‘Enhanced’ Multicellular Stem Cell Therapy Improves Clinical Outcomes in Heart Failure: ixCELL-DCM Study

Enhanced multicellular therapy produced from autologous bone marrow led to significant improvements in clinical cardiac events in patients with heart failure and reduced ejection fraction due to ischemic dilated cardiomyopathy, a new study shows. Overall, percutaneous delivery of the cell therapy resulted in a significant 37% relative reduction in the risk of all-cause mortality, hospital admissions for cardiovascular causes, and unplanned clinic visits to treat acute decompensated heart failure.

The positive results, which were presented today during the late-breaking clinical trials session and published concurrently in the Lancet, are important given the large unmet treatment need in patients with advanced heart failure, say researchers.

“Heart failure is the number one cause of morbidity and mortality in the United States,” said lead investigator Dr Timothy Henry (Cedars-Sinai Medical Center, Los Angeles, CA), during a press conference announcing the results. “There are a large percentage of patients who have class III heart failure despite optimal medical and device therapy. Regenerative therapy—or cell therapies—have been an attractive approach for this patient population.” 

The randomized, double-blind, placebo-controlled study, known as the ixCELL-DCM trial, included patients randomly assigned to ixmyelocel-T (Vericel Corporation, Cambridge, MA) or placebo. Ixmyelocel-T is an autologous bone marrow-derived multicellular therapy that selectively expands mesenchymal stem cells, monocytes, and macrophages using a proprietary cell-processing system. 

While cell-based regenerative therapy using unselected bone marrow has hinted at benefit in heart failure in the past, the improvement has been modest. “The trouble with unselected bone marrow is that as we get older, the number of stem cells and the potency of those stem cells decline” said Henry. In the present investigation, the autologous bone marrow-derived cells were expanded over 2 weeks to increase CD90+ mesenchymal stem cells and CD45+ and CD14+ macrophages and delivered via a transendocardial injection.  

The patients enrolled in the trial all had NYHA class III or IV symptomatic heart failure caused by ischemic dilated cardiomyopathy with an LVEF less than 35% and an implantable cardioverter defibrillator (ICD) in place. According to investigators, the patient population was “enriched” for individuals at high risk for clinical events, including those who had been hospitalized for heart failure within the past 6 months and those who had high brain natriuretic peptide (BNP) levels.

The primary endpoint of the study was a composite that included all-cause mortality, cardiovascular admissions to hospital, and unplanned hospital visits for the treatment of decompensated heart failure. At 1 year, 50 primary-endpoint events occurred in 25 of the 51 patients (49%) randomized to placebo in the per-protocol analysis. In contrast, there were 38 primary-endpoint events in 22 of the 58 patients (38%) randomized to treatment with ixmyelocel-T (risk ratio 0.63; 95% CI 0.42-0.97).

In terms of clinical events, the reduction was driven largely by fewer deaths and hospitalizations for cardiac causes. At 1 year, seven patients had died in the placebo arm (13.7%) compared with four patients treated with ixmyelocel-T (3.4%), with all deaths from cardiovascular causes. In total, there were 42 admissions to hospital for cardiovascular causes in the placebo arm (82.0%) compared with 30 admissions in the stem-cell therapy arm (52.0%).

Overall, there was no effect on secondary endpoints of ejection fraction or left-ventricular volumes, nor was there any effect on the 6-minute walk test or NYHA class. There were significantly fewer serious adverse events in the cell-therapy arm than in the placebo group. 

Improves Clinical Outcomes, No Effect on LVEF

John Jarcho, MD (Brigham and Women’s Hospital, Boston, MA), who was not involved in the trial, said the study is important because it focused on clinical events rather than surrogate endpoints, such as LVEF and 6-minute walk test results. Still, the lack of effect on these surrogate endpoints does raise some question about how treatment benefited patients who received the stem-cell implantation. “Although it is larger than most other trials in this space, it is still rather small,” said Jarcho. “And therefore, even though the benefit was clearly statistically significant, it’s the kind of information that would need to be replicated in larger trials.”

To TCTMD, Henry said the study was designed to assess clinical endpoints, but there is still a need for more mechanistic studies to understand the treatment effect. He speculated the treatment had a beneficial immunomodulatory effect, such as damping down inflammation. In addition, tissue remodeling, endothelial protection, and angiogenesis have also been proposed as potential mechanisms of benefit.

As for the lack of effect on LVEF, Henry said the trial used echocardiography to measure ventricular function, which is insensitive but was necessary because the patients had ICDs. Moreover, ejection fraction in studies such as these is a poor surrogate endpoint, said Henry, noting it has been difficult even in reperfusion studies with effective treatment strategies to show an improvement.

“Maybe we don’t make ventricle better, but we keep it from getting worse,” said Henry.

The trial also used a very conservative statistical approach when measuring nonclinical endpoints. For the patients who died in the placebo arm, for example, there was no final echocardiography or 6-minute walk test, leading investigators to use the “last-observation carried forward,” which could have skewed the results. “When you lose nearly 15% of your population, you lose your ability to discriminate,” he said. “The trial was designed for events, and that’s why we did it that way.”

• Patel AN, Henry TD, Quyyumi AA, et al. Ixmyelocel-T for patients with ischemic heart failure: a prospective, randomized, double-blind trial. Lancet 2016; Epub ahead of print.

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