Pandora's Box: The No-Reflow Phenomenon CIT-2008

Pandora’s s Box: The No-Reflow Phenomenon
CIT-2008
Jack P. Chen, MD, FACC, FSCAI, FCCP
Chairman of Cardiology,
Northside Hospital
&
Director of Cardiac Studies,
Saint Joseph’s s Translational Research Institute
Atlanta, GA, U.S.A.
Copyright © 2008 Saint Joseph's. All Rights Reserved.

Sister Olympic Cities
WEST
1996
TO
EAST
2008

1996 Olympic Double-Gold Medalist:
Women’s Table Tennis (China)
Ms. Deng Yaping

“No-Reflow” or “Slow-Reflow ”:
Definition
• Angiographically: Contrast dye cannot reach
(or reaches slowly) vessel terminus.
• But no significant macroscopic coronary
obstruction or dissection.
• TIMI Frame Count (TFC): Increased
(Normal is 18-27).
• TIMI Myocardial Blush Score (TBS): Decreased
• CABG is of no benefit.

Macrovascular and Microvascular
Obstruction Are Totally Different.

No-Reflow: Causes
and Sequelae
In-hospital MACE
Microvascular
Spasm
Micro-emboli
No-Reflow
Microvascular
Compression by Edematous
Myocyte
Long-term MACE/Mortality
Undetected
Dissection
Adenosine-
(Deficient) Sensitive

We Call It:
The “Cheese-grating” Effect

“No-Reflow” Phenomenon
How often does it occur
Of reperfused patients: 29-44%
Of reperfused LAD lesions: 50-80%
Forman et al. Clin Cardiol 2007;30:583-5.

Commonly Occurring
Scenarios
• Acute Coronary Syndrome (ACS).
• ST-Elevation Myocardial Infarction (STEMI).
• Old, fragile, degenerated saphenous vein
grafts (SVGs).
• Rotational atherectomy, balloon angioplasty,
stent-induced athero/thrombo-emboli.

No-Reflow Significantly Decreases Long-term
Event-free Cardiac Survival
• One report of 120 AMI
patients undergoing primary
PCI
• No-reflow seen in 30 patients.
• 5.8 + 1.2 years follow-up.
• Significant mortality
differences.
Morishima et al. J Am Coll Cardiol
2000;1202-9.

STEMI: Baseline Fibrinogen Levels
May Be Important:
• Study of 105 patients.
• Fibrinogen levels not
only predicted No-
Reflow,
• BUT (more importantly)
predicted CK levels and
anterior MI.
Fibrinogen
Level
(mg/dl)
(P=0.0004)
No-
Reflow
Reflow
523+198 395+145
Wasilewski et al. Kardiologia Polska
2006;64(9):967-72.

While previous trials reported
that TIMI Flow Grade predicted
STEMI/Primary PCI survival rate,
recent data demonstrate that
TIMI Myocardial Blush Grade
may be more accurate.

TIMI Flow and
Myocardial Blush Grade Differences:
TIMI Flow Grade measures large epicardial coronary flow
…but
myocardial perfusion is dependent on microvascular flow.
Therefore, Myocardial blush likely more accurately measures
microvascular as well as myocardial perfusion.

TIMI Myocardial Blush
Grade
Blush 0: Myocardium: no appearance of contrast blush or
opacification
Blush 1: Presence of contrast blush but no washout
(clearance) of contrast (stain is present on the next
injection)
Blush 2: Blush clears slowly – clears minimally or not at
all during three cardiac cycles
Blush 3: Normal myocardial contrast blush and washout
(contrast is only minimally persistent after three cardiac
cycles)

TIMI Flow Grade Cannot Predict
Myocardial Blush Score
Stone et al. reported: Acute MI/Primary PTCA Patients: although 94% had TIMI-3 3 Flow,
only 28% demonstrated normal Myocardial Blush.
Myocardial Blush Scores
Following PTCA in AMI
0/I
30%
II
42%
III
28%
Mortality
.
20.00%
18.00%
16.00%
14.00%
12.00%
10.00%
8.00%
6.00%
4.00%
2.00%
0.00%
0/I II
III
Myocardial Blush Score
• Stone et al. Abstract, AHA, November, 1999
Thus, normal TIMI Flow
cannot predict normal
Myocardial Blush Score.
But, more importantly:
Low Myocardial Blush
Score predicts mortality.
Microvascular obstruction is likely
due to microvascular spasm or
embolism

To Reiterate:
Myocardial Perfusion
(Myocardial Blush Grade) and
TIMI Flow are different
Well-known CADILLAC Trial:
Of all TIMI-3 Flow STEMI patients, only 17%
demonstrated normal tissue perfusion (TIMI
Blush Score).
Forman et al. Cardiovasc Drug Rev 2006;24:116-47.

