Dreaded complication in primary PCI

1. NO-REFLOW PHENOMENON
Mechanisms and Management

2. OUTLINE
INTRODUCTION
DEFINITION
INCIDENCE & CLASSIFICATION
PATHOPHYSIOLOGY & PREDICTORS
METHODS FOR DIAGNOSIS
PREVENTION OF NO REFLOW
TREATMENT OF NO REFLOW
CONCLUSION & TAKE HOME MESSAGES

3. INTRODUCTION
• Main goal of any therapeutic intervention is
restoration of patency of the epicardial
coronary artery
• But restoration of this patency does not
translate into improved tissue perfusion
• And there comes the dreaded phenomenon
during primary PCI, with poor clinical outcome
known as “NO REFLOW PHENOMENON”

4. Historical perspective
The first clinical observation of coronary no-
reflow was reported by Schofer et al. in 1985,
first coined by Ames et al in 1970s in Brain
Ischemia
Innumerable experimental models in animals have
been studied to understand the pathogenesis of
no reflow
Likewise, many drugs have been found effective
in animal models of no reflow BUT WITH LITTLE
SUCCESS IN HUMANS

6. DEFINITION
• The phenomenon of no-reflow is defined as
‘Inadequate myocardial perfusion through a given
segment of the coronary circulation without
angiographic evidence of mechanical vessel
obstruction’
• No-reflow has been documented in ≥ 30% of patients
after thrombolysis or mechanical intervention for
acute myocardial infarction in studies with
MRI/myocardial contrast echo

7. ANGIOGRAPHIC DEFINITION
Angiographic No-Reflow is defined as
the presence of TIMI ≤ 2 in absence of
dissection, spasm, stenosis or thrombus
of the epicardial vessel.
Trials have shown that TIMI flow ≤2
has worse prognosis as compared to
TIMI 3 flow post PTCA, and TIMI 2
flow is no better than 1 or 0

8. No-reflow phenomenon
Epicardial revascularization =
myocardial tissue reperfusion ?
The No-reflow is a dissociation between epicardial
artery patency and myocardial perfusion

9. Where is the problem???
• TIMI 3 FLOW ≠ Myocardial perfusion
16% of TIMI 3 flow post pPCI have noreflow as shown by
cardiac MRI (infarct extension) *Ito et al. Circulation 2007.
• NO REFLOW = MICROVASCULAR
OBSTRUCTION (MVO)
• Microvasculature <200µm

10. OPEN ARTERY HYPOTHESIS
• Late reperfusion of a persistently occluded
coronary artery can still stop adverse left
ventricular remodelling
• Time limit ?? 48 hours
Antagonists view If one can establish
‘microvascular’ reperfusion, better clinical
outcomes can be achieved
Targets:Open arteries= open microvasculature
≠ open epicardial arteries

11. %age of optimal reperfusion, CADILLAC TRIAL
100 patients with STEMI
treated by PPCI
93 patients with TIMI 3
49 patients with TIMI 3
and MBG 2 or 3
35 patients with TIMI 3
and MBG 2 or 3 and
STR>70 %
1 pt with TIMI 0-1
6 pts with TIMI 2
44 pts with MBG
0/1
14 pts with STR
< 70%
Evaluation of
post procedural
TIMI flow
Evaluation of
post procedural
MBG
Evaluation of post
procedural STR>
70%

12. CLASSIFICATION OF NO-REFLOW
MYOCARDIAL INFARCTION REPERFUSION NO-REFOW
Definition no-reflow in the setting of pharmacological and/or
mechanical revascularization for acute myocardial
infarction
INTERVENTIONAL NO REFLOW
Definition no-reflow during percutaneous coronary interventions
especially rotational atherectomy, vein graft
interventions

