pci

1. STRATEGIES & PREVENTION
OF SLOW FLOW &
NO-REFLOW PHENOMENON
DR. RAHUL ARORA
PDT CARDIOLOGY

2. OUTLINE
INTRODUCTION
IMPORTANCE
DEFINITION
HISTORICAL BACKGROUND
INCIDENCE
CLASSIFICATION
DIAGNOSIS
CLINICAL MANIFESTATIONS
PROPHYLAXSIS
TREATMENT
CONCLUSIONS
TAKE HOME MESSAGE

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 a phenomenon of great
clinical outcome which is seen after
primary PCI known as “NO REFLOW
PHENOMENON”.

4. 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)
– Left adverse ventricular remodeling
– Late repeat hospital stays for heart failure
– Mortality.

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

6. Factors Independently Associated
with No-Reflow by Multivariate
Analysis
Cardiogenic Shock 1.83 1.69-1.98 213
Lesion length 1.17 1.14-1.20 143
Age (per 10 yr) 1.14 1.12-1.17 134
High-risk lesion 1.47 1.36-1.59 102
STEMI vs NSTEMI 1.39 1.30-1.48 100
Current smoker 0.78 0.74-0.83 72
Pre-TIMI 0 flow 2.12 1.83-2.45 64
Pre-TIMI 1+ 2 flow 1.84 1.60-2.12
Bifurcation lesion 1.29 1.19-1.40 36
Symptom onset to
1.18 1.10-1.26 23
admission >12 hr
0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4
Adjusted
OR
95%
CI
Chi
square
All P values < 0.001
Odds ratio
Associated with No Reflow
9
cathPCI Registry

7. 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

8. 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 11

9. 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.
• Temporary occlusion of the artery , a prerequiste
condition for no reflow may be produced in the
experimental setting or occur during reperfusion of
an infarct related artery or following PCI.

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

11. ANGIOGRAPHIC DEFINITION
Angiographic No-Reflow is defined as the
presence of TIMI 0-1 in absence of dissection,
spasm, stenosis or thrombus of the epicardial
vessel.
Lesser degree of reduction of coronary flow
(i.e.TIMI 2 flow) is defined as Slow-flow.
Trials have shown that TIMI flow ≤2 has same
bad prognosis as compared to TIMI flow of 3
post PTCA. Thus whether it is TIMI O, 1 or 2 .
The prognosis and complications are same. No
reflow or slow flow are same regarding the
disease process is concerned.

12. No Reflow
A patient with anterior STEMI s/p primary
PCI with angiographic no-reflow
MAY 2003 JULY 2004
EDV and  EF%

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

14. THROMBOLYSIS IN MYOCARDIAL INFARCTION
FLOW GRADING SYSTEM DEFINED
Thrombolysis in Myocardial Infarction Flow Grading System
Grade
Complete occlusion of the infarct-related artery
0
Grade
1
Some penetration of contrast material beyond the point
of obstruction but without perfusion of the distal
coronary bed
Grade
2
Perfusion of the entire infarct vessel into the distal bed
but with delayed flow when compared with a normal artery
Grade
3
Full perfusion of the infarct vessel with normal flow
Chesebro JH, Knatterud G, Roberts R, et al. Circulation 1987;76:142-54. PMID: 3109764.

