Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: The TAC-HFT randomized trial

Alan W. Heldman, Darcy L. DiFede, Joel E. Fishman, Juan P. Zambrano, Barry H. Trachtenberg, Vasileios Karantalis, Muzammil Mushtaq, Adam R. Williams, Viky Y. Suncion, Ian K. McNiece, Eduard Ghersin, Victor Soto, Gustavo Lopera, Roberto Miki, Howard Willens, Robert Hendel, Raul Mitrani, Pradip Pattany, Gary Feigenbaum, Behzad OskoueiJohn Byrnes, Maureen H. Lowery, Julio Sierra, Mariesty V. Pujol, Cindy Delgado, Phillip J. Gonzalez, Jose E. Rodriguez, Luiza Lima Bagno, Didier Rouy, Peter Altman, Cheryl Wong Po Foo, Jose Da Silva, Erica Anderson, Richard Schwarz, Adam Mendizabal, Joshua M. Hare

Research output: Contribution to journalArticle

Abstract

IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than50%(September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6%(95%CI, 12.6%to 56.6%) for MSCs, 31.6% (95%CI, 12.6%-56.6%) for BMCs, and 38.1%(95%CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95%CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95%CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95%CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95%CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95%CI, -15.7%to 1.7%; within-group, P = .11) or placebo (-5.2%; 95%CI, -16.8%to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95%CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95%CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95%CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00768066

Original languageEnglish (US)
Pages (from-to)62-73
Number of pages12
JournalJournal of the American Medical Association
Volume311
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

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Mesenchymal Stromal Cells
Cardiomyopathies
Bone Marrow Cells
Placebos
Injections
Safety
Stem Cells
Heart Failure
Left Ventricular Dysfunction
Stroke Volume
Sample Size
Cardiac Arrhythmias
Hospitalization
Therapeutics
Catheters
Stroke
Myocardial Infarction
Incidence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Heldman, A. W., DiFede, D. L., Fishman, J. E., Zambrano, J. P., Trachtenberg, B. H., Karantalis, V., ... Hare, J. M. (2014). Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: The TAC-HFT randomized trial. Journal of the American Medical Association, 311(1), 62-73. https://doi.org/10.1001/jama.2013.282909

Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy : The TAC-HFT randomized trial. / Heldman, Alan W.; DiFede, Darcy L.; Fishman, Joel E.; Zambrano, Juan P.; Trachtenberg, Barry H.; Karantalis, Vasileios; Mushtaq, Muzammil; Williams, Adam R.; Suncion, Viky Y.; McNiece, Ian K.; Ghersin, Eduard; Soto, Victor; Lopera, Gustavo; Miki, Roberto; Willens, Howard; Hendel, Robert; Mitrani, Raul; Pattany, Pradip; Feigenbaum, Gary; Oskouei, Behzad; Byrnes, John; Lowery, Maureen H.; Sierra, Julio; Pujol, Mariesty V.; Delgado, Cindy; Gonzalez, Phillip J.; Rodriguez, Jose E.; Bagno, Luiza Lima; Rouy, Didier; Altman, Peter; Foo, Cheryl Wong Po; Da Silva, Jose; Anderson, Erica; Schwarz, Richard; Mendizabal, Adam; Hare, Joshua M.

In: Journal of the American Medical Association, Vol. 311, No. 1, 2014, p. 62-73.

