NO-REFLOW PHENOMENON

Mechanisms and Management

OUTLINEINTRODUCTIONDEFINITION INCIDENCE & CLASSIFICATIONPATHOPHYSIOLOGY & PREDICTORSMETHODS FOR DIAGNOSISPREVENTION OF NO REFLOWTREATMENT OF NO REFLOWCONCLUSION & TAKE HOME MESSAGES

INTRODUCTION• Main goal of any therapeutic intervention

is restoration of patency of the epicardial coronary artery

• But restoration of this patency does not translate into improved tissue perfusion

• And there comes the dreaded phenomenon during primary PCI, with poor clinical outcome known as “NO REFLOW PHENOMENON”

Historical perspective The first clinical observation of coronary no-

reflow was reported by Schofer et al. in 1985, first coined by Ames et al in 1970s in Brain Ischemia

Innumerable experimental models in animals have been studied to understand the pathogenesis of no reflow

Likewise, many drugs have been found effective in animal models of no reflow BUT WITH LITTLE SUCCESS IN HUMANS

DEFINITION• The phenomenon of no-reflow is defined as

‘Inadequate myocardial perfusion through a given segment of the coronary circulation without angiographic evidence of mechanical vessel obstruction’

• No-reflow has been documented in ≥ 30% of patients after thrombolysis or mechanical intervention for acute myocardial infarction in studies with MRI/myocardial contrast echo

ANGIOGRAPHIC DEFINITION Angiographic No-Reflow is defined as

the presence of TIMI ≤ 2 in absence of dissection, spasm, stenosis or thrombus of the epicardial vessel.

Trials have shown that TIMI flow ≤2 has worse prognosis as compared to TIMI 3 flow post PTCA, and TIMI 2 flow is no better than 1 or 0

No-reflow phenomenon

Epicardial revascularization = myocardial tissue reperfusion ?

The No-reflow is a dissociation between epicardial artery patency and myocardial perfusion

Where is the problem???

• TIMI 3 FLOW ≠ Myocardial perfusion 16% of TIMI 3 flow post pPCI have noreflow as shown by

cardiac MRI (infarct extension) *Ito et al. Circulation 2007.

• NO REFLOW = MICROVASCULAR OBSTRUCTION (MVO)

• Microvasculature <200µm

OPEN ARTERY HYPOTHESIS

• Late reperfusion of a persistently occluded coronary artery can still stop adverse left ventricular remodelling

• Time limit ?? 48 hoursAntagonists view If one can establish

‘microvascular’ reperfusion, better clinical outcomes can be achieved

Targets:Open arteries= open microvasculature ≠ open epicardial arteries

%age of optimal reperfusion, CADILLAC TRIAL

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 OF NO-REFLOW

MYOCARDIAL INFARCTION REPERFUSION NO-REFOW

Definition no-reflow in the setting of pharmacological and/or mechanical revascularization for acute myocardial infarction

INTERVENTIONAL NO REFLOW

Definition no-reflow during percutaneous coronary interventions especially rotational atherectomy, vein graft interventions

CLASSIFICATIONReperfusion No-Reflow Interventional No-ReflowOccurs in setting of pPCI Follows non-infarct PCIMay be asymptomatic Clinically is typically sudden in

onsetMay present clinically with continued chest pain and ST elevation

Presenting as acute ischemia with new onset chest pain and ECG changes

Preceded by ischemic cell injury May resolve over the course of several minutes

Confined to the irreversibly damaged necrotic zone

Affected myocardium that was not subjected to prolonged ischemia before procedure

May be exacerbated at the time of reperfusion

Patients with interventional no-reflow have higher rates of mortality

An independent predictor of adverse clinical outcome (heart failure, mortality)

Interventional No-Reflow is unpredictable and uncommonly recognized in clinical practice

TYPES OF NO REFLOW

Sustained • Result of anatomical

irreversible changes of coronary microcirculation

• Undergo ADVERSE LV remodeling

Reversible • Result of functional &

thus reversible changes of microcirculation

• Maintain their left ventricle volumes unchanged over time

INCIDENCEINCIDENCE OF ANGIOGRAPHIC NO-REFLOW IN VARIOUS PCI SETTINGSAll PCI 0.6%–2%Primary PCI 8.8%–11.5%SVG PCI 8%–40%Rotational atherectomy Upto 16%

Jaffe et al. MVO and Mechanisms. Circualtion 2008.Jaffe et al. Prevention and treatment of no reflow. JACC 2010.

