Meeting NewsPerspective

Cell therapy fails to improve cardiac recovery in advanced HF

CHICAGO — Among patients with advanced HF designated for left ventricular assist device therapy, mesenchymal precursor cells did not improve cardiac recovery, but there was a signal of benefit in ischemic HF, according to the results of the LVAD MPC-II trial.

Francis D. Pagani, MD, PhD, surgical director of the Adult Heart Transplant Program and program director for the Center for Circulatory Support at the University of Michigan Medical School, and colleagues evaluated whether immunomodulation from mesenchymal precursor cells could augment cardiac recovery and reduce adverse events in patients with advanced HF (ischemic or nonischemic) who were scheduled for LVAD implantation.

The researchers randomly assigned 159 patients (mean age, 56 years; 89% men) on a 2:1 basis to an intramyocardial injection of mesenchymal precursor cells (Mesoblast) or a sham procedure. Mean LV ejection fraction was 17.3% in the cell group and 16.2% in the control group.

The primary efficacy endpoint was successful temporary wean (at least 30 minutes) from full to minimal LVAD support at 2, 4 and 6 months. The primary safety endpoint was intervention-related adverse events, including infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction and immune sensitization.

According to the researchers, the mean proportion of successful temporary weans was 61% in the cell group and 58% in the control group (RR = 1.08; 95% CI, 0.83-1.41).

Pagani said the posterior probability of mesenchymal precursor cells increasing likelihood of successful weaning was 69%, which was below the prespecified threshold of 80%.

However, he said, in an exploratory subgroup analysis, among patients with ischemic HF, the wean rate ratio favored the mesenchymal precursor cell therapy group (RR = 1.55; 95% CI, 1.01-2.36), whereas among patients with nonischemic HF, there was no difference (RR = 0.82; 95% CI, 0.58-1.14; P for interaction = .02).

The results did not vary by indication for LVAD (destination therapy vs. bridge to transplant).

There were no safety-related stopping events in either group, and allosensitization to class I human leukocyte antigens was higher in the cell group (26% vs. 9.4%; between-group difference, 16.5 percentage points; 95% CI, 5-28), according to the researchers.

At 1 year, time to transplant did not differ between the groups (P = .31), nor did survival (HR = 0.89; 95% CI, 0.38-2.11), Pagani said.

Mucosal bleeding was lower at 6 months in the cell group (3.8 per 100 patient-months vs. 15.9 per 100 patient-months; P < .001), he said.

“Mesenchymal precursor cells did not increase the rate of cardiac recovery in LVAD-supported patients. However, in an exploratory subgroup analysis, there was a positive signal in ischemic HF,” Pagani said. “This may affect patient selection in future cardiac recovery trials. There was a clinically meaningful decrease in rate of mucosal bleeding. If this is substantiated in future trials, it may lead to a new therapeutic approach.” – by Erik Swain

Reference:

Pagani FD, et al. LBS.06 - Late Breaking Science in Coronary Revascularization. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Disclosure: Mesoblast provided the mesenchymal precursor cells and cryoprotective media for the study at no cost. Pagani reports no relevant financial disclosures.

 

 

 

 

 

 

CHICAGO — Among patients with advanced HF designated for left ventricular assist device therapy, mesenchymal precursor cells did not improve cardiac recovery, but there was a signal of benefit in ischemic HF, according to the results of the LVAD MPC-II trial.

Francis D. Pagani, MD, PhD, surgical director of the Adult Heart Transplant Program and program director for the Center for Circulatory Support at the University of Michigan Medical School, and colleagues evaluated whether immunomodulation from mesenchymal precursor cells could augment cardiac recovery and reduce adverse events in patients with advanced HF (ischemic or nonischemic) who were scheduled for LVAD implantation.

The researchers randomly assigned 159 patients (mean age, 56 years; 89% men) on a 2:1 basis to an intramyocardial injection of mesenchymal precursor cells (Mesoblast) or a sham procedure. Mean LV ejection fraction was 17.3% in the cell group and 16.2% in the control group.

The primary efficacy endpoint was successful temporary wean (at least 30 minutes) from full to minimal LVAD support at 2, 4 and 6 months. The primary safety endpoint was intervention-related adverse events, including infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction and immune sensitization.