Research output: Contribution to journalArticle

Heldman, AW, DiFede, DL, Fishman, JE, Zambrano, JP, Trachtenberg, BH, Karantalis, V, Mushtaq, M, Williams, AR, Suncion, VY, McNiece, IK, Ghersin, E, Soto, V, Lopera, G, Miki, R, Willens, H, Hendel, R, Mitrani, R, Pattany, P, Feigenbaum, G, Oskouei, B, Byrnes, J, Lowery, MH, Sierra, J, Pujol, MV, Delgado, C, Gonzalez, PJ, Rodriguez, JE, Bagno, LL, Rouy, D, Altman, P, Foo, CWP, Da Silva, J, Anderson, E, Schwarz, R, Mendizabal, A & Hare, JM 2014, 'Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: The TAC-HFT randomized trial', Journal of the American Medical Association, vol. 311, no. 1, pp. 62-73. https://doi.org/10.1001/jama.2013.282909
Heldman, Alan W. ; DiFede, Darcy L. ; Fishman, Joel E. ; Zambrano, Juan P. ; Trachtenberg, Barry H. ; Karantalis, Vasileios ; Mushtaq, Muzammil ; Williams, Adam R. ; Suncion, Viky Y. ; McNiece, Ian K. ; Ghersin, Eduard ; Soto, Victor ; Lopera, Gustavo ; Miki, Roberto ; Willens, Howard ; Hendel, Robert ; Mitrani, Raul ; Pattany, Pradip ; Feigenbaum, Gary ; Oskouei, Behzad ; Byrnes, John ; Lowery, Maureen H. ; Sierra, Julio ; Pujol, Mariesty V. ; Delgado, Cindy ; Gonzalez, Phillip J. ; Rodriguez, Jose E. ; Bagno, Luiza Lima ; Rouy, Didier ; Altman, Peter ; Foo, Cheryl Wong Po ; Da Silva, Jose ; Anderson, Erica ; Schwarz, Richard ; Mendizabal, Adam ; Hare, Joshua M. / Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy : The TAC-HFT randomized trial. In: Journal of the American Medical Association. 2014 ; Vol. 311, No. 1. pp. 62-73.
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title = "Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: The TAC-HFT randomized trial",
abstract = "IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than50{\%}(September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6{\%}(95{\%}CI, 12.6{\%}to 56.6{\%}) for MSCs, 31.6{\%} (95{\%}CI, 12.6{\%}-56.6{\%}) for BMCs, and 38.1{\%}(95{\%}CI, 18.1{\%}-61.6{\%}) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95{\%}CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95{\%}CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95{\%}CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9{\%}; 95{\%}CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0{\%}; 95{\%}CI, -15.7{\%}to 1.7{\%}; within-group, P = .11) or placebo (-5.2{\%}; 95{\%}CI, -16.8{\%}to 6.5{\%}; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95{\%}CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95{\%}CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95{\%}CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00768066",
author = "Heldman, {Alan W.} and DiFede, {Darcy L.} and Fishman, {Joel E.} and Zambrano, {Juan P.} and Trachtenberg, {Barry H.} and Vasileios Karantalis and Muzammil Mushtaq and Williams, {Adam R.} and Suncion, {Viky Y.} and McNiece, {Ian K.} and Eduard Ghersin and Victor Soto and Gustavo Lopera and Roberto Miki and Howard Willens and Robert Hendel and Raul Mitrani and Pradip Pattany and Gary Feigenbaum and Behzad Oskouei and John Byrnes and Lowery, {Maureen H.} and Julio Sierra and Pujol, {Mariesty V.} and Cindy Delgado and Gonzalez, {Phillip J.} and Rodriguez, {Jose E.} and Bagno, {Luiza Lima} and Didier Rouy and Peter Altman and Foo, {Cheryl Wong Po} and {Da Silva}, Jose and Erica Anderson and Richard Schwarz and Adam Mendizabal and Hare, {Joshua M.}",
year = "2014",
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TY - JOUR

T1 - Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy

T2 - The TAC-HFT randomized trial

AU - Heldman, Alan W.

AU - DiFede, Darcy L.

AU - Fishman, Joel E.

AU - Zambrano, Juan P.

AU - Trachtenberg, Barry H.

AU - Karantalis, Vasileios

AU - Mushtaq, Muzammil

AU - Williams, Adam R.

AU - Suncion, Viky Y.

AU - McNiece, Ian K.

AU - Ghersin, Eduard

AU - Soto, Victor

AU - Lopera, Gustavo

AU - Miki, Roberto

AU - Willens, Howard

AU - Hendel, Robert

AU - Mitrani, Raul

AU - Pattany, Pradip

AU - Feigenbaum, Gary

AU - Oskouei, Behzad

AU - Byrnes, John

AU - Lowery, Maureen H.

AU - Sierra, Julio

AU - Pujol, Mariesty V.

AU - Delgado, Cindy

AU - Gonzalez, Phillip J.

AU - Rodriguez, Jose E.

AU - Bagno, Luiza Lima

AU - Rouy, Didier

AU - Altman, Peter

AU - Foo, Cheryl Wong Po

AU - Da Silva, Jose

AU - Anderson, Erica

AU - Schwarz, Richard

AU - Mendizabal, Adam

AU - Hare, Joshua M.

PY - 2014

Y1 - 2014

N2 - IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than50%(September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6%(95%CI, 12.6%to 56.6%) for MSCs, 31.6% (95%CI, 12.6%-56.6%) for BMCs, and 38.1%(95%CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95%CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95%CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95%CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95%CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95%CI, -15.7%to 1.7%; within-group, P = .11) or placebo (-5.2%; 95%CI, -16.8%to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95%CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95%CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95%CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00768066

AB - IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than50%(September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6%(95%CI, 12.6%to 56.6%) for MSCs, 31.6% (95%CI, 12.6%-56.6%) for BMCs, and 38.1%(95%CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95%CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95%CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95%CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95%CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95%CI, -15.7%to 1.7%; within-group, P = .11) or placebo (-5.2%; 95%CI, -16.8%to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95%CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95%CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95%CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00768066

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