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Randomized Controlled Trial
. 2012 Dec 12;308(22):2380-9.
doi: 10.1001/jama.2012.28726.

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  1 , 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 Gee, Doris 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; Cardiovascular Cell Therapy Research Network (CCTRN)
Collaborators, Affiliations
Randomized Controlled Trial

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 et al. JAMA. .

Erratum in

  • JAMA. 2013 Jan 23;309(4):343
  • Data Errors in Table 3 and in Text.
    [No authors listed] [No authors listed] JAMA. 2015 Jul 7;314(1):86. doi: 10.1001/jama.2015.6074. JAMA. 2015. PMID: 26151281 No abstract available.

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 × 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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Figures

Figure 1
Figure 1
CONSORT Diagram Abbreviations: MI, myocardial infarction; PCI, percutaneous coronary intervention; EF, ejection fraction; AE, adverse event; SAE, serious adverse event; BMC, bone marrow mononuclear cell; MRI, magnetic resonance imaging *A clinical hold is an order issued by FDA to the sponsor to suspend an ongoing investigation; this hold was issued to ensure proper screening and monitoring of subjects during the investigation by excluding subjects with LV thrombus or atrial fibrillation who required anticoagulation therapy ±All MRIs contraindicated because of ICD placement
Figure 2
Figure 2
Global Left Ventricular Function and Regional Infarct and Border Zone Wall Motion BMC=bone marrow mononuclear cell; MI=myocardial infarction
Figure 2
Figure 2
Global Left Ventricular Function and Regional Infarct and Border Zone Wall Motion BMC=bone marrow mononuclear cell; MI=myocardial infarction
See this image and copyright information in PMC

Comment in

References

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    1. Frangogiannis NG. The immune system and cardiac repair. Pharmacol Res. 2008;58(2):88–111. doi: 10.1016/j.phrs.2008.06.007. - PMC - PubMed
    1. Schachinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355(12):1210–1221. doi: 10.1056/NEJMoa060186. - PubMed
    1. Traverse JH, Henry TD, Ellis SG, et al. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: The LateTIME randomized trial. JAMA. 2011;306(19):2110–2119. doi: 10.1001/jama.2011.1670. - PMC - PubMed
    1. Traverse JH, Henry TD, Vaughan DE, et al. Rationale and design for TIME: A phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction. Am Heart J. 2009;158(3):356–363. doi: 10.1016/j.ahj.2009.06.009. - PMC - PubMed

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