13. CLASSIFICATION
Reperfusion No-Reflow Interventional No-Reflow
Occurs in setting of pPCI Follows non-infarct PCI
May be asymptomatic Clinically is typically sudden in onset
May present clinically with continued
chest pain and ST elevation
Presenting as acute ischemia with new
onset chest pain and ECG changes
Preceded by ischemic cell injury May resolve over the course of
several minutes
Confined to the irreversibly damaged
necrotic zone
Affected myocardium that was not
subjected to prolonged ischemia
before procedure
May be exacerbated at the time of
reperfusion
Patients with interventional no-reflow
have higher rates of mortality
An independent predictor of adverse
clinical outcome (heart failure,
mortality)
Interventional No-Reflow is
unpredictable and uncommonly
recognized in clinical practice

14. TYPES OF NO REFLOW
Sustained
• Result of anatomical
irreversible changes of
coronary
microcirculation
• Undergo ADVERSE LV
remodeling
Reversible
• Result of functional &
thus reversible changes
of microcirculation
• Maintain their left
ventricle volumes
unchanged over time

16. INCIDENCE
INCIDENCE OF ANGIOGRAPHIC NO-REFLOW IN VARIOUS PCI
SETTINGS
All PCI 0.6%–2%
Primary PCI 8.8%–11.5%
SVG PCI 8%–40%
Rotational atherectomy Upto 16%
Jaffe et al. MVO and Mechanisms. Circualtion 2008.
Jaffe et al. Prevention and treatment of no reflow. JACC 2010.

17. PROGNOSTIC IMPORTANCE
• It has been found to be significantly
associated with poor clinical and functional
outcomes
• Patients with No-Reflow exhibit a higher
prevalence of:
– Early post-infarction complications
(arrhythmias, pericardial effusion, cardiac
tamponade, early congestive heart failure)
– Adverse left ventricular remodeling
– Recurrent hospitalisations for heart failure
– Mortality

18. No Reflow
A patient with anterior STEMI s/p primary
PCI with angiographic no-reflow
MAY 2003 JULY 2004
Full-thickness scarNo Reflow

19. No reflow occurs frequently
during PCI in STEMI and is
associated with reduced survival

20. In-Hospital Angiographic
Outcomes
No-Reflow Without No-
Reflow
P value
IABP use (%) 23 8 <0.0001
Drug eluting stent (%) 54 61 <0.0001
Final TIMI 3 flow (%) 72 95 <0.0001
Lesion success (%) * 70 93 <0.0001
• Lesion success rates = establishment of post
procedure TIMI 3 flow with residual stenosis<25%
with stent or <50% without stent
• No reflow significantly associated with unsuccessful
lesion outcome (adjusted Odds Ratio = 4.70, 95% CI
4.28-5.17, p<0.001) in multivariable analysis

21. Incidence(%)
In-Hospital Clinical Outcomes
Adjusted Odds Ratio for Mortality= 2.21, 95% CI 1.97-2.47, p<0.001
P<0.0001 for each outcome

22. Niccoli, JACC, 2009

23. OUTLINE
INTRODUCTION
DEFINITION
INCIDENCE & CLASSIFICATION
PATHOPHYSIOLOGY & PREDICTORS
METHODS FOR DIAGNOSIS
PREVENTION OF NO REFLOW
TREATMENT OF NO REFLOW
CONCLUSION & TAKE HOME MESSAGES

24. PATHOPHYSIOLOGY
In humans, no-reflow is caused
by the variable combination of 4
pathogenetic components:
1.Distal Atherothrombotic
Embolization
2.Ischemic Injury
3.Reperfusion Injury
4.Susceptibility Of Coronary
Microcirculation To Injury
Distal
embolization
Ischemic
injury
Individual
susceptibility
Reperfusion
injury
J Am Coll Cardiol. 2009;54(4):281-292.

