Principles of a Debate

Principles of a DebatePrinciples of a DebatePrinciples of a DebatePrinciples of a Debate

CP947135-83

• Facts – 20%

• Humor – 10%

• Eloquence and style – 70%

Oxford school

• Facts – 20%

• Humor – 10%

• Flexibility – 0%

• Character assassination – 70%

Modified – Cardiologist's version

Viewer Discretion AdvisedViewer Discretion Advised

CP1161902-3

The following debate contains strong language and even violence

The following debate contains strong language and even violence

Attack the meta-analyses and not the man:

Attack the meta-analyses and not the man:

CP1341084-3

A meta-analysis does nothing to address the A meta-analysis does nothing to address the quality of the studies being looked atquality of the studies being looked at

The old adage of “data quality in – data The old adage of “data quality in – data quality out” still appliesquality out” still applies

A meta-analysis does nothing to address the A meta-analysis does nothing to address the quality of the studies being looked atquality of the studies being looked at

The old adage of “data quality in – data The old adage of “data quality in – data quality out” still appliesquality out” still applies

If you lump together 10 bad studies, you If you lump together 10 bad studies, you don’t get 1 good study – you get a bad meta-don’t get 1 good study – you get a bad meta-analysisanalysis

If you lump together 10 bad studies, you If you lump together 10 bad studies, you don’t get 1 good study – you get a bad meta-don’t get 1 good study – you get a bad meta-analysisanalysis

3003771-8

Issues

• Randomization methodology

• Blinding of all trial personnel

• “True controls”

• Small numbers

• Completeness and duration of follow-up

• Use of adjunctive therapies

Methodologic Limitations in Prior TrialsMethodologic Limitations in Prior Trials

Methodological QualityAssessment of Included Studies

Methodological QualityAssessment of Included Studies

Martin-Rendon et al: EHJ, 2008Martin-Rendon et al: EHJ, 2008

Method to generateMethod to generateStudy IDStudy ID randomized sequencerandomized sequenceGe (2006)Ge (2006) AAHuang (2006)Huang (2006) BBJanssens (2006)Janssens (2006) AAKang (2006)Kang (2006) AAKarpov (2005)Karpov (2005) BBLi (2007)Li (2007) BBLunde (2006)Lunde (2006) AAMeluzin (LD) (2006)Meluzin (LD) (2006) BBMeluzin (HD) (2006)Meluzin (HD) (2006) BBMeyer (2006)Meyer (2006) AAPenicka (2007)Penicka (2007) BBRuan (2006)Ruan (2006) BBSchachinger (2006)Schachinger (2006) AASuarez de Lozo (2007)Suarez de Lozo (2007) AA

Method to generateMethod to generateStudy IDStudy ID randomized sequencerandomized sequenceGe (2006)Ge (2006) AAHuang (2006)Huang (2006) BBJanssens (2006)Janssens (2006) AAKang (2006)Kang (2006) AAKarpov (2005)Karpov (2005) BBLi (2007)Li (2007) BBLunde (2006)Lunde (2006) AAMeluzin (LD) (2006)Meluzin (LD) (2006) BBMeluzin (HD) (2006)Meluzin (HD) (2006) BBMeyer (2006)Meyer (2006) AAPenicka (2007)Penicka (2007) BBRuan (2006)Ruan (2006) BBSchachinger (2006)Schachinger (2006) AASuarez de Lozo (2007)Suarez de Lozo (2007) AA

Method ofMethod ofallocationallocation

concealmentconcealmentAABBAABBBBBBAABBBBAABBBBAAAA

Method ofMethod ofallocationallocation

concealmentconcealmentAABBAABBBBBBAABBBBAABBBBAAAA

Loss ofLoss ofparticipantparticipant

follow-up (%)follow-up (%) 00 001111

10.510.5 001717 11

10.510.5 10.510.5

881818 00

8.58.5 00

Loss ofLoss ofparticipantparticipant

follow-up (%)follow-up (%) 00 001111

10.510.5 001717 11

10.510.5 10.510.5

881818 00

8.58.5 00

A, adequate; B, unclear or not reported in the published data;; A, adequate; B, unclear or not reported in the published data;; CP1343247-3

Meta-Analyses of Clinical TrialsMeta-Analyses of Clinical Trials

CP1341094-3

What have we learned?

