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