25. DURING MI
• Metabolism shifts to anerobic glycolysis
• Less ATP generated compared to the usual
fatty acid metabolism
• Less functioning of ATP dependent channels
• Cell swelling, increased cell Ca+, increased
intracellular lactate, decreased pH
• Ischemic injury sets in

26. STAGES OF NO REFLOW EXPANSION
• MYOCYTE CHANGES- subendocardium, swollen cells,
tissue edema
• VASCULAR CHANGES- intraluminal protrusions, cell
swelling, extrinsic compression due to tissue edema
• REPERFUSION INJURY- microembolisation of thrombi,
cholesterol crystals, oxygen free radicalsaggravate
myocyte & vascular changes, microvascular spasm,
microvascular pluggingloss of cell integrity, cell break,
extravasation
• SCAR- irreversible noreflowcontracture
ISCHEMIC INJURY
(infarct formation)
PLUS
REPERFUSION INJURY
(infarct extension)
REMODELLING
(infarct expansion)

28. Reperfusion injury
• Braunwald described reperfusion as a
“Double edged sword”
• Death of viable myocardium
* Braunwald E, Kloner RA. Myocardial
reperfusion: a double-edged sword! J Clin
Invest 1985;76:1713–9.

31. 3 12 24 48

38. STAGES OF NO REFLOW EXPANSION
• MYOCYTE CHANGES- subendocardium, swollen cells,
tissue edema
• VASCULAR CHANGES- intraluminal protrusions, cell
swelling, extrinsic compression due to tissue edema
• REPERFUSION INJURY- microembolisation of thrombi,
cholesterol crystals, oxygen free radicalsaggravate
myocyte & vascular changes, microvascular spasm,
microvascular pluggingloss of cell integrity, cell break,
extravasation
• SCAR- irreversible noreflowcontracture
ISCHEMIC INJURY
(infarct formation)
PLUS
REPERFUSION INJURY
(infarct extension)
REMODELLING
(infarct expansion)

39. Individual susceptibility to No-reflow
Acquired predisposition
Timmer et al, AJC, 2005
Iwakura et al, JACC,
Diabetes and acute hyper-glycaemia

40. Golino et al, Circulation, 1987
Iwakura et al, EHJ, 2006
Individual susceptibility to No-reflow
Acquired predisposition
Hypercholesterolemia

41. Karila-Cohen et al, EHJ, 1999
Individual susceptibility to No-reflow
Acquired predispositionPre-infarction angina

42. CORONARY OCCLUSION
NO-REFLOW
PROLONGED ISCHEMIA
MICROVASCULAR
DAMAGE
PLATELET/ENDOTHELIAL
ACTIVATION
VASOCONSTRICTION
INFLAMMATORY RESPONSE
MYOCARDIAL EDEMA
OXYGEN-DERIVED FREE
RADICALS
CALCIUM OVERLOAD
DISTAL EMBOLIZATION
DURING PCI
Expanded paradigmOriginal paradigm
Summary of pathophysiology

43. PREDICTORS OF NOREFLOW

44. 3 MOST IMPORTANT DETERMINANTS
1. Time of presentation
2. Size of infarction (area and transmural extent)
3. Preinfarction angina

45. Time delay and no-reflow
Francone M et al, Jacc, 2009

46. Iwakura et al. JACC
2001.

48. DIAGNOSTIC MODALITIES
• History, ECG,
• Angiography
• Coronary doppler
• Myocardial Contrast Echocardiography
• Cardiac MRI
• Nuclear scans
• Autopsy studies with ‘Thioflavin S’ dye

49. Diagnosis
Investigation Finding
History Persistent chest pain
The Conventional 12 lead ECG Persistent ST Segment Elevation
Coronary Angiography TIMI flow, TMP grade, cTMFc
Coronary doppler Examines distal vessel integrity
Myocardial Scintigraphy Uptake/Perfusion Mismatch
Myocardial contrast Echocardiography No reflow zone
Cardiac Magnetic Resonance FPP, late GE
Several techniques may be used alone or in combination to make the
diagnosis of no reflow