• Feasibility• Feasibility

• Safety – low rates of cell survival and retention• Safety – low rates of cell survival and retention

• LV function , infarct size and perfusion

• LV function , infarct size and perfusion

Modest effectModest effectMeasurement errorMeasurement errorClinical relevanceClinical relevanceLack of standardizationLack of standardization

• Clinical endpoints – all trials are underpowered• Clinical endpoints – all trials are underpowered

3003771-7

Lack of Uniformity in Prior Trials

• Pre-specified timing of cell administration

• Dosage and type of cells

• Preparation and storage

3003771-2

Lack of Uniformity in Prior TrialsLack of Uniformity in Prior Trials

Primary Measure of Interest

• LVEF

• Regional wall motion• Volumes

• Perfusion

Methods of Measurement

• Echo

• SPECT• MRI

• Angiography

Methods and Timing of Reperfusion Therapy

• PTCA

• Stents• Fibrinolytic drugs

• CABGBMSDES

Study or subcatagoryStudy or subcatagory No. No. No. No.Ruan (2005)Ruan (2005) 9 9 11 11Ge (2006)Ge (2006) 10 10 10 10Huang (2006)Huang (2006) 20 20 20 20Janssens (2004)Janssens (2004) 30 30 30 30Kang (2006)Kang (2006) 25 25 25 25Lunde (2006)Lunde (2006) 44 44 44 44Meluzin HD (2006)Meluzin HD (2006) 22 22 22 22Meyer (2006)Meyer (2006) 30 30 30 30Schachinger (2006)Schachinger (2006) 95 95 92 92Meluzin LD (2006)Meluzin LD (2006) 22 22 22 22Li (2007)Li (2007) 35 35 23 23Penicka (2007)Penicka (2007) 14 14 10 10Suarez de Lezo (2007)Suarez de Lezo (2007) 10 10 10 10Total (95% CI)Total (95% CI) 366366 349349

Test for heterogeneity: Test for heterogeneity: 22=32.00, df=12,=32.00, df=12,(P=0.001), I(P=0.001), I22=62.5%=62.5%Test for overall effect Z=3.39 (P=0.0007)Test for overall effect Z=3.39 (P=0.0007)

Changes in LVEF and Therapy with BMSCChanges in LVEF and Therapy with BMSC

CP1345154-1

Martin-Rendon: EHJ, 2008Martin-Rendon: EHJ, 2008-10-10 -5-5 00 55 1010

Favors no BMSCFavors no BMSC Favors BMSCFavors BMSC

2.99 (1.25, 4.72)2.99 (1.25, 4.72)

Graph of all of the EF’s

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90

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Lack of Significant Associations with EFMeta-Analyses

• Duration of follow-up

• Year of publication

• Baseline EF*

• Time to PCI

• Time between symptom onset and cell infusion

*REPAIR MI the exception*REPAIR MI the exception

Martin-Rendon et al: EHJ, 2008Martin-Rendon et al: EHJ, 2008

Forest Plot of Changes in LVEDVForest Plot of Changes in LVEDVStudy or VMO (random)subcategory N N 95% CIHuang (2006) 20 20Janssens (2004) 33 34 Kang (2006) 26 25 Lunde (2006) 44 44 Meluzin HD (2006) 22 22 Meyer (2006) 30 30 Schechinger (2006) 95 92 Meluzin LD (2006) 22 22 Li (2007) 35 23 Total (95% CI) 326 312

Test for heterogeneity 2=6.89, df=8 (P=0.56), t2=0%Test for overall effect Z=1.52 (P=0.13)

Study or VMO (random)subcategory N N 95% CIHuang (2006) 20 20Janssens (2004) 33 34 Kang (2006) 26 25 Lunde (2006) 44 44 Meluzin HD (2006) 22 22 Meyer (2006) 30 30 Schechinger (2006) 95 92 Meluzin LD (2006) 22 22 Li (2007) 35 23 Total (95% CI) 326 312


-10 -5 0 5 10Favors BMSCFavors BMSC Favors no BMSCFavors no BMSC

Forest Plot of changes in Myocardial Lesion AreaForest Plot of changes in Myocardial Lesion AreaStudy or VMO (random)

subcategory N N 95% CI

Huang (2006) 20 20

Lunde (2006) 44 44

Meluzin HD (2006) 22 22

Meluzin LD (2006) 22 22

Penicka (2007) 14 10

Total (95% CI) 122 118


Study or VMO (random)

subcategory N N 95% CI

Huang (2006) 20 20

Lunde (2006) 44 44

Meluzin HD (2006) 22 22

Meluzin LD (2006) 22 22

Penicka (2007) 14 10

Total (95% CI) 122 118


-10 -5 0 5 10

Favors BMSCFavors BMSC Favors no BMSCFavors no BMSC

CP1343247-4

Effect of Wall Thickness on Measured Infarct Size

Effect of Wall Thickness on Measured Infarct Size

40

29

12

23

18

2

10

2

0

10

20

30

40

50

Schächinger: NEJM, 2006Schächinger: NEJM, 2006

REPAIR MI – 1-Year Outcomes204 Patients

REPAIR MI – 1-Year Outcomes204 Patients

PlaceboBMSCPlaceboBMSC

Pt(%)Pt

(%)

Death/MIDeath/MI

P=0.02P=0.02

Death/MIrevasc

Death/MIrevasc

P=0.01P=0.01

Death/MIIRA revascDeath/MI

IRA revasc

P=0.08P=0.08

Death/MICHF

hospitalization

Death/MICHF

hospitalization

P=0.006P=0.006

**

*6% death*6% death

3003782-4

The Rigorous Scrutiny of Large TrialsPexilizumab Post PPCI

The Rigorous Scrutiny of Large TrialsPexilizumab Post PPCI

COMMA Trial814 Patients

90-Day Mortality

Infarct size – no difference

PlaceboPexilizumabPlaceboPexilizumab

5.9

1.8

0

2

4

6

8

10

Granger: Circ, 2003Granger: Circ, 2003

Pt(%)Pt

(%)

P=0.014P=0.014

3.92 4.06

0

2

4

6

8

10

JAMA 2007JAMA 2007

All-cause

mortality

All-cause

mortality

APEX AMI5,745 Patients

30-Day Mortality

CP1250698-1

Years No.

1980-1990 7 RCTs 1,266

1987-1992 LIMIT 2 2,316

1991-1993 ISIS 4 58,050

1999-2002 MAGIC 6,213

Years No.

1980-1990 7 RCTs 1,266

1987-1992 LIMIT 2 2,316

1991-1993 ISIS 4 58,050

1999-2002 MAGIC 6,213

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Trials of Magnesium for Acute MITrials of Magnesium for Acute MI

Antman E: Lancet 360:1189, 2002Antman E: Lancet 360:1189, 2002

Magnesium better

Magnesium better

Placebo better

Placebo better

Odds ratioOdds ratioCP1343247-2

• Trials too small to demonstrate an effect on mortality or morbidity*

• Trials too small to demonstrate an effect on mortality or morbidity*

3003771-11

• BMSC treatment did not appear to be associated with an increase in adverse events

• BMSC treatment did not appear to be associated with an increase in adverse events

• Considerable clinical and statistical heterogeneity between trials – – – a number of limitations to the strength of any conclusions

ReinfarctionArrhythmiasRestenosisReadmissionTVR

ReinfarctionArrhythmiasRestenosisReadmissionTVR

**

• BMSC treatment may improve short-term LVEF outcomes with a similar trend for LVESV, LVEDV but not for infarct size

• BMSC treatment may improve short-term LVEF outcomes with a similar trend for LVESV, LVEDV but not for infarct size

Conclusions from theMeta-Analyses of Trials of BMC

Therapy

Conclusions from theMeta-Analyses of Trials of BMC

Therapy

We now know much more about what we do not know

3003782-10

3003771-12

Interpreting the Results of theMeta-Analyses

Interpreting the Results of theMeta-Analyses

Meta-analysesMeta-analyses

New directionsNew directions Identification of specific weaknesses in prior trial design

Identification of specific weaknesses in prior trial design

Some answersRaise new questions

Some answersRaise new questions

3003771-5

So – what do I really think?So – what do I really think?

CP1343804-1

“ I have opinions of my own—strong opinions---but I don,t always agree with them..”..

“ I have opinions of my own—strong opinions---but I don,t always agree with them..”..

George W. BushGeorge W. BushGeorge W. BushGeorge W. Bush

Why Proceed Clinically While Basic Questions are Unresolved?

Why Proceed Clinically While Basic Questions are Unresolved?

• Aspirin• Statins• ACE-inhibitors• Aldosterone antagonists

Trials provide some answers to preconceived hypotheses but also generate new questions

Preclinical studies will not answer complex questions re timing and methods of cell delivery

Preclinical studies will not answer complex questions re timing and methods of cell deliveryModified from J. MartinModified from J. Martin

3003782-3

Use of Stem Cells for Cardiac RepairUse of Stem Cells for Cardiac Repair

Tip of icebergTip of iceberg

Not Yet Ready for Clinical Application Outsidea Research or Trial Setting

Not Yet Ready for Clinical Application Outsidea Research or Trial Setting

Some ongoing questions?

• Which cells and to which patients• What numbers• Timing of administration• Storage and isolation procedures• Cell survival, retention & proliferation• Homing

• Cell functionAgeDiabetesComorbidities

• Electrical integration• Safety

• Clinical impact

• Mechanisms of benefit

Enhancementof function

• Modification of the microenvironmentInflammationFibrosisMicrovasc. obstructionAngiogenesesis

Impact upontiming & route of administrationand types of cells

3003782-1

EarlyLate

Cell Repair Therapy – the FutureCell Repair Therapy – the Future

• Enthusiasm and allure ahead of the science?• Lessons to be learned from developments in

angiogenesis and gene therapy• Collaborative approach to future trial design

is crucial• Use of control experiments and blinding

FlourishFlourish

FounderFounder

?

CP1308193-3

• University of BonnUniversity of Bonn

• Disagreement over conduct of operationDisagreement over conduct of operation

• Duel between 2 surgeonsDuel between 2 surgeons

• Fatal penetrating wound of thoraxFatal penetrating wound of thorax

Fatality Following a Controversy Fatality Following a Controversy Between 2 Medical MenBetween 2 Medical Men

Fatality Following a Controversy Fatality Following a Controversy Between 2 Medical MenBetween 2 Medical Men

CP947135-80JAMA, 1898JAMA, 1898

“Happily the vast majority of medical men of all nationalities are the possessors of well-balanced minds – an altogether exceptional occurrence.”

3003771-15

Clinical Events – Cell Therapy TrialsClinical Events – Cell Therapy Trials

EventsVariable (no.) P

Death 12 0.26

Re-MI 8 0.04

TVR 100 0.90

CHF rehosp 9 0.08


Death 12 0.26

Re-MI 8 0.04

TVR 100 0.90

CHF rehosp 9 0.08

Lipinskimeta-analysis


Events (no.) P

7 0.44

7 0.11

84 1.00

7 0.25

Events (no.) P

7 0.44

7 0.11

84 1.00

7 0.25

FINCELL + REGENTadded (200 pt)*

FINCELL + REGENTadded (200 pt)*

*REPAIR MI deleted*REPAIR MI deleted

TissueTissue

Morphology/HistologyMorphology/HistologyMicroarray gene expressionMicroarray gene expression

Molecular imagingMolecular imaging

Hierarchial Endpoints in TrialsHierarchial Endpoints in Trials

• LV functionLV function• RemodelingRemodeling• Infarct sizeInfarct size

Electro-physiologic

milieu

BiomarkersProteomicsCell tracking

Mortality/CHFSafety

Perfusion/metabolism

Beeres and Bax: JACC, 2007Beeres and Bax: JACC, 2007

The pivotal role of

imaging

The pivotal role of

imaging

***

***

*Current trials*Current trials

Gersh and Simari: Nature CV Med, 2006Gersh and Simari: Nature CV Med, 2006

RegionalRegional

GlobalGlobal

*

3003782-8

CP1177150-2

Milrinone in Severe CHF1,088 Patients PROMISE TrialMilrinone in Severe CHF

1,088 Patients PROMISE TrialCumulative Survival (All Pt)Cumulative Survival (All Pt)

Placebo

Milrinone

Placebo

Milrinone

Su

rviv

al p

rob

abil

ity

Su

rviv

al p

rob

abil

ity

Milrinone – actions

intracellular cyclic AMP

Improved contractility

Packer: NEJM, 1991Packer: NEJM, 1991

Month of studyMonth of studyCumulative Survival (Pt with NYHA Class IV)Cumulative Survival (Pt with NYHA Class IV)

Su

rviv

al p

rob

abil

ity

Su

rviv

al p

rob

abil

ity

Month of studyMonth of study

Mortality28%

Mortality28%

Mortality53%

Mortality53%

P=0.038P=0.038

-25-20-15-10-505

101520

10 30 50 70 90

-25-20-15-10-505

101520

10 30 50 70 90

Reproducibily and Accuracy of E Fraction Measurement110 Consecutive Patients –

Known or Suspected Heart Disease

Reproducibily and Accuracy of E Fraction Measurement110 Consecutive Patients –

Known or Suspected Heart Disease

Malm: JACC, 2004Malm: JACC, 2004CP1201806-1

*Mean 250*Mean 250

Difference in EF Between MethodsDifference in EF Between Methods

Standard Echo and MRIStandard Echo and MRI

Dif

fere

nce

EF

, E

cho

-MR

I (%

)D

iffe

ren

ce E

F,

Ech

o-M

RI

(%)

Mean EF, Echo & MRI (%)

Mean EF, Echo & MRI (%)

Contrast Echo and MRIContrast Echo and MRI

Dif

fere

nce

EF

, C

on

-MR

I (%

)D

iffe

ren

ce E

F,

Co

n-M

RI

(%)

Mean EF, Contrast & MRI (%)

Mean EF, Contrast & MRI (%)

Baseline image qualityGoodPoor

Baseline image qualityGoodPoor

3003771-9

Clinical Events in Cell Therapy TrialsClinical Events in Cell Therapy Trials


Death 12 0.26

Re-MI 8 0.04

TVR 100 0.90

CHF rehosp 9 0.09


Death 12 0.26

Re-MI 8 0.04

TVR 100 0.90

CHF rehosp 9 0.09



Events (no.) P

15 0.06

13 0.0025

126 0.24

10 0.053

Events (no.) P

15 0.06

13 0.0025

126 0.24

10 0.053

FINCELL + REGENTadded (200 pt)

FINCELL + REGENTadded (200 pt)

3003771-10

Clinical Events – Cell Therapy TrialsClinical Events – Cell Therapy Trials

BMC Control Rel Risk P

Death 3/446 4/293 0.49 0.44

Re-MI 2/395 5/243 0.25 0.11

TVR 51/445 33/293 1.02 1.00

CHF rehosp 2/206 5/174 0.38 0.25

BMC Control Rel Risk P

Death 3/446 4/293 0.49 0.44

Re-MI 2/395 5/243 0.25 0.11

TVR 51/445 33/293 1.02 1.00

CHF rehosp 2/206 5/174 0.38 0.25

Povsic TPovsic T

• 739 patients

• FINCELL and REGENT added

• REPAIR subtracted

• 739 patients

• FINCELL and REGENT added

• REPAIR subtracted

3003771-3

Outcome 4-6 Months AfterBM Cell Therapy for AMI

Outcome 4-6 Months AfterBM Cell Therapy for AMI

0

2

4

6

8

Dea

th,

re-M

I o

r H

Fh

osp

ital

izat

ion

* (%

)D

eath

, re

-MI

or

HF

ho

spit

aliz

atio

n*

(%)

*After hospital discharge*After hospital discharge

PlaceboPlacebo

BMCBMC

REPAIR trialn=204

REPAIR trialn=204

Janssensn=67

Janssensn=67

FINNCELLn=80

FINNCELLn=80

REGENTn=120

REGENTn=120

“ I have opinions of my own—strong opinions---but I don,t always agree with them..”

“ I have opinions of my own—strong opinions---but I don,t always agree with them..”

CP1290753-4

George W BushGeorge W Bush

3003771-4

Since I have no grounds to attack the man –

I shall take issue with the meta-analyses

Since I have no grounds to attack the man –

I shall take issue with the meta-analyses

Type II Error in aRandomized TrialType II Error in aRandomized Trial

CP1078272-6

• ImprovedImproved 33%33%

• UnchangedUnchanged 33%33%

• EscapedEscapedMonkey Monkey no. 3no. 3

Meta-Analysis of IC Cell TherapyMeta-Analysis of IC Cell Therapy

• AMI<14 days

• 698 pt

• AMI<14 days

• 698 pt

Lipinski:JACC, 2007Lipinski:JACC, 2007

Mean <0.1Variable (%) (%) P

• EF 3.0 1.9-0.1<0.001

Mean <0.1Variable (%) (%) P

• EF 3.0 1.9-0.1<0.001• Infarct 5.6 8.7-2.5<0.001size

• Infarct 5.6 8.7-2.5<0.001size • ESV 7.4 12.2-2.7 0.002

• ESV 7.4 12.2-2.7 0.002• EDV 4.6 10.4 to +1.1 NS• EDV 4.6 10.4 to +1.1 NS

*Trend towards reduced death, rehospitalizationfor CHF and repeat revascularization

3-Month Endpoints3-Month Endpoints

3003782-5

3003771-6

“Several trials are ongoing but it is unclear whether these will overcome the limitations of the current evidence base.”

“Several trials are ongoing but it is unclear whether these will overcome the limitations of the current evidence base.”

Martin-Rendon: Cochrane Coll, 2009Martin-Rendon: Cochrane Coll, 2009

Lipinski: JACC, 2007Lipinski: JACC, 2007

0

2

4

6

8

0 10 20 30 40 50 60Average injected cell volume (mL)Average injected cell volume (mL)

3003771-13

Injected Volume of Cells and Change in EFInjected Volume of Cells and Change in EFA

vera

ge

LV

EF

ch

ang

e (%

)A

vera

ge

LV

EF

ch

ang

e (%

)

P=0.066P=0.066

Documents

Principles of a Debate