Autologous CD34 + cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: A patient-level pooled analysis of randomized double-blinded trials

Timothy D. Henry, Douglas W. Losordo, Jay H. Traverse, Richard A. Schatz, E. Marc Jolicoeur, Gary L. Schaer, Robert Clare, Karen Chiswell, Christopher J. White, F. David Fortuin, Dean J. Kereiakes, Andreas M. Zeiher, Warren Sherman, Andrea S. Hunt, Thomas J. Povsic

Research output: Contribution to journalArticle

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Abstract

Aims Autologous CD34 + (auto-CD34 +) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34 + cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34 + cells. Methods and results Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34 + cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34 + compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 10 5 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months. Conclusion Treatment with auto-CD34 + cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.

Original languageEnglish (US)
Pages (from-to)2208-2216
Number of pages9
JournalEuropean Heart Journal
Volume39
Issue number23
DOIs
StatePublished - Jun 14 2018

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Cell- and Tissue-Based Therapy
Exercise
Mortality
Confidence Intervals
Placebos
Kaplan-Meier Estimate
Therapeutics
Meta-Analysis
Linear Models
Safety
Injections

Keywords

  • CD34 +
  • Refractory angina
  • Stem cell therapy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Autologous CD34 + cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina : A patient-level pooled analysis of randomized double-blinded trials. / Henry, Timothy D.; Losordo, Douglas W.; Traverse, Jay H.; Schatz, Richard A.; Jolicoeur, E. Marc; Schaer, Gary L.; Clare, Robert; Chiswell, Karen; White, Christopher J.; Fortuin, F. David; Kereiakes, Dean J.; Zeiher, Andreas M.; Sherman, Warren; Hunt, Andrea S.; Povsic, Thomas J.

In: European Heart Journal, Vol. 39, No. 23, 14.06.2018, p. 2208-2216.

Research output: Contribution to journalArticle

Henry, TD, Losordo, DW, Traverse, JH, Schatz, RA, Jolicoeur, EM, Schaer, GL, Clare, R, Chiswell, K, White, CJ, Fortuin, FD, Kereiakes, DJ, Zeiher, AM, Sherman, W, Hunt, AS & Povsic, TJ 2018, 'Autologous CD34 + cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: A patient-level pooled analysis of randomized double-blinded trials', European Heart Journal, vol. 39, no. 23, pp. 2208-2216. https://doi.org/10.1093/eurheartj/ehx764
Henry, Timothy D. ; Losordo, Douglas W. ; Traverse, Jay H. ; Schatz, Richard A. ; Jolicoeur, E. Marc ; Schaer, Gary L. ; Clare, Robert ; Chiswell, Karen ; White, Christopher J. ; Fortuin, F. David ; Kereiakes, Dean J. ; Zeiher, Andreas M. ; Sherman, Warren ; Hunt, Andrea S. ; Povsic, Thomas J. / Autologous CD34 + cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina : A patient-level pooled analysis of randomized double-blinded trials. In: European Heart Journal. 2018 ; Vol. 39, No. 23. pp. 2208-2216.
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abstract = "Aims Autologous CD34 + (auto-CD34 +) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34 + cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34 + cells. Methods and results Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34 + cell therapy improved TET by 46.6 s [3 months, 95{\%} confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95{\%} CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95{\%} CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95{\%} CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34 + compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 10 5 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1{\%} vs. 2.5{\%}; P = 0.0025) and numerically reduced MACE (38.9{\%} vs. 30.0; P = 0.14) at 24 months. Conclusion Treatment with auto-CD34 + cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.",
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T1 - Autologous CD34 + cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina

T2 - A patient-level pooled analysis of randomized double-blinded trials

AU - Henry, Timothy D.

AU - Losordo, Douglas W.

AU - Traverse, Jay H.

AU - Schatz, Richard A.

AU - Jolicoeur, E. Marc

AU - Schaer, Gary L.

AU - Clare, Robert

AU - Chiswell, Karen

AU - White, Christopher J.

AU - Fortuin, F. David

AU - Kereiakes, Dean J.

AU - Zeiher, Andreas M.

AU - Sherman, Warren

AU - Hunt, Andrea S.

AU - Povsic, Thomas J.

PY - 2018/6/14

Y1 - 2018/6/14

N2 - Aims Autologous CD34 + (auto-CD34 +) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34 + cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34 + cells. Methods and results Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34 + cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34 + compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 10 5 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months. Conclusion Treatment with auto-CD34 + cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.

AB - Aims Autologous CD34 + (auto-CD34 +) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34 + cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34 + cells. Methods and results Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34 + cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34 + compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 10 5 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months. Conclusion Treatment with auto-CD34 + cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.

KW - CD34 +

KW - Refractory angina

KW - Stem cell therapy

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