1 / 26

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

Andreas M. Zeiher, MD Dept. of Internal Medicine III University of Frankfurt Germany. “Progenitor Cell Therapy in AMI After Meta-Analyses Results ? Pro“. Disclosure information: Guidant (research support) t2cure (co-founder, advisor). The Heart is a Regenerating Organ

thisbe
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Andreas M. Zeiher, MD Dept. of Internal Medicine III University of Frankfurt Germany “Progenitor Cell Therapy in AMI After Meta-Analyses Results ? Pro“ Disclosure information: Guidant (research support) t2cure (co-founder, advisor)

  2. The Heart is a Regenerating Organ Undisputable Evidence from DNA Integration of C-14 – generated during nuclear bomb testing during cold war - Bergmann O et al., Science 2009; 324:98-102

  3. Cells for functional cardiac repair Embyronic-like stem cells (iPS) 4 genes: Oct4, Klf4, Sox2, myc somatic cells (skin fibroblasts) Cardiac stem cells Modified from Dimmeler et al, JCI 2005

  4. Metaanalysis of randomized and cohort studies of progenitor cell therapy in ischemic heart disease Vascularization  Apoptosis  N = 976; overall treatment effect + 3.7 percentage points increase in LV-EF ( p < 0.001 ) Paracrine factors Cardiac Regeneration Abdel-Latif, Arch Intern Med 2007; 167:989 Cell Therapy in Ischemic Heart Failure: therapeutic targets Adverse LV Remodeling  Acute Myocardial Infarction Chronic Heart Failure infarct expansion chronic LV- dilatation

  5. The patient population at risk post-AMI Effects of cell therapy in patients at risk Derivation of the clinical benefit Cell Therapy for Ischemic Heart Failure

  6. LV contractile recovery within 1 week after successful reperfusion determines clinical outcome in STEMI There is no linear correlation between mortality and ejection fraction after AMI ! Volpi et al., Circulation 1993; 88: 416-429

  7. VALIANT Valsartan in Acute Myocardial Infarction Trial 23% in 1 year 30 % in 2 years • 14703 patients • STEMI • 0.5 - 10 days • EF < 40% • Killlip I-III • Diuretics 60%, • Beta-Blocker 71% Probability of cardiac death, re-MI rehospitalisation for heart failure NEJM 2003, 349: 1893-1906

  8. DefibrillatorIN AcuteMyocardialInfarctionTrial (DINAMIT) 0.25 0.20 ICD Control p=0.66 0.15 Cumulative Risk 0.10 0.05 Number at Risk 0.0 ICD 315 299 258 211 172 123 82 25 Cntrl 318 305 272 217 172 124 79 31 0 6 12 18 24 30 36 42 48 Months from Randomization Cumulative risk of death from any cause Need for additive treatment ! STEMI 6- 40 days EF < 35% Hohnloser at al., N Engl J Med 2004

  9. The patient population at risk post-AMI Effects of cell therapy in patients at risk Cell Therapy for Ischemic Heart Failure

  10. Enhanced contractile recovery by BMC is confined to patients with failed initial recovery p for interaction = 0.020 10 p = 0.002 p = 0.81 8 6 Absolute change in global LVEF (%) 4 2 3.70.7 4.00.6 2.51.1 7.51.1 0 Placebo Placebo BMC BMC n = 52 41 40 54 Baseline LVEF by QLVA EF below median ( 48.9 %) EF above median (> 48.9 %) Schächinger et al., N Engl J Med 2006

  11. REGENT FINNCELL trial < median > median < median p = 0.04 30 BMC 25 Placebo 60 20 p=0.007 36 50 15 31 40 Change in EF (%) 10 30 5 0 20 -5 10 0 6 months 0 0 6 months 6 months Courtesy of H. Huikuri, European Heart Journal, 2008 Enhanced contractile recovery by BMC in patients with failed initial recovery – results of recent controlled trials REGENT trial Controls N=20 BMC N=46 80 80 p=0.01 p=0.73 70 70 37 40 39 39 60 60 50 50 40 40 30 30 20 20 10 10 Courtesy of M Tendera, ESC Congress Munich, 9/2008

  12. Adverse remodeling is confined to patients with failed initial recovery of EF and abrogated by BMC therapy EF > median EF < median Change of endsystolic volumes over time (MRI) p = 0.01 140 p = 0.06 120 p = 0.7 100 p = 0.9 p = 0.7 p = 0.5 BMC 80 Endsystolic volume (ml) 60 Placebo 40 20 0 Baseline 4 months 12 months Baseline 4 months 12 months Baseline EF: 56 + 2.3 % Baseline EF: 39 + 1.9 % Dill et al., AHJ 2009

  13. Reperfusion + pharmac. Rx BMC no therapy Placebo Intracoronary BMC Administration Profoundly Modifies LV Remodeling Interaction between LV ejection fraction and endsystolic volume 10 8 6 4 Change in EF (%) 2 0 - 2 - 4 -10 -5 0 5 10 15 20 EF  48.9% p = 0.007 Change in endsystolic volume (ml)

  14. The patient population at risk post-AMI Effects of cell therapy in patients at risk Derivation of the clinical benefit Cell Therapy for Ischemic Heart Failure

  15. Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit ? acute myocardialinfarction  • Ejectionfraction • End-systolicvolume Left Ventricular Remodeling ? • Mortality • Ischemicevents • Rehospitalization forheartfailure Cardiovascular Events … reduce adverse cardiovascular events Therapies preventing adverse remodelling… ACEI , ARB, ß-Blocker, Aldosteron-Ant.