PROGNOSTIC IMPORTANCE• It has been found to be significantly

associated with poor clinical and functional outcomes

• Patients with No-Reflow exhibit a higher prevalence of: – Early post-infarction complications

(arrhythmias, pericardial effusion, cardiac tamponade, early congestive heart failure)

– Adverse left ventricular remodeling– Recurrent hospitalisations for heart failure–Mortality

No ReflowA patient with anterior STEMI s/p

primary PCI with angiographic no-reflowMAY 2003 JULY 2004

Full-thickness scarNo Reflow

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

survival

In-Hospital Angiographic Outcomes

No-Reflow Without No-Reflow

P value

IABP use (%) 23 8 <0.0001Drug 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<0.001P<0.0001 for each outcome

Niccoli, JACC, 2009

OUTLINEINTRODUCTIONDEFINITION INCIDENCE & CLASSIFICATIONPATHOPHYSIOLOGY & PREDICTORSMETHODS FOR DIAGNOSISPREVENTION OF NO REFLOWTREATMENT OF NO REFLOWCONCLUSION & TAKE HOME MESSAGES

PATHOPHYSIOLOGYIn 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.

DURING MI

• Metabolism shifts to anerobic glycolysis• Less ATP generated compared to the usual

fatty acid metabolism• Less functioning of ATP dependent channels• Cell swelling, increased cell Ca+, increased

intracellular lactate, decreased pH• Ischemic injury sets in

STAGES OF NO REFLOW EXPANSION• MYOCYTE CHANGES- subendocardium, swollen cells,

tissue edema• VASCULAR CHANGES- intraluminal protrusions, cell

swelling, extrinsic compression due to tissue edema• REPERFUSION INJURY- microembolisation of thrombi,

cholesterol crystals, oxygen free radicalsaggravate myocyte & vascular changes, microvascular spasm, microvascular pluggingloss of cell integrity, cell break, extravasation

• SCAR- irreversible noreflowcontracture

ISCHEMIC INJURY(infarct formation)

PLUSREPERFUSION INJURY

(infarct extension)REMODELLING(infarct expansion)

Reperfusion injury

• Braunwald described reperfusion as a

“Double edged sword”

• Death of viable myocardium

* Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword! J Clin Invest 1985;76:1713–9.

3 12 24 48

STAGES OF NO REFLOW EXPANSION• MYOCYTE CHANGES- subendocardium, swollen cells,

tissue edema• VASCULAR CHANGES- intraluminal protrusions, cell

swelling, extrinsic compression due to tissue edema• REPERFUSION INJURY- microembolisation of thrombi,

cholesterol crystals, oxygen free radicalsaggravate myocyte & vascular changes, microvascular spasm, microvascular pluggingloss of cell integrity, cell break, extravasation

• SCAR- irreversible noreflowcontracture

ISCHEMIC INJURY(infarct formation)

PLUSREPERFUSION INJURY

(infarct extension)REMODELLING(infarct expansion)

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, 1987Iwakura et al, EHJ, 2006

Individual susceptibility to No-reflow

Acquired predispositionHypercholesterolemia

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 INFLAMMATORY RESPONSE MYOCARDIAL EDEMA OXYGEN-DERIVED FREERADICALSCALCIUM OVERLOAD

DISTAL EMBOLIZATION DURING PCI

Expanded paradigmOriginal paradigm

Summary of pathophysiology

PREDICTORS OF NOREFLOW

3 MOST IMPORTANT DETERMINANTS

1. Time of presentation

2. Size of infarction (area and transmural extent)

3. Preinfarction angina

Time delay and no-reflow

Francone M et al, Jacc, 2009

Iwakura et al. JACC 2001.

DIAGNOSTIC MODALITIES

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

Diagnosis

Investigation FindingHistory Persistent chest painThe Conventional 12 lead ECG Persistent ST Segment

ElevationCoronary Angiography TIMI flow, TMP grade, cTMFcCoronary doppler Examines distal vessel

integrityMyocardial Scintigraphy Uptake/Perfusion MismatchMyocardial contrast Echocardiography

No reflow zone

Cardiac Magnetic Resonance FPP, late GE

Several techniques may be used alone or in combination to make the diagnosis of no reflow

ECG

• ST resolution ≥70 % highly accurate predictor of TIMI3 flow

• Single lead ST resolution ≥ 50% in the lead showing maximum elevation prePCI, sensitivity 70%, specificity 54%

• Other markers- T inversion, sum of ST resolution, Id.vent.rhythm

*Krucoff et al. Cir

culation 2004.