Gibson et al. reported:
Post-PCI 30-Day to 1-Year MACE
• Of all TIMI-3
flow/PCI
patients, 30-day
to 1-year MACE
is entirely
dependent on
Myocardial
Perfusion
Grade
Gibson et al. Am Heart J 2002.
0.12
0.1
0.08
0.06
0.04
0.02
0
Cumulative 30 D-1 year
MACE
MPG = 3 MPG < 3

However, TIMI 10-B’s Data
Are Discordant:
• TIMI Grade 3 Flow (RR 0.61, p=0.047)
AND
• TIMI Myocardial Blush Grade (RR 0.50, p =
0.038)
BOTH Independently Predicted
2-Year Mortality.
Gibson et al. Circulation 2002.

Diagnosis
• Angiography.
• Magnetic Resonance Imaging (MRI).
• Myocardial Contrast Echocardiography
(MCE).

Angiographic Myocardial Perfusion Grade
(MPG)

Magnetic Resonance Imaging (MRI):
“Hyper-enhancement”
• Before No-
Reflow:
No hyperenhancement.
• After No-
Reflow:
Hyper-enhancement,
which persists for 1
year.
Riccardi et al. Circulation
2001;103:2780-3.

Myocardial Contrast Echocardiography

Therapy
• Devices (Mechanical)
– Aspiration
– Distal Protection
• Pharmacologic

Well-Known VeGAS-2 Trial
(Angiojet, Possis)
• 167 cases of SVG-PCI: Compared AngioJet thrombectomy
(N=179) and Urokinase infusion.
• AngioJet demonstrated:
– Higher procedural success rate (86% vs. 73%).
– Lower in-hospital MI rate (8% vs. 20%).
– Lower 1-year MACE rate (20% vs. 40%).
• BUT, Angiojet had NO 30-day mortality, Q-wave MI, TLR,
stroke, stent thrombosis improvement/benefit.
Cohen DJ, et al. Am Heart J 2001;142:648–56.

Recent NEJM:
TAPAS Trial (Export, Medtronic)
• Randomized Trial Reported 1,071 Cases
of STEMI/Primary PCI.
• Treatment Group: Used Export.
Only 17.1%Demonstrated Final
Myocardial Blush Grade-0/1.
• Control Group: No Export.
26.3% Demonstrated Final Myocardial
Blush Grade-0/1.
(P

SAFER Trial
(SAphenous Vein Free of Emboli Randomized)
(GuardWire, Medtronic)
• SVG-PCI Report
• 406 cases using GuardWire (Medtronic)
distal protection plus stenting
• 395 control cases of conventional (only
stenting)
• 30-day follow-up:
– MACE decreased by 6.9% absolute
reduction in (9.6% versus 16.5%, p=0.004).
Baim et al. Circulation 2002; 105:1285-90.

Pharmacologic Therapy
• Ideally, intracoronary (IC) administration
medications should be made into vessel distal
segment [via over-the-wire balloon central lumen or
dual-lumen catheter (eg, Export*)].
• Calcium blockers: diltiazem, verapamil, nicardipine,
nicorandil.
• Nitroprusside.
• Adenosine.
• Papaverine.
• () Glycoprotein IIb/IIIa inhibitor.
*Chen JP. J Invasive Cardiol 2006; 18(7): 346.

Prophylactic IIB/IIIA
Inhibitor Therapy
Reduces Short- and Long-term
STEMI Mortality.
Yip et al. Chest 2003;124:962-8.
De Luca et al. JAMA 2005;293:1759-65.

HOWEVER, Regarding SVG-PCI,
GP-IIB/IIIA Inhibitors Actually Have No
Survival Benefit
• Large GP-IIB/IIIA Inhibitor
and SVG-PCI randomized
trials Meta-analysis
included:
EPIC, EPILOG, EPISTENT,
IMPACT-2, PURSUIT all
failed to demonstrate longterm
MACE benefit.
Roffi et al. Circulation 2002;106:3063-7.

Professor Gao Run-Lin
and Fu-Wai Heart Hospital:
Reported: (Mini-swine Model)
• Fosinopril, Valsartan 1 , and Simvastatin 2 can
open K ATP Channels and increase
microvascular vasodilation,
These medications all reduced Myocardial
Contrast Echocardiographic No-Reflow.
1. Zhao et al. Coronary Art Dis 2006;17(5):463-9.
2. Yang et al. Eur J Heart Failure
2006;9:30-6.

