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Intramyocardial Injection of Mesenchymal Precursor Cells and Weaning From LVAD Support
Study Questions:
What is the efficacy and what are the adverse effects of intramyocardial injections of mesenchymal precursor cells (MPCs) during left ventricular assist device (LVAD) implant?
Methods:
The study investigators conducted a randomized phase 2 clinical trial involving patients with advanced heart failure (HF), undergoing continuous-flow LVAD implant, at 19 centers. All patients were followed up for up to 12 months after randomization or until heart transplant, whichever came first, with endpoints evaluated at 2, 4, 6, 9, and 12 months. The study intervention was comprised of intramyocardial injections of 150 million allogeneic MPCs or cryoprotective medium as a sham treatment in a 2:1 ratio (n = 106 vs. n = 53). The primary efficacy endpoint was the proportion of successful temporary weans (of three planned assessments) from LVAD support within 6 months of randomization. This endpoint was assessed using a Bayesian analysis with a predefined threshold of a posterior probability of 80% to indicate success. The 1-year primary safety endpoint was the incidence of intervention-related adverse events (myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization). There were 10 secondary endpoints including echocardiographic parameters, readmissions, and adverse events at 6-month and 1-year survival.
Results:
The final study cohort comprised 159 patients (mean age, 56 years; 11.3% women), of whom 97.5% (n = 155) completed 1 year of follow-up. The cause of HF was ischemic in 43 (40.6%) MPC patients versus 27 (50.9%) control patients. The posterior probability that MPCs increased the likelihood of successful weaning was 69%; below the 80% predefined threshold for a positive signal (data were available for 157 patients [98.7%]; 105 in the MPC group and 52 in the control group, and there were no crossovers). 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% confidence interval [CI], 0.83-1.41; p = 0.55). No patient experienced a primary safety endpoint. Of 10 prespecified secondary endpoints reported, nine 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 = 0.80). 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 = 0.63) 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 = 0.68). The 6-month cumulative incidence of serious gastrointestinal (GI) tract bleed, epistaxis, or both was 17.2% (95% CI, 10.66-25.04%) for the MPC group and 32.8% (95% CI, 20.39-45.84%) for the control group (p = 0.02)
Conclusions:
The study authors concluded that among patients with advanced HF, intramyocardial injections of MPCs, compared with injections of a cryoprotective medium as sham treatment, did not improve successful temporary weaning from LVAD support at 6 months. They also concluded that these findings do not support the use of intramyocardial mesenchymal stem cells to promote cardiac recovery, as measured by temporary weaning from device support.
Perspective:
Although it was disappointing that this trial showed the lack of efficacy of MPCs, there was a signal benefit with these cells—no trial patient suffered a primary safety event and MPC injections were associated with a delay in the time to first serious GI bleed and epistaxis and with a significant and clinically meaningful decrease in the rate of these events. Hopefully as ‘precision medicine’ continues to evolve, this therapy may have a role in carefully selected patients.
Clinical Topics: Cardiac Surgery, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Transplant, Mechanical Circulatory Support, Interventions and Imaging, Echocardiography/Ultrasound
Keywords: Cardiac Surgical Procedures, Echocardiography, Gastrointestinal Tract, Heart Failure, Heart Transplantation, Heart-Assist Devices, Mesenchymal Stem Cells, Myocarditis, Myocardial Ischemia, Neoplasms, Weaning
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