““Progenitor Cell Therapy in AMIProgenitor Cell Therapy in AMIAfter Meta-Analyses Results ? Pro“After Meta-Analyses Results ? Pro“

““Progenitor Cell Therapy in AMIProgenitor Cell Therapy in AMIAfter Meta-Analyses Results ? Pro“After Meta-Analyses Results ? Pro“

Andreas M. Zeiher, MDDept. of Internal Medicine IIIUniversity of FrankfurtGermany

Andreas M. Zeiher, MDDept. of Internal Medicine IIIUniversity of FrankfurtGermany

Disclosure information: Guidant (research support)t2cure (co-founder, advisor)

The Heart is a Regenerating OrganUndisputable Evidence from DNA Integration of C-14

– generated during nuclear bomb testing during cold war -

Bergmann O et al., Science 2009; 324:98-102

Cells for functional cardiac repairCells for functional cardiac repair

Embyronic-likestem cells

(iPS)

somatic cells(skin fibroblasts)

4 genes:Oct4, Klf4, Sox2, myc

Cardiacstem cellsCardiacstem cells

Modified from Dimmeler et al, JCI 2005

Metaanalysis of randomized and

cohort studies of progenitor cell

therapy in ischemic heart disease

N = 976; overall treatment effect

+ 3.7 percentage points increase

in LV-EF ( p < 0.001 )

Abdel-Latif, Arch Intern Med 2007; 167:989

Vascularization Apoptosis

Vascularization Apoptosis

Paracrine factorsParacrine factors

CardiacRegenerationCardiacRegeneration

AcuteAcuteMyocardialMyocardialInfarctionInfarction

AcuteAcuteMyocardialMyocardialInfarctionInfarction

ChronicChronicHeart Heart FailureFailure

ChronicChronicHeart Heart FailureFailure

chronicchronicLV- dilatationLV- dilatation

infarctinfarctexpansionexpansion

Adverse LV RemodelingAdverse LV Remodeling

Cell Therapy in Ischemic Heart Failure: Cell Therapy in Ischemic Heart Failure: therapeutic targetstherapeutic targets

Cell Therapy in Ischemic Heart Failure: Cell Therapy in Ischemic Heart Failure: therapeutic targetstherapeutic targets

Cell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart Failure

The patient population at risk post-AMIThe patient population at risk post-AMI

Effects of cell therapy in patients at riskEffects of cell therapy in patients at risk

Derivation of the clinical benefitDerivation of the clinical benefit

Volpi et al., Circulation 1993; 88: 416-429

LV contractile recovery within 1 week after successful LV contractile recovery within 1 week after successful reperfusion determines clinical outcome in STEMIreperfusion determines clinical outcome in STEMIThere is no linear correlation between mortality and ejection fraction after AMI !

VALIANTVALIANTValValsartan sartan iin n AAcute Myocardial Icute Myocardial Innfarction farction TTrialrial

• 14703 patients14703 patients• STEMISTEMI • 0.5 - 10 days0.5 - 10 days• EF < 40%EF < 40%• Killlip I-III Killlip I-III • Diuretics 60%, Diuretics 60%, • Beta-Blocker 71%Beta-Blocker 71%

Pro

bab

ility

of

ca

rdia

c d

eath

, re

-MI

reh

os

pit

alis

atio

n f

or

hea

rt f

ailu

re

NEJM 2003, 349: 1893-1906

23% in23% in 1 year1 year23% in23% in 1 year1 year

30 % in30 % in 2 years2 years30 % in30 % in 2 years2 years

0 6 12 18 24 30 36 42 48

0.0

0.05

0.10

0.15

0.20

0.25

Months from Randomization

Cum

ulat

ive

Ris

k

318 305 272 217 172 124 79 31 Cntrl315 299 258 211 172 123 82 25 ICD

Number at Risk

ICDControl

Cumulative risk of death from any cause

p=0.66

Hohnloser at al., N Engl J Med 2004

Defibrillator IN Acute Myocardial Infarction Trial (DINAMIT)

STEMISTEMI 6- 40 days6- 40 daysEF < 35%EF < 35%

Cell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart Failure

The patient population at risk post-AMIThe patient population at risk post-AMI

Effects of cell therapy in patients at risk Effects of cell therapy in patients at risk

0

2

4

6

8

10

EF below medianEF below median(( 48.9 %) 48.9 %)

Baseline LVEFBaseline LVEFby QLVAby QLVA

EF above medianEF above median((>> 48.9 %) 48.9 %)

Ab

solu

te c

han

ge

in g

lob

al L

VE

F (%

)A

bso

lute

ch

ang

e in

glo

bal

LV

EF

(%

)

Enhanced contractile recovery by BMC is confined to patients with failed initial recovery