15. MYOCARDIAL BLUSH GRADES DEFINED
Myocardial Blush Grades
Grade 0
(MBG-0)
Failure of dye to enter the microvasculature. Either minimal or no ground glass appearance
(“blush”) or opacification of the myocardium in the distribution of the culprit artery
indicating lack of tissue-level perfusion.
Grade 1
(MBG-1)
Dye slowly enters but fails to exit the microvasculature. There is the ground glass
appearance (“blush”) or opacification of the myocardium in the distribution of the culprit
lesion that fails to clear from the microvasculature, and dye staining is present on the next
injection (approximately 30 seconds between injections).
Grade 2
(MBG-2)
Delayed entry and exit of dye from the microvasculature. There is the ground glass
appearance (“blush”) or opacification of the myocardium in the distribution of the culprit
lesion that is strongly persistent at the end of the washout phase (i.e., dye is strongly
persistent after three cardiac cycles of the washout phase and either does not or only
minimally diminishes in intensity during washout).
Grade 3
(MBG-3)
Normal entry and exit of dye from the microvasculature. There is the ground glass
appearance (“blush”) or opacification of the myocardium in the distribution of the culprit
lesion that clears normally and is either gone or only mildly/moderately persistent at the end
of the washout phase (i.e., dye is gone or is mildly/moderately persistent after three cardiac
cycles of the washout phase and noticeably diminishes in intensity during the washout
phase), similar to that in an uninvolved artery. Blush that is of only mild intensity throughout
the washout phase but fades minimally is also classified as grade 3.
van 't Hof AW, Liem A, Suryapranata H, et al. Circulation 1998;97:2302-6. PMID: 9639373.

16. Historical perspective
The first clinical observation of coronary no-reflow was
reported by Schofer et al.in 1985.
In 1989, Wilson et al. observed persistent angina with ST
elevation in association with a slow angiographic antegrade
flow despite a widely patent angioplasty site in five
patients immediately after PTCA of a thrombus containing
lesion.
In 1991,Pomerantz et al. reported five more cases of no-reflow
successfully treated by intracoronary verapamil.
The first clinical case of no-reflow during PTCA for acute
myocardial infarction was reported by Feld et al. in 1992.

17. INCIDENCE
INCIDENCE OF ANGIOGRAPHIC NO-REFLOW IN VARIOUS PCI
SETTINGS
PCI Type Incidence of No-Reflow
All PCI 0.6%–2%
Primary PCI 8.8%–11.5%
SVG PCI 8%–15%
Rotational atherectomy ≤16%
Although, Rotational Atherectomy has highest incidence of no
reflow.
It has most favourable reaction to pharmacological therapy with
restoration of normal TIMI flow in 63% of cases.

18. %age of optimal reperfusion
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%

19. CLASSIFICATION, DEINITIONS AND
MECHANISMS OF NO-REflOW
Experimental no-reflow
Definition no-reflow induced under experimental conditions
Mechanisms myocardial necrosis—stunning
reperfusion injury—oxygen free radical production
α-adrenergic macro- and microvascular constriction
local increase in angiotension II receptor density
neutrophil activation—interaction with endothelium
Myocardial infarction reperfusion no-reflow
Definition no-reflow in the setting of pharmacological and/or
mechanical revascularization for acute myocardial
infarction
Mechanisms as for experimental no-reflow
Angiographic / interventional no-reflow
Definition no-reflow during percutaneous coronary
interventions
Mechanisms distal embolization of plaque and/or thrombus
local release of vasoconstrictor substance

20. CLASSIFICATION
Repurfusion No-Reflow Interventional No-Reflow
Occurs after PPCI Follows non-infarct PCI
May be asymptomatic Clinically is typically sudden in onset
May present clinically with continued
Presenting as acute ischaemia with
chest pain and ST elevation
chest pain and ECG changes
Preceded by ischaemic 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 ischaemia
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 practise

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

22. 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.

23. Predictors of pathogenic component of
No-Flow and Therapeutic Implication
Pathogenic Mechanism
of No-Flow
Predictor Therapeutic implication
Distal embolization Thrombus burden Thrombus aspiration
Ischaemia Ischaemia duration Reduction of coronary time
Ischaemia 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
Antiplatelet drugs
reactivity
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.