Flow No Reflow

ANGIOGRAPHIC NO REFLOW

• TIMI FLOW- semiquantitative, indirect, subjective, TIMI 3 flow does not mean no Noreflow

• Corrected TIMI frame count: LAD > 40 correlates with MRI estimation of noreflow

• TMP grade

MYOCARDIAL BLUSH GRADES DEFINED

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

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

REDUCTION IN ANTEGRADE SYSTOLIC FLOWSYSTOLIC FLOW REVERSAL > 10 cm/secDECELERATION OF DIASTOLIC FLOW <600 m/s

INTRACORONARY DOPPLER

Cardiac MRI

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

Clinical Follow up of MACE in Noreflow by CMR

Niccoli, EHJ, 2010

Summary of diagnostic modalities

OUTLINEINTRODUCTIONDEFINITION INCIDENCE & CLASSIFICATIONPATHOPHYSIOLOGY & PREDICTORSMETHODS FOR DIAGNOSISPREVENTION OF NO REFLOWTREATMENT OF NO REFLOWCONCLUSION & TAKE HOME MESSAGES

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

3 TARGETS FOR INTERVENTION

• Microvascular spasm

• Distal embolisation-platelet rich thrombi

• Engagement of cytoprotective pathways

• Ischemic conditioning- engagement of cytoprotective pathways

• Pharmacological agents- vasodilators (microvessels), antiplatelets and others

ISCHEMIC CONDITIONING(role in cardioprotection and prevention of noreflow)

• PRE CONDITIONING

• POST CONDITIONING

• REMOTE CONDITIONING

ISCHEMIC PRECONDITIONING

• Brief periods of ischemia PRIOR TO infarction• Clinical correlate Preinfarction angina• Pharmacological agents that act on

cytoprotective pathways- Activation of prosurvival kinases- Natriuretic peptides- ANP, BNPs- NO donors- Adenosine, Nitroprusside- Calcium channel blockerVerapamil, Nicardipine- ATP K+ channel openersAdenosine, Nicorandil- Blockage of MPTPCyclosporine

ISCHEMIC POST CONDITIONING

• Early reperfusion is interrupted by intermittent brief periods of ischaemia prior to extended reperfusion

• Able to reduce myocardial infarction, and has renewed interest in identifying potential therapeutic uses

• Primary balloon angioplasty (PTCA) provides an ideal mechanical means to implement IPostC in STEMI and six randomized translational proof-of-concepts studies have been reported

• Pharmacological agentsAdenosine, Nicorandil, Niroprusside, Verapamil

Remote Ischemic Preconditioning

Bokter HE et al, Lancet, 2010

GLYCOPROTEIN IIbIIIa INHIBITORS

• Abciximab- Upstream vs On table- Intracoronary vs Intravenous

• Tirofiban

Abciximab• Platelet inhibition - reduce downstream

embolization and local generation of thrombus, and

• Reduce release of vasoactive and chemotactic mediators from platelets

ABCIXIMAB

• RELAX-AMI study 2007 Upstream beneficial in reducing infarct size, no reflow incidence

• Thiele et al (CIRCULATION 2008)Intracoronary administration prior to PTCA beneficial

• CADILLAC 2002 No superior benefit to placebo in absence of thienopyridine loading

Abciximab

De Lemos et al., Circulation, 2000

Montalescot et al., EHJ, 2005

N=1101

Tirofiban

• ONTIME 2 STUDY 2008 Infusion of tirofiban upstream beneficial

• Reduces no reflow incidence, infarct size on follow up

Role of abciximab in saphenous vein graft ??

• For patients with saphenous vein graft disease, microvascular protection with glycoprotein IIb/IIIa antagonists may not occur.

• EPIC and EPILOG trials failed to demonstrate any clinical benefit with the active drug treatment with an 18·6% incidence of death, myocardial infarction and urgent revascularization at 30 days compared to 16·3% for placebo.

• They hypothesized that distal embolization of atheromatous plaque from the vein graft wall is less sensitive to the antiplatelet effect of abciximab.

ADENOSINE

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.

AMISTAD II Infarct AMISTAD II Infarct SizeSize

57% reduction in median infarct size with 70 μg/kg/min x 3hrs, relative to placebo

p=0.122

26%23%

11%

10%

20%

30%

40%

Placebo 50 μg 70 μg

Median LV Infarct Size (%)

p=0.028

0%

Adenosine as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction post hoc study

(n=2118)

(AMISTAD-2 et al. EHJ 2006)

Adenosine Dosage

• 1ml=2 mg1:51:10 dilution 40 μg bolus (upto 4 doses)

• 70 μg/kg/mt x 3 hrs studied in AMISTAD II

Nitroprusside• Nitroprusside is a nitric oxide donor that does not

depend on intracellular metabolism to derive nitric oxide UNLIKE NITROGLYCERINE

• Nitroglycerine DOES NOT act on microvasculature• Potent vasodilator properties as well as

antiplatelet effects• Clinical setting conflicting evidence

Nitroprusside

Pasceri V et al, AJC, 2005

N= 23(95±50 mcg)

Verapamil• Verapamil is a calcium-channel blocker that has

been utilized for the prevention of no-reflow.

