Transcript LateTIME Outcomes

The TIME Randomized Trial:
One-Year Follow-up on the Effect of
Timing of Intracoronary Delivery of
Autologous Bone Marrow
Mononuclear Cells on Left Ventricular
Function Following STEMI
Jay H. Traverse, MD
Principal Investigator, TIME Study
Minneapolis Heart Institute at Abbott Northwestern Hospital
University of Minnesota Medical School
Cardiovascular Cell Therapy Research Network (CCTRN)
2013 Scientific Sessions of the AHA
TIME Study Design
• Study Aim: Assess effects of autologous BMCs and timing of
delivery (Day 3 vs. 7) post-STEMI on measures of LV function
• Target Population: 120 pts w/first ant MI, reperfused by PCI +
stent, with residual LV dysfunction (EF≤45%)
• Treatment: 150 x 106 autologous BMCs or placebo by
intracoronary infusion (Stop Flow)
• Primary Endpoints: change in global and regional LV function
from baseline to 6 months by cMRI
• Secondary Endpoints: change in infarct size and LV volumes
• Subgroups of interest: age, LVEF
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Baseline Characteristics
3 Day
7 Day
BMC
Placebo
BMC
Placebo
N=43
N=24
N=36
N=17
PValue
55.6 (10.8)
57.0 (12.4)
58.2 (11.3)
57.0 (8.0)
0.766
Female (%)
12
13
14
12
0.992
White (%)
88
83
86
88
0.945
Diabetes
23
33
11
0
0.007
High Blood Pressure
44
63
64
77
0.087
Hyperlipidemia
65
71
53
65
0.777
Smoking
65
71
53
65
0.510
Preinfarction Angina (%)
23
29
31
41
0.606
Drug Eluting Stent (%)
77
88
81
82
0.745
LAD Infarct Artery
86
96
97
100
0.086
36.1 (6.1)
37.8 (6.6)
36.5 (6.3)
36.6 (4.1)
0.763
180.9
(42.1-1302.0)
133.0
(62.0-432.7)
402.0
(234.0-466.0)
227.0
(76.0-442.0)
0.078
Age in years, mean (SD)
History of: (%)
Qualifying LVEF (echo), mean (SD)
Peak CKMB, median* (IQR)
*N=29 BMC 3 Day, N=19 Placebo 3 Day, N=31 BMC 7 Day, N=15 Placebo 7 Day
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Cell Processing of BMCs
•
•
•
Sepax System
– Automated local cell
processing
No significant RBC Contamination
Only minuscule amounts of
heparin in final product (0.1 U/ml)
Sepax vs. Manual Ficoll
•
•
BMC
Ficoll
Manual
Sepax
•
No difference in cell recovery,
migration or CFU ability
No difference in recovery of
perfusion in murine hind-limb
ischemia model
No difference in recovery of LV fxn
in murine infarct model
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Cell Characteristics
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6-Mo Primary Endpoint: Global
No difference
in the change
in LVEF
between BMC
(n=75) and
Placebo (n=37)
groups from
baseline to 6
months
JAMA 2012; 308 (22):2380-9
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TIME at 1-Year
• Follow-up imaging at 1 and 2-years
prospectively declared.
• 112 of 120 patients had analyzable MRIs at 6months.
• 95 of 112 patients had analyzable MRIs at 1year. (ICD=3, death=1, LTF/refused=2, not
performed=1, no-show=10).
• Day-3 MRI utilized as baseline for all patients.
• Worst-case imputation for incomplete data.
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Change in LVEF over 1-Year
Day 3 vs 1-year: BMC < 0.01; Placebo = NS
Changes in Regional LV Function
Infarct Zone
3 Day vs. 1 Year:
BMC ( p< 0.001); Placebo (NS)
Border Zone
3 Day vs. 1 Year:
BMC ( p< 0.001); Placebo (p=0.002)
Change in Infarct Size
3 Day vs. 1 Year: BMC ( p< 0.001); Placebo (p<0.001)
Change in LV Volumes Over 1 Year
LVEDV (ml/m2)
LVESV (ml/m2)
Day 3
6-Month
1-Year
Day 3
6-Month 1-Year
77 ± 18
87 ± 25*
89 ± 25*
42 ±14
45 ± 20* 46 ± 21*
PLACEBO 70 ± 17
80 ± 23*
83 ± 22*
38 ± 12
40 ± 18* 43 ± 18*
BMC
*P < 0.01 versus Day 3
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Clinical/Safety Outcomes at 1 Year
Patients with events
BMC
Placebo
18/79 (23%)
9/41 (22%)
Deaths
1
0
Reinfarctions
2
3
Repeat Revascularizations
9
6
Target Vessel
4
4
Non-Target Vessel
5
2
Hospitalization Heart Failure
4
1
ICD Placements
4
5
Stroke
2
2
Total
22
17
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Conclusions
• The recovery of LV function following STEMI is
not enhanced by BMCs at any time-point.
• The improvement in global and regional function
is nearly complete by 6 months.
• Infarct size and LV Mass in both groups decreased
by 30% over the first 6-months, with a smaller,
ongoing decrease out to 1-year.
• There is a small, ongoing increase in LV volumes
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Acknowledgements
• We would like to acknowledge partial funding for this work through
the following grants: NIH NHLBI Cardiovascular Cell Therapy Network
(CCTRN) under grant# 5 UM 1HL087318-07
• Industry partners: Biosafe and Boston Scientific
• The Clinical Centers, and DCC (Cleveland Clinic, Minneapolis Heart
Institute, Texas Heart Institute, University of Florida, and Vanderbilt
University, University of Texas School of Public Health), their satellites
(University Hospitals, United Heart & Vascular Clinic, Metropolitan
Cardiology Consultants, University of Minnesota, Mayo Clinic,
DeBakey VA, and Pepin Heart Institute) and their research teams
• Core labs (Center for Cell & Gene Therapy, Baylor College of
Medicine, University of Florida cMRI and Cleveland Clinic Echo Core
Labs, University of Minnesota and University of Florida
Biorepositories)
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Sonia I. Skarlatos
1953 - 2013
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