, compared with the controls.
The high rate of death and hospitalization of patients with severe heart failure “is a very large, unmet need, so it’s a natural to go to a larger trial,” Dr. Henry said. “The cell preparation was very safe and easy to do.”
Another pressing research issue is to try to understand the mechanism by which the cell treatment improves clinical outcomes, with improved heart function or improved exercise capacity apparently excluded as mechanisms.
The trial was sponsored by Vericel, the company developing the ex vivo protocol for selective marrow cell expansion. Dr. Henry has been a consultant to or received honoraria from Abbott Vascular, Baxter, Capricor, Cytori, Eli Lilly, and the Medicines Company, and he has received research grants from Aastrom, Baxter International, Mesoblast, and Vericel.
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