predictors of no reflow during primary angioplasty for acute myocardial infarction from medical college hospital trivandrum

Another recent studyexamined the predictors of no-reflow from a large cohort.6 The authors analysed data from 781 consecutive patients who had undergone primary angioplasty from 2008 to 2

Original Article

Medical College Hospital, Trivandrum, 695011, India

A R T I C L E I N F O

Article history:

Received 1 September 2016

Accepted 12 December 2016

Available online xxx

Keywords:

No-reflow

Primary angioplasty

Predictors

A B S T R A C T Background: Primaryangioplasty (PCI)foracutemyocardialinfarction isassociated withno-reflow phenomenon,inabout5–25%ofcases.Hereweanalysedthefactorspredictingnoreflow

Methods:Thiswasacasecontrolstudyofconsecutivepatientswithacutemyocardialinfarctionwho underwentPrimaryPCIfromAugust2014toFebruary2015

Results:Of181patientswhounderwentprimaryPCI,47(25.9%)showedanangiographicno-reflow phenomenon.Themeanagewas59.19
10.25yearsandfemaleswere11%

Univariate predictorsof noreflowwereage>60years(OR=6.146,95%CI2.937–12.86,P=0<0.001), reperfusiontime>6h(OR=21.94,95%CI9.402–51.2,P=<0.001),lowinitialTIMIflow(1)(OR=12.12, 95%CI4.117–35.65,P<0.001),lowinitialTMPGflow(1)(OR=36.19,95%CI4.847–270.2,P<0.001)a highthrombusburden(OR=11.04,95%CI5.124–23.8,P<0.001),alongtargetlesion(OR=8.54,95%CI 3.794–19.23,P<0.001),KillipClassIII/IV(OR=2.937,95%CI1.112–7.756,P=0.025)andoverlapstenting (OR=3.733,95%CI1.186–11.75,P=0.017)

Multiplestepwiselogisticregressionanalysispredictorswere:longerreperfusiontime>6h(OR=13.844, 95%CI3.214–59.636,P=<0.001),age>60years(OR=8.886,95%CI2.145–36.80,P=0.003),alongtarget lesion(OR=8.637,95%CI1.975–37.768,P=0.004),lowinitialTIMIflow(1)(OR=20.861,95%CI1.739– 250.290,P=0.017)

Conclusions:Itisimportanttominimizetraumatothevessel,avoidrepetitiveballoondilatationsuse directstentingandusetheshorteststentifpossible

©2016PublishedbyElsevierB.V.onbehalfofCardiologicalSocietyofIndia.Thisisanopenaccessarticle

undertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/)

1.Introduction

Primaryangioplastyis aneffectivetreatment for myocardial

infarctioninthat iteffectivelyand rapidly opensuptheinfarct

related artery and provides sufficient information about the

diseaseinthe othermajorepicardial coronaryarteries.In spite

ofitseffectivenessincertainpatientsandinspiteofhavingaTIMI3

flow,patients experiencea phenomenon called no-reflow This

phenomenon is associated with arrhythmias, poor in-hospital

survivalandpooroneyearsurvival1,2andhasbeenfoundtooccur

in5to25percentofcases.3,4

2.Whatisno-reflow?

The phenomenon of no-reflow is defined as inadequate myocardial perfusion through a given segment of coronary circulation withoutangiographic evidence ofmechanical vessel obstruction.7Occlusionandreperfusionleadstono-reflow

3.No-reflowin2016 No-reflowhasattractedagreatdealofinterest,evenin2016 ResearchersfromLondonhavecompletedameta-analysisonthe useofintravenousandintracoronaryadenosineinpatientswith no-reflow.5

Theycalculated the pooled relativerisk via a fixed effect meta-analysis They studied the effect of adenosine administration on all-cause mortality, non-fatal myocardial infarction, and congestive heart failure They analysed 13 randomized controlled trials In patients who received intra-coronaryadenosine,theincidenceofno-reflowwasreducedand

$Presented in the National Cardiological Society Conference as an e –poster in Feb

2016 and was awarded the best paper award

* Corresponding author at: 5/2091, Near the Srikrishna Temple, Cheruvekkal,

Srikaryam,Trivandrum, 695017, India.