• In a small randomized study, 40 patients with first STEMI, intracoronary verapamil as compared with placebo was associated with better microvascular function as assessed by MCE.

• Accordingly, intracoronary verapamil has been successfully used to reverse no-reflow after PPCI

Verapamil

Werner G et al, CCI, 2002

N= 23(1 mg)

NICARDIPINE

• More potent then diltiazem/ verapamil

• 200µg intracoronary bolus

*Fuji et al. Journal of Invasive cardiology 2000

Nicorandil• Nicorandil is a hybrid drug of ATP-sensitive K+ channel

opener and nicotinamide nitrate• Decreases infarct size and incidence of arrhythmias after

coronary ligation and reperfusion in the experimental model, probably by suppressing free radical generation and by modulation of neutrophil activation.

• It exerts also stimulating effect on preconditioning and has vasodilator properties. A single intravenous administration of nicorandil before PPCI was shown to improve angiographic indexes of no-reflow and clinical outcome.

• Intravenous infusion of nicorandil for 24 h after PPCIpostconditioning, resulted in better angiographic, functional, and clinical outcome as compared with placebo in 2 randomized studies

Nicorandil

Ito et al, JACC, 1999

Upstream Intravenous/ Single IV bolus PRIOR to PCI

SUGGESTED INTRACORONARY DRUG ADMINISTRATION REGIMENS FOR PREVENTION/TREATMENT OF NO-REFLOWVerapamil Boluses of 100–200 µg up to four doses

upto 1000µgNicardipine 200µg bolus intracoronaryAdenosine Boluses of 24 µg up to four doses or

70µg/kg/mt infusion for 3 hoursSodium nitroprusside

Boluses of 100 µg up to total of 1,000 µg

Nitroglycerin

Boluses of 100–200 µg up to four doses

Nicorandil Bolus of 2 mg intracoronary

Other drugs…• Atrial natriuretic peptide has been tested recently in a large-

scale randomized trial- J-WIND trial (n=227) demonstrated that atrial natriuretic peptide treatment was associated with a reduction of 14.7% in infarct size, an increase in the 6 to 12 months of LV ejection fraction by 5%, and an improved myocardial perfusion

• Cyclosporine, which blocks the m-PTP, has been recently shown to reduce infarct size by 20% when administered intravenously in patients undergoing pPCI. Finally, ischemic pre-conditioning might also reduce infarct size by blockade of m-PTP (Piot et al, NEJM 2008)

• Intracoronary papaverine/ Leucocyte antibodies / ET antagonists/ C1 esterase inhibitors / Fucoidin-p selectin inhibitor/ erythropoeitin

Endothelin antagonists

• Canine model

Intracoronary thrombolysis

• Only 1 small RCT showing reduction in infarct size

• Not recommended for clinical practice• However the study throws light on the role of

microvascular thombi in pathogenesis of no reflow

* Sezer et al. NEJM 2007. Role of intracoronary STK after pPCI

HYPEROXEMIC REPERFUSION

• Infusion of aqueous oxygen

• Studied in Canine models ONLY—AMIHAT trial

• Not recommended in practice

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

THROMBUS ASPIRATION

• Conflict of evidence• DEAR MI, REMEDIA, TAPAS vs TASTE, TOTAL

trials• For now, recommended for large thrombus

burden

Impact of Thrombectomy with EXPort catheter in Infarct Related Artery on procedural and clinical outcome in patients with AMI

(EXPIRA Trial).

(G.Sardella et al J. Am. Coll. Cardiol 2009;53;309-315 )

TGCG

TGCG

TAPAS trial (n=1071)

Svilaas, NEJM, 2008

DISTAL EMBOLIC PROTECTION DEVICES

• GUARDWIRE- SAFE, PREPARE, EMERALD studies-NEGATIVE trials

• MGUARD STENT- MASTER trial 2012 JACC, superior benefits to DES in reduction of incidence of Noreflow

• Venous graft interventions- Baim et al. 2002 CIRCULATION. Beneficial in preventing atheroembolism

DIRECT STENTING

• Hypothesis avoiding predilation can reduce microembolisation and hence has lesser infarct sizes than those with predilation and stenting