Enhanced contractile recovery by BMC is confined to patients with failed initial recovery

2.52.5 1.11.1 7.5 1.17.5 1.1 3.73.7 0.70.7

p = 0.002p = 0.002p = 0.002p = 0.002 p = 0.81p = 0.81p = 0.81p = 0.81

4.0 0.64.0 0.6

PlaceboPlacebo BMCBMC PlaceboPlacebo BMCBMCn =n = 5252 4141 4040 5454

p for interaction = p for interaction = 0.0200.020p for interaction = p for interaction = 0.0200.020

Schächinger et al., N Engl J Med 2006

REGENTREGENT

Courtesy of M Tendera, ESC Congress Munich, 9/2008

39 39 37 40

Controls N=20

10

20

30

40

50

60

70

80

BMCN=46

10

20

30

40

50

60

70

80

p=0.73 p=0.01

0 6 months 0 6 months

REGENT trialREGENT trial

36

31

0 6 months10

20

30

40

50

60

p=0.007

< median

-5

0

5

10

15

20

25

30

FINNCELL trialFINNCELL trial

< median > median

Ch

ang

e in

EF

(%

)

BMC

Placebo

Courtesy of H. Huikuri, European Heart Journal, 2008

p = 0.04

Enhanced contractile recovery by BMC in patients with failed initial recovery – results of recent controlled trialsEnhanced contractile recovery by BMC in patients with failed initial recovery – results of recent controlled trials

En

dsy

sto

lic

volu

me

(ml)

EF < median

Baseline 4 months 12 months

EF > median

BMC

Placebo

Baseline EF: 39 + 1.9 % Baseline EF: 56 + 2.3 %

Adverse remodeling is confined to patients with failed Adverse remodeling is confined to patients with failed initial recovery of EF and abrogated by BMC therapyinitial recovery of EF and abrogated by BMC therapy

Dill et al., AHJ 2009

Change of endsystolic volumes over time (MRI)

0

20

40

60

80

100

120

140

Baseline 4 months 12 months

p = 0.7

p = 0.06

p = 0.01

p = 0.9 p = 0.7 p = 0.5

Change in endsystolic volume (ml)Change in endsystolic volume (ml)

-10-10 -5-5 00 55 1010 1515 2020

Ch

an

ge

in E

F (

%)

Ch

an

ge

in E

F (

%)

00

22

44

66

88

1010

EF EF 48.9% 48.9%p = 0.007p = 0.007

BMCBMC

PlaceboPlacebo

Intracoronary BMC Administration Profoundly Modifies LV RemodelingIntracoronary BMC Administration

Profoundly Modifies LV Remodeling

- 4- 4

- 2- 2

Interaction between LV ejection fraction and endsystolic volumeInteraction between LV ejection fraction and endsystolic volume

no therapyno therapy

ReperfusionReperfusion ++pharmac. Rxpharmac. Rx

Cell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart Failure

The patient population at risk post-AMIThe patient population at risk post-AMI

Effects of cell therapy in patients at risk Effects of cell therapy in patients at risk

Derivation of the clinical benefitDerivation of the clinical benefit

Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit ?

Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit ?

??

Therapies preventingadverse remodelling…Therapies preventingadverse remodelling…

… reduce adverse cardiovascular events… reduce adverse cardiovascular events

ACEI , ARB, ß-Blocker, Aldosteron-Ant.

Death, Re-MI, Heart Failure at 4-6 MonthsDeath, Re-MI, Heart Failure at 4-6 Monthsin randomized, (placebo)-controlled BMC trialsin randomized, (placebo)-controlled BMC trials

Death, Re-MI, Heart Failure at 4-6 MonthsDeath, Re-MI, Heart Failure at 4-6 Monthsin randomized, (placebo)-controlled BMC trialsin randomized, (placebo)-controlled BMC trials

0

2

4

6

8

REPAIR

Jans

sens

FINNCELL

REG

ENT

Placebo

BMC

Dea

th,

re-M

I, h

osp

ital

isat

ion

fo

r h

eart

fai

lure

* (

%)

N=204 N=67 N=80 N=120

* after hospital discharge

TOTAL

N=471

13 / 217

3 / 254

p<0.005

BMC therapy is associated with improved clinical outcome at 2 years

BMC therapy is associated with improved clinical outcome at 2 years

daysdays00 100100 200200 300300 400400 500500 600600 7007000

60

70

80

90

100

p = 0.009p = 0.009(log rank)

PlaceboPlacebo

BMCBMC

Eve

nt-

free

su

rviv

al (

%)

Eve

nt-

free

su

rviv

al (

%)

(dea

th,

myo

card

ial i

nfar

ctio

n,(d

eath

, m

yoca

rdia

l inf

arct

ion,

reh

osp

italiz

atio

n f

. h

eart

fai

lure

)re

hosp

italiz

atio

n f

. h

eart

fai

lure

)

# exposedto risk

Placebo 103 93 90 86 86

BMC 101 99 98 97 95

- Death, MI, Rehospitalization for heart failure -- Death, MI, Rehospitalization for heart failure -

Do potential effects persist ?Do potential effects persist ?

