Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: The time randomized trial

Jay H. Traverse, Timothy D. Henry, Carl J. Pepine, James T. Willerson, David X M Zhao, Stephen G. Ellis, John R. Forder, R. David Anderson, Antonis K. Hatzopoulos, Marc S. Penn, Emerson C. Perin, Jeffrey Chambers, Kenneth W. Baran, Ganesh Raveendran, Charles Lambert, Amir Lerman, Daniel I. Simon, Douglas E. Vaughan, Dejian Lai, Adrian P. GeeDoris A. Taylor, Christopher R. Cogle, James D. Thomas, Rachel E. Olson, Sherry Bowman, Judy Francescon, Carrie Geither, Eileen Handberg, Casey Kappenman, Lynette Westbrook, Linda B. Piller, Lara M. Simpson, Sarah Baraniuk, Catalin Loghin, David Aguilar, Sara Richman, Claudia Zierold, Daniel B. Spoon, Judy Bettencourt, Shelly L. Sayre, Rachel W. Vojvodic, Sonia I. Skarlatos, David J. Gordon, Ray F. Ebert, Minjung Kwak, Lemuel A. Moyé, Robert D. Simari

Research output: Contribution to journalArticle

256 Citations (Scopus)

Abstract

Context: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. Objectives: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. Design, Setting, and Patients: A randomized, 2 x 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. Interventions: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. Main Outcome Measures: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. Results: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P=.96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (-0.9% [95% CI, -6.6% to 4.9%], P=.76) or day 7 (1.1% [95% CI, -4.7% to 6.9%], P=.70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. Conclusion: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. Trial Registration: clinicaltrials.gov Identifier: NCT00684021.

Original languageEnglish (US)
Pages (from-to)2380-2389
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume308
Issue number22
DOIs
StatePublished - Dec 12 2012

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Left Ventricular Function
Bone Marrow Cells
Myocardial Infarction
Percutaneous Coronary Intervention
Placebos
Stroke Volume
Cell- and Tissue-Based Therapy
National Heart, Lung, and Blood Institute (U.S.)
Therapeutics
Left Ventricular Dysfunction
Reperfusion
Magnetic Resonance Imaging
Outcome Assessment (Health Care)
Clinical Trials
Research

ASJC Scopus subject areas

  • Medicine(all)

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Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction : The time randomized trial. / Traverse, Jay H.; Henry, Timothy D.; Pepine, Carl J.; Willerson, James T.; Zhao, David X M; Ellis, Stephen G.; Forder, John R.; Anderson, R. David; Hatzopoulos, Antonis K.; Penn, Marc S.; Perin, Emerson C.; Chambers, Jeffrey; Baran, Kenneth W.; Raveendran, Ganesh; Lambert, Charles; Lerman, Amir; Simon, Daniel I.; Vaughan, Douglas E.; Lai, Dejian; Gee, Adrian P.; Taylor, Doris A.; Cogle, Christopher R.; Thomas, James D.; Olson, Rachel E.; Bowman, Sherry; Francescon, Judy; Geither, Carrie; Handberg, Eileen; Kappenman, Casey; Westbrook, Lynette; Piller, Linda B.; Simpson, Lara M.; Baraniuk, Sarah; Loghin, Catalin; Aguilar, David; Richman, Sara; Zierold, Claudia; Spoon, Daniel B.; Bettencourt, Judy; Sayre, Shelly L.; Vojvodic, Rachel W.; Skarlatos, Sonia I.; Gordon, David J.; Ebert, Ray F.; Kwak, Minjung; Moyé, Lemuel A.; Simari, Robert D.

In: JAMA - Journal of the American Medical Association, Vol. 308, No. 22, 12.12.2012, p. 2380-2389.