50. ECG
• ST resolution ≥70 % highly
accurate predictor of TIMI3
flow
• Single lead ST resolution ≥
50% in the lead showing
maximum elevation prePCI,
sensitivity 70%, specificity
54%
• Other markers- T inversion,
sum of ST resolution,
Id.vent.rhythm
*Krucoff et al. Cir
Flow No Reflow

51. ANGIOGRAPHIC NO REFLOW
• TIMI FLOW- semiquantitative, indirect,
subjective, TIMI 3 flow does not mean no
Noreflow
• Corrected TIMI frame count: LAD > 40
correlates with MRI estimation of noreflow
• TMP grade

52. MYOCARDIAL BLUSH GRADES DEFINED
van 't Hof AW, Liem A, Suryapranata H, et al. Circulation 1998;97:2302-6. PMID: 9639373.

53. Myocardial contrast
echocardiography
Good reflow No reflow
Myocardial contrast echocardiograms in patients with acute anterior wall myocardial infarction: good reflow and
noreflow
Both patients had total occulusion in the proximal left anterior descending coronary artery . After PCI, Both had
patent artery. Post injection of sonicated contrast medium into LCA, in case of left , all of the myocardium shows
normal enhancement implying success of coronary reperfusion at the myocardial level . In the right case, substantial
defects were observed in the distal septum and in the cardiac apex implying the occurrence of no reflow phenomenon

55. REDUCTION IN ANTEGRADE SYSTOLIC FLOW
SYSTOLIC FLOW REVERSAL > 10 cm/sec
DECELERATION OF DIASTOLIC FLOW <600 m/s
INTRACORONARY DOPPLER

56. Cardiac MRI
J Am Coll Cardiol. 2009;54(4):281-292.

58. Clinical Follow up of MACE in Noreflow by CMR

59. Niccoli, EHJ, 2010
Summary of diagnostic modalities

60. OUTLINE
INTRODUCTION
DEFINITION
INCIDENCE & CLASSIFICATION
PATHOPHYSIOLOGY & PREDICTORS
METHODS FOR DIAGNOSIS
PREVENTION OF NO REFLOW
TREATMENT OF NO REFLOW
CONCLUSION & TAKE HOME MESSAGES

61. Prevention of no-reflow
•Before the onset of infarction pain
•Before reperfusion
•In the cath lab

62. Management of ischaemia
related injury
1. By reducing pain-onset-to-balloon time thus
reducing total ischemic time.
2. By reducing the severity of ischaemia and
improving myocardial perfusion with drugs
that reduce myocardial oxygen consumption.
3. The beneficial effects of carvedilol,
fosinopril, statins and valsartan on coronary
no-reflow have indeed been recently
demonstrated

63. 3 TARGETS FOR INTERVENTION
• Microvascular spasm
• Distal embolisation-platelet rich thrombi
• Engagement of cytoprotective pathways

65. • Ischemic conditioning- engagement of
cytoprotective pathways
• Pharmacological agents- vasodilators
(microvessels), antiplatelets and others

66. ISCHEMIC CONDITIONING
(role in cardioprotection and prevention of noreflow)
• PRE CONDITIONING
• POST CONDITIONING
• REMOTE CONDITIONING

67. ISCHEMIC PRECONDITIONING
• Brief periods of ischemia PRIOR TO infarction
• Clinical correlate Preinfarction angina
• Pharmacological agents that act on
cytoprotective pathways
- Activation of prosurvival kinases
- Natriuretic peptides- ANP, BNPs
- NO donors- Adenosine, Nitroprusside
- Calcium channel blockerVerapamil, Nicardipine
- ATP K+ channel openersAdenosine, Nicorandil
- Blockage of MPTPCyclosporine