24. Pathophysiology
J Am Coll Cardiol. 2009;54(4):281-292.

25. Distal Embolization
• Distal embolization Emboli
of different sizes can
originate from epicardial
coronary thrombus and
fissured atherosclerotic
plaques, in particular during
PPCI.
• Experimental observations
have shown, that myocardial
blood flow decreases
irreversibly, when
microspheres obstruct more
than 50 % of coronary
capillaries

26. • Yip et al. proposed a score to assess thrombus burden
on the basis of the following features:
– 1) an angiographic thrombus with the greatest
linear dimension more than 3 times the reference
lumen diameter;
– 2) cutoff pattern (lesion morphology with an
abrupt cutoff without taper before the occlusion);
– 3) presence of accumulated thrombus (5 mm of
linear dimension) proximal to the occlusion;
– 4) presence of floating thrombus proximal to the
occlusion;
– 5) persistent contrast medium distal to the
obstruction; and
– 6) reference lumen diameter of the infarct-related
artery (IRA) 4.0 mm.

27. Ischemia related Injury
• No-Reflow area gets swollen. Certain morphological
changes are seen that results to no reflow
phenomenon
– The capillary endothelium damaged
– Areas of regional swelling with intraluminal
protrusions, that in some plug the capillary lumen.
– Cellular edema compressing the capillaries
– Cell contracture in the ischemic zone also may
contribute to the microvascular compression.

28. Reperfusion Related Injury
Massive infiltration of coronary microcirculation by neutrophils and
platelets at the time of reperfusion
Subsequent adhesion at the endothelial surface and migration in the
surrounding tissue
Release of oxygen free radicals, proteolytic enzymes and pro-inflammatory
mediators
Tissue and endothelial damage
Finally vasoconstrictors released by damaged endothelial cells,
neutrophils and platelets
Sustained vasoconstriction of coronary microcirculation. Neutrophils
also form aggregates with platelets, that plug capillaries thus
mechanically blocking flow

29. Individual susceptibility to No-reflow
Acquired predisposition
Diabetes and acute hyper-glycaemia
Timmer et al, AJC, 2005 Iwakura et al, JACC,
2003

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

31. Individual susceptibility to No-reflow
Acquired predisposition
Prior drug therapy
Niccoli et al, AJC, 2010

32. Individual susceptibility to No-reflow
Acquired predisposition Pre-infarction angina
Karila-Cohen et al, EHJ, 1999

33. No-Reflow phenomenon
CORONARY OCCLUSION
PROLONGED ISCHEMIA
MICROVASCULAR
DAMAGE
NO-REFLOW
PLATELET/ENDOTHELIAL
ACTIVATION
VASOCONSTRICTION
(PARADOXICAL)
INFLAMMATORY RESPONSE
MYOCARDIAL EDEMA
OXYGEN-DERIVED FREE
RADICALS
CALCIUM OVERLOAD
DISTAL EMBOLIZATION
DURING PCI
Potential targets
for intervention
1) Reduced
ischemic time
2) Platelet inhibitors
(ASA, clopidogrel, Abciximab)
3) Vasodilators
(adenosine, nitroprusside,
verapamil)
4) Anti-inflammatory
agents (statins)
5)Anti-thrombotic
agents [+2)]
(heparins,bivalirudin)
6) Thrombectomy/
Thrombus aspiration
Original paradigm Expanded paradigm

34. Diagnosis
Several techniques may be used alone or in combination to make the
diagnosis of no reflow
Investigation Finding
The Conventional 12 lead ECG Persistent ST Segment Elevation
Coronary Angiography(Conventional) TIMI<3 flow
Coronary Angiography(Subselective) Examines distal vessel integrity
Myocardial Scintigraphy Uptake/Perfusion Mismatch
Myocardial Tc-99m sestamibi
No reflow zone
scintigraphy
Myocardial contrast Echocardiography No reflow zone
Nuclear Magnetic Resonance Studies No reflow zone
Positron Emission Tomography No reflow zone
Intracoronary Doppler Registration Typical Doppler Pattern
Distal Coronary Pressure measurement
No significant pressure
gradient
Corrected TIMI Frame Count < 40