E-mail address: ninigupta@gmail.com (P.N Gupta).

http://dx.doi.org/10.1016/j.ihj.2016.12.012

0019-4832/© 2016 Published by Elsevier B.V on behalf of Cardiological Society of India This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

xxx–xxx

ContentslistsavailableatScienceDirect

j o u r n a lh o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / i h j

Intravenousadenosinedidnotimprovetheincidenceofno-reflow

ornewheartfailure

Another recent studyexamined the predictors of no-reflow

from a large cohort.6 The authors analysed data from 781

consecutive patients who had undergone primary angioplasty

from 2008 to 2012 Of these,189 patients had no-reflow The

patientswhohadno-reflow wereolder,lowerTIMIflowsand a

higherthrombusscore(morethan4).Accordingtothe

multivari-ateanalysis,thepresenceofcardiogenicshock,ageofmorethan60

years,thrombusscoreofmorethan4andballoontimeofmore

than360minwereindependentpredictorsofno-reflow

4.Stentingandno-reflow

17%ofpatientsdevelopedno-reflowimmediatelyafter

stent-ing.6

4.1.Deathandreinfarction

Patientswithno-reflowhadahigherincidenceofdeathat12

months.(13%versus6%p<0.003).6

Withthisbackgroundwedecidedtopublishourstudyon

no-reflow

5.Whendoesno-reflowdevelop?

Temporaryocclusionoftheartery,aprerequisiteconditionfor

no-reflow,may be produced in the experimental setting occur

during reperfusion of an infarct-related artery or following

percutaneous coronary intervention.7,8 No-reflow is associated

with abnormal tissue perfusion, and persistent no-reflow is

associatedwithhigherclinicalcomplicationrates8,9.Theconcept

ofcoronaryno-reflowwasfirstdescribedinexperimentalmodels

in 196610 and then in the clinical setting of reperfusion after

myocardialinfarctionin1985.10,11

No-reflow has been documented in 30% of patients after

thrombolysis or mechanical intervention for acute myocardial

infarction8,9,12.Comparedtosimilarpatientswithadequatereflow,

thosewithno-reflowaremorelikelytoexhibitcongestiveheart

failureearlyaftermyocardialinfarctionanddemonstrate

progres-siveleftventricularcavitydilatationintheconvalescentstageof

theinfarction.8,9Persistent no-reflow hasbeen associated with

increasedmortalityandahighincidenceofrecurrentmyocardial

infarction.13,14Hence,thepredictorsofno-reflowwouldbehelpful

inidentifyingpatientsathighriskandthosewithahigherchance

ofdeath

6.Materialsandmethods

6.1.Aim

To identify the predictors of no-reflow/slow-flow during

primary percutaneous coronary intervention in patients with

acutemyocardialinfarctioninourinstitution

Thisisacasecontrolstudyofconsecutivepatientswithacute

myocardialinfarctionwhowereadmittedtoMCHTrivandrumand

underwentprimaryPCIfromAugust2014toFebruary2015

6.2.Inclusioncriteria

PatientsadmittedtoMCHTrivandrumwithadiagnosisofacute

ST elevation myocardial infarction within 12h of onset of

symptoms who underwent primary PCI were included The

patientswereclassifiedasthosewithno-reflowandthosewithout no-reflow

 Cases: The patients were considered to exhibit a no-reflow phenomenonifbloodflowintheIRA(infarctrelatedartery)was

aTIMI2flowdespitesuccessfuldilatationandintheabsenceof mechanicalcomplications,suchasdissection,spasmor exten-sive angiographically evident distal embolization, at the completionoftheprocedure

 Controls: Patients who did not have no-reflow/slow-flow phenomenonand hadaTIMIIIIflowatthecompletionofthe procedure