68. ISCHEMIC POST CONDITIONING
• Early reperfusion is interrupted by intermittent brief
periods of ischaemia prior to extended reperfusion
• Able to reduce myocardial infarction, and has
renewed interest in identifying potential therapeutic
uses
• Primary balloon angioplasty (PTCA) provides an ideal
mechanical means to implement IPostC in STEMI and
six randomized translational proof-of-concepts
studies have been reported
• Pharmacological agentsAdenosine, Nicorandil,
Niroprusside, Verapamil

69. Remote Ischemic
Preconditioning
Bokter HE et al, Lancet, 2010

70. GLYCOPROTEIN IIbIIIa INHIBITORS
• Abciximab
- Upstream vs On table
- Intracoronary vs Intravenous
• Tirofiban

71. Abciximab
• Platelet inhibition - reduce downstream embolization
and local generation of thrombus, and
• Reduce release of vasoactive and chemotactic
mediators from platelets

72. ABCIXIMAB
• RELAX-AMI study 2007 Upstream beneficial
in reducing infarct size, no reflow incidence
• Thiele et al (CIRCULATION
2008)Intracoronary administration prior to
PTCA beneficial
• CADILLAC 2002 No superior benefit to
placebo in absence of thienopyridine loading

73. Abciximab
De Lemos et al., Circulation, 2000 Montalescot et al., EHJ, 2005
N=1101

74. Tirofiban
• ONTIME 2 STUDY 2008 Infusion of tirofiban
upstream beneficial
• Reduces no reflow incidence, infarct size on
follow up

75. Role of abciximab in
saphenous vein graft ??
• For patients with saphenous vein graft disease,
microvascular protection with glycoprotein IIb/IIIa
antagonists may not occur.
• EPIC and EPILOG trials failed to demonstrate any
clinical benefit with the active drug treatment with
an 18·6% incidence of death, myocardial infarction
and urgent revascularization at 30 days compared to
16·3% for placebo.
• They hypothesized that distal embolization of
atheromatous plaque from the vein graft wall is less
sensitive to the antiplatelet effect of abciximab.

76. ADENOSINE

77. Adenosine
• Adenosine is an endogenous nucleoside mainly produced by the
degradation of adenosine triphosphate, which antagonizes
platelets and neutrophils, reduces calcium overload and oxygen-
free radicals, and induces vasodilation.
• Interestingly, in a small randomized trial, intracoronary
administration of 4 mg of adenosine before complete vessel re-
opening resulted in a lower rate of no-reflow when compared
with the control arm.
• Of note, a large trial of a lower dose of adenosine (120 µg) after
thrombus aspiration did not result in better STR when compared
with placebo, thus suggesting that appropriate doses may be
relevant.

78. AMISTAD II InfarctAMISTAD II Infarct
SizeSize
57% reduction in median infarct size with 70 μg/kg/min x 3hrs,
relative to placebo
p=0.122
26%
23%
11%
10%
20%
30%
40%
Placebo 50 μg 70 μg
Median LV Infarct Size (%)
p=0.028
0%

79. Adenosine as an Adjunct to Reperfusion in
the Treatment of Acute Myocardial
Infarction post hoc study (n=2118)
(AMISTAD-2 et al. EHJ 2006)

80. Adenosine Dosage
• 1ml=2 mg1:51:10 dilution 40 μg bolus
(upto 4 doses)
• 70 μg/kg/mt x 3 hrs studied in AMISTAD II

81. Nitroprusside
• Nitroprusside is a nitric oxide donor that does not
depend on intracellular metabolism to derive nitric
oxide UNLIKE NITROGLYCERINE
• Nitroglycerine DOES NOT act on microvasculature
• Potent vasodilator properties as well as antiplatelet
effects
• Clinical setting conflicting evidence

82. Nitroprusside
Pasceri V et al, AJC, 2005
N= 23
(95±50 mcg)

83. Verapamil
• Verapamil is a calcium-channel blocker that has been
utilized for the prevention of no-reflow.
• In a small randomized study, 40 patients with first
STEMI, intracoronary verapamil as compared with
placebo was associated with better microvascular
function as assessed by MCE.
• Accordingly, intracoronary verapamil has been
successfully used to reverse no-reflow after PPCI

