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Post-MI Alginate to Prevent Remodelling

Post-MI Alginate to Prevent Remodelling. Mitchell W. Krucoff MD FACC, FAHA, FSCAI Professor of Medicine / Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute. Conflicts. Research Grants & Consulting: Ikaria Medtronic

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Post-MI Alginate to Prevent Remodelling

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  1. Post-MI Alginate to Prevent Remodelling Mitchell W. KrucoffMD FACC, FAHA, FSCAI Professor of Medicine / Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute

  2. Conflicts Research Grants & Consulting: • Ikaria • Medtronic • Abbot Vascular

  3. 50 years of Mortality reduction in stemi • 1960-1978: CCU observation: 20-25% • 1978-1998: Thrombolytics: 10-15% • 1998-2004: Direct PCI: <10% • 2005-2011: DTBT < 5% 30% 15% 1980 1990 2000 2010

  4. STEMI SURVIVORS STILL HAVE BIG MI’S • Late presentations • Rural presentations • Reperfusion “injury” • Microvascular obstruction • Cellular toxicity Yellon D et al, N Engl J Med 2007;357:1121-35

  5. Elderly: growing survivor populationLittle knowledge, much morbidity “Heart failure and pulmonary edema, complications along this spectrum of adverse occurrences, occur in more than half of patients 75 years and 65% of patients 85 years of age.” Circulation. 2007;115:2570-2589

  6. Post-MI Lv dilatation 3 decades of signal

  7. 15 10 5 1 End-Systolic Volume Post-MI:Mortality risk Relative Risk Normal End-Systolic Volume  SD End-Systolic Volume, ml 50 100 150 200 White et al. Circulation. 1987;76:44

  8. LVIDD 1.0 0.9 Q1 0.8 Proportion Alive Q2 Q3 0.7 P < 0.00001 Q4 0.6 0 4 8 12 16 20 24 28 32 Baseline LVIDD and All Cause Mortality Months Wong M et al. J Am Coll Cardiol. 2002;40:970−975.

  9. Therapies for Established Post-MI LV dilatation:Treating Established HF & Arrhythmias • CHF meds: • Afterload reducers • Preload reducers • Diuretics/nitrates • CRT • VADs • Transplantation • Cell therapy

  10. Biomaterials to Reverse or Prevent LV Dilatation Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629 UCSD

  11. Biomaterials For MI Treatment:Post-MI LV remodelling • LV restraints • Epicardial patches • Injectable therapies Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629

  12. Injectable Biomaterials • Mechanisms: • Cell delivery vehicles • Bio-degradable: material degradation allowing for cell infiltration • Inherent bioactivity • Gelation with percutaneous delivery: • Alginate • Myocardial matrix • Outcome objectives: • Prevent remodelling • Improve Efx • Reduce MI size • Increase neovascularization Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629

  13. Injectable Alginate: Seaweed derived polysaccharide • Gelation scaffold in MI zone • Enhance scar thickness • Bioabsorbable material (>6 months) • Pre-clinical: • Porcine 1 week post-MI • Rodent 1 week post-MI • Prevent LV remodelling/dilatation/EDVI • FIM Clinical IRA injection in acute STEMI Mukherjee R et al Ann Thorac Surg 2008;86:1268 –77 Landa N et al Circulation 2008;117:1388 –96 BioLineRx L. Safety and Feasibility of the Injectable BL-1040 Implant. Study NCT00557531, 2009. Available at: http:// www.ClinicalTrials.gov. Accessed March 19, 2012

  14. Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction

  15. PRESERVATION 1: A Study of IK5001 Bioabsorbable Cardiac Matrix (BCM) After Large STEMI Mechanistic assumption: Calcium concentration in sub-acute MI zone will activate alginate cross-linking sufficient to provide structural resistance to post-MI LV remodelling over 6 months prior to bio-absorption Clinical Hypothesis: Sub-selective infusion of IK5001 BCM will prevent LV remodelling and associated functional debility and heart failure following “big” MIs.