Research output: Contribution to journalArticle

Traverse, JH, Henry, TD, Pepine, CJ, Willerson, JT, Zhao, DXM, Ellis, SG, Forder, JR, Anderson, RD, Hatzopoulos, AK, Penn, MS, Perin, EC, Chambers, J, Baran, KW, Raveendran, G, Lambert, C, Lerman, A, Simon, DI, Vaughan, DE, Lai, D, Gee, AP, Taylor, DA, Cogle, CR, Thomas, JD, Olson, RE, Bowman, S, Francescon, J, Geither, C, Handberg, E, Kappenman, C, Westbrook, L, Piller, LB, Simpson, LM, Baraniuk, S, Loghin, C, Aguilar, D, Richman, S, Zierold, C, Spoon, DB, Bettencourt, J, Sayre, SL, Vojvodic, RW, Skarlatos, SI, Gordon, DJ, Ebert, RF, Kwak, M, Moyé, LA & Simari, RD 2012, 'Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: The time randomized trial', JAMA - Journal of the American Medical Association, vol. 308, no. 22, pp. 2380-2389. https://doi.org/10.1001/jama.2012.28726
Traverse, Jay H. ; Henry, Timothy D. ; Pepine, Carl J. ; Willerson, James T. ; Zhao, David X M ; Ellis, Stephen G. ; Forder, John R. ; Anderson, R. David ; Hatzopoulos, Antonis K. ; Penn, Marc S. ; Perin, Emerson C. ; Chambers, Jeffrey ; Baran, Kenneth W. ; Raveendran, Ganesh ; Lambert, Charles ; Lerman, Amir ; Simon, Daniel I. ; Vaughan, Douglas E. ; Lai, Dejian ; Gee, Adrian P. ; Taylor, Doris A. ; Cogle, Christopher R. ; Thomas, James D. ; Olson, Rachel E. ; Bowman, Sherry ; Francescon, Judy ; Geither, Carrie ; Handberg, Eileen ; Kappenman, Casey ; Westbrook, Lynette ; Piller, Linda B. ; Simpson, Lara M. ; Baraniuk, Sarah ; Loghin, Catalin ; Aguilar, David ; Richman, Sara ; Zierold, Claudia ; Spoon, Daniel B. ; Bettencourt, Judy ; Sayre, Shelly L. ; Vojvodic, Rachel W. ; Skarlatos, Sonia I. ; Gordon, David J. ; Ebert, Ray F. ; Kwak, Minjung ; Moyé, Lemuel A. ; Simari, Robert D. / Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction : The time randomized trial. In: JAMA - Journal of the American Medical Association. 2012 ; Vol. 308, No. 22. pp. 2380-2389.
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title = "Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: The time randomized trial",
abstract = "Context: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. Objectives: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. Design, Setting, and Patients: A randomized, 2 x 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤45{\%}) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. Interventions: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. Main Outcome Measures: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. Results: The mean (SD) patient age was 56.9 (10.9) years and 87.5{\%} of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2{\%} [95{\%} CI, 42.8{\%} to 47.6{\%}] to 48.3{\%} [95{\%} CI, 45.3{\%} to 51.3{\%}) vs the placebo group (44.5{\%} [95{\%} CI, 41.0{\%} to 48.0{\%}] to 47.8{\%} [95{\%} CI, 43.4{\%} to 52.2{\%}]) (P=.96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (-0.9{\%} [95{\%} CI, -6.6{\%} to 4.9{\%}], P=.76) or day 7 (1.1{\%} [95{\%} CI, -4.7{\%} to 6.9{\%}], P=.70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. Conclusion: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. Trial Registration: clinicaltrials.gov Identifier: NCT00684021.",
author = "Traverse, {Jay H.} and Henry, {Timothy D.} and Pepine, {Carl J.} and Willerson, {James T.} and Zhao, {David X M} and Ellis, {Stephen G.} and Forder, {John R.} and Anderson, {R. David} and Hatzopoulos, {Antonis K.} and Penn, {Marc S.} and Perin, {Emerson C.} and Jeffrey Chambers and Baran, {Kenneth W.} and Ganesh Raveendran and Charles Lambert and Amir Lerman and Simon, {Daniel I.} and Vaughan, {Douglas E.} and Dejian Lai and Gee, {Adrian P.} and Taylor, {Doris A.} and Cogle, {Christopher R.} and Thomas, {James D.} and Olson, {Rachel E.} and Sherry Bowman and Judy Francescon and Carrie Geither and Eileen Handberg and Casey Kappenman and Lynette Westbrook and Piller, {Linda B.} and Simpson, {Lara M.} and Sarah Baraniuk and Catalin Loghin and David Aguilar and Sara Richman and Claudia Zierold and Spoon, {Daniel B.} and Judy Bettencourt and Sayre, {Shelly L.} and Vojvodic, {Rachel W.} and Skarlatos, {Sonia I.} and Gordon, {David J.} and Ebert, {Ray F.} and Minjung Kwak and Moy{\'e}, {Lemuel A.} and Simari, {Robert D.}",
year = "2012",
month = "12",
day = "12",
doi = "10.1001/jama.2012.28726",
language = "English (US)",
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pages = "2380--2389",
journal = "JAMA - Journal of the American Medical Association",
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TY - JOUR