84. Verapamil
Werner G et al, CCI, 2002
N= 23
(1 mg)

85. NICARDIPINE
• More potent then diltiazem/ verapamil
• 200µg intracoronary bolus
*Fuji et al. Journal of Invasive cardiology 2000

86. Nicorandil
• Nicorandil is a hybrid drug of ATP-sensitive K+ channel opener
and nicotinamide nitrate
• Decreases infarct size and incidence of arrhythmias after
coronary ligation and reperfusion in the experimental model,
probably by suppressing free radical generation and by
modulation of neutrophil activation.
• It exerts also stimulating effect on preconditioning and has
vasodilator properties. A single intravenous administration of
nicorandil before PPCI was shown to improve angiographic
indexes of no-reflow and clinical outcome.
• Intravenous infusion of nicorandil for 24 h after
PPCIpostconditioning, resulted in better angiographic,
functional, and clinical outcome as compared with placebo in 2
randomized studies

87. Nicorandil
Ito et al, JACC, 1999
Upstream Intravenous/ Single IV bolus PRIOR to PCI

88. SUGGESTED INTRACORONARY DRUG ADMINISTRATION
REGIMENS FOR PREVENTION/TREATMENT OF NO-REFLOW
Verapamil Boluses of 100–200 µg up to four doses upto
1000µg
Nicardipine 200µg bolus intracoronary
Adenosine Boluses of 24 µg up to four doses or
70µg/kg/mt infusion for 3 hours
Sodium
nitroprusside
Boluses of 100 µg up to total of 1,000 µg
Nitroglycerin Boluses of 100–200 µg up to four doses
Nicorandil Bolus of 2 mg intracoronary

89. Other drugs…
• Atrial natriuretic peptide has been tested recently in a large-
scale randomized trial- J-WIND trial (n=227) demonstrated
that atrial natriuretic peptide treatment was associated with a
reduction of 14.7% in infarct size, an increase in the 6 to 12
months of LV ejection fraction by 5%, and an improved
myocardial perfusion
• Cyclosporine, which blocks the m-PTP, has been recently shown
to reduce infarct size by 20% when administered intravenously
in patients undergoing pPCI. Finally, ischemic pre-conditioning
might also reduce infarct size by blockade of m-PTP (Piot et al,
NEJM 2008)
• Intracoronary papaverine/ Leucocyte antibodies / ET
antagonists/ C1 esterase inhibitors / Fucoidin-p selectin
inhibitor/ erythropoeitin

90. Endothelin antagonists
• Canine model

91. Intracoronary thrombolysis
• Only 1 small RCT showing reduction in infarct
size
• Not recommended for clinical practice
• However the study throws light on the role of
microvascular thombi in pathogenesis of no
reflow
* Sezer et al. NEJM 2007. Role of intracoronary
STK after pPCI

92. HYPEROXEMIC REPERFUSION
• Infusion of aqueous oxygen
• Studied in Canine models ONLY—AMIHAT trial
• Not recommended in practice

93. Mechanical interventions
• Thrombus aspiration
• Distal embolic protection devices
• Direct stenting
• IABP

94. THROMBUS ASPIRATION
• Conflict of evidence
• DEAR MI, REMEDIA, TAPAS vs TASTE, TOTAL
trials
• For now, recommended for large thrombus
burden

95. Impact of Thrombectomy with EXPort catheter in Infarct Related Artery on
procedural and clinical outcome in patients with AMI
(EXPIRA Trial).
(G.Sardella et al J. Am. Coll. Cardiol 2009;53;309-315 )
TGCG
TG
CG