Cell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart Failure

Sustained benefit after 2 years – MRI subgroup analysis -

P = 0.98 #

0

70

90

110

130

150

170

190

Abs

olu

te e

nddi

asto

lic v

olum

e[m

l]; (

mea

n ±

SE

M)

P = 0.049 *

0

2

4

6

8

10

12

14

16

Re

lati

ve

in

farc

t s

ize

[%

]; (

me

an

± S

EM

)

0

10

20

30

40

50P = 0.009

Wa

ll t

hic

ke

nin

g o

f in

farc

ted

se

gm

en

ts [

%];

(m

ea

n ±

SE

M)

Placebo

BMC

P = 0.16 #

0

60

70

80

90

100

110

Abs

olu

te e

ndsy

stol

ic v

olu

me

[ml];

(m

ean

± S

EM

)

P = 0.009 #

0

35

40

45

50

55

Ab

so

lute

LV

eje

cti

on

fra

cti

on

[%

]; (

me

an

± S

EM

)

N = 58 patients; ANCOVA model# adjusted for baseline value (LVA)* Adjusted for baseline value (MRI)

LVEF EDV ESV

Infarct Size Infarct Wall ThickeningA.Rolf, Bad Nauheim

90

80

70

60

50

40

30

Baseline 4 months 1 year

MR

I L

VE

F (

%)

2 years

p < 0.001 p = 0.008 p = 0.04

5 years

p < 0.001

p = 0.03

Improvement of MRI - determined LVEF isImprovement of MRI - determined LVEF issustained 5 years after progenitor cell therapysustained 5 years after progenitor cell therapy

Mean ± SDN

46 ± 10N = 31

52 ± 11N = 30

57 ± 13N = 30

62 ± 11N = 28

59 ± 8N = 31

Persistently low NT-pro BNP serum levels at 5 years Persistently low NT-pro BNP serum levels at 5 years indicate absence of adverse LV remodelingindicate absence of adverse LV remodeling

1.000

500

0

Baseline 4 months 1 year 2 years 5 years

Mean ± SDN

917 ± 920N = 39

283 ± 283N = 34

285 ± 346N = 25

304 ± 602N = 19

213 ± 308N = 39

NT

-pro

BN

P s

eru

m l

evel

s[p

g/m

l]

p < 0.001 p = 0.20 p = 0.97

p = 0.03

p = 0.97

2.500

Bone Marrow Cell Therapy for Post-Infarction Heart Failure

Bone Marrow Cell Therapy for Post-Infarction Heart Failure

Intracoronary administration of BMC …Intracoronary administration of BMC …

abrogates adverse left ventricular remodeling abrogates adverse left ventricular remodeling in patients at risk in patients at risk - - failure of initial contractile recovery after reperfusionfailure of initial contractile recovery after reperfusion- persistently elevated NT-proBNP acutely- persistently elevated NT-proBNP acutely

abrogates adverse left ventricular remodeling abrogates adverse left ventricular remodeling in patients at risk in patients at risk - - failure of initial contractile recovery after reperfusionfailure of initial contractile recovery after reperfusion- persistently elevated NT-proBNP acutely- persistently elevated NT-proBNP acutely

is associated with enhanced LV contractile is associated with enhanced LV contractile recovery and improved coronary flow reserverecovery and improved coronary flow reserveis associated with enhanced LV contractile is associated with enhanced LV contractile recovery and improved coronary flow reserverecovery and improved coronary flow reserve

is associated with improved clinical is associated with improved clinical outcome at 2 yearsoutcome at 2 yearsis associated with improved clinical is associated with improved clinical outcome at 2 yearsoutcome at 2 years

demonstrates a cell bioactivity - contractile demonstrates a cell bioactivity - contractile recovery response relationship recovery response relationship demonstrates a cell bioactivity - contractile demonstrates a cell bioactivity - contractile recovery response relationship recovery response relationship

prevents adverse remodelling over 5 yearsprevents adverse remodelling over 5 yearsprevents adverse remodelling over 5 yearsprevents adverse remodelling over 5 years

ConclusionConclusion

In patients with acute post-infarction heart failure In patients with acute post-infarction heart failure despite successful reperfusion therapydespite successful reperfusion therapy

a large-scale clinical endpoint trial is a large-scale clinical endpoint trial is warranted to document the effects on warranted to document the effects on mortality and morbiditymortality and morbidity

a large-scale clinical endpoint trial is a large-scale clinical endpoint trial is warranted to document the effects on warranted to document the effects on mortality and morbiditymortality and morbidity

