0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letter |

One-Year Follow-up of Intracoronary Stem Cell Delivery on Left Ventricular Function Following ST-Elevation Myocardial Infarction FREE

Jay H. Traverse, MD1; Timothy D. Henry, MD1; Carl J. Pepine, MD2; James T. Willerson, MD3; Stephen G. Ellis, MD4
[+] Author Affiliations
1Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, Minnesota
2University of Florida Medical School, Gainesville
3Texas Heart Institute at St Luke’s Episcopal Hospital, Houston
4Cleveland Clinic Foundation, Cleveland, Ohio
JAMA. 2014;311(3):301-302. doi:10.1001/jama.2013.282674.
Text Size: A A A
Published online

The Timing In Myocardial Infarction Evaluation (TIME) trial1,2 assessed whether the timing of stem cell delivery affects the recovery of left ventricular (LV) function following myocardial infarction (MI). Patients with anterior ST-elevation MI (STEMI) who were reperfused with primary percutaneous coronary intervention and stenting and had at least moderate LV dysfunction (LV ejection fraction [LVEF] ≤45%) were randomized (2:1) to 150 million autologous bone marrow mononuclear cells (BMCs) or placebo with intracoronary delivery performed on day 3 (n = 67) or day 7 (n = 53). At 6 months, no benefit of cell therapy was observed compared with placebo following cell delivery at either time. We now report outcomes at 1 year. The collection of clinical end point and cardiac magnetic resonance imaging (MRI) data was prespecified but the analysis plan was post hoc.

TIME was approved by each center’s institutional review board with written informed consent collected from all participants. Ninety-five patients (65 in BMC group, 30 in placebo group) of the original 112 analyzed at 6 months (75 in BMC group, 37 in placebo group) had analyzable MRI data through 1 year. Baseline characteristics of those analyzed at 6 months and 1 year were not different. Reasons for the drop-off between 6 months and 1 year included 3 implantable cardioverter-defibrillator placements, 1 death, 12 lost to follow-up or refused to participate, and 1 MRI not performed. Follow-up was completed by November 12, 2012.

The primary analyses were changes in LVEF and regional (infarct and border zone) LV function between baseline and 6 months by cardiac MRI. Primary and secondary outcomes at 1 year appear in Table 1. Safety outcomes appear in Table 2. Because an effect of timing was not observed, data are presented as the aggregate of the means of day 3 and day 7 delivery. Differences in the changes in primary and secondary end points between therapy groups and trajectories over time were assessed using repeated-measures analysis of variance. Worst-case imputation (substituting worst value in the cohort for the missing value) was also conducted. All hypothesis testing was 2-tailed. Results with P < .05 were considered statistically significant. Analyses were performed with SAS version 9.3 (SAS Institute Inc).

Table Graphic Jump LocationTable 1.  Cardiac Magnetic Resonance Imaging Results From the Timing In Myocardial Infarction Evaluation Trial
Table Graphic Jump LocationTable 2.  Clinical and Safety Outcomes From Baseline to 1 Year

Levels of LVEF increased from baseline to 6 months in both the BMC (46.2% [95% CI, 43.9%-48.5%] to 50.1% [95% CI, 47.2%-53.0%]) and the placebo groups (46.3% [95% CI, 43.3%-49.3%] to 51.5% [95% CI, 47.5%-55.5%]) (P < .001) but did not improve further between 6 months and 1 year in either group (BMC, 49.5% [95% CI, 46.5%-52.5%]; placebo, 49.6% [95% CI, 45.8%-53.4%]). Regional LV function increased in infarct and border zones between baseline and 6 months in both groups with no further increase between 6 months and 1 year (Table 1). There were no differences at any time between the BMC and placebo groups.

Between baseline and 1 year, there were increases in LV volumes in both the BMC and placebo groups, with no significant differences between groups (Table 1). The results were unchanged in the worst-case imputation analysis.

Infarct size decreased in the BMC and placebo groups between baseline and 6 months with a smaller reduction between 6 months and 1 year. The reduction in infarct size was accompanied by a similarly significant reduction in LV mass through 1 year (Table 1). There were no differences in the reduction in infarct size and LV mass between the BMC and placebo groups at any time.

