Infused AMI: Intracoronary IIb/IIIa Infusion for STEMI Brij Maini MD, FACC Chair Structural Heart Program Co-Chair Cardiovascular Research Pinnacle Health System, Harrisburg, PA

Brijeshwar S. Maini, MD DISCLOSURES Consulting Fees Atrium Medical Corporation, Abiomed, Inc Grants/Contracted Research Abbott Vascular, Abiomed, Inc., AGA Medical Corporation, Cordis, a Johnson & Johnson company, ev3, Inc., InfraReDx, Inc, Medtronic CardioVascular, Inc. Honoraria Abiomed, Inc., Abbott Vascular, ev3, Inc., Medtronic CardioVascular, Inc. I intend to reference unlabeled/unapproved uses of drugs or devices in my presentation. I intend to reference unapproved devices in clinical trials such as Impella, LAA devices such as Watchman, thoracic and abdominal stentgrafts in trials including endostapling devices.

Coronary Thrombosis in acute coronary syndrome Plaque rupture 55-60% Plaque erosion 30-35% Calcified nodule 2-7% IMAGE COURTESY: Virmani, R. et al. J Am Coll Cardiol 2006

IWMI stent Distal Embolization Rxed with aspiration only

How Big Is the Clot?

Re-perfusing the capillaries restores blood flow to the Reperfusion of the Capillaries After acute myocardial infarction (AMI), the immediate therapeutic goal is to establish patency of the infarcted related artery. The successful restoration of epicardial coronary artery patency, however, does not necessarily translate into improved tissue perfusion. Copyright CM Gibson Copyright CM Gibson Re-perfusing the capillaries restores blood flow to the muscle bed preventing damage to the heart muscle.

Macroscopic distal embolization Patients with distal embolization had lower incidence of ST resolution, poor blush grades, larger infarcts, and significantly higher long term mortality. N=178. Henriques, et al. Eur Heart J, 2002; 23: 1112–1117. 7

Angiography is a Poor Tool for Thrombus Detection Angiography underestimates the presence of thrombus, particularly in the setting of total occlusions. A recent study of Lower extremity patients with <6 months of symptoms showed that via IVUS, thrombus was present 94% of the time, whereas under angiography, it was only present in 11% of patients. Shammas et al. Prevalence of thrombus in patients with a recent history of claudication or rest limb pain: An intravascular assessment. New Cardiovascular Horizions Sept., 2007.

Mortality is three to four times higher In patients with MBG 0-2 Tissue Level Perfusion In CADILLAC Trial N=1,301 patients Mortality is three to four times higher In patients with MBG 0-2 even with TIMI3 Costantini, C. O. And GW Stone et al. J Am Coll Cardiol 2004;44:305-312

Chao-Wei Hwang, MD, PhD, MIT (Circulation. 2005;111:1619-1626. Thrombus apposed on stents creates large variations in drug uptake, making it highly variable, unless the clot can be adequately controlled or removed.

Available now online from European Heart Journal http://eurheartj.oxfordjournals.org/cgi/content/full/ehp348 11

Thrombectomy ± IIb/IIIa inhibitors 4% 2% 8% 6% MORTALITY 7.4% P=0.02 5.0% 4.8% 3.3% IIb/IIIa inhib - Thrombectomy - IIb/IIIa inhib + Thrombectomy - IIb/IIIa inhib – Thrombectomy + IIb/IIIa inhib + Thrombectomy + 12

PRE-PCI SUBGROUPS Risk of death DIABETES IIb/IIIa INHIBITORS TIME TO REPERFUSION INFARCT RELATED ARTERY TIMI FLOW Thrombectomy better Standard PCI better 13

CONCLUSIONS The present pooled analysis of individual patient data from 11 STEMI trials shows that: - Thrombectomy (in particular when performed by manual thrombectomy catheters) improves survival - Thrombectomy and IIb/IIIa inhibitors may synergistically improve the clinical outcome 14

Impact of Thrombus Burden 798 STEMI patients treated with DES Small Thrombus Large Thrombus Final TIMI 3 94.9% 83.6%* TMPG-3 53.2% 35.4%* No-reflow 0.5% 4.0%* Distal embolization 3.5% 17.3%* P<0.001 risk stent thrombosis Sianos G. JACC 2007;50:573-83

TAPAS Study Patients have a 5 times higher death rate if left with a Blush Score of 0/1 compared to a Blush Score of 3. 14.1% % of Pts. 8.8% 5.2% 30 day data 4.2% 2.9% 1% Svilaas, et al, NEJM, Feb. 2008

TAPAS one year outcome: Myocardial blush grade and death at 1 year P =death/reinfarction a 0.001 Both associations p=0.001 Svilaas T et al. NEJM 2008;358-557 - FZ 2008-9 Myocardial blush grade FZ 2008-12 17 17

In Vitro Disaggregation Data 100 X IV dose At 100 times the usual systemic IV dose GP IIb/IIIa inhibitor disaggregates virtually all clot in vitro. Clear Way delivers close to 600 times systemic concentration 100 10 X IV dose 90 80 70 60 IV dose 50 Disaggregation Potency (%) 40 30 20 10 0.1875 µg/ml 0.375 µg/ml 3.76 µg/ml Moser M, et al. J Cardiovasc Pharmacology 41:586-592, 2003.