Stefanie DimmelerStefanie DimmelerBirgit AssmusBirgit AssmusVolker SchächingerVolker Schächingerwww.REPAIR-AMI.org

Steering CommitteeSteering Committee

HamburgHamburg

LeipzigLeipzigBad BerkaBad Berka

SuhlSuhl

Bad OeynhausenBad Oeynhausen

LippeLippe

Homburg/SaarHomburg/Saar

ZürichZürich

MannheimMannheim

LudwigshafenLudwigshafen Frankfurt(2 centers)Frankfurt(2 centers)

BadNauheimBadNauheimGiessenGiessen

MainzMainz

KasselKassel

Study Centers and Core FacilitiesStudy Centers and Core Facilities

S. Erbs / R. HambrechtS. Erbs / R. Hambrecht

V. Schächinger /V. Schächinger /B. Assmus / S. DimmelerB. Assmus / S. Dimmeler

A. M. Zeiher (PI)A. M. Zeiher (PI)

A. Elsässer / M. Stanisch /A. Elsässer / M. Stanisch /T. Dill / Ch. HammT. Dill / Ch. Hamm

W. HaberboschW. Haberbosch

H. Hölschermann /H. Hölschermann /H. TillmannsH. Tillmanns

J. Yu / B. LauerJ. Yu / B. Lauer

R. Corti / T. LüscherR. Corti / T. Lüscher

D. Mathey / T. TüblerD. Mathey / T. Tübler

T. Süselbeck / M. Brückmann /T. Süselbeck / M. Brückmann /K. HaaseK. Haase

G. Nickenig / N. Werner /G. Nickenig / N. Werner /M. BöhmM. Böhm

J. HaaseJ. Haase

C. Hansen / J. NeuznerC. Hansen / J. Neuzner

A. Germing / A. MüggeA. Germing / A. Mügge

B. Mark / J. SengesB. Mark / J. Senges

C. Hoffmann / M. Farr /C. Hoffmann / M. Farr /D. HorstkotteD. Horstkotte

A. Cuneo / U. TebbeA. Cuneo / U. Tebbe

S. Genth-Zotz /S. Genth-Zotz /T. MünzelT. Münzel

BochumBochum

Cell Processing CenterCell Processing Center

T. Tonn / N. Krzossok/T. Tonn / N. Krzossok/E. SeifriedE. Seifried

Safety CommitteeSafety CommitteeT. Bonzel / W. KasperT. Bonzel / W. Kasper

Coordinating CenterCoordinating Center

H. BraunH. Braun

MRI Core LabMRI Core Lab

Doppler Core LabDoppler Core Lab

Echo Core LabEcho Core Lab

Angio Core LabAngio Core Lab

www.REPAIR-AMI.orgwww.REPAIR-AMI.org400 km400 km

Klinikum derKlinikum derJohann Wolfgang Goethe UniversitätJohann Wolfgang Goethe Universität

Frankfurt am MainFrankfurt am Main

Dept. of HematologyDept. of Hematology

H. Martin / W. HofmannH. Martin / W. HofmannD. HoelzerD. Hoelzer

Dept. of RadiologyDept. of Radiology

N. Abolmaali / J. SchmittN. Abolmaali / J. SchmittT. VoglT. Vogl

Experimental StudiesExperimental StudiesC. Urbich, C. Urbich, A. KühbacherA. KühbacherM. Potente M. Potente A. AicherA. Aicher E. Chavakis, G. CarmonaE. Chavakis, G. CarmonaL. Rössig, D. Scharner L. Rössig, D. Scharner M. Koyanagi, M. IwasakiM. Koyanagi, M. IwasakiTh. Ziebart, C. YoonTh. Ziebart, C. Yoon

& technical help (Andrea, Nicole,& technical help (Andrea, Nicole,Ariane, Marion, Tino)Ariane, Marion, Tino)

Red Cross FrankfurtRed Cross Frankfurt

T. Tonn / SeifriedT. Tonn / SeifriedT. Brühl, M. Vasa,T. Brühl, M. Vasa,K. Sasaki, C. Badorff, C. HeeschenK. Sasaki, C. Badorff, C. Heeschen

Clinician Scientists:Clinician Scientists:J. Honold, R. Lehmann J. Honold, R. Lehmann U. Fischer-RasokatU. Fischer-RasokatS. Fichtlscherer S. Fichtlscherer F. Seeger, C.KisselF. Seeger, C.KisselK.SpyridopoulosK.SpyridopoulosN. Bellera GotardaN. Bellera Gotarda

Kerckhoff ClinicKerckhoff Clinic

C. Hamm / T. DillC. Hamm / T. Dill