Download - Post-MI Alginate to Prevent Remodelling
20090417
Post-MI Alginate to Prevent Post-MI Alginate to Prevent RemodellingRemodelling
Mitchell W. Krucoff Mitchell W. Krucoff MDMD
FACC, FAHA, FSCAIFACC, FAHA, FSCAI
Professor of Medicine / CardiologyProfessor of Medicine / Cardiology
Duke University Medical CenterDuke University Medical Center
Director, Cardiovascular Devices UnitDirector, Cardiovascular Devices Unit
Duke Clinical Research InstituteDuke Clinical Research Institute
20090417
ConflictsConflicts
Research Grants & Consulting:Research Grants & Consulting: IkariaIkaria MedtronicMedtronic Abbot VascularAbbot Vascular
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%
3
30%
15%
1980 201020001990
STEMI SURVIVORS STILL HAVE BIG MI’S
• Late presentations• Rural presentations • Reperfusion “injury”
– Microvascular obstruction
– Cellular toxicity
4Yellon D et al, N Engl J Med 2007;357:1121-35Yellon D et al, N Engl J Med 2007;357:1121-35
Elderly: growing survivor populationLittle knowledge, much morbidity
5Circulation. 2007;115:2570-2589
“Heart failure and pulmonary edema, complications along this spectrum of adverse occurrences, occur inmore than half of patients 75 years and 65% of patients 85 years of age.”
Post-MI Lv dilatation
3 decades of signal
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50 100 150 200
15
10
5
1
Rela
tive R
isk
Normal End-Systolic
Volume SD End-Systolic Volume, ml
End-Systolic Volume Post-MI:Mortality risk
White et al. Circulation. 1987;76:44
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Baseline LVIDD and All Cause Mortality
Wong M et al. J Am Coll Cardiol. 2002;40:970−975.
Months
1.0
0.9
0.8
0.7
0.6
0 4 8 12 16 20 24 28 32
Q1
Q2
Q3
Q4
LVIDDP
rop
ort
ion
Alive
P < 0.00001
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Therapies for Established Post-MI LV dilatation:Therapies for Established Post-MI LV dilatation:Treating Established HF & ArrhythmiasTreating Established HF & Arrhythmias
CHF meds:CHF meds: Afterload reducersAfterload reducers Preload reducersPreload reducers Diuretics/nitratesDiuretics/nitrates
CRTCRT
VADsVADs
TransplantationTransplantation
Cell therapyCell therapy
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Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629UCSD
Biomaterials to Reverse or Prevent LV DilatationBiomaterials to Reverse or Prevent LV Dilatation
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Biomaterials For MI Treatment:Biomaterials For MI Treatment:Post-MI LV remodellingPost-MI LV remodelling
LV restraintsLV restraints
Epicardial patchesEpicardial patches
Injectable therapiesInjectable therapies
Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629
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Injectable BiomaterialsInjectable Biomaterials
Mechanisms:Mechanisms: Cell delivery vehiclesCell delivery vehicles Bio-degradable: Bio-degradable:
material degradation material degradation allowing for cell allowing for cell infiltrationinfiltration
Inherent bioactivityInherent bioactivity
Gelation with Gelation with percutaneous deliverypercutaneous delivery:: AlginateAlginate Myocardial matrix Myocardial matrix
Outcome objectives:Outcome objectives: Prevent remodellingPrevent remodelling Improve EfxImprove Efx Reduce MI sizeReduce MI size Increase Increase
neovascularizationneovascularization
Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629
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Injectable Alginate: Injectable Alginate: Seaweed derived polysaccharideSeaweed derived polysaccharide
Gelation scaffold in MI zoneGelation scaffold in MI zone
Enhance scar thicknessEnhance scar thickness
Bioabsorbable material (>6 months)Bioabsorbable material (>6 months)
Pre-clinical:Pre-clinical: Porcine 1 week post-MIPorcine 1 week post-MI Rodent 1 week post-MIRodent 1 week post-MI
Prevent LV remodelling/dilatation/EDVIPrevent LV remodelling/dilatation/EDVI
FIM Clinical IRA injection in acute STEMIFIM Clinical IRA injection in acute STEMI
Mukherjee R et al Ann Thorac Surg 2008;86:1268 –77Landa 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
Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute
Myocardial Infarction
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.
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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)
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
IN-HOSPITAL PROTOCOL
Successful Index PCI For STEMI
Day 0
Screening
ConsentSPECT/MRIEcho, ECG6 min walk
KCCQNYHA classNT-Pro-BNP
Labs, UA
DeploymentProcedure(Index visit)
Day 2-5
Coronary angioRandomization
24-hr ECGCKMB
PK sample
Post-Deployment
Coronary angio24-hr ECG
EchoLabs incl. CKMB
Discharge
Clinical outcomesUrinalysisPK sample
Randomize3 second sub-selective IK5001 BCM deployment into IRA
“Big MI” criteriaConsent
POST-DISCHARGE PROTOCOL
1-month± 3 d
EchoECG
KCCQ6-min walk
NYHA ClassNT-Pro-BNP
LabsPK Sample
3 months± 7d
6 months± 14d
EchoECG
KCCQ6-min walk
NYHA ClassNT-Pro-BNP
LabsPK Sample
EchoECG
KCCQ6-min walk
NYHA ClassNT-Pro-BNP
LabsHealthcare Utilization and
Clinical outcomes
12 months± 14d
EchoKCCQ
6-min walkNYHA Class
Healthcare Utilization and Clinical outcomes
Primary Endpoint
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
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Conclusion: Conclusion: Injectables To Prevent LV DilatationInjectables To Prevent LV Dilatation Many challenges remainMany challenges remain
Stiffness vs. elasticityStiffness vs. elasticity
Optimal degradation rateOptimal degradation rate
Inflammatory responseInflammatory response
Stand-alone vs. Stand-alone vs. cell/compound loadedcell/compound loaded
Timing & modality of Timing & modality of administrationadministration
Endpoint selection:Endpoint selection: ImagingImaging Ventricular twist modelsVentricular twist models Electro-mechanical modelsElectro-mechanical models
Human studiesHuman studies
PRESERVATION I:•First RCT in human subjects•Challenges:
• Timely “Big” MI definition• Optimal imaging F/U• Assessment of HF prevention
20090417
Post-MI Alginate to Prevent Post-MI Alginate to Prevent RemodellingRemodelling
Mitchell W. Krucoff Mitchell W. Krucoff MDMD
FACC, FAHA, FSCAIFACC, FAHA, FSCAI
Professor of Medicine / CardiologyProfessor of Medicine / Cardiology
Duke University Medical CenterDuke University Medical Center
Director, Cardiovascular Devices UnitDirector, Cardiovascular Devices Unit
Duke Clinical Research InstituteDuke Clinical Research Institute