Adenosine and Primary PCI:
In AMISTAD-2 Trial post-hoc analysis Reported:
• If Primary PCI was beyond 3 hours, adenosine
conferred no survival benefit ;
• However, if WITHIN 3 hours, earlier administration
adenosine actually demonstrated significant
6-month mortality/MACE benefits.
• Adenosine (50-70 mcg/kg/min) IV vs. placebo during
reperfusion therapy (within 3 hours of infarct)...
Reductions in:
6-month mortality: 7.3% vs. 11.2%, p=0.033.
6-month cumulative MACE: 12.0% vs. 17.2%,
p=0.022.
Kloner et al. European Heart J 2006;27(20):2400-5.

Verapamil / Diltiazem /
Nicardipine
• Very effective in reversal of No-Reflow.
• However, verapamil and diltiazem may
lead to bradycardia, heart block.
Werner et al. Cathet Cardiovasc Interv 2002;57:444-51.
Wayrens et al. Am J Cardiol 1995;75:849-50.

Intracoronary Nitroprusside :
Prof. Wang reported 11 Cases of AMI Slow-reflow
or No-reflow
• In 9 patients, TIMI
Flow increased at
least 1 Grade (82%,
p=0.007).
• In 8 cases had
normal TIMI-3 flow
(73%).
Wang et al. Cathet Cardiovasc
Interv 2004;63:171-6.

SCAI Recommendations
Klein et al. Cathet Cardiovasc Interv 2003;60:194-201.
PREVENTION:
When treating diffuse disease or bulky, old friable SVG lesions,
consider distal protection devices.
For rotational atherectomy, consider use of nitroglycerin,
verapamil, and heparin combination in the flush solution
During acute coronary syndrome PCI, consider pretreatment with
IIB/IIIA inhibitors.
Minimize balloon inflations, consider direct stent deployment ,
especially in SVGs.
Pretreatment with verapamil or adenosine.

SCAI Recommendations
TREATMENT
Administer IC-nitroglycerine (100–200 μg up to 4 doses) to
exclude epicardial spasm
Consider administering a glycoprotein IIB/IIIA receptor
inhibitor
Administer pharmacologic agents through an infusion
catheter or the balloon catheter central lumen to ensure drug
delivery to the distal bed

SCAI Recommendations
CLASS-I INDICATIONS: (Strong Clinical
Evidence)
•Adenosine (10–20 mcg bolus)
•Verapamil (100–200 mcg boluses or 100 mcg/min
up to 1,000 mcg total dose; with temporary
pacemaker on standby)
•Nitroprusside (50–200 mcg bolus, up to 1,000 mcg
total dose)

SCAI Recommendations
CLASS-II INDICATIONS: (Evidence Less
Strong
•Rapid, moderately forceful injection of saline or blood (to unplug
microvasculature)
•Diltiazem (0.5–2.5 mg over 1 min up to 5 mg)
•Papavarine (10–20 mcg)
•Nicardipine (200 mcg)
•Nicorandil (2 mcg)
•Epinephrine (50–200 mcg)

SCAI Recommendations
CLASS-III: (Don’t Do It!)
•Intracoronary nitroglycerin (for microvascular causes)
•CABG (contraindicated)
•Stent placement (if site of original stenosis is patent)
•Thrombolytics (e.g., urokinase, t-PA)

Unusual Case
Chen JP. J Invasive Cardiol 2007; 19: E89-92.
• 19 year-old college student abusing massive quantities of
Methamphetamine (stimulant similar to cocaine) sustained acute
anterolateral STEMI/shock.
• Cath: all coronary systems had “No-Reflow”, without visible epicardial
stenoses.
• EF=25%.
• Thrombo-aspiration (Export Catheter) and IC-administration of
adenosine/nitroprusside in all 3 coronary systems: No improvement.
• Intra-aortic balloon pump placed.
• Peak CK-MB: 6.8; Peak Troponin: 3.5.
• Stabilized over next week.
• Lost to follow-up post-discharge.
• First reported case of methamphetamine-induced global “No-reflow” in the
absence of visible coronary stenoses.
• Mechanism unknown: Diffuse microvascular spasm vs. thrombi

“In Greek mythology, Pandora was the first woman on earth and had a
jar which she was not to open under any circumstance. Impelled by her
natural curiosity, Pandora opened the jar, and all evil contained escaped
and spread over the earth, except for one thing, which lay at the bottom,
and that was Hope.”
-Encyclopedia Mythica

Similarly, when interventional cardiologists dare to open their Pandora’s
NO-REFLOW Box and unleash all the associated Evils, we too, need Hope.
(and some good drugs and devices)

Professor Andreas Gruentzig’s
Original 1976 AHA Poster
on First Angioplasty Experiment:
On Display at
Saint Joseph’s s Translational Research Institute

Thank you for your attention.