StudySite:MedicalCollegeHospitalThiruvananthapuram Thishospitalisatertiarycaregovernmenthospitalandisan importantreferralhospitalinKerala;itcaterstopatientsmainly fromSouthKerala.Wecareforalargepopulationandseepatients fromall over South Kerala.Hence,a samplepopulationthat is takenfromthishospitalmightberepresentativeofthepopulation

inSouthKerala

In allof thepatientsa detailed history wasobtained, and a physical,electrocardiographic,echocardiographic andlaboratory examinationwasperformedandtherelevantcatheterizationdata were collected prospectively from the Trivandrum MCH cath registry(acomputerizedregistrystartedinDecember2013)

7.Definitions New myocardial infarction was defined as new ischemic symptomsthatlasted>20minandneworrecurrentST-segment elevationordepression>1mminatleast2contiguousleadsthat was associated with a>20% increase in the cardiac biomarker values that was not attributable tothe evolution of the index myocardialinfarction

Post-proceduralbleedingwasconsideredtobeanyovertand actionablehaemorrhagenotrelatedtocoronaryarterybypassgraft witha3g/dldecreaseinhaemoglobinthat requireda prompt evaluationbyahealthcareprofessionaland ledtoanincreased levelofcare.Bleedingwasfurthercategorizedasaccesssiterelated

or non–access site related according to its relationship to the arterialvascularaccess

No-reflow: Angiographic evidence of the reopening of an occludedcoronaryarterywithanacutereductionincoronaryflow (TIMIgrade0–1)intheabsenceofdissection,thrombus,spasm,or high-graderesidualstenosisattheoriginaltargetlesion Slowflow:Lesserdegreesofflowimpairment(TIMIgrade2)are generallyreferredtoas“slow-flow.”

Highthrombusburden:wasdefinedasthrombusgrade4and grade5

Longtargetlesions:weredefinedastargetlesionsthatwere morethan20mminlength

8.Laboratoryandechocardiographicevaluation All of the subjects underwent routine investigations that included a haemogram,electrocardiogram, renal function tests andliverfunctiontestsatthetimeofadmissiontotheICCU.All patientsunderwentanechocardiogramoncetheywerestabilized

9.Inclusioncriteria Patientswhowereatleast18yearsofagewhopresentedwithin

12hof theonsetof chestpain withaSTEMI defined asan ST-segmentelevationof1mm ofmorein twoormorecontiguous leads,anewleftbundle-branchblock,oratrueposteriorMIwith ST-segmentdepressionofatleast1mmwereincludedinthestudy

xxx–xxx

PatientswithanAMIonsetof>12h,patientswhoweretreated

conservativelyforcoronaryarteryspasmorhada<50%diameter

stenosisof theculprit lesionwithnormal coronary blood flow,

patients who had undergone CABG (post coronary bypass

grafting),patientswhoweretakinganticoagulationmedications

foranyreason,andpatientswhohadundergonearescuePCIwere

excluded

11.Samplingtechniques

DeterminationofSampleSizerequirementforCase–Control

Studies

Let

q3

f be the prevalence of exposure to the factor in the population In

most epidemiological studies of rare diseases,the prevalence of the

exposure factor in the control group provides a good approximation

of f

R Relative Risk of disease regared as important to detect.

P3 Prevalence of the exposure factor among the cases It is estimated as

f R

1þf ð R1 Þ

q3 1 p3

2 1 þ R

1þf ð R1 Þ

Z alpha ThisistheZvaluecorrespondingtothealphaerror.Whenlooking

this up in a table, You must always use the two-tailed value,unless

you have a good reason for choosing a 1-sided test.For example,if

alpha is 0.01,0.05.or 0.10 the corresponding (two tailed) Z values are

2.58,1.96,and 1.65 respectively.

Z beta This is the Z value corresponding to the beta error.The Z-value for

beta is always based on a one-tailed test (ask if you are really

interested in why!)So if the beta is 0.05,0.10,0.20 pr 0.30,the

corresponding Z values are 1.65,1.28,o.85 and 0.52 respectively.

