The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34+ Cell Administration in Patients With Refractory Angina

Thomas J. Povsic; Timothy D. Henry; Jay H. Traverse; F. David Fortuin; Gary L. Schaer; Dean J. Kereiakes; Richard A. Schatz; Andreas M. Zeiher; Christopher J. White; Duncan J. Stewart; E. Marc Jolicoeur; Theodore Bass; David A. Henderson; Patricia Dignacco; Ziangoiong Gu; Hussein R. Al-Khalidi; Candice Junge; Adel Nada; Andrea S. Hunt; Douglas W. Losordo; RENEW Investigators

doi:10.1016/j.jcin.2016.05.003

The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34⁺ Cell Administration in Patients With Refractory Angina

Thomas J. Povsic, Timothy D. Henry, Jay H. Traverse, F. David Fortuin, Gary L. Schaer, Dean J. Kereiakes, Richard A. Schatz, Andreas M. Zeiher, Christopher J. White, Duncan J. Stewart, E. Marc Jolicoeur, Theodore Bass, David A. Henderson, Patricia Dignacco, Ziangoiong Gu, Hussein R. Al-Khalidi, Candice Junge, Adel Nada, Andrea S. Hunt, Douglas W. LosordoRENEW Investigators

Medicine - Cardiology Division

Research output: Contribution to journal › Article › peer-review

92 Scopus citations

Abstract

Objectives This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34⁺ cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. Background IM administration of autologous CD34⁺ cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. Methods RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34⁺ administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. Results The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34⁺ cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34⁺]). Conclusions Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34⁺ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910)

Original language	English (US)
Pages (from-to)	1576-1585
Number of pages	10
Journal	JACC: Cardiovascular Interventions
Volume	9
Issue number	15
DOIs	https://doi.org/10.1016/j.jcin.2016.05.003
State	Published - Aug 8 2016

Bibliographical note

Funding Information:
The full rationale and design of the RENEW trial has been published elsewhere (22) . RENEW was a randomized, double-blind, multicenter trial conducted at 45 centers in the United States ( NCT01508910 ). An academic steering committee with sponsor representation helped to design the trial and was responsible for its conduct and for presentation and publication of the results. The trial was monitored by a data and safety monitoring board of independent physicians and a statistician with expertise in cardiovascular diseases and hematology; the data and safety monitoring board had access to unblinded data. The protocol was approved by appropriate regulatory and ethical boards at each site and conducted in compliance with the provisions of the Declaration of Helsinki. The trial was sponsored by Baxter Healthcare (Deerfield, Illinois).

Publisher Copyright:
© 2016 American College of Cardiology Foundation

Keywords

CD34
angina
angiogenesis
interventional therapy
progenitor cell
stable coronary disease
stem cell

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10.1016/j.jcin.2016.05.003

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Povsic, T. J., Henry, T. D., Traverse, J. H., Fortuin, F. D., Schaer, G. L., Kereiakes, D. J., Schatz, R. A., Zeiher, A. M., White, C. J., Stewart, D. J., Jolicoeur, E. M., Bass, T., Henderson, D. A., Dignacco, P., Gu, Z., Al-Khalidi, H. R., Junge, C., Nada, A., Hunt, A. S., ... RENEW Investigators (2016). The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34⁺ Cell Administration in Patients With Refractory Angina. JACC: Cardiovascular Interventions, 9(15), 1576-1585. https://doi.org/10.1016/j.jcin.2016.05.003

Povsic, TJ, Henry, TD, Traverse, JH, Fortuin, FD, Schaer, GL, Kereiakes, DJ, Schatz, RA, Zeiher, AM, White, CJ, Stewart, DJ, Jolicoeur, EM, Bass, T, Henderson, DA, Dignacco, P, Gu, Z, Al-Khalidi, HR, Junge, C, Nada, A, Hunt, AS, Losordo, DW & RENEW Investigators 2016, 'The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34⁺ Cell Administration in Patients With Refractory Angina', JACC: Cardiovascular Interventions, vol. 9, no. 15, pp. 1576-1585. https://doi.org/10.1016/j.jcin.2016.05.003

