Principles of a Debate CP 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 Advised CP The following debate contains strong language and even violence Attack the meta-analyses and not the man: CP 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 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 dont get 1 good study you get a bad meta- analysis 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 Trials Methodological Quality Assessment of Included Studies Martin-Rendon et al: EHJ, 2008 Method to generate Study IDrandomized 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 Method to generate Study IDrandomized 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 Method of allocation concealment ABABBBABBABBAA ABABBBABBABBAA Loss of participant follow-up (%) Loss of participant follow-up (%) A, adequate; B, unclear or not reported in the published data;; CP Meta-Analyses of Clinical Trials CP What have we learned? Feasibility Safety low rates of cell survival and retention LV function, infarct size and perfusion Modest effect Measurement error Clinical relevance Lack of standardization Clinical endpoints all trials are underpowered Lack of Uniformity in Prior Trials Pre-specified timing of cell administration Dosage and type of cells Preparation and storage Lack 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 CABG BMS DES Study or subcatagory No. No. Ruan (2005) 9 11 Ge (2006) Huang (2006) Janssens (2004) Kang (2006) Lunde (2006) Meluzin HD (2006) Meyer (2006) Schachinger (2006) Meluzin LD (2006) Li (2007) Penicka (2007) Suarez de Lezo (2007) Total (95% CI) Test for heterogeneity: 2 =32.00, df=12, (P=0.001), I 2 =62.5% Test for overall effect Z=3.39 (P=0.0007) Changes in LVEF and Therapy with BMSC CP Martin-Rendon: EHJ, Favors no BMSC Favors BMSC 2.99 (1.25, 4.72) Graph of all of the EFs 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 Martin-Rendon et al: EHJ, 2008 Forest Plot of Changes in LVEDV Study orVMO (random) subcategory NN95% CI Huang (2006) Janssens (2004) Kang (2006) Lunde (2006) Meluzin HD (2006) Meyer (2006) Schechinger (2006) Meluzin LD (2006) Li (2007) Total (95% CI) Test for heterogeneity 2 =6.89, df=8 (P=0.56), t 2 =0% Test for overall effect Z=1.52 (P=0.13) Study orVMO (random) subcategory NN95% CI Huang (2006) Janssens (2004) Kang (2006) Lunde (2006) Meluzin HD (2006) Meyer (2006) Schechinger (2006) Meluzin LD (2006) Li (2007) Total (95% CI) Test for heterogeneity 2 =6.89, df=8 (P=0.56), t 2 =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 orVMO (random) subcategory NN95% CI Huang (2006) Lunde (2006) Meluzin HD (2006) Meluzin LD (2006) Penicka (2007) Total (95% CI) Test for heterogeneity 2 =3.03, df=4 (P=0.55), t 2 =0% Test for overall effect Z=2.85 (P=0.004) Study orVMO (random) subcategory NN95% CI Huang (2006) Lunde (2006) Meluzin HD (2006) Meluzin LD (2006) Penicka (2007) Total (95% CI) Test for heterogeneity 2 =3.03, df=4 (P=0.55), t 2 =0% Test for overall effect Z=2.85 (P=0.004) Favors BMSC Favors no BMSC CP Effect of Wall Thickness on Measured Infarct Size Schchinger: NEJM, 2006 REPAIR MI 1-Year Outcomes 204 Patients Placebo BMSC Placebo BMSC Pt (%) Pt (%) Death/MI P=0.02 Death/MI revasc Death/MI revasc P=0.01 Death/MI IRA revasc Death/MI IRA revasc P=0.08 Death/MI CHF hospitalization Death/MI CHF hospitalization P=0.006 * * *6% death The Rigorous Scrutiny of Large Trials Pexilizumab Post PPCI COMMA Trial 814 Patients 90-Day Mortality Infarct size no difference Placebo Pexilizumab Placebo Pexilizumab Granger: Circ, 2003 Pt (%) Pt (%) P=0.014 JAMA 2007 All- cause mortality APEX AMI 5,745 Patients 30-Day Mortality CP YearsNo RCTs 1, LIMIT 2 2, ISIS 458, MAGIC 6,213 YearsNo RCTs 1, LIMIT 2 2, ISIS 458, MAGIC 6,213 Trials of Magnesium for Acute MI Antman E: Lancet 360:1189, 2002 Magnesium better Placebo better Odds ratio CP 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 Considerable clinical and statistical heterogeneity between trials a number of limitations to the strength of any conclusions Reinfarction Arrhythmias Restenosis Readmission TVR Reinfarction Arrhythmias