Autologous BONe Marrow Mononucleated Cell Infusion for Acute Myocardial Infarction
in Patients with Severe Left Ventricular Dysfunction:
J Roncalli, F Mouquet, C Piot, JN Trochu, Y Neuder, E Teiger, P Lemarchand* on behalf of the BONAMI investigators.
Toulouse, Lille, Montpellier, Nantes, Grenoble, and Creteil University Hospital, FRANCE
*Principal investigator and corresponding author
Results of the BONAMI trial (ClinicalTrials.gov number NCT00200707)
- Previous trials that assessed the efficacy of intracoronary administration of autologous bone marrow cells (BMCs) after acute myocardial infarction have yield mixed results.
- REPAIR-AMI: cell-based therapy seems to be more effective in patients
BACKGROUND
BONAMI trial, Madrid 2009
receiving cell therapy at least 5 days after MI
with decreased left ventricular ejection fraction
N Engl J Med 2006;355:1210-21
To assess the beneficial effect of cell therapy in patients with decreased left ventricular ejection fraction after acute myocardial infarction, and to identify predictive factors of successful therapy.
AIM OF THE BONAMI TRIAL
BONAMI trial, Madrid 2009
STUDY DESIGN
Randomized, multicenter controlled trial 6 academic hospitals in France
Main exclusion criteria:- Multivessel disease- Drug eluting stent
Main inclusion criteria:- Inaugural acute MI - Single coronary lesion and successful angioplasty- LVEF ≤ 45% - Impairment of myocardial viability: > 2/17 non viable segments
2
1
3
4
5
678
9
10
11
1213
1415
1617
AHA Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Cerqueira MD et al, Circ 2002;105:539-542.
LV segmentation
BONAMI trial, Madrid 2009
PRIMARY ENDPOINT
- Myocardial viability at 3 months after MI evaluated by resting Thallium 201-SPECT
- All measurements were performed by 2 blinded investigators of an independent core lab.
- Criterion for cell therapy success: viability improvement of ≥ 2/17 segments (2 non viable become viable)
100%
0%
50%
Short- axis apical median basal
M0
M3
BONAMI trial, Madrid 2009
DESIGN OF THE BONAMI TRIAL
BM harvestIntra coronary injection
Acute MI, Primary angioplasty
SPECT and radionuclide angio
>2/17 non viable segments and LVEF ≤45%
Randomization(n=101)
Control (n= 49)
BMC(n= 52)
Echo LVEF ≤ 50% (n= 122)Day 0-4
Day 4-7
Day 7-10
Day 0
(n= 21)
Month 3 SPECT, radionuclide angio
Diabetes Revascularization < 12h
Myocardial viability, or LVEF >45%
BONAMI trial, Madrid 2009
CELL THERAPY PROCEDURE
Cell therapy product:
- 50 cc of bone marrow were harvested under local anesthesia
- Bone marrow mononucleated cells were isolated by ficoll gradient
- 100 x 106 autologous mononucleated cells (in 10cc)
- Intra coronary cell injection:
- The same day as BM collection
- Mean delay btw acute MI and BMC infusion: 9.3 ± 1.7 days
BONAMI trial, Madrid 2009
RESULTS: Baseline Characteristics
Control
(n= 49)
BMC
(n= 52)
p
Age (years) 55 ±11 56 ±12 NS
Male gender, % 89.8 80.8 NS
Hypertension, % (n) 34.7 (17/49) 34.6 (18/52) NS
Dyslipemia, % (n) 34.7 (17/49) 46.2 (24/52) NS
Diabetes mellitus, % (n) 18.4 (9/49) 21.2 (11/52) NS
Active smokers, % (n) 53.1 (26/49) 53.8 (28/52) NS
Timing of revasc <12h ,% (n) 76 (37/49) 75 (39/52) NS
Culprit artery (LAD) , % (n) 96 (45/47) 92 (45/49) NS
LVEF (%, by RNA) 37.0 ±6.7 (47) 35.6 ±7 (50) NS
BONAMI trial, Madrid 2009
RESULTS: Assessment of Cell Therapy Success
- The number of patients with myocardial viability improvement was twice greater in the BMC group
- Prespecified criterion of cell therapy success = 2 non viable segments becoming viable 3 months after myocardial infarction
BONAMI trial, Madrid 2009
16 %
34 %
0
10
20
30
40
Pe
rce
nta
ge
of
pa
tie
nts
p=0.06
n= 7/43
n= 16/47
control BMC
≥ 2/17 segments
Secondary Endpoint: Change of Ejection Fraction
BONAMI trial, Madrid 2009
LV
Eje
ctio
n F
ract
ion
(%
)
1 0
1 5
2 0
2 5
3 0
3 5
4 0
4 5
5 0
5 5
6 0
J0 3 Mo J0 3 Mo
Time after myocardial infarction
Control P<0.01 BMC P<0.01
Day 0 Day 03 Mo 3 Mo
60
55
50
45
40
35
30
25
20
15
10
= + 3.3%= + 4.3% p=0.62
yes no
4,5
4
3,5
3
2,5
2
1,5
1
5
0
2.89
0.880.83
1
n=3
n=8 n=12
n=9
.
