FOCUS-CCTRN: Negative Trial, But Hints for Future of Cell Therapy in Heart Failure

March 24, 2012

March 24, 2012 (Chicago, Illinois)The largest study to date of autologous bone-marrow-cell therapy in patients with chronic ischemic heart failure--FOCUS-CCTRN--has shown no significant effect on the prespecified end points of left ventricular end-systolic volume (LVESV), maximal oxygen consumption, or reversibility on single-photon-emission computed tomography (SPECT) [1].

However, an exploratory analysis showed a significant improvement in left ventricular ejection fraction (LVEF), and the study also suggested the improvement in ejection fraction correlated with the number of progenitor cells (CD34+ and CD133+) in the bone marrow.

The study was presented today at the American College of Cardiology 2012 Scientific Sessions and simultaneously published online in the Journal of the American Medical Association.

In the paper, the authors, led by Dr Emerson Perin (Texas Heart Institute, Houston), conclude that the findings "provide evidence for further studies to determine the relationship between the composition and function of bone-marrow product and clinical end points."

"An Incredibly Important Trial"

Study investigator Dr Timothy Henry (Minneapolis Heart Institute, MN) is quoted in a press release issued by the Minneapolis Heart Institute as saying: "FOCUS is an incredibly important trial, as it has informed the cell-therapy community how to better treat this high-risk patient population and allows us to enter into an exciting, next generation of stem-cell therapy armed with more data.”

The researchers explain that a previous pilot study and phase 1 study (FOCUS-HF) have shown that transendocardial delivery of bone-marrow cells is feasible and appeared safe in patients with ischemic heart failure but that a definitive assessment of efficacy was not possible in these preliminary studies due to the small number of patients.

The current trial enrolled 92 patients with coronary artery disease, LVEF of <45%, limiting angina and/or congestive heart failure, a perfusion defect by SPECT, and no revascularization options while receiving guideline-based medical therapy. They were randomized to receive bone-marrow aspiration and transendocardial injection of 100 million bone-marrow cells or placebo (in the ratio of 2 to 1).

There were no significant differences between the two groups in any of the three co–primary end points assessed at six months.

FOCUS-CCTRN: Main Results

Outcome Change with bone-marrow cells 95% CI p
LVESV (mL/m2) −0.9 −6.1-4.3 0.73
Maximal oxygen consumption 1.0 −0.42-2.34 0.17
Reversible defect on SPECT -1.2 −12.50-10.12 0.84

There were also no differences found in any of the secondary outcomes, including myocardial defect percentage, total defect size, fixed defect size, regional wall motion, and clinical improvement.

Improvement in LV Function Related to Cell Type

But an exploratory analysis looking at LVEF showed more promising results, with an increase in LVEF of 1.4% in the cell-therapy group compared with a decrease of −1.3% in the placebo group, a significant 2.7% difference.

The researchers also examined the relationship between LVEF and the bone-marrow characteristics of the patient and found that improvements in LVEF correlated with the percentage of CD34 and CD133 cells in cell samples. Every 3% higher level of CD34 cells was associated with on average a 3.0% greater absolute unit increase in LVEF. And every 3% higher level of CD133 cells was associated with an average 5.9% greater absolute unit increase in LVEF.

"These findings are revealing the importance of certain cell types that are delivered and that modifying the cells may create more robust cells capable of achieving better results in future studies," the authors say.

They note that both CD133 and CD34 cell populations have been shown to give rise to endothelial and vascular progenitor cells and to secrete chemokines and cytokines capable of recruiting cells and promoting cell survival, which supports the idea that CD34 and CD133 cells might improve myocardial oxygenation and LV function in areas of ischemia or hibernating myocardium.

This study was conducted by the Cardiovascular Cell Therapy Research Network (CCTRN), a group supported by the US National Heart, Lung and Blood Institute (NHLBI), to evaluate novel stem-cell–based treatment strategies for individuals with cardiovascular disease.