Stem Cell Adjunct to LVAD Trial Negative, But 'Intriguing'

November 15, 2018

CHICAGO — The largest trial to date investigating the use of stem cells to enhance myocardial recovery in patients who have received a left ventricular assist device (LVAD) missed the primary end point of improved cardiac function, but has shown some intriguing results.

The study, which investigated the injection of allogeneic mesenchymal progenitor cells into the myocardium of patients receiving an LVAD device, did appear to show an improvement in patients with ischemic heart failure. In addition, there was a large reduction in gastrointestinal (GI) bleeding in patients who received the stem cells, compared with control subjects.

"There was a signal of benefit in patients with heart failure of an ischemic origin," lead investigator Francis D. Pagani, MD, University of Michigan, Ann Arbor, told theheart.org | Medscape Cardiology. "These results suggest that going forward it would be appropriate to focus on these patients as the target population for such treatment."

The reduction in GI bleeding in this study is an "exciting finding," Pagani said. LVADs often induce a systemic inflammation that can affect the GI blood vessels, and around 30% of recipients, or more, experience regular GI bleeding, he noted. "Our results showing a clinically meaningful reduction in mucosal bleeding are encouraging and, if substantiated, may lead to a new therapeutic approach."

As well as their postulated role of strengthening the myocardium, these cells could have an anti-inflammatory role secreting anti-inflammatory proteins, such as IL-10 and VEGF, he added.

"We believe this systemic anti-inflammatory role contributed to the observed reduction in bleeding in this study. A previous pilot study also suggested a benefit in GI bleeding," he said. "This gives us some idea of the mechanisms at play in stem cell therapy. There appears to be effects throughout the body, not just in the heart."

Pagani presented the results of the LVAD MPC-II trial at the recent American Heart Association Scientific Sessions 2018.

Designated discussant for the study, Joseph C. Wu, MD, PhD, Stanford University School of Medicine, California, commended Pagani and colleagues for conducting "a well-designed and very well balanced, fair, and objective study."

"These LVAD patients are quite sick so any kind of novel therapy that can improve their morbidity is welcomed," Wu commented to theheart.org | Medscape Cardiology.

"These allogeneic mesenchymal progenitor cells are multipotent cells that have been shown to secrete antiapoptotic and proangiogenic factors. The results of this are actually quite intriguing and I hope would stimulate the investigators to conduct follow-up studies on why MPCs benefit ischemic patients more and why they reduce incidence of mucosal bleeding," he added.

Pagani noted that a previous exploratory study in 30 patients suggested a benefit of using a low dose of skeletal muscle-derived MPCs in improved temporary LVAD weaning without safety concerns.

The current trial was a phase 2 follow-up study to evaluate intramyocardial injection of a higher dose (150 million) of bone marrow derived MPCs in patients undergoing LVAD implantation.

The study enrolled 159 patients with advanced heart failure from ischemic or nonischemic etiology undergoing LVAD implantation. They were randomized 2:1 to MPCs or sham control (cryoprotective media alone).

The primary efficacy end point was the number of successful temporary weans (out of three planned assessments) from full to minimal LVAD support in the 6 months after randomization.

Temporary weaning was performed at 2, 4, 6, 9, and 12 months after LVAD implantation. A successful wean was defined as the ability to tolerate temporary weaning from LVAD support for 30 minutes without sustained symptoms of worsening heart failure.

Results showed the average proportion of successful temporary weans was 61% in the stem cell group and 58% in the control group, a nonsignificant difference (RR, 1.08; 95% CI, 0.83 - 1.41; P = .55).

However, on subgroup analysis, there did appear to be a benefit in patients with ischemic cardiomyopathy (RR, 1.55, 95% CI, 1.01 - 2.36).

There was a large reduction in GI bleeding, with an event rate per 100 patient-months of 3.8 in the stem cell group and 15.9 in the control group (P < .001).

In terms of safety, no patient developed a primary safety stopping event (adverse events, including infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization).

But there was an increase in allosensitization to class I HLA antigens (26% in the stem cell group vs 9.4% in the control group).

"This is the development of antibodies to the stem cells," Pagani explained. "This could be problematic in patients who are awaiting a transplant, but in elderly patients in whom a transplant is not appropriate, this is not really clinically relevant.

"We are particularly encouraged by the reduction in GI bleeding shown in this study. We still have further blood and tissue samples to analyze then we will discuss how to go forward," he said.

The trial was sponsored by the US National Institutes of Health (NIH), and the Canadian Institutes for Health Research (CIHR). Pagani reports no disclosures.

American Heart Association (AHA) Scientific Sessions 2018: Session LBS.06. Presented November 11, 2018.

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