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

2. 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

3. 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

4. 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

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

6. 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

7. Reffelmannand Kloner. Heart 2002;87:162-168

8. Extensive RBC extravasation and neutrophil infiltration, swollen myocytes

9. 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

10. 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

11. 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

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

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

14. Reperfusion No Reflow: Acute MI

15. Interventional No Reflow: Elective Setting

16. Rezkalla SH, CCI 2008; 72:950–957

17. 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

18. 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

19. 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

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

21. 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

22. TIMI flow
Percentage

23. 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

24. 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

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

26. 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.

27. 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

28. 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.

29. 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)

30. 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