yes no
(95%
IC
) in
crea
se i
n v
iab
le s
eg
me
nt
nu
mb
er
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
0.58
0.8
0.53
0.5
BMC
Control
n=4
n=5
n=17
n=19
Tobacco status: non smoker, former smokerTobacco status: smoker
Segment(s) with no-reflow Segment(s) with no-reflow
Significant interaction between Tobacco, no-reflow and treatment group (p=0.01)
PREDICTIVE FACTORS OF CELL THERAPY SUCCESS
Multiple linear regression (n=77)
- The BONAMI trial is a randomized multicenter trial aimed to investigate the beneficial effect of coronary injection of autologous BMC on myocardial viability as a primary endpoint.
- In this trial, coronary autologous BMC injection, 9 days after acute MI, to patients with low EF, failed to reach the primary endpoint, although a strong trend was observed.
- The negative impact of active smoking and relative role of no-reflow on myocardial viability after cardiac cell therapy should be further documented.
CONCLUSION
BONAMI trial, Madrid 2009
NantesNantes- P. Lemarchand- J-N. Trochu- D. Crochet- A. Tirouvanziam- A. Bammert- Y. Goueffic- G. Lamirault- V. Probst- S. Abbey
- F. Valette- J Hélias- C. Perigaud- V. Forest- M. Audrain- C. Hémont- G. Follea- J-M. Nguyen- B Delasalle
H. MondorH. Mondor- E. Teiger- J-L. Dubois-Randé- P. Le Corvoisier- S. Champagne- L. Boudali- O. Montagne- JL. Monin- J. Rosso- JF. Deux- C. Focseneanu- ML. Bourhis
LilleLille- F. Mouquet- E. Van Belle- S. Susen- P-V. Ennezat- T. Le Tourneau- V. Gaxotte- C. Foucher
- J-P. Jouet- F. Villard- I. Yakoub-Agha- J-P. Bérégi- P. Asseman- J-J. Bauchart- B. Jude
SPECT core labSPECT core lab- D. Agostini - A. Manrique
Sponsors: Ministère de la Santé, Fondation de France, Association Française contre les Myopathies (AFM)
MontpellierMontpellier- Ch. Piot- B. Klein- ZH. Lu- M. Baudard- JF. Rossi- D. Dietz- JC. Macia- D. Mariano-Goulart
ToulouseToulouse- J. Roncalli- M. Galinier- A. Parini- P. Bourin- A. Huynh- M. Attal- D. Carrié- M. Elbaz- JM. Fauvel- P. Massabuau- R. Cagnac- MJ. Allibeli-Chemarin- V. Chabbert- H. Rousseau- L. Daudé- H. Coulier- S. Cappellesso-Fleury- C. Rage- J. Gaudé
GrenobleGrenoble- Y. Neuder- G. Vanzetto- M. Favrot- MJ. Richard- C. Saunier- D. Fagret- A. Calizzano- JY. Cahn- CE. Bulabois- F.Garban- F. Thony- S. Mouret- S. Bouzon
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