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20090417 Post-MI Alginate to Prevent Remodelling Mitchell W. Krucoff MD FACC, FAHA, FSCAI Professor of Medicine / Cardiology Duke University Medical Center.

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Presentation on theme: "20090417 Post-MI Alginate to Prevent Remodelling Mitchell W. Krucoff MD FACC, FAHA, FSCAI Professor of Medicine / Cardiology Duke University Medical Center."— Presentation transcript:

1 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

2 Conflicts Research Grants & Consulting: l Ikaria l Medtronic l Abbot Vascular

3 50 YEARS OF MORTALITY REDUCTION IN STEMI : CCU observation: 20-25% : Thrombolytics: 10-15% : Direct PCI:<10% : DTBT< 5% 3 30% 15%

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

5 ELDERLY: GROWING SURVIVOR POPULATION LITTLE KNOWLEDGE, MUCH MORBIDITY 5 Circulation. 2007;115: “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.”

6 POST-MI LV DILATATION 3 DECADES OF SIGNAL 6

7 Relative Risk Normal End-Systolic Volume  SD End-Systolic Volume, ml END-SYSTOLIC VOLUME POST-MI: MORTALITY RISK White et al. Circulation. 1987;76:44

8 Baseline LVIDD and All Cause Mortality Wong M et al. J Am Coll Cardiol. 2002;40:970−975. Months Q1 Q2 Q3 Q4 LVIDD Proportion Alive P <

9 Longitudinal & Circumferential Strain VALIANT Echo substudy: 603 pts CHF 5 days post MI Hung CL et al, J Am Coll Cardiol 2010;56:1812–22

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

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

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

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

14 Injectable Alginate: Seaweed derived polysaccharide n Gelation scaffold in MI zone n Enhance scar thickness n Bioabsorbable material (>6 months) n Pre-clinical: l Porcine 1 week post-MI l Rodent 1 week post-MI n Prevent LV remodelling/dilatation/EDVI n 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 NCT , Available at: Accessed March 19, 2012

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

16 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

17 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)

18 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

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

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

21 Key Inclusion Criteria 3-5 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

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

23 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


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