96. TAPAS trial (n=1071)
Svilaas, NEJM, 2008

97. DISTAL EMBOLIC PROTECTION DEVICES
• GUARDWIRE- SAFE, PREPARE, EMERALD
studies-NEGATIVE trials
• MGUARD STENT- MASTER trial 2012 JACC,
superior benefits to DES in reduction of
incidence of Noreflow
• Venous graft interventions- Baim et al. 2002
CIRCULATION. Beneficial in preventing
atheroembolism

98. DIRECT STENTING
• Hypothesis avoiding predilation can reduce
microembolisation and hence has lesser
infarct sizes than those with predilation and
stenting
• Thrombus aspiration + Direct stenting is a
preferred strategy by many to reduce
incidence of noreflow
*Morice et al. JACC 2002. Direct stenting vs Conventional PCI

99. ROLE OF IABP
• Last stage measure especially in cardiogenic
shock post PCI
• Helps improve coronary blood flow at
microvascular level, ONLY AFTER EPICARDIAL
FLOW IS ESTABLISHED
• No conclusive evidence
* Kern MJ, Aguirre F, Bach R, Donohue T, Siegel R, Segal J. Augmentation of
coronary blood flow by intraaortic balloon pumping in patients after coronary
angioplasty. Circulation 1993;87:500-11
*Sjauw KD, Engstrom AE, Vis MM, et al. A systematic review and meta-analysis of
intra-aortic balloon pump therapy in ST-elevation myocardial infarction: should we
change the guidelines? Eur Heart J 2009;30:459–68

100. TREATMENT OF NO REFLOW

101. Treatment of No Reflow
• Means REVERSAL OF NO REFLOW
• NoREFLOW postPCI suggests SEVERE MVO
WITH LARGE INFARCTION
• Very few case reports/series suggesting
various agents like adrenaline, nicorandil,
nitroprusside, adenosine, nicardipine,
abciximab
• NO RCT hence no conclusive evidence

102. Adrenaline
Skelding KA et al., CCI, 2002
50-200μg intracoronary
boluses

103. Adenosine in graft interventions
• Adenosine reverses no reflow occuring
because of graft interventions
* Sdringola S, Assali A, Ghani M, Yepes A, Rosales O, Schroth GW, Fujise K,
Anderson HV, Smalling RW. Adenosine use during aorto coronary vein
graft interventions reverses but does not prevent the slow- No-reflow
phenomenon. Cathet cardiovasc Intervent 2000;51:394-9

105. CONCLUSIVE RECOMMENDATIONS
• Always better to prevent than treat no reflow
situation, hence suspicion of same to occur with
“clinical variables like DM, late presentation, large
infarction, absence of preinfarction angina” can help
prevention
• Methods to preventEarly PCI, upstream abciximab,
intracoronary abciximab, adenosine infusion, prePCI
intracoronary nicorandil, nitroprusside, diltiazem,
thrombus aspiration can prevent
• Methods to treatOnce reflow has occurred post
PCI, not much can be donei.c adrenaline and i.c
vasodilators, nicorandil can be tried

106. Current guidelines suggested approach
for no-reflow prevention
ESC guidelines, EHJ, 2014

107. Predictors of pathogenic component of
No-Flow and Therapeutic Implication
Pathogenic Mechanism
of No-Flow
Predictor Therapeutic implication
Distal embolization Thrombus burden Thrombus aspiration
Ischemia Ischemia duration Reduction of coronary time
Ischemia extent Reduction of oxygen consumption
Reperfusion Neutrophil count Specific anti-neutrophil drug
ET-1 levels ET-1 r antagonist
TXA2 levels TXA2 r antagonist
Mean platelet volume or
reactivity
Antiplatelet drugs
Individual
susceptibility
Diabetes Correction of hyperglycemia
Acute hyperglycemia Correction of hyperglycemia
Hypercholestrolemia Statin therapy
Lack of preconditioning Nicorandil
ET= Endothelin; TXA2= Thromboxane A2
J Am Coll Cardiol. 2009;54(4):281-292.

