View Full Version : Stem Cells Flop in Heart Failure Study, but another study underway(see first 2 posts)

03-24-2012, 12:18 PM
Am I missing something? The first study that flopped was published today. The press release announcing a new study using bone marrow stem cells for ischemic heart disease was issued today as well. Scientists are forever complaining and worrying about limited funding and yet a lot of research seems to be duplication of previous research. Maybe, I am just not thinking clearly. I know I am confused by such news. Perhaps, several clinical trials need to be done in order to validate the results more accurately or maybe researchers just don't trust other researchers' work. I don't really know.

ACC: Stem Cells Flop in Heart Failure Study
By Crystal Phend, Senior Staff Writer, MedPage Today
Published: March 24, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

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 six 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.

The study was funded by the National Heart, Lung, and Blood Institute.

The CCTRN reported industry partnerships with Biosafe, Biologics Delivery Systems Group, and Cordis.

All the authors reported research grant funding and travel support from the NHLBI.

Primary source: Journal of the American Medical Association
Source reference:
Perin EC, et al "Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: The FOCUS-CCTRN Trial" JAMA 2012; DOI: 10.1001/jama.2012.418.

03-24-2012, 12:28 PM
Public release date: 24-Mar-2012

Contact: Kristin Wincek
Minneapolis Heart Institute Foundation
Cell therapy using patient's own bone marrow may present option for heart disease

CHICAGO— Cell therapy may present an option for patients with ischemic heart disease to use their own bone marrow cells to repair the damaged areas of their hearts, and may pave the way for future treatment options, according to the FOCUS trial, which will be presented as a late-breaking clinical trial March 24 at the 61st annual American College of Cardiology (ACC) scientific session.

This is the largest study to date to look at stem cell therapy, using a patient's own stem cells, to repair damaged areas of the heart in patients with chronic ischemic heart disease and left ventricular dysfunction. Researchers found that left ventricular ejection fraction (the percentage of blood leaving the heart's main pumping chamber) increased by a small but significant amount (2.7 percent) in patients who received stem cell therapy. The study also revealed that the improvement in ejection fraction correlated with the number of progenitor cells (CD34+ and CD133+) in the bone marrow; and this information will help in evaluating and designing future therapies and trials.

"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," said study investigator Timothy D. Henry, MD, an interventional cardiologist at the Minneapolis Heart Institute® (MHI) at Abbott Northwestern Hospital in Minneapolis and director of research with the Minneapolis Heart Institute Foundation.

This multicenter study was conducted by the Cardiovascular Cell Therapy Research Network (CCTRN), which is supported through a research grant from the National Institutes of Health's National, Heart, Lung and Blood Institute (NHLBI), with the goal to evaluate novel stem cell-based treatment strategies for individuals with cardiovascular disease.

FOCUS will be presented at ACC.12 by its lead investigator Emerson C. Perin, MD, PhD, director of clinical research for cardiovascular medicine at the Texas Heart Institute, one of the five sites in the CCTRN. The Minneapolis Heart Institute is another site of the five in the network, and a large number of CCTRN patients were enrolled in Minnesota.

For this study, which took place between April 2009 and April 2011, the five sites randomly selected 92 patients to receive stem cell treatment or placebo. The symptomatic patients, with an average age 63, all had chronic ischemic heart disease and an ejection fraction of less than 45 percent (baseline 34 percent) along with heart failure and/or angina and were no longer candidates for revascularization. "These patients had no other options, as medical management failed to improve their symptoms," explained the study's co-investigator Jay Traverse, MD, an interventionalist cardiologist at the Minneapolis Heart Institute at Abbott Northwestern Hospital and physician researcher with the Minneapolis Heart Institute Foundation.

Bone marrow was aspirated from the patients and processed to obtain just the mononuclear fraction of the marrow. In patients randomly selected to receive stem cell therapy, physicians inserted a catheter into the heart's left ventricle to inject 100 million stem cells in more than 15 sites that showed damage on the electromechanical mapping image of the heart.

"Studies such as these are able to be completed much faster because of the team approach of the network" said Sonia I. Skarlatos, PhD, NHBLI's deputy director of the division of cardiovascular sciences and program director of CCTRN.

The FOCUS trial was designed to determine whether left ventricular end systolic volume and myocardial oxygen consumption improved in patients who received stem cell treatment. Researchers also wanted to see if nuclear scans of the heart showed a reversible change in perfusion defects in patients who had received the treatment.

While the study did not achieve its primary endpoint, the researchers found that those patients with more progenitor cell types had much better improvement with ejection fraction, explained Henry, and demonstrated a linear relationship between the number of CD34+ cells and the improvement in ejection fraction.

"As a result, 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," concluded Traverse.

The study will be simultaneously published in the Journal of the American Medical Association.

Minneapolis Heart Institute Foundation

The Minneapolis Heart Institute Foundation is dedicated to creating a world without heart disease through groundbreaking clinical research and innovative education programs. MHIF's mission is to promote and improve cardiovascular health, quality of life and longevity for all.

Minneapolis Heart Institute®

The Minneapolis Heart Institute® is recognized internationally as one of the world's leading providers of heart and vascular care. This state-of-the-art facility combines the finest in personalized patient care with sophisticated technology in a unique, family-oriented environment. The Institute's programs, a number of which are conducted in conjunction with Abbott Northwestern Hospital, address the full range of heart and vascular health needs: prevention, diagnosis, treatment and rehabilitation.