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Principles of a Debate

Oxford school. Facts – 20% Humor – 10% Eloquence and style – 70%. Modified – Cardiologist's version. Facts – 20% Humor – 10% Flexibility – 0% Character assassination – 70%. Principles of a Debate. CP947135-83. Viewer Discretion Advised.

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Principles of a Debate

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  1. Oxford school • Facts – 20% • Humor – 10% • Eloquence and style – 70% Modified – Cardiologist's version • Facts – 20% • Humor – 10% • Flexibility – 0% • Character assassination – 70% Principles of a Debate CP947135-83

  2. Viewer Discretion Advised The following debate contains strong language and even violence CP1161902-3

  3. Attack the meta-analyses and not the man: A meta-analysis does nothing to address the quality of the studies being looked at The old adage of “data quality in – data quality out” still applies If you lump together 10 bad studies, you don’t get 1 good study – you get a bad meta-analysis CP1341084-3

  4. Methodologic Limitations in Prior Trials Issues • Randomization methodology • Blinding of all trial personnel • “True controls” • Small numbers • Completeness and duration of follow-up • Use of adjunctive therapies 3003771-8

  5. Methodological QualityAssessment of Included Studies Method of allocation concealment A B A B B B A B B A B B A A Loss of participant follow-up (%) 0 0 11 10.5 0 17 1 10.5 10.5 8 18 0 8.5 0 Method to generateStudy ID randomized sequence Ge (2006) A Huang (2006) B Janssens (2006) A Kang (2006) A Karpov (2005) B Li (2007) B Lunde (2006) A Meluzin (LD) (2006) B Meluzin (HD) (2006) B Meyer (2006) A Penicka (2007) B Ruan (2006) B Schachinger (2006) A Suarez de Lozo (2007) A A, adequate; B, unclear or not reported in the published data;; Martin-Rendon et al: EHJ, 2008 CP1343247-3

  6. Meta-Analyses of Clinical Trials What have we learned? • Feasibility • Safety – low rates of cell survival and retention Modest effect Measurement error • LV function , infarct size and perfusion Clinical relevance Lack of standardization • Clinical endpoints – all trials are underpowered CP1341094-3

  7. Lack of Uniformity in Prior Trials • Pre-specified timing of cell administration • Dosage and type of cells • Preparation and storage 3003771-7

  8. 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 • CABG BMS DES Lack of Uniformity in Prior Trials 3003771-2

  9. Changes in LVEF and Therapy with BMSC Study or subcatagory No. No. Ruan (2005) 9 11 Ge (2006) 10 10 Huang (2006) 20 20 Janssens (2004) 30 30 Kang (2006) 25 25 Lunde (2006) 44 44 Meluzin HD (2006) 22 22 Meyer (2006) 30 30 Schachinger (2006) 95 92 Meluzin LD (2006) 22 22 Li (2007) 35 23 Penicka (2007) 14 10 Suarez de Lezo (2007) 10 10 Total (95% CI) 366 349 Test for heterogeneity: 2=32.00, df=12,(P=0.001), I2=62.5% Test for overall effect Z=3.39 (P=0.0007) 2.99 (1.25, 4.72) -10 -5 0 5 10 Favors no BMSC Favors BMSC Martin-Rendon: EHJ, 2008 CP1345154-1

  10. Graph of all of the EF’s

  11. Lack of Significant Associations with EF Meta-Analyses • Duration of follow-up • Year of publication • Baseline EF* • Time to PCI • Time between symptom onset and cell infusion *REPAIR MI the exception 3003771-1

  12. Forest Plot of Changes in LVEDV Study or VMO (random) subcategory N N 95% CI Huang (2006) 20 20 Janssens (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) Favors BMSC Favors no BMSC Forest Plot of changes in Myocardial Lesion Area 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) Favors BMSC Favors no BMSC Martin-Rendon et al: EHJ, 2008 CP1343247-4

  13. Effect of Wall Thickness on Measured Infarct Size

  14. Placebo BMSC REPAIR MI – 1-Year Outcomes204 Patients P=0.02 P=0.01 P=0.08 P=0.006 Pt (%) * Death/MI Death/MI revasc Death/MI IRA revasc Death/MI CHF hospitalization *6% death Schächinger: NEJM, 2006 3003782-4

  15. COMMA Trial 814 Patients 90-Day Mortality APEX AMI 5,745 Patients Infarct size – no difference 30-Day Mortality P=0.014 All-cause mortality Pt (%) Granger: Circ, 2003 JAMA 2007 Placebo Pexilizumab The Rigorous Scrutiny of Large TrialsPexilizumab Post PPCI CP1250698-1

  16. Trials of Magnesium for Acute MI Magnesium better Placebo better YearsNo. 1980-1990 7 RCTs 1,266 1987-1992 LIMIT 2 2,316 1991-1993 ISIS 4 58,050 1999-2002 MAGIC 6,213 Odds ratio Antman E: Lancet 360:1189, 2002 CP1343247-2

  17. * Reinfarction Arrhythmias Restenosis Readmission TVR • Trials too small to demonstrate an effect on mortality or morbidity* • BMSC treatment did not appear to be associated with an increase in adverse events • BMSC treatment may improve short-term LVEF outcomes with a similar trend for LVESV, LVEDV but not for infarct size • Considerable clinical and statistical heterogeneity between trials – – – a number of limitations to the strength of any conclusions 3003771-11

