Meta-analysis: Bone Marrow Mononuclear Cell Therapy Fails to Show Efficacy in Acute MI

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A meta-analysis of stem cell infusion therapy in patients with acute myocardial infarction (MI) demonstrates that the novel treatment is safe but does not enhance cardiac function or improve clinical outcome. Most of the trials included in the analysis, published online March 25, 2014, ahead of print in Circulation: Cardiovascular Interventions, used bone marrow-derived mononuclear cells (BMMNCs).

Researchers led by Henricus J. Duckers, MD, PhD, of Erasmus University Medical Center (Rotterdam, the Netherlands), included 30 randomized trials conducted between July 2002 and September 2013 of 2,037 patients with acute MI. In total, 1,218 patients were treated with an intracoronary or intravenous injection of BMMNCs (22 trials), mesenchymal stem cells (3 trials), bone marrow progenitors (4 trials), or cardiosphere-derived cells (1 trial).

BMMNC infusion increased LVEF, decreased LV end systolic volume, and reduced infarct size. Though differences did not reach significance, the therapy also tended to decrease LV end diastolic volume (table 1).

Table 1. BMMNC Outcomes

 
In a subgroup analysis of 21 BMMNC trials at 6 months, LVEF increased by 2.08% compared with controls (P = 0.008). This benefit was maintained at 1 year (3.04%; P = 0.0008). However, at follow-up 36 to 60 months postprocedure, the treatment effect disappeared (1.19%; P = 0.55). “This increase in LVEF up to 18 months of follow-up was mainly because of a preservation of LVESV in the BMMNC group (as opposed to the control group),” Dr. Duckers and colleagues write.

Looking at only the 9 trials of BMMNCs that employed MRI, the effect of treatment on LVEF diminished (0.13%; P = 0.93), as did its influence on LV volumes and infarct size. “This finding could indicate that BMMNC therapy is not beneficial in patients with [acute] MI,” they suggest.

Regarding other cell types, bone marrow progenitor and mesenchymal stem cells increased LVEF by 2.67% (P = 0.05) and 6.28% (P = 0.09), respectively. When data from all of the stem cell types were combined, LVEF increased by 2.51% compared with controls (P = 0.0001).

Infarct location—anterior wall vs elsewhere—did not change the likelihood of benefitting from stem cell therapy and neither did baseline LVEF.

Clinical outcome was not affected by stem cell therapy, as neither MACCE nor any of its individual components were reduced in those treated with BMMNCs at 6 months. However, bone marrow progenitor cell infusion resulted in fewer hospitalizations for heart failure (OR 0.14; 95% CI 0.04-0.52; P = 0.003), and mesenchymal stem cell transplantation reduced ventricular fibrillation/ventricular tachycardia (OR 0.08; 95% CI 0.01-0.79; P = 0.03) and cardioverter defibrillator implantations (OR 0.08; 95% CI 0.01-0.79; P = 0.03).

Looking Toward BAMI

“We think that the current meta-analysis shows strong indications that BMMNC therapy in patients with [acute] MI is not effective in improving clinical outcome,” the authors write. “Although the number of patients treated with next-generation cell therapies is still too low, and studies performed to date were primarily designed to prove safety and feasibility, these new therapies might prove to be more effective.”

They highlight the ongoing BAMI trial in Germany, which will enroll 3,000 randomized STEMI patients, as “designed to shed more light on the value of BMMNC therapy in improving clinical outcome.”

In a telephone interview with TCTMD, Jason Kovacic, MD, PhD, of Mount Sinai School of Medicine (New York, NY), said the researchers behind the BAMI trial “strongly believe that bone marrow mononuclear cell therapy works in their hands and with their protocols…. I think we will have the definitive answer on bone marrow mononuclear cell therapy in due time.”

After 2 US National Heart, Lung, and Blood Institute (NHLBI)-funded trials of roughly 100 patients each, TIME and LateTIME, came back negative for BMMNCs, there will likely be a shift in focus in domestic stem cell research, he explained. “There’s a lot of interest in America in moving away from bone marrow mononuclear cells and moving toward alternative cell populations,” Dr. Kovacic reported, adding that the 3 most exciting ongoing studies to watch out for are SCIPIO, POSEIDON, and CADEUCEUS.

“It is thought that mesenchymal cell populations or cardiac-derived stem cells exhibit more cardioprotective and regenerative potential,” Dr. Duckers and colleagues observe. “Importantly, preclinical and preliminary clinical evidence shows promising benefits of these cell types.

“Moreover, [mesenchymal stem cells] are immune-privileged cells and can be administered in an allogeneic setting,” they continue. “This renders the possibility of an allogeneic off-the-shelf cell product, which is readily available directly after primary PCI. This has several logistical advantages, but might also enhance outcome, because it was shown that stem cells derived from young and healthy donors perform better and have more regenerative potential compared with autologous stem cells from typically elderly cardiovascular patients.”

Dr. Kovacic agreed, adding that research will also focus on developing stem-cell activating mechanisms that can be deployed through various biologics.

“The future is looking for ways and mechanisms to better understand endogenous stem cells and [searching] for ways to stimulate these cells in the body,” he said. “There are many studies that have shown that some animals have the capacity to repair the heart, and there is intense research going on now to try and better understand how that happens, what controls it, what cells are involved, and how we can unlock those mechanisms in humans.”

Study Details

The average patient age was 68 years, and the median follow-up in all studies was 6 months. Patients were infused with a median of 100 million viable cells after a median duration of 7 days.

 

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Source:
de Jong R, Houtgraaf JH, Samiei S, et al. Intracoronary stem cell infusion after acute myocardial infarction: a meta-analysis and update on clinical trials. Circ Cardiovasc Interv. 2014;Epub ahead of print.

 

 

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