TY - JOUR
T1 - Intramyocardial Injection of Mesenchymal Precursor Cells and Successful Temporary Weaning from Left Ventricular Assist Device Support in Patients with Advanced Heart Failure
T2 - A Randomized Clinical Trial
AU - Yau, Terrence M.
AU - Pagani, Francis D.
AU - Mancini, Donna M.
AU - Chang, Helena L.
AU - Lala, Anuradha
AU - Woo, Y. Joseph
AU - Acker, Michael A.
AU - Selzman, Craig H.
AU - Soltesz, Edward G.
AU - Kern, John A.
AU - Maltais, Simon
AU - Charbonneau, Eric
AU - Pan, Stephanie
AU - Marks, Mary E.
AU - Moquete, Ellen G.
AU - O'Sullivan, Karen L.
AU - Taddei-Peters, Wendy C.
AU - McGowan, Lydia K.
AU - Green, China
AU - Rose, Eric A.
AU - Jeffries, Neal
AU - Parides, Michael K.
AU - Weisel, Richard D.
AU - Miller, Marissa A.
AU - Hung, Judy
AU - O'Gara, Patrick T.
AU - Moskowitz, Alan J.
AU - Gelijns, Annetine C.
AU - Bagiella, Emilia
AU - Milano, Carmelo A.
N1 - Funding Information:
cooperative agreement (U01 HL088942) funded by the National Heart, Lung, and Blood Institute and the National Institutes of Neurological Disorders and Stroke, of the National Institutes of Health (NIH), and the Canadian Institutes for Health Research. Mesoblast provided no financial support but did provide study product (MPCs and control).
Funding Information:
reported receiving honoraria from Abbott, Atricure, and Abiomed and royalties from Jace Medical. Dr Kern reported previously serving on a medical advisory board for Sorin. Dr Rose reported that he is a corporate director at Mesoblast Ltd and Abiomed Inc and is the chair of the strategic advisory board of Broadview Ventures. Dr O’Gara reported receiving grant funding from Delta Dental Research and Data Institute and consulting fees from Medtronic and Edwards Lifesciences. Dr Milano reported receiving consulting fees from Medtronic and Abbott, chairing the corporate board of SIGA Technologies Inc, and serving on the scientific advisory board of Broadview Ventures. No other disclosures were reported.
Funding Information:
Funding/Support: The trial was supported by a
Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2019/3/26
Y1 - 2019/3/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85063350851&partnerID=8YFLogxK
U2 - 10.1001/jama.2019.2341
DO - 10.1001/jama.2019.2341
M3 - Article
C2 - 30912838
AN - SCOPUS:85063350851
SN - 0002-9955
VL - 321
SP - 1176
EP - 1186
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 12
ER -