According to the researchers, the mean proportion of successful temporary weans was 61% in the cell group and 58% in the control group (RR = 1.08; 95% CI, 0.83-1.41).

Pagani said the posterior probability of mesenchymal precursor cells increasing likelihood of successful weaning was 69%, which was below the prespecified threshold of 80%.

However, he said, in an exploratory subgroup analysis, among patients with ischemic HF, the wean rate ratio favored the mesenchymal precursor cell therapy group (RR = 1.55; 95% CI, 1.01-2.36), whereas among patients with nonischemic HF, there was no difference (RR = 0.82; 95% CI, 0.58-1.14; P for interaction = .02).

The results did not vary by indication for LVAD (destination therapy vs. bridge to transplant).

There were no safety-related stopping events in either group, and allosensitization to class I human leukocyte antigens was higher in the cell group (26% vs. 9.4%; between-group difference, 16.5 percentage points; 95% CI, 5-28), according to the researchers.

At 1 year, time to transplant did not differ between the groups (P = .31), nor did survival (HR = 0.89; 95% CI, 0.38-2.11), Pagani said.

Mucosal bleeding was lower at 6 months in the cell group (3.8 per 100 patient-months vs. 15.9 per 100 patient-months; P < .001), he said.

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“Mesenchymal precursor cells did not increase the rate of cardiac recovery in LVAD-supported patients. However, in an exploratory subgroup analysis, there was a positive signal in ischemic HF,” Pagani said. “This may affect patient selection in future cardiac recovery trials. There was a clinically meaningful decrease in rate of mucosal bleeding. If this is substantiated in future trials, it may lead to a new therapeutic approach.” – by Erik Swain

Reference:

Pagani FD, et al. LBS.06 - Late Breaking Science in Coronary Revascularization. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Disclosure: Mesoblast provided the mesenchymal precursor cells and cryoprotective media for the study at no cost. Pagani reports no relevant financial disclosures.

 

 

 

 

 

 

    Perspective
    Douglas W. Losordo

    Douglas W. Losordo

    This is a well-designed study exploring the utility of mesenchymal precursor cells in LVAD patients. The interesting finding of the “off-target” effect of reduced bleeding is potentially important and worthy of further study. 

    There are no implications for clinical practice yet, although if the reduction in bleeding was confirmed, this could be a novel preventive therapy in these very ill patients. 

    It could be interesting to examine the effect of mesenchymal precursor cells on bleeding in other settings where GI bleeding is problematic, eg, ICU patients. A different (noncardiac) route of administration could be explored. 

    • Douglas W. Losordo, MD
    • Cardiology Today Editorial Board Member Caladrius Biosciences

    Disclosures: Losordo reports he is an employee of Caladrius Biosciences, which develops cell-based therapies to treat heart disease.

    Perspective
    Randall C. Starling

    Randall C. Starling

    I was not surprised by the results of this study, in that it did not show efficacy with respect to a greater number of patients that were weanable from the LVAD. The biggest surprise, which I don’t have an explanation for, is the intriguing reduction in mucosal bleeding. One of the biggest unsolved problems with LVADs is gastrointestinal bleeding, the mechanisms of which have only been speculated. This was a very curious observation.

    Also not surprising was that allosensitization was significantly elevated in the mesenchymal cell group. The implications are that it could have an impact on heart transplant survival and allocation of organs. In short-term follow-up, the survival was the same, but we need longer-term follow-up to see how that plays out.

    The bottom line is that the target population based on this study looks skewed toward ischemic cardiomyopathy as opposed to dilated cardiomyopathy, and there is possibly an intriguing role for stem cells to reduce mucosal bleeding. It would be quite tedious to deploy that type of therapy for that purpose.

    In my opinion, the whole stem-cell world remains exploratory with respect to the best cells and correct dose.

    • Randall C. Starling, MD, MPH
    • Professor of Medicine Section of Heart Failure and Cardiac Transplant Medicine Medical Director, Kaufman Center for Heart Failure Staff Cardiologist, Robert and Suzanne Tomsich Department of Cardiovascular Medicine Vice Chairman, Cardiovascular Medicine Operations Cleveland Clinic President, Heart Failure Society of America

    Disclosures: Starling reports he was a site investigator for this trial.

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