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
20090417
Conflicts
Research Grants & Consulting:
 Ikaria
 Medtronic
 Abbot Vascular
20090417
50 YEARS OF MORTALITY REDUCTION IN STEMI
•
•
•
•
1960-1978:
1978-1998:
1998-2004:
2005-2011:
CCU observation: 20-25%
Thrombolytics:
10-15%
Direct PCI:
<10%
DTBT
< 5%
30%
15%
1980
1990
2000
2010
3
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
4
ELDERLY: GROWING SURVIVOR POPULATION
LITTLE 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
5
POST-MI LV DILATATION
3 DECADES OF SIGNAL
6
END-SYSTOLIC VOLUME POST-MI:
MORTALITY RISK
Relative Risk
15
10
5
Normal
End-Systolic
Volume  SD
End-Systolic Volume, ml
1
50
100
150
200
White et al. Circulation. 1987;76:44
Baseline LVIDD and All Cause Mortality
LVIDD
Proportion Alive
1.0
0.9
Q1
0.8
Q2
Q3
0.7
P < 0.00001
Q4
0.6
0
4
8
Months
12
16
20
24
28
32
Wong M et al. J Am Coll Cardiol. 2002;40:970−975.
20090417
Therapies for Established Post-MI LV dilatation:
Treating Established HF & Arrhythmias

CHF meds:
 Afterload reducers
 Preload reducers
 Diuretics/nitrates

CRT

VADs

Transplantation

Cell therapy
20090417
Biomaterials to Reverse or Prevent LV
Dilatation
Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629
UCSD
20090417
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
20090417
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
20090417
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
20090417
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 subacute 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)
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
“Big MI” criteria
Consent
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
PostDeployment
Coronary angio
24-hr ECG
Echo
Labs incl. CKMB
Randomize
3 second sub-selective IK5001 BCM deployment into IRA
Discharge
Clinical outcomes
Urinalysis
PK sample
POST-DISCHARGE PROTOCOL
Primary Endpoint
1-month
±3d
3 months
± 7d
6 months
± 14d
12 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
ECG
KCCQ
6-min walk
NYHA Class
NT-Pro-BNP
Labs
Healthcare Utilization and
Clinical outcomes
Echo
KCCQ
6-min walk
NYHA Class
Healthcare Utilization and
Clinical outcomes
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
Conclusion: Injectables To Prevent LV Dilatation
Many 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
PRESERVATION I:
•First RCT in human subjects
•Challenges:
• Timely “Big” MI definition
• Optimal imaging F/U
• Assessment of HF prevention
Human studies
20090417
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
20090417