Between 6 months and 1 year, there were 2 more infarctions, 4 repeat revascularizations, and 3 implantable cardioverter-defibrillator placements (Table 2).

In this post hoc analysis, the administration of BMCs following moderate to large anterior STEMIs was not associated with improved recovery of global and regional LV function at 1 year, irrespective of cell delivery at 3 or 7 days. The recovery of LV function following STEMI appeared complete by 6 months because no additional improvement in LV function was observed in either group between 6 months and 1 year. Our results do not support the administration of BMCs following MI. However, because we were unable to obtain 1-year MRIs on all patients, the precision of our estimates for change in LV function was reduced.

Section Editor: Jody W. Zylke, MD, Senior Editor.

Corresponding Author: Jay H. Traverse, MD, Minneapolis Heart Institute, 920 E 28th St, Ste 300, Minneapolis, MN 55407 (trave004@umn.edu).

Published Online: November 18, 2013. doi:10.1001/jama.2013.282674.

Author Contributions: Dr Traverse had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Traverse, Henry, Willerson, Ellis.

Acquisition of data: Traverse, Henry, Pepine, Willerson.

Analysis and interpretation of data: Traverse, Henry, Willerson.

Drafting of the manuscript: Traverse, Henry, Willerson.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Traverse, Willerson.

Obtained funding: Traverse, Pepine, Willerson.

Administrative, technical, or material support: Pepine, Willerson.

Study supervision: Traverse, Ellis.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Henry reported serving as a consultant for Capricor and Johnson & Johnson; and receiving grant support from Capricor and OSIRIS. Dr Pepine reported receiving funding for writing assistance, medicine, equipment, or administrative support from the National Heart, Lung, and Blood Institute, BDS Cordis Corp, and Biosafe; and receiving several institutional grants from several pharmaceutical companies and government institutions. Dr Willerson reported receiving funding from the National Heart, Lung, and Blood Institute for participation in review activities. Dr Ellis reported receiving travel support from Abbott Vascular and Boston Scientific. No other disclosures were reported.

Funding/Support: Funding for this trial was provided by the National Heart, Lung, and Blood Institute under cooperative agreement 5 UO1 HL087318-04. Support for cell processing (Sepax) was provided by Biosafe SA Inc. Angioplasty catheters were provided by Boston Scientific Corporation.

Role of the Sponsor: The National Heart, Lung, and Blood Institute had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We acknowledge all the contributions by the Investigators of the Cardiovascular Cell Therapy Research Network and the leadership and vision of the late Sonia Skarlatos, PhD (formerly with the National Heart, Lung, and Blood Institute).

Trial Registration: clinicaltrials.gov Identifier: NCT00684021

Traverse  JH, Henry  TD, Pepine  CJ,  et al; Cardiovascular Cell Therapy Research Network (CCTRN).  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. 2012;308(22):2380-2389.
PubMed   |  Link to Article
Traverse  JH, Henry  TD, Vaughan  DE,  et al; Cardiovascular Cell Therapy Research Network (CCTRN).  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 [published correction appears in Am Heart J. 2009;158(6):1045]. Am Heart J. 2009;158(3):356-363.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Cardiac Magnetic Resonance Imaging Results From the Timing In Myocardial Infarction Evaluation Trial
Table Graphic Jump LocationTable 2.  Clinical and Safety Outcomes From Baseline to 1 Year

References

Traverse  JH, Henry  TD, Pepine  CJ,  et al; Cardiovascular Cell Therapy Research Network (CCTRN).  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. 2012;308(22):2380-2389.
PubMed   |  Link to Article
Traverse  JH, Henry  TD, Vaughan  DE,  et al; Cardiovascular Cell Therapy Research Network (CCTRN).  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 [published correction appears in Am Heart J. 2009;158(6):1045]. Am Heart J. 2009;158(3):356-363.
PubMed   |  Link to Article
CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 3

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles