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
3003771-1
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
Test for heterogeneity 2=6.89, df=8 (P=0.56), t2=0%Test for overall effect Z=1.52 (P=0.13)
-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
Test for heterogeneity 2=3.03, df=4 (P=0.55), t2=0%Test for overall effect Z=2.85 (P=0.004)
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
Test for heterogeneity 2=3.03, df=4 (P=0.55), t2=0%Test for overall effect Z=2.85 (P=0.004)
-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
EventsVariable (no.) P
Death 12 0.26
Re-MI 8 0.04
TVR 100 0.90
CHF rehosp 9 0.08
Lipinskimeta-analysis
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
EventsVariable (no.) P
Death 12 0.26
Re-MI 8 0.04
TVR 100 0.90
CHF rehosp 9 0.09
EventsVariable (no.) P
Death 12 0.26
Re-MI 8 0.04
TVR 100 0.90
CHF rehosp 9 0.09
Lipinskimeta-analysis
Lipinskimeta-analysis
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