108. NonInfarct PCI
• Distal embolic protection devices, Nicorandil
*Jaffe et al. JACC 2010

109. Management of individual susceptibility
to microcirculatory injury
• The DIGAMI (Diabetes Mellitus Insulin-Glucose Infusion in
Acute Myocardial Infarction) study demonstrated that
periprocedural reduction of blood glucose was associated with a
reduction of infarct size
• Iwakura et al. have demonstrated that chronic statin therapy in
patients with or without hypercholesterolemia is associated with
lower prevalence of no-reflow and better functional recovery
• Avoidance of substances potentially blocking pre-conditioning
like Glibenclamide (Glyburide) and high doses of alcohol block
ATP K+ channels

110. Rotational atherectomy
• The following preventive technical measures have
been suggested:
1. a low burr to artery ratio (0·6–9·8) followed by
conventional PTCA (conservative rotational
atherectomy) and/or
2. a low rotational speed (140 000 rounds per minute).
3. Cocktail saline flush with verapamil (10μg/mL),
nitroglycerin (4μg/mL), and heparin (20U/mL) for
intracoronary perfusion, under pressure, in the
lateral sheath of the rotablator

111. Summary of management

112. Main RCTs for Management of No-Reflow
Treatment No.
of Pt
Dose Administration
Timing
Primary End pt. Event
Rate
NNT
T/T Control
Thrombectomy 1071 - During PCI MBG 0–1 17.1 26.3 10.7
Adenosine IV 2118 50/70 μg/kg/min Pre-post PCI Clinical 16.3 17.9 59.0
Adenosine IC 54 4 mg Pre-PCI TIMI flow grade
3
0.0 30.0 3.4
Adenosine IC 51 60 mg Post-PCI STR 67.0 91.0 4.1
Nitroprusside IC 98 60 μg During PCI STR 48.3 48.8 1200
Nicorandil IV 81 4mg bolus+
6mg/infusion+ora
l nicorandil
Pre-post PCI MCE 15.0 33.0 5.2
Nicorandil IV+IC 92 0.5 mg IC +4
mg IV bolus and
continuous
infusion of 6
mg/h
Pre-post PCI Clinical 9.6 33.3 4.2
Abciximab IV 2082 0.25 mg/kg +12
h infusion
Pre-during-
post PCI
Clinical 10.2 20.0 10.0
Abciximab IV 90 0.25 mg/kg +12
h infusion
Pre-during-
post PCI
LV Remodelling 7.0 30.0 4.3
J Am Coll Cardiol. 2009;54(4):281-292

113. Future Perspectives
The understanding of the prevailing pathogenetic mechanisms of
No-Reflow in the individual patients is probably important in the
selection of the most appropriate therapeutic approach.
New drugs such as ET/1 and TxA2 antagonists and the
combination of old drugs should be tested in large controlled
randomized trials in patients at high risk of reperfusion injury.
Optimal and prompt risk factor control and induction of
preconditioning represent additional therapeutic options, that,
should be tested in large controlled randomized trials.

114. CASE EXAMPLES IN SGPGI

115. • 65 yr old DM, HTN
• CTO of RCA
• INTERVENTIONAL
NOREFLOW

116. • 55 yr old DM, HTN, Acute AWMI, Late Presentation 4 days
• Reperfusion Noreflow

117. • 60 yr old HTN, Acute AWMI, Presentation 10 hrs.
• Successful TIMI 3 flow

118. Conclusions
•No-reflow phenomenon after PPCI still negates
benefits of coronary recanalization despite a
more widespeard use of thrombus aspiration and
GpIIb-IIIa inhibitors
•A successfull prevention/treatment strategy for
noreflow can become a ‘breakthrough’ in
management of acute MI
•For now, knowing when to treat and when not to
is the best strategy to circumvent noreflow post
PCI

119. OPEN ARTERY HYPOTHESIS
Open arteries
= Open microvasculature +
epicardial arteries
≠ Open epicardial arteries only

120. Thank You