Formula

n¼ Za

ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi

2mð1mÞ

p

þZb ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi

fð1fÞþp3q3 p

fp3

DataCollection(prospectivelycollectedfromTrivandrumMCH

cathregistry)

-Baselinecharacteristics,includingrelevantdetailsofthePCIwill

becollectedprospectivelyfromthecathregistry

12.Dataanalysis

Thedatathuscollectedwouldbeusedtoassessthepredictors

ofno-reflow/slow-flowinpatientswithprimaryPCIviaodd’sratio,

univariateandmultivariateanalyses

TheprotocolhasbeenclearedbytheResearchCommitteeand

has been cleared by the Institutional Ethical Committee The

patient records will be keptconfidential at all points of time

Patientconsentwasobtainedfromallpatients

13.Statisticalanalysis

ThedatabasethatwasusedfordatacollectionwasMicrosoft

Access, the spreadsheet that was used for export and data

conversion was Microsoft Excel The data were analysed with

SPSS(opensource)

ThegraphshavebeenpreparedwithMicrosoftExcel

TheChisquaretestwasusedtocomparecategoricalvariables and Student’s t-test was usedfor comparisons betweenmeans (continuousvariables)

Significancewasassumedatp<0.05

Univariate andmultivariate analyses for significant variables were performed The odds ratio for different predictors was calculated The confidence intervals were stated and their statistical significance was calculated The significant variables thatwereidentifiedintheunivariateanalysis(exceptCPKMB,see below)wereincludedinthemultivariateanalysiswiththevariable

as the independent variable and no-reflow as the dependent variable.Theresultsarestatedbelow

14.Results

A total of 181 patients with a diagnosis of ST elevation myocardial infarctionwere admitted tothe Intensive Coronary Care Unit, MCH Trivandrum, and underwent primary PCI from August2014toFebruary2015

14.1.Baselinecharacteristics Thebaselineparametersthathaveacontinuousdistributionare giveninTable1andthecategoricalparametersaregiveninTable2 Importantbaselinecharacteristicswereasfollows:

Themeanagewas59.19
10.25yearsold

Maleswerepredominant,accountingforalmost88.9%ofthe studypopulation

A history of Type 2 diabetes mellitus and systemic arterial hypertensionwerepresentin40.3%and33.1%ofthepopulation, respectively

Dyslipidaemiawaspresentin63%ofthepopulation

6 Patients in the study cohort exhibited anterior wall myocardial infarctions (43.6%) and inferior wall myocardial infarctions(55.2%)

A positive familyhistory of CADwas present in 9.9%of the population

The mean ejection fraction of the study cohort was 51.93
9.51%

Thebaselinemeancreatininewas0.99
0.23mg/dl 14.2.Baselineclinicalcharacteristics

Inthe181patientswhohadundergoneprimaryPCI,47(25.9%) showed an angiographic no-reflow phenomenon The baseline clinicalcharacteristicsareshowninTables1and2(Fig.1)

Table 1 Baseline clinical data in the no-reflow and reflow groups – continuous variables (N = 181).

No-reflow (N = 47) Reflow (N = 134) t p

Age 63.19 9.62 55.19 10.88 4.462 < 0.001

Peak CKMB 403.00 144.15 234.71 136.21 7.178 < 0.001

Creatinine 0.99 0.24 0.99 0.22 0.038 0.970 Total Cholesterol 219.53 51.30 217.74 50.05 0.207 0.836

DM Duration 2.96 6.70 2.95 5.19 0.010 0.992 HTN Duration 2.87 6.77 2.14 4.40 0.843 0.401

xxx–xxx

andtheno-reflowgroupintermsofgender,hypertension,diabetes

mellitus, hypercholesterolemia, smoking status, blood pressure

(both systolic and diastolic), family history of coronary artery

disease, previousMI, blood urea, serum creatinine and infarct

localization (P>0.05 for all) The mean ejection fraction was

51.93
9.51%; there was no statistically significant differences

among no-reflow and the reflow groups [50.82
9.32 vs

53.05
9.71;p=0.182](Fig.2)

Compared with the reflow group, patients in the no-reflow

grouphadahighermeanage(63.19
9.62vs.55.19
10.88years

forno-reflowandreflow,respectively),alongermeanreperfusion

time(6.35
1.61vs.4.29
1.25h,respectively),ahigherlevelof

CKMB(403
144.15vs.234.71
136.21U/L,respectively)(p<0.05

forall).Moreover,thereweresignificantdifferencesbetweenthe

no-reflowandreflowgroupswithrespecttoahigherlevelofKillip

class(III/IV)(19.1vs.7.5,respectively)(p<0.05)

