Results of CRYSTAL AMI: A Pilot Trial Before INFUSE AMI, the Concept and Evolution in Thrombus Management Saihari Sadanandan, MD, FACC, FASE, Dip. CBNC, FSCAI Associate Professor of Clinical Medicine Director, Vascular Interventions Division of Cardiology IU- Health Indiana University Indianapolis

Disclosure - I Speaker Bureau – Sanofi Aventis Bristol Myers Squibb Daichi Sankyo/Lilly Educational Grant from Atrium Medical towards IRB fees to collect data on the case Studies CRYSTAL – AMI slide courtesy – R. Dave, MD

Acute Inferior MI:Primary PCI for STEMI

Primary PCI for STEMI: Predilation and Stent

Distal Embolization during primary PCI for STEMI

5 year outcomes of No-reflow during Primary PCI for STEMI N = 1406 Pts with STEMI undergoing PCI No reflow defined as TIMI <3 flow or TMPG 0-1 after successful PCI Occurred in 30% of pts 7-14 day infarct size 15% vs. 8% p< year mortality 18.2% vs. 9.5%, p < Ndrepepa G, et al.. J Am Coll Cardiol. 2010;55:

Distal embolization and small distal vessel cutoff is neither infrequent nor benign!!!! Occurs in about 15% of patients undergoing PCI for STEMI Associated with larger infarct size, lower LVEF and increased long term Mortality (Eur H J 2002:

N=178 No DE n = 151 (85%) DE n = 27 (15%) P Value LVEF (%)51 ± 942 ± Cardiac enzyme 847 ± ± Mortality15 (9%)12 (44%)< (Eur H J 2002: ) Distal embolization during Primary PCI for STEMI

IMPACT OF MYOCARDIAL BLUSH GRADE

Mortality (%) 6.2% 4.4% 2.0% n=203 n=46 n=434 TMP Grade 3 P=0.05 n=79 5.1% Normal ground-glass appearance of blush. Dye mildly persistent at end of washout. Dye strongly persistent at end of washout. Gone by next injection. Stain present. Blush persists on next injection. No or minimal blush. TMP Grade 2 TMP Grade 1 TMP Grade 0 Adapted from Gibson CM, et al. Circulation. 2000;101: TIMI Myocardial Perfusion (TMP) Grades

/1 100 Cumulative Survival (%) Final Blush Score (patients with final TIMI 3 flow) Blush 1-Year Mortality 3 2 0/1 6.8% 13.2% 18.3% P=0.004 Myocardial Perfusion After Primary PCI is the Strongest Predictor of Mortality independently from IRA reopening

No reflow/ slow flowPoor TIMI flow Poor MBGLarger Infarct size Thrombus Effects of Thrombo embolization during Primary PCI

Meta-Analysis of Various Devices—Mortality Bavry AA, Kumbhani D, Bhatt DL. Eur Heart J. 2008;29: Mechanical thrombectomy Catheter thrombus aspiration Embolic protection P = P = P = 0.69 Mortality, %

FZ TAPAS one year outcome: Myocardial blush grade and death Death/reinfarction P= Svilaas T et al. NEJM 2008; FZ Myocardial blush grade

Burzotta et al. European Heart Journal (2009) 30,

Thrombectomy ± IIb/IIIa inhibitors 7.4% 5.0% 4.8% 3.3% IIb/IIIa inhib - Thrombectomy - IIb/IIIa inhib + Thrombectomy - IIb/IIIa inhib – Thrombectomy + IIb/IIIa inhib + Thrombectomy + 4% 2% 8% 6% MORTALITY P=0.02

Summary of Current Limitations in STEMI PCI No optimal method of thrombus management Once embolization occurs in primary PCI, it is a challenging scenario Higher MACE, Infarct size with poor MBG Aspiration catheters are good, but not uniformly effective. There may be a synergistic effect between thrombectomy and GP-IIBIIIA receptor inhibitors

HOW CAN WE IMPROVE ON THIS FURTHER IN STEMI PCI? COMBINE THE MECHANICAL APPROACH WITH PHARMACOLOGY -(INTRACORONARY DRUG) MINIMIZE BLEEDING & MAXIMIZE DETHROMBOSIS

Meta Analysis of IC Versus IV Abciximab administration of peer reviewed studies (N=2,301) 997 STEMI, 1304 NSTEMI Hansen et al. Journal of Invasive Cardiology Vol 22; 6. June

Clearway Catheter and Intracoronary Abciximab

Localized Drug Delivery via ClearWay for Pharmacological Thrombectomy and Prevention of Distal Embolization

Occlusion Containment Infusion During inflation, drug is being infused through the microporous balloon pores while blood flow is occluded, maximizing drug availability without substantial dilution by the systemic circulation. Containment of the treatment zone provides extended residence time to help local drug bioavailability, concentration and dose Controlled infusion at 1-4 ATM throughout the entire length of the targeted treatment zone provides increased residence time and uptake

IC vs. Clearway Abciximab: The Coctail Study Tamburino, Capodanno, et al. J Cardiovasc Med 2009

Pre ReoPro through ClearWay Post ReoPro through Clearway

Coctail study: Change in Thrombus score P=0.002 N= 20N =21 Tamburino, Capodanno, et al. J Cardiovasc Med 2009

Coctail study: Final TIMI MBG P=0.24 N 20N 21 Tamburino, Capodanno, et al. J Cardiovasc Med 2009

CRYSTAL AMI: Study Design Single center, prospectively randomized IV Abciximab ClearWay™ IC Abciximab R 1:1 PCI as per standard of care, Evaluate MBG, TIMI flow, ST Resolution, LV Function at Discharge 30 day follow up, Echo, Resting Sestamibi STEMI within 6 hours, Heparin, 600mg Clopidogrel (n=50)

CRYSTAL- AMI: Demographics (N=48) Treatment armIC =25IV=23 Male/FemaleM=23, F=2M=18, F=5 Age HTN14 Angina52 CHF10 Prior PCI62 CABG31 DM86 Lipids149 SmokingC=9, F=2C=6, F=0

Manual/Mechanical Extraction catheter use (discretion of operator) (n = 25)(n = 23)

TIMI Flow Comparison (N=48) (n = 25) (n = 23) TIMI Flow 96%

Primary Endpoint: TIMI Myocardial Blush Grade (MBG) >2 (N=48) (n = 25)(n = 23) MBG 92% of IC versus 86% of IV patients

MBG 3 and ST Resolution Rates comparison In Tapas, MBG 3 was only achieved in 45% of patients in extraction arm (identical to IV Abciximab group), but was directly linked to 5 times increase in mortality. IC Abciximab Administration through ClearWay™ has resulted in 72% of patients leaving the lab with a blush score of 3. (n = 25)(n = 23) 72% 80% 52% 70%

Clinical Outcomes (N=48) ICIV Readmissions02 Death01

Conclusions Our understanding of evaluation of surrogate markers which directly correlates to Mortality and Myocardial preservation has improved significantly Improving myocardial preservation also has profound economic impacts: low cost of care, better QOL, less need for ICD Localized superselective drug delivery (GP 2b3a inhibitors and vasodilators) with ClearWay as a stand alone device or when combined with Aspiration devices significantly improves MBG Series of data already promising, INFUSE AMI is underway…