T1 - Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction

T2 - The time randomized trial

AU - Traverse, Jay H.

AU - Henry, Timothy D.

AU - Pepine, Carl J.

AU - Willerson, James T.

AU - Zhao, David X M

AU - Ellis, Stephen G.

AU - Forder, John R.

AU - Anderson, R. David

AU - Hatzopoulos, Antonis K.

AU - Penn, Marc S.

AU - Perin, Emerson C.

AU - Chambers, Jeffrey

AU - Baran, Kenneth W.

AU - Raveendran, Ganesh

AU - Lambert, Charles

AU - Lerman, Amir

AU - Simon, Daniel I.

AU - Vaughan, Douglas E.

AU - Lai, Dejian

AU - Gee, Adrian P.

AU - Taylor, Doris A.

AU - Cogle, Christopher R.

AU - Thomas, James D.

AU - Olson, Rachel E.

AU - Bowman, Sherry

AU - Francescon, Judy

AU - Geither, Carrie

AU - Handberg, Eileen

AU - Kappenman, Casey

AU - Westbrook, Lynette

AU - Piller, Linda B.

AU - Simpson, Lara M.

AU - Baraniuk, Sarah

AU - Loghin, Catalin

AU - Aguilar, David

AU - Richman, Sara

AU - Zierold, Claudia

AU - Spoon, Daniel B.

AU - Bettencourt, Judy

AU - Sayre, Shelly L.

AU - Vojvodic, Rachel W.

AU - Skarlatos, Sonia I.

AU - Gordon, David J.

AU - Ebert, Ray F.

AU - Kwak, Minjung

AU - Moyé, Lemuel A.

AU - Simari, Robert D.

PY - 2012/12/12

Y1 - 2012/12/12

N2 - Context: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. Objectives: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. Design, Setting, and Patients: A randomized, 2 x 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. Interventions: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. Main Outcome Measures: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. Results: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P=.96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (-0.9% [95% CI, -6.6% to 4.9%], P=.76) or day 7 (1.1% [95% CI, -4.7% to 6.9%], P=.70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. Conclusion: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. Trial Registration: clinicaltrials.gov Identifier: NCT00684021.

AB - Context: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. Objectives: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. Design, Setting, and Patients: A randomized, 2 x 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. Interventions: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. Main Outcome Measures: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. Results: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P=.96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (-0.9% [95% CI, -6.6% to 4.9%], P=.76) or day 7 (1.1% [95% CI, -4.7% to 6.9%], P=.70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. Conclusion: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. Trial Registration: clinicaltrials.gov Identifier: NCT00684021.

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U2 - 10.1001/jama.2012.28726

DO - 10.1001/jama.2012.28726

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JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

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