ixCELL-DCM Study: Stem-Cell Therapy Improves Clinical Cardiac Outcomes in Heart Failure

Patrice Wendling

April 05, 2016

CHICAGO, IL — Stem-cell therapy injected into the myocardium significantly reduced clinical cardiac events in patients with ischemic heart failure[1].

At 1 year, patients treated with ixmyelocel-T had a 37% relative reduction in the risk of all-cause mortality, cardiovascular-related hospital admissions, and unplanned clinic visits to treat acute decompensated heart failure.

But the multicellular therapy had no effect on the secondary end points of LVEF or left ventricular volumes, Dr Timothy D Henry (Cedars Sinai Heart Institute, Los Angeles, CA) reported at the American College of Cardiology (ACC) 2016 Scientific Sessions; the study was simultaneously published online in the Lancet.

Several panelists questioned the mechanism behind the improved clinical outcomes when the injections were presumably done to improve some facet of cardiac function.

"At 6 months, there's maybe a 1-point delta in ejection fraction, but an amazing difference in deaths and cardiovascular hospitalizations, which actually seems to start even earlier than that. So what's the mechanism?" panelist Dr James Udelson (Tufts Medical Center, Boston, MA) asked.

Dr Timothy Henry

Henry said the greater effect on clinical events than LVEF is actually consistent with other cell-therapy trials. Measurement of LVEF and LV volumes in the ixCELL-DCM trial was also done with echocardiography rather than higher-resolution MRI because patients had ICDs, which could affect both function and volumes.

At the same time, the double-blind trial used a very conservative statistical approach to analyze secondary outcomes, he said. For example, 15% of patients in the control arm were not alive to have a final echo or other measures, so they used "last observation carried forward," which may have narrowed the gap between groups.

Boosting Stem-Cell Therapy

Stem-cell therapy has been attempted in a number of heart-failure trials and been shown to be a safe but generally weak therapy. There is a lot of variability in cells from one patient to the next because as people age, the number of stem cells and their potency decline, Henry said.

To get around this, bone-marrow cells were extracted and expanded over 2 weeks to increase two key types of mononuclear cells: CD90+ mesenchymal stem cells and CD45+ and CD14+ macrophages.

The ixmyelocel-T product or placebo were then randomly assigned to 126 patients with NYHA class 3/4 symptomatic heart failure due to ischemic cardiomyopathy with an LVEF of 35% or less and an ICD in place. Patients were also required to have one of three high-risk characteristics: heart-failure hospitalization within 6 months, elevated brain natriuretic peptide (BNP) or N-terminal proBNP, or a 6-minute-walk <400 m.

At 1 year, there were 50 primary efficacy events in 25 of 51 controls (49%) and 38 events in 22 of 58 patients in the ixmyelocel-T arm (38%). This translated into a 37% reduction in events in the per-protocol analysis (risk ratio [RR] 0.63; P=0.034).

This was driven by both fewer deaths and cardiac hospitalizations, Henry said. Rates of these two events in the cell-treated and placebo arms were 3.4% and 13.7%, respectively, and 38% vs 47%, respectively.

Only two patients, both in the ixmyelocel-T arm, had unplanned clinic visits for heart failure.

There was no significant effect on secondary end points of EF, left-ventricular volumes, NYHA class, or 6-minute-walk test.

Serious adverse events were significantly reduced in this very sick population from a rate of 75% with placebo to 53% with cell therapy (P=0.019), Henry said.

"Ixmyelocel-T appears to be an attractive option for NYHA class 3/4 patients with ischemic heart failure who have exhausted optimal medical and device therapy," he said.

Dr John Jarcho

Dr John Jarcho (Brigham and Women's Hospital, Boston, MA), who was not involved in the study, told heartwire from Medscape that there's been a lot of discussion about whether the benefit of cell therapy might occur not as a result of simply restoring mechanical function to the heart, but as a result of paracrine mechanisms or the production of biochemical mediators by the tissue. But there's limited evidence up to this point. "My concern about this is that it's clear they got a statistically significant results, but it's a small trial," which calls into question the robustness of the data and the need for replication in larger trials, he added.

Henry told heartwire it's too early to detail plans for another trial because the data are just 3 weeks old but that cell therapy would be a feasible option for these patients because the process is simple, well-tolerated, and very much needed. "I actually think if you repeat this in a larger trial it would be used a lot; certainly a lot simpler than doing a heart transplant or an LVAD," he said.

The trial was sponsored by Vericel Corp. Henry received financial support from Vericel in the form of grants and personal fees; he reports consultant fees/honoraria from Abbott Vascular, Baxter, Capricor, Cytori, Eli Lilly, and the Medicines Company and research for or research grants from Aastrom and Baxter. Disclosures for the coauthors are listed in the article. Udelson reports consultant fees/honoraria from Lantheus Medical Imaging, serving on a data safety monitoring board for Gilead and GlaxoSmithKline, and serving as a Heart Failure Society of America executive. Jarcho reports no relevant financial relationships.

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