no reflow and slow flow phenomenon during pci
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STRATEGIES & PREVENTION OF SLOW FLOW &
NO-REFLOW PHENOMENON
DR. RAHUL ARORA PDT CARDIOLOGY
OUTLINEINTRODUCTIONIMPORTANCEDEFINITIONHISTORICAL BACKGROUNDINCIDENCECLASSIFICATIONDIAGNOSISCLINICAL MANIFESTATIONSPROPHYLAXSISTREATMENTCONCLUSIONSTAKE HOME MESSAGE
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”.
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.
No reflow occurs frequently during PCI in STEMI and is associated with reduced
survival
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 admission >12 hr
1.18 1.10-1.26
23
1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.40.8
Adjusted OR
95% CI
Chi square
All P values < 0.001
Odds ratio
Associated with No Reflow
9cathPCI Registry
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 <0.0001Lesion 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
Inci
denc
e (%
)In-Hospital Clinical
Outcomes
Adjusted Odds Ratio for Mortality= 2.21, 95% CI 1.97-2.47, p<0.00111P<0.0001 for each outcome
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.
No-reflow phenomenon
Epicardial revascularization = myocardial tissue reperfusion ?
The No-reflow is a dissociation between epicardial artery patency and myocardial perfusion.
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.
No ReflowA patient with anterior STEMI s/p
primary PCI with angiographic no-reflowMAY 2003 JULY 2004
EDV and EF%
No ReflowA patient with anterior STEMI s/p
primary PCI with angiographic no-reflowMAY 2003 JULY 2004
Full-thickness scarNo Reflow
THROMBOLYSIS IN MYOCARDIAL INFARCTION FLOW GRADING SYSTEM DEFINED
Thrombolysis in Myocardial Infarction Flow Grading System
Grade 0
Complete occlusion of the infarct-related artery
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.
MYOCARDIAL BLUSH GRADES DEFINED
Myocardial Blush GradesGrade 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.
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.
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.
%age of optimal reperfusion
100 patients with STEMI treated by PPCI
93 patients with TIMI 3
49 patients with TIMI 3and MBG 2 or 3
35 patients with TIMI 3and MBG 2 or 3 and
STR>70 %
1 pt with TIMI 0-16 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%
CLASSIFICATION, DEINITIONS AND MECHANISMS OF NO-REflOW
Experimental no-reflow
Definition no-reflow induced under experimental conditions
Mechanisms myocardial necrosis—stunningreperfusion injury—oxygen free radical productionα-adrenergic macro- and microvascular constrictionlocal increase in angiotension II receptor densityneutrophil 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 thrombuslocal release of vasoconstrictor substance
CLASSIFICATIONRepurfusion 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 chest pain and ST elevation
Presenting as acute ischaemia with 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
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
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
Reperfusioninjury
J Am Coll Cardiol. 2009;54(4):281-292.
Predictors of pathogenic component of No-Flow and
Therapeutic ImplicationPathogenic 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 reactivity
Antiplatelet drugs
Individual susceptibility
Diabetes Correction of hyperglycemia
Acute hyperglycemia Correction of hyperglycemia
Hypercholestrolemia Statin therapy
Lack of preconditioning NicorandilET= Endothelin; TXA2= Thromboxane A2 J Am Coll Cardiol. 2009;54(4):281-292.
Pathophysiology
J Am Coll Cardiol. 2009;54(4):281-292.
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
• 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.
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.
Reperfusion Related InjuryMassive infiltration of coronary microcirculation by
neutrophils and platelets at the time of reperfusion
Release of oxygen free radicals, proteolytic enzymes and pro-inflammatory mediators
Subsequent adhesion at the endothelial surface and migration in the surrounding tissue
Tissue and endothelial damage
Sustained vasoconstriction of coronary microcirculation. Neutrophils also form aggregates with platelets, that plug
capillaries thus mechanically blocking flow
Finally vasoconstrictors released by damaged endothelial cells, neutrophils and platelets
Individual susceptibility to No-reflow
Acquired predisposition
Timmer et al, AJC, 2005 Iwakura et al, JACC, 2003
Diabetes and acute hyper-glycaemia
Golino et al, Circulation, 1987 Iwakura et al, EHJ, 2006
Individual susceptibility to No-reflow
Acquired predispositionHypercholesterolemia
Individual susceptibility to No-reflow
Acquired predisposition Prior drug therapy
Niccoli et al, AJC, 2010
Karila-Cohen et al, EHJ, 1999
Individual susceptibility to No-reflow
Acquired predispositionPre-infarction angina
CORONARY OCCLUSION
NO-REFLOW
PROLONGED ISCHEMIA
MICROVASCULAR DAMAGE
PLATELET/ENDOTHELIAL ACTIVATIONVASOCONSTRICTION (PARADOXICAL)INFLAMMATORY RESPONSE MYOCARDIAL EDEMA OXYGEN-DERIVED FREERADICALSCALCIUM 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
Expanded paradigmOriginal paradigm
No-Reflow phenomenon
Diagnosis
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 scintigraphy
No reflow zone
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 gradient
No significant pressure
Corrected TIMI Frame Count < 40
Several techniques may be used alone or in combination to make the diagnosis of no reflow
Diagnosis of no-reflow
Niccoli, EHJ, 2010
Prognosis and no-reflow
Niccoli, JACC, 2009
ECGFlow No Reflow
J Am Coll Cardiol. 2009;54(4):281-292.