35. Diagnosis of no-reflow
Niccoli, EHJ, 2010

36. Prognosis and no-reflow
Niccoli, JACC, 2009

37. ECG
Flow No Reflow
J Am Coll Cardiol. 2009;54(4):281-292.

38. 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

39. INTRACORONARY DOPPLER
Coronary blood flow velocity patterns in a case of microemboli and in a case of capillary
obstruction
In a case of microemboli to coronary resistance vessels, coronary flow velocity falls during
the cardiac cycle. In a case of capillary obstruction , the myocadial blood volume
decreases significantly, and thus coronary flow rapidly fulfills the unstressed volume of
coronary microcirculation to cause rapid deceleration of diastolic flow velocity. Due to the
obstruction of capillaries ad venules, an increase in systolic myocardial stress causes the
reverse flow, called systolic flow reversal

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

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

42. 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, and valsartan on coronary no-reflow
have indeed been recently
demonstrated

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

44. Management of Reperfusion-related
Injury
• Patients at high risk of No-Reflow on the
basis of the presence of reperfusion-related
injury can be treated with drugs like
– Glycoprotein IIb/IIIa antagonists
– Adenosine
– Nicorandil aimed at counteracting endothelial
platelet and neutrophil activation.
– Selective ET-1 or TxA2 antagonism might
represent novel therapeutic aproaches.
Curr Treat Options Cardiovasc Med. 2005 May;7(1):75-80.

45. ABCIXIMAB
• Platelet inhibition - reduce downstream embolization
and local generation of thrombus, and reduce release
of vasoactive and chemotactic mediators from
platelets.
• Among glycoprotein IIb/IIIa antagonists, abciximab
has been found to improve myocardial perfusion when
started during PPCI and infused for 12 h thereafter,
as assessed by a higher rate of STR 50% at 60 min
after PCI (73% vs.57%, p < 0.05). Intracoronary
abciximab has been proven to be superior to
intravenous abciximab in patients treated by primary
PPCI approaches.

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

47. Intracoronary Abciximab
N=154
Thiele H et al, Circulation, 2008

48. Role of abciximab in
saphenous vein graft
For patients with saphenous vein graft disease,
microvascular protection with glycoprotein IIb/IIIa
antagonists may not occur. Ellis and colleagues[53]
analysed 102 vein graft stenoses from the EPIC and
EPILOG trials and 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
athermomatous plaque from the vein graft wall is less
sensitive to the antiplatelet effect of abciximab.

49. 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.

50. WWhhyy UUssee AAddeennoossiinnee ttoo PPrreevveenntt tthhee
NNoo--RReeffllooww PPhheennoommeennoonn??
Reperfusion
Platelets TxA , PAF,
2Leukocytes Calcium Oxygen
Ang II, NE, ET-1
A2A/2B Angiogenesis
Vasculogenesis
MPO
Proteases
Cellular Calcium
Overload
Platelet
Aggregation
Vasoconstriction
Oxygen
Free
Radicals
No Reflow
Vascular
Plugging
Cell Death
A2A A2A
A2A
A1/3
A1/3
ADENOSINE

51. Lab Bench
Bedside
Prospective clinical trials
• ATTACC STUDY
• AMISTAD TRIAL
• AMISTAD II TRIAL

52. AAMMIISSTTAADD IIII
2118 Patients with
Anterior STEMI & Reperfusion
Therapy within 6 Hrs of Symptoms
Placebo
Adenosine
50 μg/Kg/min
X 3h
Adenosine
70 μg/Kg/min
X 3h
Fibrinolysis or PTCA
Infarct size (³5 d)
(243 patients)
Follow-up for 6 months
13 Countries
390 Study Sites

