Intracoronary injection of mononuclear bone marrow cells after acute myocardial infarction

Lessons from the ASTAMI trial

Ketil Lunde, Rikshospitalet University Hospital, Oslo, Norway

The 4th Symposium on Stem Cell Therapy and Cardiovascular Biology, Madrid, 26thApril 2007

Presenter disclosure information :

No conflicts of interest

Nature 2001;410:701-705

Circulation 2002;106:1913-1918

Background

Study power

• Primary end-point: LVEF

• 5 % difference between groups of the ∆ LVEF (Baseline – 6 months) by

SPECT

• 80 % power, significance level 5 %

Day 0: Acute Anterior Wall Myocardial Infarction

PCI with stent on LAD culprit lesion

Day 3-5: Randomization

2-3 weeks: MRI, bicycle exercise tests, SF-36

mBMC group

n=50

Control group

n=50

Day 4-8:

Bone marrow aspiration and intracoronary mBMC injection

6 months follow-up:99mTc-MIBI SPECT, Echocardiography, MRI, Coronary angiography, SF-36

Study design

12 months follow up: Echocardiography

3 months follow up: Echocardiography

Day 4-7: Baseline recordings, 99mTc-MIBI SPECT, Echocardiography

Cell harvesting and preparation

• Local anesthesia

• Aspirated volume: 50 ml

• Density gradient centrifugation on ficoll-hypaque

• mBMC: 68 x 106 cells

• CD34+ cells: 0.7 x 106

• Viability: 95 %

• GMP accredited laboratory

Values are median

Cell preparation in ASTAMI

• The ASTAMI Study protocol for– Isolation of mononuclear cells– Overnight storage– Viability testing

• Proven successful for treatment of patients with hematological diseases

Egeland et al, Eur Heart J 2007;letter to editor (in press)

Intracoronary mBMC injection

• Time point 6.0 (1.3) days after PCI

• Total volume injected 10 ml mBMC suspension

• Procedure Over-the-wire balloon balloon inflation for 1.5 min with no-

flow and distal injection of apprx 3.3ml mBMC suspension

injections repeated twice with 5 min re-flow between balloon inflations

Baseline characteristics

mBMC group (n=50) Control group (n=50) p

Age (years) 58 (8) 57 (10) 0.42

Diabetes mellitus (%) 10 8 0.73

Smokers (%) 40 48 0.72

Symptom start to PCI (min) 262 (142) 274 (135) 0.66

*CK-MB mass max (µg/L) 400 (223-444) 357 (220-400) 0.50

Values are mean (SD), proportion (%) or *median (interquartile range)

Medication at discharge

mBMC group (n=50) Control group (n=50)

ASA 100% 100%

Clopidogrel 100% 100%

ACE inhibitor/ATII-blocker

100% 100%

Beta-blockers 98% 100%

Statins 100% 100%

Change in LVEF

Baseline 6 months Change

mBMC Control mBMC Control mBMC Control

SPECT 41.3 42.6 49.3 49.3 8.1 7.0

Echocardiography 45.7 46.9 48.8 49.0 3.1 2.1

MRI 54.8 53.6 56.2 58.1 1.2 4.3

Values are mean with SEM error bars, p = ANCOVA N Engl J Med 2006;355:1199-1209

0.0

2.5

5.0

7.5

10.0

p=0.77

mBMC Control

% p

oin

ts

0.0

2.5

5.0

7.5

10.0

mBMC Control

p=0.70

% p

oin

ts

Echocardiography

0.0

2.5

5.0

7.5

10.0

mBMC Control

p=0.054

% p

oin

ts

SPECT MRI

0 25 50 75 100 125 150 175 200

-30

-20

-10

0

10

20

30

40

r=0.03, P=0.82

mBMC (x106)

L

VE

F (

% p

oin

ts)

Dose-response

0 1 2 3 4

-30

-20

-10

0

10

20

30

40

r=0.12, P=0.44

CD34+ cells (x106)

LV

EF

(%

po

ints

)

Change in Infarct Size

Baseline 6 months Change

mBMC Control mBMC Control mBMC Control

SPECT 43.8 38.3 32.8 30.5 -11.0 -7.8

MRI 22.0 22.2 20.9 19.6 -0.7 -2.6

Values are mean with SEM error bars, p = ANCOVA Lunde et al, N Engl J Med 2006;355:1199-1209