• Thrombus aspiration + Direct stenting is a preferred strategy by many to reduce incidence of noreflow

*Morice et al. JACC 2002. Direct stenting vs Conventional PCI

ROLE OF IABP

• Last stage measure especially in cardiogenic shock post PCI

• Helps improve coronary blood flow at microvascular level, ONLY AFTER EPICARDIAL FLOW IS ESTABLISHED

• No conclusive evidence * Kern MJ, Aguirre F, Bach R, Donohue T, Siegel R, Segal J. Augmentation of coronary blood

flow by intraaortic balloon pumping in patients after coronary angioplasty. Circulation 1993;87:500-11

*Sjauw KD, Engstrom AE, Vis MM, et al. A systematic review and meta-analysis of intra-aortic balloon pump therapy in ST-elevation myocardial infarction: should we change the guidelines? Eur Heart J 2009;30:459–68

TREATMENT OF NO REFLOW

Treatment of No Reflow• Means REVERSAL OF NO REFLOW• NoREFLOW postPCI suggests SEVERE MVO

WITH LARGE INFARCTION

• Very few case reports/series suggesting various agents like adrenaline, nicorandil, nitroprusside, adenosine, nicardipine, abciximab

• NO RCT hence no conclusive evidence

Adrenaline

Skelding KA et al., CCI, 2002

50-200μg intracoronary boluses

Adenosine in graft interventions

• Adenosine reverses no reflow occuring because of graft interventions

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

CONCLUSIVE RECOMMENDATIONS• Always better to prevent than treat no reflow

situation, hence suspicion of same to occur with “clinical variables like DM, late presentation, large infarction, absence of preinfarction angina” can help prevention

• Methods to preventEarly PCI, upstream abciximab, intracoronary abciximab, adenosine infusion, prePCI intracoronary nicorandil, nitroprusside, diltiazem, thrombus aspiration can prevent

• Methods to treatOnce reflow has occurred post PCI, not much can be donei.c adrenaline and i.c vasodilators, nicorandil can be tried

Current guidelines suggested approach for no-reflow prevention

ESC guidelines, EHJ, 2014

Predictors of pathogenic component of No-Flow and

Therapeutic ImplicationPathogenic Mechanism of No-Flow

Predictor Therapeutic implication

Distal embolization Thrombus burden Thrombus aspirationIschemia Ischemia duration Reduction of coronary time

Ischemia extent Reduction of oxygen consumption

Reperfusion Neutrophil count Specific anti-neutrophil drugET-1 levels ET-1 r antagonistTXA2 levels TXA2 r antagonistMean platelet volume or reactivity

Antiplatelet drugs

Individual susceptibility

Diabetes Correction of hyperglycemia

Acute hyperglycemia Correction of hyperglycemiaHypercholestrolemia Statin therapyLack of preconditioning Nicorandil

ET= Endothelin; TXA2= Thromboxane A2 J Am Coll Cardiol. 2009;54(4):281-292.

NonInfarct PCI

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

Management of individual susceptibility to microcirculatory

injury• The DIGAMI (Diabetes Mellitus Insulin-Glucose Infusion in

Acute Myocardial Infarction) study demonstrated that periprocedural reduction of blood glucose was associated with a reduction of infarct size

• Iwakura et al. have demonstrated that chronic statin therapy in patients with or without hypercholesterolemia is associated with lower prevalence of no-reflow and better functional recovery

• Avoidance of substances potentially blocking pre-conditioning like Glibenclamide (Glyburide) and high doses of alcohol block ATP K+ channels

Rotational atherectomy• The following preventive technical measures have

been suggested: 1. a low burr to artery ratio (0·6–9·8) followed by

conventional PTCA (conservative rotational atherectomy) and/or

2. a low rotational speed (140 000 rounds per minute).

3. Cocktail saline flush with verapamil (10μg/mL), nitroglycerin (4μg/mL), and heparin (20U/mL) for intracoronary perfusion, under pressure, in the lateral sheath of the rotablator

Summary of management

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 4.1Nitroprusside 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

Future PerspectivesThe 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.

CASE EXAMPLES IN SGPGI

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

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

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

Conclusions•No-reflow phenomenon after PPCI still negates benefits of coronary recanalization despite a more widespeard use of thrombus aspiration and GpIIb-IIIa inhibitors

•A successfull prevention/treatment strategy for noreflow can become a ‘breakthrough’ in management of acute MI

•For now, knowing when to treat and when not to is the best strategy to circumvent noreflow post PCI

OPEN ARTERY HYPOTHESIS

Open arteries

= Open microvasculature + epicardial arteries

≠ Open epicardial arteries only

Thank You