53. AAMMIISSTTAADD IIII –– AAddvveerrssee
EEvveennttss
PLACEBO ADENOSINE
50 μg/Kg/min
ADENOSINE
70 μg/Kg/min
Hypotension 14% 19% 18%
Bradycardia 2% 3% 3%
Tachycardia 4% 2% 4%
Nausea/Vomiting 7% 7% 8%
Premature Drug
4% 6% 5%
Discontinuation
Second-degree AV
Block
0% 0% 0%
Third-degree AV Block 0% 0% 0%

54. AAMMIISSTTAADD IIII IInnffaarrcctt
SSiizzee
Median LV Infarct Size (%)
p=0.122
26%
p=0.028
23%
11%
57% reduction in median infarct size with 70
μg/kg/min group relative to placebo
40%
30%
20%
10%
Placebo 50 μg 70 μg
0%

55. Primary Clinical End Points AMISTAD II:
INTENT-TO-TREAT
End Point Placebo Pooled
Adenosine
P-value
n 703 1,414
Death 83 (11.8%
)
146 (10.3%) 0.29
In-hospital CHF 28 (4.0%) 60 (4.2%) 0.75
Re-hospitalization
for CHF
30 (4.3%) 56 (4.0%) 0.81
Composite 126 (17.9
%)
231 (16.3%) 0.43
JACC 2005, 45: 1775-80.

56. “…because animal studies demonstrate that
adenosine’s beneficial effects are lost if myocardial
ischemia occurs for more than 3 h , adenosine would
prevent reperfusion injury only in patients receiving
adenosine within the first 3 h after coronary
occlusion. Therefore, a subset analysis of the
adenosine groups who were reperfused within 3 h
may yield an even greater reduction in clinical end
points.”
JACC 47, 1235, March , 2006
(letter to editor of JACC by Forman and Jackson)

57. European Heart Journal 27: 2400-2405, Oct., 2006
Aims The purpose of this analysis was to determine whether the efficacy of adenosine
vs. placebo was dependent on the timing of reperfusion therapy in the second Acute
Myocardial Infarction Study of Adenosine (AMISTAD-II).
Methods and Results Patients presenting with ST-segment elevation anterior AMI
were randomized toreceive placebo vs. adenosine (50 or 70 mg/kg/min) for 3 h starting
within 15 min of reperfusiontherapy. In the present post hoc hypothesis generating
study, the results were stratified according to the timing of reperfusion, i.e. or , the
median 3.17 h, and by reperfusion modality. In patients receiving reperfusion
<3.17 h, adenosine compared with placebo significantly reduced
1-month mortality (5.2 vs. 9.2%, respectively, P=0.014), 6-
month mortality (7.3 vs. 11.2%, P =0.033), and the occurrence
of the primary 6-month composite clinical endpoint of death, in-hospital
CHF, or rehospitalization for CHF at 6 months (12.0 vs.
17.2%, P =0.022). Patients reperfused beyond 3 h did not
benefit from adenosine.
Conclusion In this post hoc analysis, 3 h adenosine infusion
administered as an adjunct to reperfusion therapy within the
first 3.17 h onset of evolving anterior ST-segment elevation
AMI enhanced early and late survival, and reduced the composite
clinical endpoint of death or CHF at 6 months.

58. DDeeaatthh aatt 66 mmoonntthhss iiff tthheerraappyy
wwiitthhiinn 33 hhoouurrss
Adenosine: 7.3% (n=716)
Placebo: 11.2% (n=350)
P=0.033
Adenosine: 800,000/y x 0.073 = 58,400/y
Placebo: 800,000/y x 0.112 = 89,600/y
Lives Saved: 89,600/y – 58,400/y =
31,200/y

59. KKeeyy PPooiinnttss
AMI patients who undergo reperfusion therapy:
– Adenosine reduces infarct size
– Adenosine reduces risk of death

