Cardiopoietic cell therapy for advanced ischaemic heart failure: Results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Jozef Bartunek, Andre Terzic, Beth A. Davison, Gerasimos S. Filippatos, Slavica Radovanovic, Branko Beleslin, Bela Merkely, Piotr Musialek, Wojciech Wojakowski, Peter Andreka, Ivan G. Horvath, Amos Katz, Dariouch Dolatabadi, Badih El Nakadi, Aleksandra Arandjelovic, Istvan Edes, Petar M. Seferovic, Slobodan Obradovic, Marc Vanderheyden, Nikola JagicIvo Petrov, Shaul Atar, Majdi Halabi, Valeri L. Gelev, Michael K. Shochat, Jaroslaw D. Kasprzak, Ricardo Sanz-Ruiz, Guy R. Heyndrickx, Noemi Nyolczas, Victor Legrand, Antoine Guédès, Alex Heyse, Tiziano Moccetti, Francisco Fernandez-Aviles, Pilar Jimenez-Quevedo, Antoni Bayes-Genis, Jose Maria Hernandez-Garcia, Flavio Ribichini, Marcin Gruchala, Scott A. Waldman, John R. Teerlink, Bernard J. Gersh, Thomas J. Povsic, Timothy D. Henry, Marco Metra, Roger J. Hajjar, Michal Tendera, Atta Behfar, Bertrand Alexandre, Aymeric Seron, Wendy Gattis Stough, Warren Sherman, Gad Cotter, William Wijns

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n= 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving> 24 million mesenchymal stem cells (n=315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n=157) or sham procedure (n= 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n= 151 sham). The primary efficacy endpoint was a Finkelstein Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann Whitney estimator 0.54, 95% confidence interval [CI] 0.47 0.61 [value> 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370mL (60% of patients) (Mann Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Original languageEnglish (US)
Pages (from-to)648-660
Number of pages13
JournalEuropean Heart Journal
Volume38
Issue number9
DOIs
StatePublished - Mar 1 2017

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Cell- and Tissue-Based Therapy
Heart Failure
Clinical Trials
Mesenchymal Stromal Cells
Stroke Volume
Confidence Intervals
Biological Therapy
Sudden Cardiac Death
Therapeutics
Catheters
Bone Marrow
Guidelines
Safety
Mortality

Keywords

  • Cardiopoiesis
  • Cardiovascular disease
  • Disease severity
  • Marker
  • Precision medicine
  • Regenerative medicine
  • Stem cell
  • Target population

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Cardiopoietic cell therapy for advanced ischaemic heart failure : Results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. / Bartunek, Jozef; Terzic, Andre; Davison, Beth A.; Filippatos, Gerasimos S.; Radovanovic, Slavica; Beleslin, Branko; Merkely, Bela; Musialek, Piotr; Wojakowski, Wojciech; Andreka, Peter; Horvath, Ivan G.; Katz, Amos; Dolatabadi, Dariouch; El Nakadi, Badih; Arandjelovic, Aleksandra; Edes, Istvan; Seferovic, Petar M.; Obradovic, Slobodan; Vanderheyden, Marc; Jagic, Nikola; Petrov, Ivo; Atar, Shaul; Halabi, Majdi; Gelev, Valeri L.; Shochat, Michael K.; Kasprzak, Jaroslaw D.; Sanz-Ruiz, Ricardo; Heyndrickx, Guy R.; Nyolczas, Noemi; Legrand, Victor; Guédès, Antoine; Heyse, Alex; Moccetti, Tiziano; Fernandez-Aviles, Francisco; Jimenez-Quevedo, Pilar; Bayes-Genis, Antoni; Hernandez-Garcia, Jose Maria; Ribichini, Flavio; Gruchala, Marcin; Waldman, Scott A.; Teerlink, John R.; Gersh, Bernard J.; Povsic, Thomas J.; Henry, Timothy D.; Metra, Marco; Hajjar, Roger J.; Tendera, Michal; Behfar, Atta; Alexandre, Bertrand; Seron, Aymeric; Stough, Wendy Gattis; Sherman, Warren; Cotter, Gad; Wijns, William.

In: European Heart Journal, Vol. 38, No. 9, 01.03.2017, p. 648-660.

