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CHICAGO -- An injection of bone marrow stem cells into the heart doesn't boost its performance in chronic ischemic heart failure, according to an early phase randomized trial.

No measure of cardiac function, perfusion, or viability showed a significant benefit from the stem cell therapy atop maximal medical therapy, said Emerson Perin, MD, PhD, of the Texas Heart Institute in Houston.

Symptoms also failed to improve compared with placebo in the phase II trial reported at today at the opening session of the American College of Cardiology meeting.

However, the autologous stem cells raised left ventricular ejection fraction in an exploratory analysis, suggesting it's too early to give up on the strategy in ischemic heart failure, Perin argued.

He spent half of his late-breaking clinical trial session presentation on the positive aspects of the negative trial.

The left ventricular ejection fraction rose 1.4 percentage points over 6 months with stem cell treatment but fell 1.3 percentage points with placebo (P=0.03).

That improvement correlated with the proportion of bone marrow stem cells in a patient's sample positive for CD34 and CD133.

Every 3% higher level of CD34 cells correlated with a 3-percentage point greater improvement in ejection fraction after adjustment for age and treatment (P=0.04).

Likewise, every 3% higher level of CD133 cells correlated with a 5.9 percentage point greater improvement in ejection fraction (P=0.04).

Those associations were independent of age and treatment group.

Younger patients, those under the median age of 62, also showed a ejection fraction benefit of 4.7 percentage points with intracoronary stem cell injections compared with placebo (P=0.015).

"If we would have picked left ventricular ejection fraction [as the primary endpoint], this would have been a positive study," Perin said at a press conference. "Stem cells are not something we're at the end of the road with…we don't even know what the right endpoint is."

The main message of the trial was that characterizing the functionality of stem cells before treating with them is going to be key if better results are to be found, Andreas M. Zeiher, MD, of the University of Frankfurt, Germany, agreed at the late-breaking trial session.

However, other discussants blasted Perin for attempting to spin the trial as anything but negative.

"This is a resoundingly negative study, not just a somewhat negative study," argued Robert Califf, MD, director of the Duke Translational Medicine Institute in Durham, N.C., "They have three primary hypotheses, all of which are not a scintilla of positivity."

With ejection fraction just one of over 20 secondary hypotheses, "you would need a P-value with something like 10 zeros to fall anywhere the conventional level of statistical significance," he explained.

"I don't think anyone should leave this room thinking there's anything reproducible in these results," he warned at the session.

Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute in Los Angeles, also questioned the ejection fraction endpoint as evaluated by echocardiography.

"We can distinguish severe from moderate to mild ventricular dysfunction, but to say that someone's ejection fraction is 36.7% -- especially when many of the patients are post-CABG [coronary artery bypass grafting] -- exceeds the capacity of echo at centers I've been at," he said at the session.

Acknowledging criticism at the press conference, Perin nonetheless expressed optimism that these issues will be worked out.

"There are always skeptics. I have no doubt in my mind that cell therapy, regeneration therapy is one of the great avenues of the future in all of cardiology," he told reporters. "It's just a matter of figuring it out. We're at the very beginning of all of this."

His group's FOCUS trial of the National Heart, Lung, and Blood Institute's Cardiovascular Cell Therapy Research Network was the first adequately powered to study any cell therapy for chronic ischemic heart disease with reduced ejection fraction in the United States.

Yet the trial may have been hamstrung by a relatively small sample size that required overly ambitious targets for endpoint improvements to show a significant treatment effect, Perin's group said.

Prior, typically small, studies have had mixed results with various types of stem cell injections into the heart after myocardial infarction. In chronic heart failure, an open-label nonrandomized study had suggested improved ventricular function and even survival with autologous bone marrow stem cells.

FOCUS-CCTRN included 92 patients with symptomatic heart failure from ischemic causes not amenable to revascularization and a left ventricular ejection fraction of 45% or less.

Six months after injection of either 100 million autologous bone marrow stem cells or placebo into viable areas in the heart, none of the co-primary endpoints showed significant differences between treatment groups.

Left ventricular end-systolic volume improved from 57.9 to 57.0 mL/m2 with stem cells while the placebo group held steady at 65.0 ml/m2, but the difference wasn't significant (P=0.73).

Maximal oxygen consumption increased from 14.6 to 15.0 mL/kg per minute with stem cells but declined from 15.3 to 14.7 mL/kg per minute with placebo, again without a significant difference (P=0.17).

Reversible defect seen on SPECT imaging fell in both groups, and the 1.2 percentage point difference between groups favoring stem cells wasn't significant (P=0.84).

Secondary endpoints of percent myocardial defect, total defect size, fixed defect size, and regional wall motion didn't show a significant advantage from stem cell treatment either.

The proportion of patients who improved clinically from New York Heart Association class III to class II likewise didn't differ between groups.

The limited sample size precluded looking at harder clinical endpoints, like survival, the researchers noted.

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