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CHICAGO – An attempt to employ stem cells to rescue patients from left ventricular assist devices (LVAD) failed to provide benefit to the patients in an National Institutes of Health-supported clinical trial, researchers reported here.
After 6 months treatment, temporary wean from percutaneous LVAD therapy was successful for 61% of patients receiving mesenchymal precursor stem cells compared with 58% of control patients (P=0.55), reported Francis Pagani, MD, a surgeon at the University of Michigan in Ann Arbor.
The posterior probability that allogeneic mesenchymal precursor cells increased the likelihood of successful weaning -- tolerating 30 minutes off the pump without sustained symptoms of worsening heart failure, or explant due to myocardial recovery -- was 69%, which failed to achieve the pre-defined threshold of 80%.
But secondary and exploratory findings might be worth pursuing, Pagani said here in his oral late-breaking trial presentation at the annual scientific sessions of the American Heart Association.
For instance, among LVAD patients whose cardiomyopathy was due to ischemic events, there was a significant improvement in the wean rate (P=0.02). There was no significant difference among patients whose cardiomyopathy was caused by non-ischemic events.
The researchers also found that there appeared to be less mucosal bleeding at 6 months among patients receiving the stem cells (3.8% versus 15.9% per 100 patient-months, P<0.001).
Key secondary endpoints of time to heart transplant and overall survival were not statistically different between the groups.
The LVAD MPC-II trial, conducted through the Cardiothoracic Surgical Trials Network, was a phase II trial to evaluate the efficacy and safety of intramyocardial injection of a single, high-dose (150 million) of mesenchymal precursor cells in patients undergoing LVAD implantation.
"We hypothesized that intramyocardial injection would be superior to a sham-control in promoting myocardial functional recovery, without concerns about key safety endpoints," Pagani explained in his presentation.
Between July 2015 and August 2017, the researchers assessed 637 patients and from that group randomized 159 patients. The patients had been diagnosed with advanced heart failure and were undergoing LVAD implantation as bridge-to-transplant or destination therapy. The patients were randomized 2:1 to stem cell therapy or sham-control (cryoprotective media alone) injection during LVAD implantation.
Ten of the stem cell recipients died during the trial; eight were transplanted. There were six deaths in the sham group, and six others were transplanted.
Mean patient age was 56, and almost 90% were women. The baseline average left ventricular ejection fraction was about 17%. Two-thirds of the patients were using the LVAD as a bridge to transplant.
Roxana Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York City, noted the overwhelming negative findings. “This was a very, very sick patient population and they weren’t able to get them off the LVAD,†she told 51˶, although suggesting that the lack of effect could have been due to VAD-related complications overriding any benefit.
However, Mehran said that the secondary finding of benefit in the small number of patients in the study with an ischemic etiology for their heart failure warrants further evaluation. “The door is not closed on this therapy,†she said.
She also noted that GI bleeding in these patients is a common, and worrisome problem, because all are heavily anticoagulated. "I was very intrigued that there was a finding of a reduction in gastrointestinal bleeding that could have to do with mucosal lining [that] may be associated with these mesenchymal precursor cells. This is an interesting hypothesis that should be explored," she said, noting biologic plausibility.
She cautioned, however, that the researchers didn't report levels of anticoagulation for the patients, so it may simply be that the patients who didn't bleed were not as heavily anticoagulated as the patients who did bleed.
Mehran also emphasized that researchers were not connected with the Harvard/Brigham and Women's Hospital lab where there have been , and "the cell line is completely different from that fraudulent work."
The type of cells around which the questions have been raised were c-kit+ stem cells. Both c-kit+ cells and mesenchymal stem cells from bone marrow are being tested in the landmark CONCERT-HF trial for chronic heart failure with reduced ejection fraction from ischemic causes, although it was recently put on hold while the impact of the misconduct is assessed.
"Innovation and research has to continue in this arena," Mehran said. "We just can't give up because no one believes the data anymore. That would be really, really sad."
Disclosures
Pagani disclosed no relevant relationships with industry.
Mehran disclosed relationships with AstraZeneca, Bayer, Beth Israel Deaconess, BMS, CSL Behring, Eli Lilly/DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Claret Medical, Abbott Laboratories, Abiomed, Boston Scientific, Siemens Medical Solutions, Medscape, Spectranetics, The Medicines Company, Roivant Sciences, Bristol Myers Squibb, Janssen Pharmaceuticals, Osprey Medical, and Watermark Research Partners.
Primary Source
American Heart Association
Pagani F, et al “Intramyocardial injection of mesenchymal precursor cells in left ventricular assist device recipients: Impact on myocardial recovery and morbidity” AHA 2018.