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

Terrence M. Yau, Francis D. Pagani, Donna M. Mancini, Helena L. Chang, Anuradha Lala, Y. Joseph Woo, Michael A. Acker, Craig H. Selzman, Edward G. Soltesz, John A. Kern, Simon Maltais, Eric Charbonneau, Stephanie Pan, Mary E. Marks, Ellen G. Moquete, Karen L. O'Sullivan, Wendy C. Taddei-Peters, Lydia K. McGowan, China Green, Eric A. RoseNeal Jeffries, Michael K. Parides, Richard D. Weisel, Marissa A. Miller, Judy Hung, Patrick T. O'Gara, Alan J. Moskowitz, Annetine C. Gelijns, Emilia Bagiella, Carmelo A. Milano

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1176-1186
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume321
Issue number12
DOIs
StatePublished - Mar 26 2019

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Heart-Assist Devices
Weaning
Randomized Controlled Trials
Heart Failure
Injections
Placebos
Safety
Control Groups
Bayes Theorem
Myocarditis
Random Allocation
Mesenchymal Stromal Cells
Rupture
Hypersensitivity
Stem Cells
Outcome Assessment (Health Care)
Clinical Trials
Equipment and Supplies
Survival
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. / Yau, Terrence M.; Pagani, Francis D.; Mancini, Donna M.; Chang, Helena L.; Lala, Anuradha; Woo, Y. Joseph; Acker, Michael A.; Selzman, Craig H.; Soltesz, Edward G.; Kern, John A.; Maltais, Simon; Charbonneau, Eric; Pan, Stephanie; Marks, Mary E.; Moquete, Ellen G.; O'Sullivan, Karen L.; Taddei-Peters, Wendy C.; McGowan, Lydia K.; Green, China; Rose, Eric A.; Jeffries, Neal; Parides, Michael K.; Weisel, Richard D.; Miller, Marissa A.; Hung, Judy; O'Gara, Patrick T.; Moskowitz, Alan J.; Gelijns, Annetine C.; Bagiella, Emilia; Milano, Carmelo A.

In: JAMA - Journal of the American Medical Association, Vol. 321, No. 12, 26.03.2019, p. 1176-1186.

Research output: Contribution to journalArticle

Yau, TM, Pagani, FD, Mancini, DM, Chang, HL, Lala, A, Woo, YJ, Acker, MA, Selzman, CH, Soltesz, EG, Kern, JA, Maltais, S, Charbonneau, E, Pan, S, Marks, ME, Moquete, EG, O'Sullivan, KL, Taddei-Peters, WC, McGowan, LK, Green, C, Rose, EA, Jeffries, N, Parides, MK, Weisel, RD, Miller, MA, Hung, J, O'Gara, PT, Moskowitz, AJ, Gelijns, AC, Bagiella, E & Milano, CA 2019, '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', JAMA - Journal of the American Medical Association, vol. 321, no. 12, pp. 1176-1186. https://doi.org/10.1001/jama.2019.2341
Yau, Terrence M. ; Pagani, Francis D. ; Mancini, Donna M. ; Chang, Helena L. ; Lala, Anuradha ; Woo, Y. Joseph ; Acker, Michael A. ; Selzman, Craig H. ; Soltesz, Edward G. ; Kern, John A. ; Maltais, Simon ; Charbonneau, Eric ; Pan, Stephanie ; Marks, Mary E. ; Moquete, Ellen G. ; O'Sullivan, Karen L. ; Taddei-Peters, Wendy C. ; McGowan, Lydia K. ; Green, China ; Rose, Eric A. ; Jeffries, Neal ; Parides, Michael K. ; Weisel, Richard D. ; Miller, Marissa A. ; Hung, Judy ; O'Gara, Patrick T. ; Moskowitz, Alan J. ; Gelijns, Annetine C. ; Bagiella, Emilia ; Milano, Carmelo A. / 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. In: JAMA - Journal of the American Medical Association. 2019 ; Vol. 321, No. 12. pp. 1176-1186.
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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.",
author = "Yau, {Terrence M.} and Pagani, {Francis D.} and Mancini, {Donna M.} and Chang, {Helena L.} and Anuradha Lala and Woo, {Y. Joseph} and Acker, {Michael A.} and Selzman, {Craig H.} and Soltesz, {Edward G.} and Kern, {John A.} and Simon Maltais and Eric Charbonneau and Stephanie Pan and Marks, {Mary E.} and Moquete, {Ellen G.} and O'Sullivan, {Karen L.} and Taddei-Peters, {Wendy C.} and McGowan, {Lydia K.} and China Green and Rose, {Eric A.} and Neal Jeffries and Parides, {Michael K.} and Weisel, {Richard D.} and Miller, {Marissa A.} and Judy Hung and O'Gara, {Patrick T.} and Moskowitz, {Alan J.} and Gelijns, {Annetine C.} and Emilia Bagiella and Milano, {Carmelo A.}",
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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.

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.

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