The Current Strategies in Treatment of No Reflow Ron waksman, md Gabriel maluenda, md, washington Hospital cENTER, wASHINGTON dc

Faculty Disclosures Ron Waksman, MD Gabriel maluenda, MD Consultant : Biotronik, Medtronic, Boston Scientific. Abbott Vascular Speaker Biotronik BSC, Medtronic, Abbott Vascular Research Grants: Biotronik, Medtronic, Boston Scientific, GSK, Medicine Company, Abbott Vascular, Atrium Gabriel maluenda, MD Nothing to Disclose

definition Inability to reperfusemyocardium despite removal of large epicardial coronary artery occlusion, manifested by reduced myocardial flow after opening an occluded artery with the presence of a patent epicardial coronary artery Pathophysiology based on microvasculardamage –contracture and neutrophil plugs

Clinical implications It is associated with poor prognosis limiting the benefit of primary PCI: higher rate of post infarction complications: arrhythmias, pericardial effusion, cardiac tamponade, early congestive heart failure adverse ventricular remodeling late repeat hospital stays for heart failure higher mortality

Adverse prognosis of no reflow Niccoli G et al, JACC 2009;54:281-92

pathophysiology Endothelial swelling: diffuse and focal blebs Neutrophils Plugs Disruption of endothelium Endothelial gaps Loss of fluid from vessels Increased viscosity Rouleaux formation Platelet plugs Rarely compression of capillaries between swollen myocytes

Reffelmannand Kloner. Heart 2002;87:162-168

Extensive RBC extravasation and neutrophil infiltration, swollen myocytes

MECHANISMS FOR NO REFLOW Four interacting mechanisms (distal embolization, ischemia-related injury, reperfusion related injury, and individual susceptibility to microvascular injury) are responsible for no-reflow phenomenon. The individual contribution of these mechanisms to the pathogenesis of no-reflow is likely to vary in different patients. Niccoli G et al, JACC 2009;54:281-92

Patients with no-reflow seen by MRI have reduced event-free survival compared to those without no-reflow Adapted from Wu KC et al. Circulation 1998;97:768

Sustained vs reversible nr No-reflow detected 24 h after successful PCI spontaneously improves over time in approximately 50% of patients (*) Sustained no-reflow: anatomical irreversible changes of coronary microcirculation → unfavorable LV remodeling Reversible no-reflow: result of functional and, thus reversible, changes of microcirculation “Reperfusion” NR versus “Interventional” NR GaliutoL et al. Heart 2003;89:731–7

Effects of Duration of Preceeding Ischemia on No Reflow >20% Primary PCI <2% Elective PCI

Pathophysiology and therapeutic implications Niccoli G et al, JACC 2009;54:281-92

Reperfusion No Reflow: Acute MI

Interventional No Reflow: Elective Setting

Rezkalla SH, CCI 2008; 72:950–957

Medical Treatment Options Adenosine: decreases arteriolar resistance, ATP- sensitive K+ Channels, inhibit neutrophilmigation/ superoxide generation/endothelin Nitroprusside/NTG (nitric oxide donors) Nicorandil: KATP opener/nitrates/?block mitochondrial permeability transition pore CCB: HR & BP effects, vasospasm Glycoprotein IIb/IIIa inhibitors

Nicardipine and No-Reflow Dihydropyridine CCB Similar to nifedipine but more selective for cerebral and coronary blood vessels No intrinsic decrease in myocardial contractility Huang et al CCI 2006: retrospective study 72 pts, mean 460 mcg Restoration TIMI-3 flow in 71/72 pts No adverse hemodynamic effects

Reducing No-Reflow/Low Reflow could have the following benefits: Enhance removal of necrotic debris and speed healing Reduce remodeling by improved healing Enhance delivery of drugs (such as antiarrhythmic drugs) to injured areas In my opinion, it will probably not reduce infarct size Allow for viable vessels that can serve as a source of collaterals

Main Randomized Trials for the Management of No-Reflow From Niccoli G et al., JACC 2009;54:281

Aim: to assess the feasibility and safety aspects of the perfusion catheter and its claim to improve no-reflow phenomena after PCI Population: 30 patients with ACS who developed no-reflow during subsequent PCI Primary end-point: normal TIMI 3 flow with myocardial blush grade (MBG) ≥2 or an increase in TIMI flow by ≥2 grades with a MBG ≥2 after intracoronary drug infusion via the CW catheter Maluenda G et al, J IntervenCardiol 2010;23:109–113

TIMI flow Percentage

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

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:  GennaroSardella, 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

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

management and vasodilators for no reflow via the perfusion CW Intracoronary Drug Infusion Via Perfusion Coronary Catheter to Improve Thrombus Burden and/or No-Reflow Phenomenon Results from the ClearWay Multicenter Registry Data collected for 15 centers who used the ClearWay catheter Baseline Post-CW use End of PCI p TIMI flow 76 (54.7) 11 (7.9) 4 (2.9) < 0.001 1 17 (12.2) 12 (8.6) 1 (0.7) 2 30 (21.6) 50 (36.0) 3 16 (11.5) 66 (47.5) 122 (87.8) Visible thrombus 120 (86.3) 58 (41.7) 10 (7.2) Intracoronary infusion of IIb/IIIa inhibitors for intracoronary thrombus management and vasodilators for no reflow via the perfusion CW catheter were associated with reduction in the thrombus burden and improvement of the coronary flow Ron Waksman, MD, et al.

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

MBG 3 and ST Resolution Rates comparison 80% 70% 72% 52% (n = 25) (n = 23) 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.

INFUSE-AMI Trial Design 452 pts with anterior STEMI Anticipated sx to PCI <5 hrs, TIMI 0/1 flow in prox or mid LAD PCI with bivalirudin IC abcx bolus (ClearWay RX) PCI with bivalirudin Standard of care R 1:1 Aspiration (6F Export) No aspiration R 1:1 PI: Gregg W. Stone; Co-PI: C. Michael Gibson Primary endpoint: Infarct size at 30 days (MRI) 2º endpoints: TIMI flow, blush, ST-resolution, MACE (30d, 1 yr)

No Reflow Take Home Message No reflow phenomenon could be devastating resulted in myocardial damage and should be treated promptly The main approaches is removal of debris with aspiration catheters Reduce the thrombotic burden with IC antiplatelet agents Improve distal circulatory flow with vasodilators Use of local IC infusion is easy safe and attractive but require studies to prove superiority on IC infusion via guiding catheter and superiority over peripheral infusion