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

61. Nitroprusside
Nitroprusside is a nitric oxide donor that does not depend on
intracellular metabolism to derive nitric oxide, with potent
vasodilator properties as well as antiplatelet effects.
The only randomized trial for the prevention of no-reflow using
nitroprusside in the PPCI setting was conducted by Amit et
al. in 98 patients presenting with STEMI in whom
intracoronary nitroprusside was given beyond the occlusion
prior to balloon dilatation. Angiographic parameters, cTFC
and myocardial blush grade (MBG), and STR were similar
between nitroprusside and control groups.
Conversely, 2 small registries showed an improvement of final
TIMI flow grade after administration of intracoronary
nitroprusside given in the attempt to reverse no-reflow

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

63. Nitroprusside
Amit et al, AHJ, 2006

64. Verapamil
• Verapamil is a calcium-channel blocker that
has been utilized for the prevention of no-reflow.
• In a small randomized study by Taniyama et
al. in 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

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

66. Nicorandil
Nicorandil is a hybrid drug of ATP-sensitive K+ channel opener and
nicotinamide nitrate and has been shown to decrease 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 resulted in
better angiographic, functional, and clinical outcome as
compared with placebo in 2 randomized studies

67. Nicorandil
Ito et al, JACC, 1999

68. Adrenaline
Skelding KA et al., CCI, 2002

69. Other drugs……..
• Atrial natriuretic peptide has been tested recently in a large-scale
randomized trial. Indeed, Kitakaze et al. in the J-WIND
(Japan-Working Groups of Acute Myocardial Infarction for the
Reduction of Necrotic Damage) trial, which randomized 227
patients to receive intravenous atrial natriuretic peptide and
292 patients to placebo, 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 (31). Finally, ischemic pre-conditioning
might also reduce infarct size by blockade of m-PTP
(32).

72. Current guidelines suggeted approach
for no-reflow prevention
ESC guidelines, EHJ, 2008

73. SUGGESTED INTRACORONARY DRUG ADMINISTRATION
REGIMENS FOR TREATMENT OF SLOW FLOW AND NO-REFLOW
Drug Administration
Verapamil Boluses of 100–200 μg up to four doses upto
1000μg
Adenosine Boluses of 24 μg up to four doses
Sodium
nitroprusside
Boluses of 100 μg up to total of 1,000 μg
Nitroglycerin Boluses of 100–200 μg up to four doses
Epinephrine Intracoronary dose 50–200 μg

74. 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.
• Induction of ischemic pre-conditioning by drugs or
nonpharmacologic stimuli such as remote ischemia of the arms
• Avoidance of substances potentially blocking pre-conditioning
like sulfonylureas and high doses of alcohol

75. Exploitation of endogenous
protective mechanisms
The most potent endogenous mechanism to limit infarction is
ischaemic preconditioning (IPC).
– reduces the infarct size by half after coronary ligation and reperfusion
– also prevent IR injury at a microcirculatory level
– reduces cell swelling which may also reduce myocardial obstruction by
external compression.
– prevent endothelial alterations during reperfusion
These observations suggest that stimulating IPC may be a target
for no-reflow prevention
Drugs such as nitrates have been shown to produce a late
preconditioning effect both in animals and in humans, while
chronic nitrate therapy is associated with a shift from STEMI
in favour of NSTEMI and with less release of markers of
cardiac necrosis, suggesting that nitrates may pharmacologically
precondition the heart towards ischaemic episodes.

76. Types of IPC
• Beyond that, IPC may be stimulated both before (by remote
preconditioning in those patients in which IPC was not operating as
occlusion occurred not preceded by repetitive IR phases) and after
reperfusion in the cath-lab (by postconditioning)
• Brief ischaemia in an organ that is distant or remote from the heart,
such as limb, also reduces myocardial infarction in experimental models.
• Cycles of intermittent limb ischaemia provide an acceptable method for
inducing cardioprotection, and early proof-of-concept studies have
confirmed the effectiveness of remote IPC in cardiac surgery and
coronary angioplasty, as assessed by reduced markers of cardiac injury.
• Remote ischaemia is unique in that it can also be applied during
myocardial ischaemia prior to Interestingly, Rentoukas et al.showed
that the beneficial effect of remote IPC on STR in patients treated by
PPCI is increased by the concomitant administration of morphine.
Finally, the remote conditioning stimulus has complex effects on
neutrophil adhesion function

