THE CURRENT STRATEGIES IN TREATMENT OF NO REFLOW

THE CURRENT STRATEGIES IN TREATMENT OF NO REFLOW RON WAKSMAN, MD GABRIEL MALUENDA, MD, WASHINGTON HOSPITAL CENTER, WASHINGTON DC

FACULTY DISCLOSURES Ron Waksman, 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

MECHANISMS FOR NO REFLOW 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 Galiuto. L 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, ATPsensitive 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 noreflow phenomena after PCI • Population: 30 patients with ACS who developed noreflow 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 Interven. Cardiol 2010; 23: 109– 113

0. 6 Percentage 0. 5 0. 4 Pre CW use 0. 3 Post CW use 0. 2 0. 1 TIMI flow 0 0 1 2 3 Post CW Pre C

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 Clear. Way™ 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 Clear. Way 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 Clear. Way™ 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 Clear. LY – 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 Clear. Way™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: Clear. Way 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 Clear. Way™ RX Local Therapeutic Infusion Catheter for all coronary indications

Thrombus score changeby OCT 35, 5% P<0. 01 3, 7% N 19 N 20

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 Clear. Way catheter Baseline Post-CW use End of PCI p 0 76 (54. 7) 11 (7. 9) 4 (2. 9) 1 17 (12. 2) 12 (8. 6) 1 (0. 7) < 0. 001 2 30 (21. 6) 50 (36. 0) 12 (8. 6) < 0. 001 3 16 (11. 5) 66 (47. 5) 122 (87. 8) < 0. 001 Visible thrombus 120 (86. 3) 58 (41. 7) 10 (7. 2) < 0. 001 TIMI flow 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, 600 mg Clopidogrel (n=50) R 1: 1 IV Abciximab Clear. Way™ 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% 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 Clear. Way™ 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 R 1: 1 PCI with bivalirudin IC abcx bolus (Clear. Way RX) PCI with bivalirudin Standard of care R 1: 1 Aspiration (6 F Export) No aspiration Primary endpoint: Infarct size at 30 days (MRI) 2º endpoints: TIMI flow, blush, ST-resolution, MACE (30 d, 1 yr) PI: Gregg W. Stone; Co-PI: C. Michael Gibson

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 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