Thedoortoballoontimewascomparableintheno-reflowand

the reflow group (no-reflow 93.69
50.26min vs reflow

88.64
44.89min,p=0.1)

14.3.AngiographicfindingsandprimaryPCIcharacteristics Theangiographic dataand proceduralfeaturesrevealedthat out of 181 patients, 47 had no-reflow No-reflow was more commoninpatientswhohadalow(1)initialTIMIflow(91.5%vs 47%, p<0.001) and a low initial TMPG (1) (97.5% vs 56%,

p<0.001)comparedtothereflowgroup.Ofthetotalcohortofthe STEMIpopulation,primaryPCIwasperformedviafemoralarterial accessin44.7%ofpatientsandviaradialaccessin55.3%ofpatients andtherewasnosignificantdifferencebetweenthetwogroups AWMIwascommoninbothgroups.Therewasnosignificant differenceintheincidenceofmultivesseldiseasebetweenthetwo groups.LADasatargetvesselwasmorecommoninbothofthe groups(Fig.3)

ThestentsthatwereusedinallofthepatientswereDESs(drug elutingstents).Atotalcut-offocclusionwasmorecommoninthe no-reflow group (72.3% vs 61.2%) but was not significantly differentwhen compared with (p=0.59) thereflowgroup The meanreferencevesseldiameterwasslightlylowerintheno-reflow

Table 2

Baseline Clinical data in the no-reflow and reflow groups  categorical variables (N = 181).

p

0.7

18.380 0 < 0.001

Fig 1 The distribution of angiographic no-reflow, slow-flow and reflow in the

study population Fig 2 The distribution of risk factors in the no-reflow and reflow groups.

xxx–xxx

3.07
0.61,p=0.18).Thenumberoftargetlesionswassignificantly

higherintheno-reflowgroup(28.17
14.08vs.21.07
9.73mm,

p<0.001)

Itwasalsoobservedthattheno-reflowgroupmainlyconsisted

of patients with delayed reperfusion of 6h (70.2% vs 9.7%,

p<0.001)andahighthrombusburden(66%vs.14.9%,p<0.001)

However, the presence of multivessel disease, the IRA, the

targetlesionlocations,thepercentageofstenosis,andthetypeof

lesionwerenotdifferentbetweenthe2groups(p>0.05forall)

The number ofpatients withan ST resolution of <70%was

significantly lower in the no-reflow group (87.2% vs 26.9%

p<0.001)

Theamountofcontrastvolumethatwasusedfortheprimary

PCI was slightly higher in the no-reflow group, but was not

statistically significantly different (163.47
57.7ml vs

167.03
76.11ml;p=0.51).Themeanfluoroscopictimerequired

forthecompletionoftheprimaryPCIwasslightlyhigherforthe

no-reflowgroup,butthisdifferencewasnotstatisticallysignificant

(12.28
8.17minvs.11.47
13.8min;p=0.7)(Table3and4)

Amongtheproceduralfeatures,theincidenceofno-reflowwas

significantlylowerinthedirectstentinggroupthaninthegroup

withstentingwithpre-dilatationorwithballoonangioplasty(6/96

(8.6%),22/75(29.3%),5/8(62.5%),respectively)

There was a significant difference in the use of aspiration

thrombectomy between the no-reflow and the reflow groups

(61.7% vs 31.3%; p<0.001) but this association is by chance

becauseofthehighthrombusburden thatledtotheno-reflow

phenomenon

Tirofibanusewasalsosignificantlyassociatedwithno-reflow

(34%vs.9.7%;p<0.001)buttheassociationisbychancebecause

thehighthrombusburdenledtotheno-reflowphenomenonin

spiteofpharmacologicaltreatmentandtreatmentwithaspiration

thrombectomy

There was no significant difference in the use of repeated

balloondilatationandpost-dilatationbetweenthetwogroups

15.Complicationsandno-reflow Therewasonecaseofsustainedventriculartachycardia(VT)in theno-reflowgroupandnoneinthereflowgroup(NS,2.1%vs.0;

p=0.09)