77. • In recent years, the notion of ischaemic postconditioning
(IPostC) developed through an increased understanding of the
pathobiology of reperfusion. This prompted studies in which
early reperfusion was interrupted by intermittent brief periods
of ischaemia prior to extended reperfusion which was able to
reduce myocardial infarction, and has renewed interest in
identifying potential therapeutic uses.
• Primary angioplasty provides an ideal mechanical means to
implement IPostC in STEMI and six randomized translational
proof-of-concepts studies have been reported.

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

79. Ischemic post-conditioning
Lonborg J et al, AHJ, 2010

80. 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).
• The randomized STRATAS trial comparing conservative with
aggressive or stand-alone rotational atherectomy (burr to
arterio ratios of 0·7–0·9 and low pressure PTCA) failed to
demonstrate differences in clinical outcomes between the
techniques.
• In the porcine model, Reisman et al.[55] demonstrated fewer
and smaller sized platelet aggregates at the minimum approved
speed of140 000 rounds per minute.
• Plasma-free haemoglobin, a measure of cell damage, also
decreased with decreasing rotational speed. Low speed
rotational atherectomy would therefore appear to be a useful
technical measure to prevent angiographic no-reflow.

81. 3. In the management of complex lesions, one can use saline solutions with
verapamil (10μg/mL), nitroglycerin (4μg/mL), and heparin (20U/mL) for
intracoronary perfusion, under pressure, in the lateral sheath of the
rotablator®.
4. It is important to use a pacemaker electrode, especially when the right
coronary and the circumflex artery are the vessels considered, because
atrioventricular blocks frequently occur.
5. When dealing with saphenous bypasses with thrombosed lesions, it
seems useful to infuse streptokinase by systemic via, 24 hours prior to
the intervention, to induce lysis of the thrombotic component of the
plate, thus reducing the chance of microembolizations.
6. Another option is urokinase. It can be injected into the saphenous
bypass via infusion catheter, prior to the mechanical approach of the
lesion, with the advantage of being administered in a short period of
time and having a more selective effect than streptokinase.

82. Management of Distal Embolization
1. Direct Stent Implantation: by avoiding balloon-induced
thrombus fragmentation and by entrapping
the atherothrombus under the stent struts, has
been suggested as a possible technique to reduce
distal embolization.
2. Thrombectomy Devices & Distal Filters:
– REMIDIA Trial: manual thrombectomy was safe & resulted
in better myocardial perfusion indexes.
– TAPAS Trial: thrombectomy improved tissue perfusion &
reduced cardiac death

84. Thrombectomy Devices & Distal Filters

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

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

87. Current rate of no-reflow based on
guidelines suggested approach
N=1071
Svilaas et al, NEJM 2008

88. Management of no-reflow

89. 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

90. Does current therapy for no-reflow
really work?
I guess that there is still much
more to do
Reasons for failure
•Route of administration (ic vs iv)
•Inadequate dosing (Adenosine)
•Coexistence of multiple mechanisms
•Lack of stimulation of protective pathways
•Gradual increase of area of no reflow with time
•Irreversible manner of no reflow once its set in.

91. 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.

92. Future perspectives
Niccoli et al., JACC, 2009

93. Conclusions
•No-reflow phenomenon after PPCI still negates
benefits of coronary recanalization despite a
more widespeard use of thrombus aspiration and
GpIIb-IIIa inhibitors
•Future studies should better address strategies
for both no-reflow prevention and treatment as
well as how to favourably affect no-reflow
evolution

94. Thanks for
Patient Hearing