Advances in Stem-Cell Therapy for Heart Failure

Despite negative primary end points, positive clues are promising
Value-Based Care in Cardiometabolic Health May 2012, Vol 1, No 1
Mary Mosley

Chicago, IL—A phase 2 study of autologous bone marrow–cell therapy in patients with chronic ischemic heart disease and left-ventricular dysfunction showed no significant differences for the primary end points, but there were hints of benefit from the prespecified exploratory analyses that point to refinements for future studies that will build on these results, according to the study’s lead investigator, Emerson C. Perin, MD, PhD, Director of Clinical Research for Cardiovascular Medicine, Texas Heart Institute, Houston. The results were presented at the 2012 American College of Cardiology meeting.

The First Mononuclear Cells Injected in the US (FOCUS) Cardiovascular Cell Therapy Research Network (CCTRN) study is the largest trial to use a patient’s own stem cells in a patient population. A key element of the CCTRN is a biorepository of samples from all study patients, which Dr Perin explained is a treasure trove for researchers to tease out cell functions from and try to correlate them with other end points in this study and additional clinical outcomes. “Developing a cell biorepository is a huge step forward for the future of autologous therapy, because the composition and function of cells in the bone marrow may play a significant role in outcome,” Dr Perin noted.

This double-blind randomized multicenter study of 61 treated patients and 31 controls (median age, 62 years) used first-generation cell product— one of the most studied clinically. The patients’ qualifying left-ventricular ejection fraction (LVEF) was approximately 30%.

In this ongoing study, the patients are chronically ill and are out of treatment options; these patients belong to a population for whom we need to find treatment solutions, said Dr Perin. Medical therapy is insufficient, not enough hearts are available for transplants, and left-ventricular assist devices are expensive and have complications. “I believe cell therapy will be one of the solutions for these patients,” he maintained.

The 6-month data showed that LVEF, an exploratory end point, was significantly improved by 2.7% in the treated patients—an increase of 1.7% versus a decline of 1.3% in the control patients. No differences between the treated and control patients were seen in the primary end points of change from baseline in maximal oxygen consumption, change in left-ventricular end systolic volume on echocardiography, and change in ischemic defect size as assessed by single-photon emission tomography imaging.

Stem-Cell Variation in Individual Patients

There is a large variation within individuals’ own cells, noted Dr Perin, and the potency of the cells depends on the individual—which is much different from giving a fixed dose of a drug in a tablet. Younger patients responded significantly, which may reflect effects of aging, comorbidities, genetics, and possible unknown factors.

In this trial, patients aged ≤62 years had a significant 4.7% change in LVEF from baseline compared with only a 0.6% change in patients aged >62 years. The researchers also found that certain cell types provided clinical benefit. There was a relationship between CD34+ and CD133+, endothelial progenitor cells, and improvement in LVEF, as shown by a multiple variable model that included age and treatment. For each 3% higher level of CD34+ cells, there was an associated average 3.0% absolute unit increase in LVEF. Each 3% higher level of CD133+ cells was associated with an average 5.9% absolute unit increase in LVEF.

The investigators found that younger patients had distinctly better bone marrow–cell function, which was also seen in the prior pilot and small phase 1 FOCUS-HF studies. Change in maximal oxygen consumption, a good evaluation of the patient’s ability to perform, was significantly positively affected in the younger patients in the prior studies and in FOCUS CCTRN.

Dr Perin noted that maximal oxygen consumption status is used to move patients on and off the transplant list; although the results of this study cannot be used in that regard, it does show that the small changes achieved with this therapy have a significant impact. For example, maximal oxygen consumption changed from 14.6 to 15.3 in the treated patients and from 15.2 to 13.4 in the control patients. Despite the small difference between the 2 groups, the change is sufficient to move the treated patients off the transplant list, whereas the control patients would be added to the list.

“These are meaningful things that we are seeing, and perhaps we can use this information prospectively to select those patients and those cells that can fine-tune the therapy for the next generation of studies,” said Dr Perin, who noted that new related studies were beginning soon.

Roberto Bolli, MD, FAHA, Professor of Medicine and Executive Vice President, Department of Medicine and Chief, Division of Cardiovascular Medicine, University of Louisville, KY, commented in a press conference that there is a huge potential for the bone marrow to become useful therapeutically, but there is much that is unknown about bone marrow and what it does and how it works. “The subanalyses from FOCUS give us some very tantalizing hints that we may be able to select out patients in whom bone marrow transplantation is therapeutically beneficial. If we can select the patients in whom the bone marrow is still functional, we will see a beneficial effect,” Dr Bolli pointed out.

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