  16. PRESERVATION I: Operations Study Co-PIs: Sunil Rao MD, Uwe Zeimer MD Study Chair: Mitchell Krucoff MD DSMC Chair: E. Magnus Ohman MD Study Sponsor: Ikaria Data Center: Duke Clinical Research Institute (DCRI) Echo Core Lab: DCRI (Pam Douglas MD) Angio Core Lab: Perfuse (Michael Gibson MD)

  17. PRESERVATION I: Design Multicenter, 2:1 randomized, double blind, placebo‑controlled 306 “Big MI” STEMI patients 60 sites: EU, Australia, Canada, Middle East, USA Dedicated 3-7 day post-MI deployment procedure: 4 cc sub-selective IRA-IC IK5001 BCM infusion over 30 seconds Mechanistic primary endpoint: LV End-diastolic dimension index by 3-D echo Secondary endpoint: new onset CHF

  18. IN-HOSPITAL PROTOCOL “Big MI” criteria Consent Successful Index PCI For STEMI Day 0 Deployment Procedure (Index visit) Day 2-5 Screening Post- Deployment Discharge Consent SPECT/MRI Echo, ECG 6 min walk KCCQ NYHA class NT-Pro-BNP Labs, UA Coronary angio Randomization 24-hr ECG CKMBPK sample Coronary angio 24-hr ECG Echo Labs incl. CKMB Clinical outcomes Urinalysis PK sample Randomize 3 second sub-selective IK5001 BCM deployment into IRA

  19. POST-DISCHARGE PROTOCOL Primary Endpoint 1-month ± 3 d 12 months ± 14d 3 months ± 7d 6 months ± 14d Echo ECG KCCQ 6-min walk NYHA Class NT-Pro-BNP Labs PK Sample Echo ECG KCCQ 6-min walk NYHA Class NT-Pro-BNP Labs PK Sample Echo KCCQ 6-min walk NYHA Class Healthcare Utilization and Clinical outcomes Echo ECG KCCQ 6-min walk NYHA Class NT-Pro-BNP Labs Healthcare Utilization and Clinical outcomes

  20. Key Inclusion Criteria3-5 day “Big” MI after Successful Acute STEMI PCI • “Big” MI defined as: • Peak cardiac enzyme value within 48 hours of symptom onset as follows: • Creatine kinase MB fraction (CK-MB) > 30x the upper limit of normal OR • Troponin I > 200x upper limit of normal OR • Troponin T > 60x the upper limit of normal • AND at least 1 of the following 3 criteria: • Delayed presentation with PCI > 6 hours from onset of symptoms • Significant new Q waves in ≥ 2 anterior leads or anterior ST segment elevation of at least 3 mm persistent at 24 hours after PCI • New onset of congestive heart failure (CHF) (Killip class 3-4) or cardiogenic shock persistent at 24 hours after PCI • AND at least 1 of the following 2 criteria: • MI ≥ 20% by Single Photon Emission Computed Tomography scan (SPECT) or cardiac MRI with defect in the appropriate distribution • Ejection fraction ≤ 35% at baseline imaging assessment with wall motion abnormality in the appropriate distribution

  21. Conclusion: Injectables To Prevent LV DilatationMany challenges remain • Stiffness vs. elasticity • Optimal degradation rate • Inflammatory response • Stand-alone vs. cell/compound loaded • Timing & modality of administration • Endpoint selection: • Imaging • Ventricular twist models • Electro-mechanical models • Human studies • PRESERVATION I: • First RCT in human subjects • Challenges: • Timely “Big” MI definition • Optimal imaging F/U • Assessment of HF prevention

  22. Post-MI Alginate to Prevent Remodelling Mitchell W. KrucoffMD FACC, FAHA, FSCAI Professor of Medicine / Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute

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