Research output: Contribution to journalArticle

Bartunek, J, Terzic, A, Davison, BA, Filippatos, GS, Radovanovic, S, Beleslin, B, Merkely, B, Musialek, P, Wojakowski, W, Andreka, P, Horvath, IG, Katz, A, Dolatabadi, D, El Nakadi, B, Arandjelovic, A, Edes, I, Seferovic, PM, Obradovic, S, Vanderheyden, M, Jagic, N, Petrov, I, Atar, S, Halabi, M, Gelev, VL, Shochat, MK, Kasprzak, JD, Sanz-Ruiz, R, Heyndrickx, GR, Nyolczas, N, Legrand, V, Guédès, A, Heyse, A, Moccetti, T, Fernandez-Aviles, F, Jimenez-Quevedo, P, Bayes-Genis, A, Hernandez-Garcia, JM, Ribichini, F, Gruchala, M, Waldman, SA, Teerlink, JR, Gersh, BJ, Povsic, TJ, Henry, TD, Metra, M, Hajjar, RJ, Tendera, M, Behfar, A, Alexandre, B, Seron, A, Stough, WG, Sherman, W, Cotter, G & Wijns, W 2017, 'Cardiopoietic cell therapy for advanced ischaemic heart failure: Results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial', European Heart Journal, vol. 38, no. 9, pp. 648-660. https://doi.org/10.1093/eurheartj/ehw543
Bartunek, Jozef ; Terzic, Andre ; Davison, Beth A. ; Filippatos, Gerasimos S. ; Radovanovic, Slavica ; Beleslin, Branko ; Merkely, Bela ; Musialek, Piotr ; Wojakowski, Wojciech ; Andreka, Peter ; Horvath, Ivan G. ; Katz, Amos ; Dolatabadi, Dariouch ; El Nakadi, Badih ; Arandjelovic, Aleksandra ; Edes, Istvan ; Seferovic, Petar M. ; Obradovic, Slobodan ; Vanderheyden, Marc ; Jagic, Nikola ; Petrov, Ivo ; Atar, Shaul ; Halabi, Majdi ; Gelev, Valeri L. ; Shochat, Michael K. ; Kasprzak, Jaroslaw D. ; Sanz-Ruiz, Ricardo ; Heyndrickx, Guy R. ; Nyolczas, Noemi ; Legrand, Victor ; Guédès, Antoine ; Heyse, Alex ; Moccetti, Tiziano ; Fernandez-Aviles, Francisco ; Jimenez-Quevedo, Pilar ; Bayes-Genis, Antoni ; Hernandez-Garcia, Jose Maria ; Ribichini, Flavio ; Gruchala, Marcin ; Waldman, Scott A. ; Teerlink, John R. ; Gersh, Bernard J. ; Povsic, Thomas J. ; Henry, Timothy D. ; Metra, Marco ; Hajjar, Roger J. ; Tendera, Michal ; Behfar, Atta ; Alexandre, Bertrand ; Seron, Aymeric ; Stough, Wendy Gattis ; Sherman, Warren ; Cotter, Gad ; Wijns, William. / Cardiopoietic cell therapy for advanced ischaemic heart failure : Results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. In: European Heart Journal. 2017 ; Vol. 38, No. 9. pp. 648-660.
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abstract = "Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n= 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving> 24 million mesenchymal stem cells (n=315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n=157) or sham procedure (n= 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n= 151 sham). The primary efficacy endpoint was a Finkelstein Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann Whitney estimator 0.54, 95{\%} confidence interval [CI] 0.47 0.61 [value> 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370mL (60{\%} of patients) (Mann Whitney estimator 0.61, 95{\%} CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9{\%}) cardiopoietic cell patient and 9 (5.4{\%}) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.",
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TY - JOUR

T1 - Cardiopoietic cell therapy for advanced ischaemic heart failure

T2 - Results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

AU - Bartunek, Jozef

AU - Terzic, Andre

AU - Davison, Beth A.

AU - Filippatos, Gerasimos S.

AU - Radovanovic, Slavica

AU - Beleslin, Branko

AU - Merkely, Bela

AU - Musialek, Piotr

AU - Wojakowski, Wojciech

AU - Andreka, Peter

AU - Horvath, Ivan G.

AU - Katz, Amos

AU - Dolatabadi, Dariouch

AU - El Nakadi, Badih

AU - Arandjelovic, Aleksandra

AU - Edes, Istvan

AU - Seferovic, Petar M.

AU - Obradovic, Slobodan

AU - Vanderheyden, Marc

AU - Jagic, Nikola

AU - Petrov, Ivo

AU - Atar, Shaul

AU - Halabi, Majdi

AU - Gelev, Valeri L.

AU - Shochat, Michael K.

AU - Kasprzak, Jaroslaw D.

AU - Sanz-Ruiz, Ricardo

AU - Heyndrickx, Guy R.

AU - Nyolczas, Noemi

AU - Legrand, Victor

AU - Guédès, Antoine

AU - Heyse, Alex

AU - Moccetti, Tiziano

AU - Fernandez-Aviles, Francisco

AU - Jimenez-Quevedo, Pilar

AU - Bayes-Genis, Antoni

AU - Hernandez-Garcia, Jose Maria

AU - Ribichini, Flavio

AU - Gruchala, Marcin

AU - Waldman, Scott A.

AU - Teerlink, John R.

AU - Gersh, Bernard J.

AU - Povsic, Thomas J.

AU - Henry, Timothy D.

AU - Metra, Marco

AU - Hajjar, Roger J.

AU - Tendera, Michal

AU - Behfar, Atta

AU - Alexandre, Bertrand

AU - Seron, Aymeric

AU - Stough, Wendy Gattis

AU - Sherman, Warren

AU - Cotter, Gad

AU - Wijns, William

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n= 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving> 24 million mesenchymal stem cells (n=315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n=157) or sham procedure (n= 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n= 151 sham). The primary efficacy endpoint was a Finkelstein Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann Whitney estimator 0.54, 95% confidence interval [CI] 0.47 0.61 [value> 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370mL (60% of patients) (Mann Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

AB - Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n= 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving> 24 million mesenchymal stem cells (n=315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n=157) or sham procedure (n= 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n= 151 sham). The primary efficacy endpoint was a Finkelstein Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann Whitney estimator 0.54, 95% confidence interval [CI] 0.47 0.61 [value> 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370mL (60% of patients) (Mann Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

KW - Cardiopoiesis

KW - Cardiovascular disease

KW - Disease severity

KW - Marker

KW - Precision medicine

KW - Regenerative medicine

KW - Stem cell

KW - Target population

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