@article{ca64b934095d4e48a58ce3322c5954b4,

title = "The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34+ Cell Administration in Patients With Refractory Angina",

abstract = "Objectives This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34+ cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. Background IM administration of autologous CD34+ cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. Methods RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34+ administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. Results The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34+ cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34+]). Conclusions Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910)",

keywords = "CD34, angina, angiogenesis, interventional therapy, progenitor cell, stable coronary disease, stem cell",

author = "Povsic, {Thomas J.} and Henry, {Timothy D.} and Traverse, {Jay H.} and Fortuin, {F. David} and Schaer, {Gary L.} and Kereiakes, {Dean J.} and Schatz, {Richard A.} and Zeiher, {Andreas M.} and White, {Christopher J.} and Stewart, {Duncan J.} and Jolicoeur, {E. Marc} and Theodore Bass and Henderson, {David A.} and Patricia Dignacco and Ziangoiong Gu and Al-Khalidi, {Hussein R.} and Candice Junge and Adel Nada and Hunt, {Andrea S.} and Losordo, {Douglas W.} and {RENEW Investigators}",

note = "Funding Information: The full rationale and design of the RENEW trial has been published elsewhere (22) . RENEW was a randomized, double-blind, multicenter trial conducted at 45 centers in the United States ( NCT01508910 ). An academic steering committee with sponsor representation helped to design the trial and was responsible for its conduct and for presentation and publication of the results. The trial was monitored by a data and safety monitoring board of independent physicians and a statistician with expertise in cardiovascular diseases and hematology; the data and safety monitoring board had access to unblinded data. The protocol was approved by appropriate regulatory and ethical boards at each site and conducted in compliance with the provisions of the Declaration of Helsinki. The trial was sponsored by Baxter Healthcare (Deerfield, Illinois). Publisher Copyright: {\textcopyright} 2016 American College of Cardiology Foundation",

year = "2016",

month = aug,

day = "8",

doi = "10.1016/j.jcin.2016.05.003",

language = "English (US)",

volume = "9",

pages = "1576--1585",

journal = "JACC: Cardiovascular Interventions",

issn = "1936-8798",

publisher = "Elsevier Inc.",

number = "15",

}

TY - JOUR

T1 - The RENEW Trial

T2 - Efficacy and Safety of Intramyocardial Autologous CD34+ Cell Administration in Patients With Refractory Angina

AU - Povsic, Thomas J.

AU - Henry, Timothy D.

AU - Traverse, Jay H.

AU - Fortuin, F. David

AU - Schaer, Gary L.

AU - Kereiakes, Dean J.

AU - Schatz, Richard A.

AU - Zeiher, Andreas M.

AU - White, Christopher J.

AU - Stewart, Duncan J.

AU - Jolicoeur, E. Marc

AU - Bass, Theodore

AU - Henderson, David A.

AU - Dignacco, Patricia

AU - Gu, Ziangoiong

AU - Al-Khalidi, Hussein R.

AU - Junge, Candice

AU - Nada, Adel

AU - Hunt, Andrea S.

AU - Losordo, Douglas W.

AU - RENEW Investigators

N1 - Funding Information: The full rationale and design of the RENEW trial has been published elsewhere (22) . RENEW was a randomized, double-blind, multicenter trial conducted at 45 centers in the United States ( NCT01508910 ). An academic steering committee with sponsor representation helped to design the trial and was responsible for its conduct and for presentation and publication of the results. The trial was monitored by a data and safety monitoring board of independent physicians and a statistician with expertise in cardiovascular diseases and hematology; the data and safety monitoring board had access to unblinded data. The protocol was approved by appropriate regulatory and ethical boards at each site and conducted in compliance with the provisions of the Declaration of Helsinki. The trial was sponsored by Baxter Healthcare (Deerfield, Illinois). Publisher Copyright: © 2016 American College of Cardiology Foundation

PY - 2016/8/8

Y1 - 2016/8/8

N2 - Objectives This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34+ cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. Background IM administration of autologous CD34+ cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. Methods RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34+ administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. Results The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34+ cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34+]). Conclusions Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910)

AB - Objectives This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34+ cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. Background IM administration of autologous CD34+ cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. Methods RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34+ administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. Results The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34+ cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34+]). Conclusions Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910)

KW - CD34

KW - angina

KW - angiogenesis

KW - interventional therapy

KW - progenitor cell

KW - stable coronary disease

KW - stem cell

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