Intramyocardial Injection of Mesenchymal Precursor Cells and Successful Temporary Weaning From Left Ventricular Assist Device Support in Patients With Advanced Heart Failure: A Randomized Clinical Trial

Abstract

Importance: Left ventricular assist device (LVAD) therapy improves myocardial function, but few patients recover sufficiently for explant, which has focused attention on stem cells to augment cardiac recovery.

Objective: To assess efficacy and adverse effects of intramyocardial injections of mesenchymal precursor cells (MPCs) during LVAD implant.

Design, setting, and participants: A randomized phase 2 clinical trial involving patients with advanced heart failure, undergoing LVAD implant, at 19 North American centers (July 2015-August 2017). The 1-year follow-up ended August 2018.

Interventions: Intramyocardial injections of 150 million allogeneic MPCs or cryoprotective medium as a sham treatment in a 2:1 ratio (n = 106 vs n = 53).

Main outcomes and measures: The primary efficacy end point was the proportion of successful temporary weans (of 3 planned assessments) from LVAD support within 6 months of randomization. This end point was assessed using a Bayesian analysis with a predefined threshold of a posterior probability of 80% to indicate success. The 1-year primary safety end point was the incidence of intervention-related adverse events (myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization). Secondary end points included readmissions and adverse events at 6 months and 1-year survival.

Results: Of 159 patients (mean age, 56 years; 11.3% women), 155 (97.5%) completed 1-year of follow-up. The posterior probability that MPCs increased the likelihood of successful weaning was 69%; below the predefined threshold for success. The mean proportion of successful temporary weaning from LVAD support over 6 months was 61% in the MPC group and 58% in the control group (rate ratio [RR], 1.08; 95% CI, 0.83-1.41; P = .55). No patient experienced a primary safety end point. Of 10 prespecified secondary end points reported, 9 did not reach statistical significance. One-year mortality was not significantly different between the MPC group and the control group (14.2% vs 15.1%; hazard ratio [HR], 0.89; 95%, CI, 0.38-2.11; P = .80). The rate of serious adverse events was not significantly different between groups (70.9 vs 78.7 per 100 patient-months; difference, -7.89; 95% CI, -39.95 to 24.17; P = .63) nor was the rate of readmissions (0.68 vs 0.75 per 100 patient-months; difference, -0.07; 95% CI, -0.41 to 0.27; P = .68).

Conclusions and relevance: Among patients with advanced heart failure, intramyocardial injections of mesenchymal precursor cells, compared with injections of a cryoprotective medium as sham treatment, did not improve successful temporary weaning from left ventricular assist device support at 6 months. The findings do not support the use of intramyocardial mesenchymal stem cells to promote cardiac recovery as measured by temporary weaning from device support.

Trial registration: clinicaltrials.gov Identifier: NCT02362646.

Figure 1.. Enrollment, Randomization, and Follow-up of Patients in the Left Ventricular Assist Device and Mesenchymal Precursor Cells Trial

ICD indicates implantable cardioverter-defibrillator; MPC, mesenchymal precursor cells. ^aThe 3 most common reasons for not meeting inclusion criteria were not being an acceptable candidate for a left ventricular assist device, having more than 10% anti-HLA antibody titer specific to MPC donor HLA antigens, and having a history of cancer within 3 years prior to screening. Patients could be excluded for more than 1 reason. ^bThe primary safety end point includes patients until the month-12 visit, transplant, withdrawal of consent, or death.

Figure 2.. Cumulative Incidence for Transplant and Hazard for Death

A, Nonparametric estimates of the cumulative incidence functions for heart transplant with death as a competing risk. The P value was computed using the Gray test. The median observation time was 7.1 months (interquartile range [IQR], 5.2-9.3 months) for the mesenchymal precursor cells (MPC) treatment group and 8.2 months (IQR, 4.6-9.7 months) for the control group. B. Kaplan-Meier estimates of the cumulative hazard for death. The hazard ratio was based on the Cox proportional hazards model and the P value was computed from log-rank test. Median observation time was 5.0 months (IQR, 1.4-8.2 months) for the MPC group and 3.5 months (IQR, 2.6-6.9 months) for the control group.

Figure 3.. Cumulative Incidence for Gastrointestinal Tract Bleeding or Epistaxis

Nonparametric estimates of the cumulative incidence functions for gastrointestinal (GI) tract bleeding or epistaxis with death as a competing risk and the P value was computed from the Gray test. Median observation time was 1.9 months (IQR, 0.9-2.6 months) for the mesenchymal precursor cells (MPC) treatment group and 1.0 months (IQR, 0.4-3.4 months) for the control group. Rate of GI tract bleed or epistaxis for MPC was 24 events (3.79 per 100 patient-months; total patient-months of 632.5) compared with 48 events (15.94 per 100 patient-months; total patient-months of 301.2) in the control (rate difference, −12.14; 95% CI, −20.90 to −3.39; P = .007). There were 18 patients (17%) in the MPC group and 17 patients (32.1%) in the control group who experienced a GI tract bleed or epistaxis.