Cardiogenicshockwasslightlyhigherintheno-reflowgroup butwasnotstatisticallysignificant(6.4%vs.2.2%;p=0.172) The rateof post-interventionalbleeding complications (TIMI minor)washigher inthereflow groupbut wasnotstatistically significant(noTIMIminorbleedintheno-reflowgroupvs.2.2%in thereflowgroup,p=0.301).TherewerenocasesofTIMImajor bleedinginthiscohort

Therewere6casesofin-hospitaldeathsintheno-reflowgroup and7casesinthereflowgroup.Thisdifferencewasnotstatistically significant(p=0.0848)(Figs.4and5)

16.Independentpredictorsoftheno-reflowphenomenon Univariate analyses identified that age>60years (OR=6.146, 95%CI 2.937–12.86,p<0.001),reperfusiontime>6h(OR=21.94, 95%CI9.402–51.2,p<0.001),lowinitialTIMIflow(1)(OR=12.12, 95%CI 4.117–35.65,p<0.001),low initialTMPG flow (1) (OR= 36.19, 95%CI 4.847–270.2, p<0.001), a high thrombus burden (OR=11.04,95%CI 5.124–23.8, p<0.001), a long target lesion

Fig 3 Myocardial infarction types in the no-reflow and the reflow groups.

Table 3

Angiographic data in the no-reflow and reflow groups – continuous variables (N = 181).

Fig 4 STR and in-hospital mortality in the reflow and no-reflow groups.

Fig 5 Independent predictors of the no-reflow phenomenon xxx–xxx

2.937,95%CI 1.112–7.756,p=0.025) and overlap stenting (OR=

3.733,95%CI1.186–11.75,p=0.017)weretheindependent

predic-torsofno-reflow(Table5).CPKMBwasnotincludedasapredictor

as it was a consequence of no-reflow and not a predictor (it

occurredaftertheno-reflow)(Fig.6)

Multiple stepwise logisticregression analysis identified that

reperfusiontime>6h(OR=13.844,95%CI3.214–59.636,p<0.001),

age>60years (OR=8.886,95%CI 2.145–36.80, p=0.003),a long

targetlesion(OR=8.637,95%CI1.975–37.768,p=0.004),lowinitial

TIMIflow(1)(OR=20.861,95%CI1.739–250.290,p=0.017)were

foundtobesignificantlyassociatedwithno-reflowandwerethe

independentpredictorsoftheno-flowphenomenon(Table6)in

ourstudy(7)

Wealsoincluded30-daymortality.The30daymortalityinthe no-reflowgroupwas6%andinthereflowgroupwas7%(NS)

17.Discussion 17.1.Historicaloverviewofnore-flow Thetermno-reflowwasfirstusedbyMajnoandcolleaguesin thesettingofcerebralischaemiain1967.15Thisphenomenonwas initially described by Krug et al.10 during the induction of myocardialinfarctioninthecaninemodelin1966andagainby Kloneretal.7in1974,atwhichtimeitoccurredfor90minafter temporary epicardial coronary artery occlusion Myocardial tracers,suchascarbonblackorthioflavinS(afluorescentstain

Table 4

Angiographic data in the no-reflow and reflow groups – categorical variables (N = 181).