SPECT MRI

-12.5

-10.0

-7.5

-5.0

-2.5

0.0

p=0.21

mBMC Control

%

-12.5

-10.0

-7.5

-5.0

-2.5

0.0

p=0.07

mBMC Control

%

Change in exercise capacity

Baseline 6 months Change

mBMC Control mBMC Control mBMC Control

Exercise time (minutes) 8.6 8.8 10.6 9.9 2.1 1.2

Peak VO2 (ml/kg/min) 19.8 18.8 22.4 20.9 2.8 2.4

Values are mean with SEM error bars, p = ANCOVA

0.0

0.5

1.0

1.5

2.0

2.5

p < 0.01

mBMC Control

Exercise time

Min

ute

s

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

p = 0.62

Peak VO2

mBMC Control

.

ml/

kg/m

in

Lunde et al, Eur Heart J 2006;27(Suppl 1):280[abstract#1680)

mBMCControl

12 months follow-up

*p = SPSS mixed models for difference between groups over time

Baseline 3 months 6 months 12 months

mBMC 45.7 48.9 48.8 48.7

Control 46.9 49.3 49.0 48.5

Left ventricular ejection fraction

Baseline 3 mo 6 mo 12 mo

35

40

45

50

55

60

p = 0.75*%

Lunde et al, AHA Scientific Sessions 2006; Abstract#2717

Moller et al. Am Heart J 2006;151:419-425

mBMCControl

12 months follow-up

*p = SPSS mixed models for difference between groups over time

Wall motion score index

Baseline 3 mo 6 mo 12 mo

1.2

1.4

1.6

1.8

2.0

p = 0.88*

Baseline 3 months 6 months 12 months

mBMC 1.78 1.55 1.59 1.56

Control 1.74 1.52 1.55 1.51

Lunde et al, AHA Scientific Sessions 2006; Abstract#2717

12 months clinical follow-up

Values are number of patients

mBMC (n=50) Control (n=50) p

Mortality 0 0 1.00

Reinfarction 1 0 1.00

Revascularisation 13 11 0.81

Baseline Day 1 p

mBMC 6.6 8.2

Control 8.0 4.9

< 0.01

Interleukin 6

Values are median (picog/L), p=ANCOVA for the change between groups

Solheim et al, JACC 2007;49(Suppl 1):189[abstract#1001-132]

Conclusion I

In this randomized trial investigating effects of intracoronary injections of autologous bone marrow cells after acute MI

- There was a similar improvement in LV function

- The clinical outcome was excellent

- Adverse event rates were similar and low

In both groups during 12 months follow-up

Results on LVEF in randomized BMC trials

N Follow-up

(months)

Primary Imaging modality

Change in control group

Change in BMC group

p

BOOST 60 18 MRI 3.1±9.6 5.9±8.9 0.27

Janssens et al 67 4 MRI 2.2±7.3 3.4±6.9 0.36

ASTAMI 100 6 SPECT 7.0±9.6 8.1±11.2 0.77

REPAIR-AMI 204 4 LV angio 3.0±6.5 5.5±7.3 0.01

Clinical follow-up in BMC trialsBOOST

(N=60)

18 mo

Janssens et al

(N=67)

4 mo

ASTAMI

(N=100)

12 mo

REPAIR-AMI

(N=204)

12 mo

BMC

Mortality 0 3 % 0 2 %

Reinfarction 3 % 0 2 % 0

Revascularization 17 % 6 % 26 % 22 %

Control / Placebo

Mortality 3 % 0 0 6 %

Reinfarction 0 3 % 0 6 %

Revascularization 13 % 3 % 22 % 36 %

Conclusion II

• Intracoronary administration of BMC after AMI seems to be safe

• Efficacy is not established

• Results of ongoing adequately powered studies with accurate assessment of LV function are awaited

ASTAMI investigatorsSteering committeeK Forfang (chair), S Aakhus, H Arnesen, T Egeland, K Endresen, A Ilebekk,A Mangschau

Study investigatorsS Aakhus, M Abdelnoor, H Arnesen, P Aukrust, R Bjørnerheim, M Brekke,L Brinch, JE Brinchmann, T Egeland, K Endresen, JG Fjeld, K Forfang,HK Grøgaard, E Hopp, A Ilebekk, TO Kjellevand, NE Kløw, K Lunde, A Mangschau, C Mϋller, A Ragnarsson, I Seljeflot, HJ Smith, S Solheim, E Taraldsrud

Data and safety monitoring boardK Rasmussen, L Wallentin, R Wiseth

AcknowledgementsK Lunde and S Solheim are recipients of research fellowships from the Norwegian Council on Cardiovascular diseases

TOPCARE-AMI

Britten et al, Circulation 2003;108:2212-2218