Restenosis Readmission TVR * * BMSC treatment may improve short-term LVEF outcomes with a similar trend for LVESV, LVEDV but not for infarct size Conclusions from the Meta-Analyses of Trials of BMC Therapy We now know much more about what we do not know Interpreting the Results of the Meta-Analyses Meta-analyses New directions Identification of specific weaknesses in prior trial design Some answers Raise new questions Some answers Raise new questions So what do I really think? CP I have opinions of my ownstrong opinions---but I don,t always agree with them... George W. Bush 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 Modified from J. Martin Use of Stem Cells for Cardiac Repair Tip of iceberg Not Yet Ready for Clinical Application Outside a 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 function Age Diabetes Comorbidities Electrical integration Safety Clinical impact Mechanisms of benefit Enhancement of function Modification of the microenvironment Inflammation Fibrosis Microvasc. obstruction Angiogenesesis Impact upon timing & route of administration and types of cells Early Late 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 design is crucial Use of control experiments and blinding Flourish Founder ? CP University of Bonn University of Bonn Disagreement over conduct of operation Disagreement over conduct of operation Duel between 2 surgeons Duel between 2 surgeons Fatal penetrating wound of thorax Fatal penetrating wound of thorax Fatality Following a Controversy Between 2 Medical Men CP JAMA, 1898 Happily the vast majority of medical men of all nationalities are the possessors of well-balanced minds an altogether exceptional occurrence. Clinical Events Cell Therapy Trials Events Variable(no.) P Death Re-MI TVR CHF rehosp Events Variable(no.) P Death Re-MI TVR CHF rehosp Lipinski meta-analysis Events (no.) P Events (no.) P FINCELL + REGENT added (200 pt)* *REPAIR MI deleted TissueMorphology/Histology Microarray gene expression Molecular imaging Hierarchial Endpoints in Trials LV function LV function Remodeling Remodeling Infarct size Infarct size Electro- physiologic milieu Biomarkers Proteomics Cell tracking Mortality/CHF Safety Perfusion/metabolism Beeres and Bax: JACC, 2007 The pivotal role of imaging ****** ****** *Current trials Gersh and Simari: Nature CV Med, 2006 Regional Global * CP Milrinone in Severe CHF 1,088 Patients PROMISE Trial Cumulative Survival (All Pt) Placebo Milrinone Placebo Milrinone Survival probability Milrinone actions intracellular cyclic AMP Improved contractility Packer: NEJM, 1991 Month of study Cumulative Survival (Pt with NYHA Class IV) Survival probability Month of study Mortality 28% Mortality 53% P=0.038 Reproducibily and Accuracy of E Fraction Measurement 110 Consecutive Patients Known or Suspected Heart Disease Malm: JACC, 2004 CP *Mean 250 Difference in EF Between Methods Standard Echo and MRI Difference EF, Echo- MRI (%) Mean EF, Echo & MRI (%) Contrast Echo and MRI Difference EF, Con-MRI (%) Mean EF, Contrast & MRI (%) Baseline image quality Good Poor Clinical Events in Cell Therapy Trials Events Variable(no.) P Death Re-MI TVR CHF rehosp Events Variable(no.) P Death Re-MI TVR CHF rehosp Lipinski meta-analysis Events (no.) P Events (no.) P FINCELL + REGENT added (200 pt) Clinical Events Cell Therapy Trials BMCControlRel RiskP Death 3/446 4/ Re-MI 2/395 5/ TVR51/44533/ CHF rehosp 2/206 5/ BMCControlRel RiskP Death 3/446 4/ Re-MI 2/395 5/ TVR51/44533/ CHF rehosp 2/206 5/ Povsic T 739 patients FINCELL and REGENT added REPAIR subtracted 739 patients FINCELL and REGENT added REPAIR subtracted Outcome 4-6 Months After BM Cell Therapy for AMI Death, re-MI or HF hospitalization* (%) *After hospital discharge Placebo BMC REPAIR trial n=204 Janssens n=67 FINNCELL n=80 REGENT n=120 I have opinions of my ownstrong opinions---but I don,t always agree with them.. CP George W Bush 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 a Randomized Trial CP Improved33% Improved33% Unchanged33% Unchanged33% EscapedMonkey no. 3 EscapedMonkey no. 3 Meta-Analysis of IC Cell Therapy AMI