  16. p<0.005 13 / 217 3 / 254 TOTAL N=471 Death, Re-MI, Heart Failure at 4-6 Monthsin randomized, (placebo)-controlled BMC trials Placebo 8 BMC 6 4 Death, re-MI, hospitalisation for heart failure * (%) 2 0 Janssens REPAIR FINNCELL REGENT N=204 N=67 N=80 N=120 * after hospital discharge

  17. BMC therapy is associated with improved clinical outcome at 2 years - Death, MI, Rehospitalization forheartfailure - 100 BMC 90 Placebo 80 Event-freesurvival (%) (death, myocardialinfarction, rehospitalization f. heartfailure) p = 0.009 70 (log rank) 60 0 days 0 100 200 300 400 500 600 700 Placebo 103 93 90 86 86 BMC 101 99 98 97 95 # exposed to risk

  18. Cell Therapy for Ischemic Heart Failure Do potential effects persist ?

  19. Sustained benefit after 2 years – MRI subgroup analysis - P = 0.009 # P = 0.98 # P = 0.16 # 55 190 170 50 Absolute enddiastolic volume [ml]; (mean ± SEM) Absolute LV ejection fraction [%]; (mean ± SEM) 150 50 Absolute endsystolic volume [ml]; (mean ± SEM) 45 130 110 40 40 90 35 70 30 0 0 20 P = 0.009 P = 0.049 * 10 110 16 14 0 100 12 Placebo Wall thickening of infarcted segments [%]; (mean ± SEM) Relative infarct size [%]; (mean ± SEM) 90 10 BMC 80 8 6 70 4 60 2 0 0 ESV EDV LVEF N = 58 patients; ANCOVA model # adjusted for baseline value (LVA) * Adjusted for baseline value (MRI) Infarct Size Infarct Wall Thickening A.Rolf, Bad Nauheim

  20. Improvement of MRI - determined LVEF is sustained 5 years after progenitor cell therapy 90 p = 0.03 80 70 60 50 40 30 p < 0.001 p < 0.001 p = 0.008 p = 0.04 MRI LVEF (%) Baseline 4 months 1 year 2 years 5 years Mean ± SD N 46 ± 10 N = 31 52 ± 11 N = 30 57 ± 13 N = 30 62 ± 11 N = 28 59 ± 8 N = 31

  21. Persistently low NT-pro BNP serum levels at 5 years indicate absence of adverse LV remodeling p = 0.97 p = 0.03 p < 0.001 p = 0.20 p = 0.97 2.500 1.000 NT-proBNP serum levels [pg/ml] 500 0 Baseline 4 months 1 year 2 years 5 years Mean ± SD N 917 ± 920 N = 39 283 ± 283 N = 34 285 ± 346 N = 25 304 ± 602 N = 19 213 ± 308 N = 39

  22. abrogates adverse left ventricular remodeling in patients at risk - failure of initial contractile recovery after reperfusion - persistently elevated NT-proBNP acutely demonstrates a cell bioactivity - contractile recovery response relationship prevents adverse remodelling over 5 years is associated with improved clinical outcome at 2 years Bone Marrow Cell Therapy for Post-Infarction Heart Failure Intracoronary administration of BMC … is associated with enhanced LV contractile recovery and improved coronary flow reserve

  23. a large-scale clinical endpoint trial is warranted to document the effects on mortality and morbidity Conclusion In patients with acute post-infarction heart failure despite successful reperfusion therapy

  24. Stefanie Dimmeler Birgit Assmus Volker Schächinger www.REPAIR-AMI.org

  25. Study Centers and Core Facilities  Steering Committee  Echo Core Lab  Doppler Core Lab  MRI Core Lab  Angio Core Lab H. Braun  Coordinating Center T. Tonn / N. Krzossok/ E. Seifried  Cell Processing Center T. Bonzel / W. Kasper  Safety Committee D. Mathey / T. Tübler C. Hoffmann / M. Farr /D. Horstkotte C. Hansen / J. Neuzner Hamburg A. Cuneo / U. Tebbe J. Yu / B. Lauer A. Germing / A. Mügge S. Erbs / R. Hambrecht Bad Oeynhausen A. Elsässer / M. Stanisch /T. Dill / Ch. Hamm Lippe Kassel W. Haberbosch Bochum Bad Berka Bad Nauheim Leipzig J. Haase H. Hölschermann /H. Tillmanns Giessen Suhl V. Schächinger / B. Assmus / S. Dimmeler A. M. Zeiher (PI) Mainz S. Genth-Zotz /T. Münzel Frankfurt(2 centers) Ludwigshafen Homburg/ Saar Mannheim B. Mark / J. Senges G. Nickenig / N. Werner /M. Böhm T. Süselbeck / M. Brückmann /K. Haase Zürich R. Corti / T. Lüscher 400 km www.REPAIR-AMI.org

  26. Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main Clinician Scientists: J. Honold, R. Lehmann U. Fischer-Rasokat S. Fichtlscherer F. Seeger, C.Kissel K.Spyridopoulos N. Bellera Gotarda Experimental Studies C. Urbich, A. Kühbacher M. Potente A. Aicher E. Chavakis, G. Carmona L. Rössig, D. Scharner M. Koyanagi, M. Iwasaki Th. Ziebart, C. Yoon & technical help (Andrea, Nicole,Ariane, Marion, Tino) Dept. of Hematology H. Martin / W. Hofmann D. Hoelzer Kerckhoff Clinic C. Hamm / T. Dill Dept. of Radiology N. Abolmaali / J. Schmitt T. Vogl Red Cross Frankfurt T. Tonn / Seifried T. Brühl, M. Vasa,K. Sasaki, C. Badorff, C. Heeschen

More Related