Myocardial contrast echocardiography
Good reflow No reflowMyocardial contrast echocardiograms in patients with acute anterior wall myocardial infarction: good reflow and noreflowBoth 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
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
INTRACORONARY DOPPLER
Cardiac MRI
J Am Coll Cardiol. 2009;54(4):281-292.
Prevention of no-reflow
•Before the onset of infarction pain
•Before reperfusion
•In the cath lab
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
Time delay and no-reflow
Francone M et al, Jacc, 2009
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.
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.
Abciximab
De Lemos et al., Circulation, 2000
Montalescot et al., EHJ, 2005
N=1101
Intracoronary Abciximab
Thiele H et al, Circulation, 2008
N=154
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.
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.
Reperfusion
Why Use Adenosine to Prevent the Why Use Adenosine to Prevent the
No-Reflow Phenomenon?No-Reflow Phenomenon?
LeukocytesTxA2, PAF,Ang II, NE, ET-1
Calcium OxygenPlatelets
A2A/2B AngiogenesisVasculogenesis
MPOProteases
Cellular CalciumOverload
PlateletAggregation
VasoconstrictionOxygen
FreeRadicals
No Reflow
Vascular Plugging
Cell Death
A2A A2AA2A
A1/3
A1/3
ADENOSINE
Lab Bench
Bedside
Prospective clinical trials
• ATTACC STUDY • AMISTAD TRIAL • AMISTAD II TRIAL
AMISTAD IIAMISTAD II
2118 Patients withAnterior STEMI & Reperfusion
Therapy within 6 Hrs of Symptoms
PlaceboAdenosine
50 μg/Kg/minX 3h
Adenosine70 μg/Kg/min
X 3h
Fibrinolysis or PTCA
Follow-up for 6 months
Infarct size (5 d)(243 patients)
13 Countries390 Study Sites
AMISTAD II – Adverse AMISTAD II – Adverse EventsEvents
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 Discontinuation
4% 6% 5%
Second-degree AV Block
0% 0% 0%
Third-degree AV Block
0% 0% 0%
AMISTAD II Infarct AMISTAD II Infarct SizeSize
57% reduction in median infarct size with 70 μg/kg/min group 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%
Primary Clinical End Points AMISTAD II: INTENT-TO-TREAT
End Point PlaceboPooled
AdenosineP-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 CHF30 (4.3%) 56 (4.0%) 0.81
Composite 126 (17.9%)
231 (16.3%) 0.43
JACC 2005, 45: 1775-80.
“…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)
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.
European Heart Journal 27: 2400-2405, Oct., 2006
Death at 6 months if Death at 6 months if therapy within 3 hourstherapy within 3 hoursAdenosine: 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
Key PointsKey Points
– Adenosine reduces infarct size
– Adenosine reduces risk of death
AMI patients who undergo reperfusion therapy:
Adenosine as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction post hoc study
(n=2118)
(AMISTAD-2 et al. EHJ 2006)
NitroprussideNitroprusside 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
Nitroprusside
Pasceri V et al, AJC, 2005
N= 23(95±50 mcg)
Nitroprusside
Amit et al, AHJ, 2006
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
Verapamil
Werner G et al, CCI, 2002
N= 23(1 mg)
NicorandilNicorandil 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
Nicorandil
Ito et al, JACC, 1999
Adrenaline
Skelding KA et al., CCI, 2002
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).
Current guidelines suggeted approach for no-reflow prevention
ESC guidelines, EHJ, 2008
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
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
Exploitation of endogenous
protective mechanismsThe 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.
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
• 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.
Remote Ischemic Preconditioning
Bokter HE et al, Lancet, 2010
Ischemic post-conditioning
Lonborg J et al, AHJ, 2010
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.
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.
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
Thrombectomy Devices & Distal Filters
Impact of Thrombectomy with EXPort catheter in Infarct Related Artery on procedural and clinical outcome in patients with AMI
( EXPIRA Trial ).
Primary End-points
(G.Sardella et al J. Am. Coll. Cardiol 2009;53;309-315 )
TGCG
TGCG
TAPAS trial (n=1071)
Svilaas, NEJM, 2008
Svilaas et al, NEJM 2008
Current rate of no-reflow based on guidelines suggested
approachN=1071
Management of no-reflow
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+oral nicorandil
Pre-post PCI MCE 15.0 33.0 5.2
Nicorandil IV+IC
92 0.5 mg IC +4 mg IV bolus andcontinuous 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 4.3J Am Coll Cardiol. 2009;54(4):281-292
I guess that there is still much more to do
Does current therapy for no-reflow really work?
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.
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.
Future perspectives
Niccoli et al., JACC, 2009
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
Thanks for Patient Hearing