Bolus only strategy may reduce cost to facility There was a cost difference, too, with the bolus-only strategy reducing drug costs by more than 50%, from an average of $706 per case to $325 per case. In addition, the GPI bolus-only group had a higher incidence of ambulatory PCI, or same-day discharge after the procedure (13.1% vs. 3.2%, P<0.01), and a reduced length of hospitalization (1.1 days vs. 1.6 days, P<0.01). Similar results with Epifibitide (Integrilin) Strategy Kini AS, Chen VHT, Krishnan P, et al. Bolus-only versus bolus + infusion of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention. Am Heart J 2008

(20% to 54% along treatment zone) Bolus only ReoPro Infusion with ClearWay RX measured by OCT in NSTEMI- no extraction COCKTAIL Study A B B A Area 1.91 mm2 20% Improvement in MLD (20% to 54% along treatment zone) A B B A Area 2.30 mm2

Change in Lumen Diameter Post ClearWay™ RX Infusion of ReoPro Pre administration Area 3.34 Area 3.38 Area 1.91 Area 1.28 Post administration Area 4.45 Area 4.70 Area 2.30 Area 2.51

No residual thrombus post infusion Final result after stenting No residual thrombus post infusion

COCTAIL Study Thrombus score change 35,5% P<0.01 3,7% RHR N 19 N 20

CRYSTAL AMI- Abciximab administration IC (through ClearWay) vs IV in STEMI

Ongoing Coronary ClearWay Clinical Trials Title:  INFUSE AMI Principal Investigator(s):  Gregg Stone, MD – Columbia Presbyterian (New York, NY) and CO-PI Michael Gibson, MD – Beth Israel Deaconess Medical Center (Boston, MA) Description:  A four-Arm, prospective, randomized, multicenter, single-blind evaluation of intracoronary (IC) Abciximab infusion via ClearWay™ RX and aspiration thrombectomy in patients undergoing percutaneous coronary intervention for anterior ST-segment elevation myocardial infarction (STEMI). Primary Endpoint:  Reduced infarct size at 30 days measured by cardiac MRI Title:  COCTAIL Study Principal Investigator:  Francesco Prati, MD – Rome Heart Center (Rome, Italy) Description:  A prospective, multi-center study examining the effects of localized intracoronary infusion of abciximab through the ClearWay RX catheter compared to localized infusion through a guide catheter.  Primary Endpoint:  Reduction of thrombus burden measured by OCT Title:  CRYSTAL MI Principal Investigator:  Rajesh Dave, MD – Harrisburg Hospital (Harrisburg, PA) Description: A randomized, single center, open-label evaluation of local intracoronary (IC) delivery of Abciximab via the ClearWay™ RX catheter versus standard intravenous (IV) delivery of Abciximab in patients with ST-segment elevation MI (STEMI). Primary Endpoints:  Improvement in Myocardial Blush Grade (MBG), ST resolution, and Ejection Fraction Title: IC ClearLY – Principal Investigators:  Gennaro Sardella, MD, - Policlinico Umberto (Rome, Italy) and Michael Gibson, MD – Beth Israel Deaconess Medical Center (Boston, MA) Description:  A randomized, open-label, multicenter, trial to evaluate the effect of an intracoronary (IC) bolus dose of Abciximab delivered using the ClearWay™RX catheter versus an intravenous (IV) bolus of Abciximab for ST-segment elevation myocardial infarction (STEMI) with angiographically visible thrombus.  Primary Endpoint:  Reduction of infarct size measured by cardiac MRI Title: ClearWay RX Registry Principal Investigator:  Ron Waksman, MD - Washington Hospital Center (Washington, DC) Description:  The primary goal of this registry is to collect clinical data regarding the use of the ClearWay™ RX Local Therapeutic Infusion Catheter for all coronary indications

IC infusion- is it a necessary tool in the lab May reduce time to reperfusion by targeting thrombus burden at site of lesion in the most efficient manner May reduce no reflow phenomenon May address residual thrombus to prevent SAT May reduce cost with bolus only strategy

Intact, Internal Elastic Lamina How is ClearWay different from other drug delivery balloons of the past? No barrow trauma No wire exchange needed Intact, Internal Elastic Lamina Virmani