Cell Therapy No Help for Cardiac Recovery in HF Patients With LVADs
The trial did not meet its primary endpoint for successful LVAD weaning but did show less mucosal bleeding—an important take home for future trials.
CHICAGO, IL—An intramyocardial injection of mesenchymal precursor cells (MPCs) does not increase the rate of cardiac recovery in heart failure patients receiving left ventricular assist device (LVAD) support compared with a sham control, according to new data.
A positive signal for the therapy observed among a subgroup of patients with ischemic heart failure “could influence patient selection in future cardiac recovery trials,” said Francis Pagani, MD, PhD (University of Michigan, Ann Arbor), who presented the results yesterday at the American Heart Association 2018 Scientific Sessions.
For the study, Pagani and colleagues randomized 159 advanced heart failure patients undergoing LVAD implantation as either a bridge-to-transplant or destination therapy to receive 150 million allogeneic MPCs or a sham-control injection (cryoprotective media alone) between July 2015 and August 2017.
There were no differences between the MPC and sham-control groups in the number of successful temporary weans at 2, 4, and 6 months (primary efficacy endpoint) from full to minimal LVAD support within 6 months (61% vs 58%; RR 1.08; 95% CI 0.83-1.41). However, in the subgroup of patients with ischemic heart failure, the wean rate ratio favored the MPC injection (RR 1.55; 95% CI 1.01-2.36).
No patients in either cohort reported a primary safety stopping event, including myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization. Allosensitization to class I human leukocyte antigen (HLA) markers was higher for the MPC arm than for controls (26% vs 9.4%), but there was no between-group difference with respect to allosensitization of class II HLA markers. There were also no differences between the treatments in either the time to heart transplant (P = 0.31) or survival (P = 0.80).
The rate of mucosal bleeding at 6 months was higher for controls than those who received the MPC injection (15.9 vs 3.8 event rate per 100-patient-months; P < 0.001). Controls also reported numerically higher rates than study patients in the following secondary outcomes at 6 months: major infections, any bleeding, any serious adverse events, and hospitalization for GI bleeding or for any reason.
If the clinically meaningful decrease in the rate of mucosal bleeding is sustained for the MPC injection in future trials, this “may lead to a new treatment for this prevalent and morbid complication of LVAD therapy,” according to Pagani.
Not the Controversial Stem Cells
Discussing the trial during the session, Joseph Wu, MD, PhD (Stanford School of Medicine, CA), specified that the stem-cell line used in this analysis are different from those previously investigated by Harvard researcher Piero Anversa, MD, whose work has been retracted from major medical journals amid allegations of research fraud. “These MPCs are multipotent and they have been shown to have antiapoptotic as well as pro-angiogenic effects,” he explained. “I just want to emphasize comparing apples to oranges, because these are really two different stem-cell types.”
This study was “very well balanced, fair, and objective,” Wu said, adding that he hopes the results will stimulate the researchers to conduct a follow-up study. “It's giving us a lot of insight into how you deliver stem cells into this very difficult patient population.”
Session co-moderator Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai Hospital, New York, NY), called this a “very important study for the field.” While the overall trial was negative for its primary endpoint, the secondary findings for mucosal bleeding suggest a potential use for high-bleeding-risk patients who are awaiting transplant, she suggested. “Are you thinking about that as the next strategy, or are you going to move ahead and go forward for the hypothesis generation of the ischemic patient population in this group?” Mehran asked.
“The older patients are generally the ischemic population, and they actually have a higher incidence of bleeding, so a therapy that could help bleeding in the older population would be significant,” Pagani responded. “One could imagine a trial with bleeding as a primary endpoint, but that you could give either a systemic administration or a localized intramuscular administration and repeat the administration over time so that there’s a prolonged effect. There are many types of trial design that could potentially be considered.”
Additionally, panel member Marc Ruel, MD, MPH (University of Ottawa Heart Institute, Canada), observed that “we all realize that it’s easier to achieve vasculogenesis than achieve myogenesis. Often vasculogenesis or angiogenesis can be nonspecific from injecting anything—saline or even going with a kitchen fork for that matter. So it’s possible here that the ischemic patients may have had this perhaps inflammatory nonspecific response, which should be relatively short-lived and certainly not last beyond 6 months.”
True, Pagani agreed. “We had a response out to 6 months, but I think in a trial going forward you could look at the efficacy of a multidose regimen or a serial administration so that you have a prolonged response,” he said.
Pagani F. Intramyocardial injection of mesenchymal precursor cells in left ventricular assist device recipients: the LVAD MPC-II trial. Presented at: AHA 2018. November 11, 2018. Chicago, IL.
- This study was supported by a cooperative agreement funded by NHLBI and NINDS, of the National Institutes of Health (NIH), and the Canadian Institutes for Health Research (CIHR). Mesoblast provided MPCs and cryoprotective medium.
- Pagani and Wu report no relevant conflicts of interest.
- Mehran reports receiving institutional research grant support from Eli Lilly/Daiichi Sankyo, Bristol-Myers Squibb, AstraZeneca, The Medicines Company, OrbusNeich, Bayer, CSL Behring, Abbott Laboratories, Watermark Research Partners, Novartis Pharmaceuticals, Medtronic, AUM Cardiovascular, and Beth Israel Deaconess Medical Center. She is a member of the executive committees for Janssen Pharmaceuticals and Osprey Medical; a member of the data safety monitoring board of Watermark Research Partners; and a consultant for Medscape, The Medicines Company, Boston Scientific, Merck & Company Cardiovascular Systems, Sanofi USA, Shanghai BraccoSine Pharmaceutical, and AstraZeneca. She holds equity in Claret Medical and Elixir Medical Corporation.
- Ruel reports receiving honoraria from Abbott, research grant support from Medtronic (MIST Trial), and other research support from Edwards and Cryolife.