No reflow and slow flow phenomenon during pci

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