Stem Cell Therapy Fails to Show Benefit in Chronic Ischemic Heart Failure

CHICAGO, IL—Patients with chronic ischemic heart disease and left ventricular (LV) dysfunction do not appear to benefit from treatment with autologous bone marrow stem cells (BMSCs). In a presentation March 24, 2012, at the annual American College of Cardiology/i2 Scientific Sessions, there were few positives to report from the phase II FOCUS-CCTRN trial, but the primary investigator and most of the panel discussants felt that the research should continue to identify patients in whom the therapy may prove effective.

The data were simultaneously published online in the Journal of the American Medical Association.

Emerson C. Perin, MD, PhD, of the Texas Heart Institute at St. Luke’s Episcopal Hospital (Houston, TX), presented data on 92 patients with chronic ischemic heart disease and LV dysfunction with heart failure and/or angina who were randomized to receive cell-free placebo or transendocardial injection of 100 x 10⁶ total BMSCs given in 15 separate injections between April 2009 and April 2011. The injections were delivered to LV endocardial regions identified as viable on electromechanical mapping.

The trial was a follow up to the phase I randomized FOCUS-HF trial, the first trial of autologous bone marrow stem cell therapy for heart failure in the United States.

No Difference at 6 Months

The researchers assessed changes in LV end-systolic volume on echocardiography as well as maximal oxygen consumption and reversibility on SPECT and found no statistically significant differences between the treatment and placebo groups (table 1).

Table 1. Six-Month Follow Up

 

 

In addition, there were no signficant differences in the change between the 2 groups over time for percent total myocardial defect (-0.9%; 95% CI -5.0 to 3.3), total defect size (-1.6; 95% CI -5.1 to 1.9) or fixed defect size (-0.7; 95% CI -4.8 to 3.4).

There was a significant decrease over time in the percentage of patients in the BMSC group who were NYHA class III, from 40% to 20% (P = 0.02). This decrease was not seen in the placebo group. However, in the between-group analysis, the finding was not statistically significant.

Other measures in which there were no differences between groups included:

• Change in angina class
• Serum BNP levels
• Probrain-type natriuretic peptide
• Decrease in need for antianginal medications

“Thus, considering the analysis of the prespecified primary endpoints and the appropriate rigor of clinical trials, this was a negative trial,” Dr. Perin said.

One area where there was a notable difference in the BMSC group, however, was in LVEF, which improved by 2.7% from baseline compared with the placebo group. In a prespecified analysis, the researchers also looked at changes by age of the cohort (cutoff of ≤ 62 years). Again, there were no significant differences between the treatment and placebo groups for the effect of age on LV end-systolic volume, maximal oxygen consumption and percent reversibility on SPECT. But when LEVF was assessed, patients 62 years or younger showed a statistically significant effect of BMSC therapy, with an improvement of 4.7% compared with the placebo group, with LVEF improving from 35.1% at baseline to 38.2% at follow up (table 2).

Table 2. Change in LVEF

 

 

Dr. Perin also noted that in a prespecified bone marrow analysis, patients with higher CD34 counts had a greater absolute increase in LVEF and a weak but significant correlation between change in LVEF and amount of CD34 cells in bone marrow. Importantly, he added, the relationship between change in LVEF and CD34 did not disappear after adjustment for age and therapy (P = 0.043) “and therefore is not just a surrogate for these parameters.” According to Dr. Perin, a 3% higher level of CD34 cells was associated with a 3% greater absolute increase in LVEF (P = 0.04). A similar effect was seen for CD133 cells.

‘Resoundingly Negative’

Following Dr. Perin’s preentation, the panel universally acknowledged the negative results of the trial.

Eduardo Marbán, MD, PhD, of Cedars-Sinai Heart Institute (Los Angeles, CA), said while the researchers managed to pull off a challenging, logistical study, the trial “is resoundingly negative and we have to think about why that might be.” He added that a major limitation of the study is the use of echocardiography as a major functional endpoint.

“Although this is a negative study, I think that it raises some important questions and moves us forward,” said Roberto Bolli, MD, of the University of Louisville (Louisville, KY). He said the challenge in the future may be to phenotype BMCs thoroughly to identify those patients in whom bone marrow stem cells are capable of producing a therapeutic effect.

Robert M. Califf, MD, of Duke University Medical Center (Durham, NC), echoed the other panelists’ negative feelings toward the overall outcome of the trial by saying there was “not a scintilla of positivity” for any of the primary endpoints and secondary endpoints to be of any relevance.

“I don’t think anyone should leave this room thinking there is anything reproducible in these results,” Dr. Califf said. But he acknowledged that another study is needed to see if any of the P values “mean anything when replicated.”

Source:

Perin EC. Effect of transendocardial autologous bone marrow mononuclear cell delivery on functional capacity, left ventricular function and perfusion in chronic ischemic heart failure: The FOCUS-CCTRN randomized trial. JAMA. 2012;Epub ahead of print.

 

Related Stories:

• Interdisciplinary Approach Needed for Cardiac Stem Cell Therapy to Move Forward
• Stem Cell Therapy Moderately Improves Cardiac Function After Acute MI
• SCIPIO: Cardiac Stem Cell Treatment Looks Promising in Early Results