  18. Conclusions from theMeta-Analyses of Trials of BMC Therapy We now know much more about what wedo not know 3003782-10

  19. Interpreting the Results of theMeta-Analyses Meta-analyses Some answers Raise new questions New directions Identification of specific weaknesses in prior trial design 3003771-12

  20. So – what do I really think? 3003771-5

  21. “ I have opinions of my own—strong opinions---but I don,t always agree with them..”. George W. Bush CP1343804-1

  22. Why Proceed Clinically While Basic Questions are Unresolved? Trials provide some answers to preconceived hypotheses but also generate new questions • Aspirin • Statins • ACE-inhibitors • Aldosterone antagonists Preclinical studies will not answer complex questions re timing and methods of cell delivery Modified from J. Martin 3003782-3

  23. Use of Stem Cells for Cardiac Repair 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 Tip of iceberg • Modification of the microenvironment • Inflammation • Fibrosis • Microvasc. obstruction • Angiogenesesis Impact upontiming & route of administrationand types of cells • Cell function • Age • Diabetes • Comorbidities Enhancementof function • Electrical integration • Safety • Clinical impact • Mechanisms of benefit Early Late 3003782-1

  24. Flourish Founder ? Cell 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 designis crucial • Use of control experiments and blinding CP1308193-3

  25. “Happily the vast majority of medical men of all nationalities are the possessors of well-balanced minds – an altogether exceptional occurrence.” Fatality Following a Controversy Between 2 Medical Men • University of Bonn • Disagreement over conduct of operation • Duel between 2 surgeons • Fatal penetrating wound of thorax JAMA, 1898 CP947135-80

  26. Lipinskimeta-analysis FINCELL + REGENTadded (200 pt)* EventsVariable (no.) P Death 12 0.26 Re-MI 8 0.04 TVR 100 0.90 CHF rehosp 9 0.08 Events (no.) P 7 0.44 7 0.11 84 1.00 7 0.25 Clinical Events – Cell Therapy Trials *REPAIR MI deleted 3003771-15

  27. Hierarchial Endpoints in Trials Mortality/CHF Safety Regional Global Biomarkers Proteomics Cell tracking • LV function • Remodeling • Infarct size Electro-physiologicmilieu * * * * Perfusion/metabolism Tissue Morphology/Histology Microarray gene expression Molecular imaging The pivotal role of imaging *Current trials Gersh and Simari: Nature CV Med, 2006 Beeres and Bax: JACC, 2007 3003782-8

  28. Milrinone in Severe CHF1,088 Patients PROMISE Trial Cumulative Survival (All Pt) Milrinone – actions Survival probability Mortality28%  P=0.038  intracellular cyclic AMP  Improved contractility Month of study Cumulative Survival (Pt with NYHA Class IV) Survival probability Placebo Milrinone Mortality53%  Packer: NEJM, 1991 Month of study CP1177150-2

  29. Reproducibily and Accuracy of E Fraction Measurement110 Consecutive Patients – Known or Suspected Heart Disease Difference in EF Between Methods Standard Echo and MRI Contrast Echo and MRI Difference EF, Echo-MRI (%) Difference EF, Con-MRI (%) Mean EF, Echo & MRI (%) Mean EF, Contrast & MRI (%) *Mean 250 Baseline image qualityGood Poor Malm: JACC, 2004 CP1201806-1

  30. Lipinskimeta-analysis FINCELL + REGENTadded (200 pt) EventsVariable (no.) P 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 Clinical Events in Cell Therapy Trials 3003771-9

  31. Clinical Events – Cell Therapy Trials • 739 patients • FINCELL and REGENT added • REPAIR subtracted 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 T 3003771-10

  32. Placebo BMC Death, re-MI or HFhospitalization* (%) REPAIR trialn=204 Janssensn=67 FINNCELLn=80 REGENTn=120 *After hospital discharge Outcome 4-6 Months AfterBM Cell Therapy for AMI 3003771-3

  33. “ I have opinions of my own—strong opinions---but I don,t always agree with them..” George W Bush CP1290753-4

  34. Since I have no grounds to attack the man – I shall take issue with the meta-analyses 3003771-4

  35. Improved 33% • Unchanged 33% Type II Error in aRandomized Trial • EscapedMonkey no. 3 CP1078272-6

  36. Meta-Analysis of IC Cell Therapy 3-Month Endpoints • AMI<14 days • 698 pt • Mean <0.1 Variable (%) (%) P • EF  3.0 1.9-0.1 <0.001 • Infarct 5.6 8.7-2.5 <0.001size  • ESV  7.4 12.2-2.7 0.002 • EDV  4.6 10.4 to +1.1 NS *Trend towards reduced death, rehospitalizationfor CHF and repeat revascularization Lipinski:JACC, 2007 3003782-5

  37. “Several trials are ongoing but it is unclear whether these will overcome the limitations of the current evidence base.” Martin-Rendon: Cochrane Coll, 2009 3003771-6

  38. Injected Volume of Cells and Change in EF Average LVEF change (%) P=0.066 Average injected cell volume (mL) Lipinski: JACC, 2007 3003771-13

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