No-reflow (N = 47) Reflow (N = 134) x2

p

xxx–xxx

for theendothelium),were injectedtodocument uniformflow

distributionacrossthemyocardialtissueafter40minofocclusion

After 90min, persistent subendocardial perfusion defects were

seenwithno-reflow

17.2.Electronmicroscopicfindingsinno-reflow

Electron microscopic examination shows severe myocardial

capillary damage with a loss of pinocytotic vesicles in the

endothelial cells, endothelial blisters or blebs and endothelial

gapswithneutrophilinfiltration.Intraluminalcapillaryplugging

by neutrophils and/or micro thrombi with myocardial cell

swellingwasalsonoted

Kloner et al.7 added theconcept of ‘coronary’ no-reflow, in

accordancewiththedescriptionsofthisphenomenoninthebrain,

kidneyandskintissues.15,16

17.3.Thefirstclinicalobservationofno-reflow

The first clinical observation of coronary no-reflow was

reported by Schofer et al.11 in 1985 in 16 patients who had

experiencedafirstanteriormyocardialinfarction.Thesepatients

wereevaluatedwithdualscintigraphicstudiesusingthallium-201

(myocardialuptake)andtechnecium–99mmicroalbumin

aggre-gates (myocardial perfusion) Amongst 11 patients who were

studiedpriortoandimmediatelyafterthrombolysis,onepatient

whohadidenticaldefectsaccordingtobothtechniques priorto

thrombolysisdevelopedafurtherextensionoftheperfusiondefect

afterthrombolysiswithtechnecium–99mwithoutachangeinthe

sizeofthethallium-201uptakedefect.Therefore,Schoferetal.11

concluded that no-reflow also occurredin humans during the

reperfusionofacutemyocardialinfarction.11

Oneyearlater,Batesetal.reportedtheangiographiccorrelation

ofno-reflowasanabnormallyslowantegradecontrastfillinginthe

infarct-related artery.17 In 1991, Pomerantz et al reportedfive

more cases of no-reflow that were successfully treated by

intracoronary verapamil.18 The first clinical case of no-reflow

duringPTCAforacutemyocardialinfarctionwasreportedbyFeld

etal.in1992.19

17.4.Pathophysiologyofno-reflow Thelongertheischemia,themoreseveretheno-reflow.7

Aftertheprolonged cessation of coronaryocclusionand the restorationofbloodflowtotheepicardialcoronaryarteries,there

issufficientstructuraldamagetothemicrovasculaturetoprevent therestorationofnormalbloodflowtothecardiacmyocytes.20The structural damage is more pronounced with longer periods of coronaryocclusion.7No-reflowappearstobeaprocessratherthan

an immediateevent thatoccurs at themomentof reperfusion Experimental studiesshowed that theno-reflowareaincreases withtimeafterreperfusion.21,22

17.5.Microscopicexaminationinno-reflow Microscopicexaminationshowedthatmyocardialcellswithin theno-reflowareawereswollen.Thecapillaryendotheliumwas damaged and had areas of regional swelling with large intra-luminal protrusions that, in some cases, appeared to plug the capillarylumen.7

Intravascularpluggingbyfibrinorplateletsmayalsocontribute

totheno-reflowphenomenon.23,24Treatmentwiththefollowing

Table 5

Univariate analysis.

Table 6

Multivariate analysis (binary logistic regression).

Lower Upper Reperfusion time <0.001 13.844 3.214 59.636

Target lesion length 0.004 8.637 1.975 37.768

Initial TIMI flow 0.017 20.861 1.739 250.290

KiIlip class III/IV 0.698 1.468 0.210 10.249

Overlap stenting 0.487 0.456 0.050 4.181 Fig.6. Theforestplotforfactorsassociatedwithno-reflow derived from univariate

analysis of binary logistic regression.

xxx–xxx

drugsimproves no-reflow:ibuprofen25,prostaglandin E126,and

vascularwashoutwithheparinizedsaline.27

Leukocyteintravascularpluggingappearstoplayanimportant

roleinthepathophysiologyofno-reflow.Researchers28 showed

that the no-reflow areas had evidence of capillary leukocyte

plugging.28Neutropenicanimalsdonotdevelopno-reflow.29

Diminishedflowthroughthemicrovasculaturecomparedwith

normalzonesisusuallyreferredtoas‘lowreflow.’30

No-reflowcan also occur in vein grafts or even in native coronaries Distal

protectiondevicesmaypreventno-reflow

17.6.Thedefinitionofno-reflow

The no-reflow phenomenon was originally observed in

experimental models of acute myocardial infarction (MI) and

wasdescribedasafailuretorestorenormalmyocardialbloodflow

despitethe removal of the coronary obstruction.7,31 Since that

time, no-reflow has been shown to complicate thrombolytic

therapyandpercutaneousrevascularizationwithPTCA.32,18

Defined angiographically, no-reflow manifests as an acute

reduction in coronaryflow (TIMI grade 0–1) in theabsence of

dissection,thrombus,spasm,orhigh-graderesidualstenosisatthe

originaltargetlesion.Alesserdegreeof flowimpairment(TIMI

grade2)isgenerallyreferredtoas“slow-flow”

17.7.Classesofpatientswhomaydevelopno-reflow

No-reflowhasbeenobservedaftersystemicthrombolysisfor

myocardialinfarction,afterprimaryangioplastyandafterPTCAto

veingrafts.Italsooccursafterrotablationatherectomy.(2–9%)

No-reflowhasbeenfoundtocorrelatewiththetotalburractivation

time33,34andhasbeenfoundtobereversiblein60%ofthecases Intracoronarycalciumantagonistspreventorrestoreflowandso microvascularspasmhasbeenbelievedtobeacauseofno-reflow Longlesions,recentunstableanginaandtheuseofbeta-blockers within24hcanalsocauseno-reflowduringrotablation.35–37 No-reflowafterTECatherectomyisusuallyirreversible.38

No-reflowcanalsooccurafterrescuePCI

17.8.Theclinicalpresentationofno-reflow Theclinicalpresentationoftheno-reflowphenomenonvaries greatlyanddepends ontheclinicalsetting, despiteoftenbeing related to the moment of reperfusion.39 In the catheterization laboratory, theclinical presentation of no-reflow during short-terminterventioninmyocardialinfarctionpatientsisoftensudden anddramatic.Thedyestagnatesinthecoronaryartery,thepatient complains of chest pain, and hemodynamic compromise soon follows The sudden hemodynamic deterioration may also be relatedtoathero-embolismandtheslowingofbloodflowinthe non-culpritarteries.40,41

In the coronary care unit, the presentation is usually less dramatic.Afterthrombolytictherapy,thepatientwillexperience chestpainandST-segmentelevationandmayhavehemodynamic deterioration.32 NewQwaves mayappear42and someofthose patients may be diagnosed as having infarct extensions Older patientswithalowerincidenceofpreinfarctionangina had

no-reflowmoreoften.43Thismaybebecauseischemic precondition-ingpermitsthedevelopmentofcollateralsthatmayprevent

no-reflow.44Theno-reflowphenomenonwasalsofoundinpatients withventriculararrhythmias.45

No-reflowcanalsobeassociatedwithearlycongestiveheart failure,andevencardiacrupture.7,46Todeterminetheprognosisof theno-reflowphenomenon,researchersfollowedup30patients withno-reflowforameanperiodof1.2years.47Theycompared thisgrouptoa controlgroupof90patients, andno-reflowwas associated with more malignant arrhythmias, a lower ejection fraction,andmorecardiacdeath

17.9.Howtodiagnoseno-reflowandslow-flow Slowflowandno-reflowwithimpairedmyocardialperfusion canbediagnosedangiographicallyorbyusingadjunctiveimaging modalities that can quantify myocardial perfusion, such as myocardialcontrastechocardiography

17.10.Myocardialcontrastechocardiography Myocardial contrastechocardiographycan beusedtoassess microvascularfunctionandhasbecomethegoldstandardforthe non- invasive investigation of the no-reflow phenomenon Myocardialcontrastechocardiographywasfirstperformedduring coronary angiography after the injection of microbubbles into infarctrelated arteries afterangioplasty No-reflow zones were seenin25–30%ofpatientswithacutemyocardialinfarction(AMI) despitethedetectionofopenarteriesonangiography.8

Myocardialcontrastechocardiographycanbeperformedatthe bedsidewiththeintravenousinjectionofcommerciallyavailable contrast agents The perfusion defects that are observed on contrastechocardiographywillreflecttheregionsofmicrovascular obstruction, but the infarct size is underestimated After a vasodilatorstress,thedefectsshouldmatchtheinfarctsize.48

17.11.Coronaryangiography Thrombolysisinmyocardialinfarction(TIMI)bloodflowgrades areusedtoevaluatethequalityofcoronaryflowduringcoronary

Fig 7 The forest plot for factors associated with no-reflow derived from

multivariate analysis of binary logistic regression.

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of reperfusion and a TIMI II/III flow identified patients with

successfulreperfusion.50

17.12.Myocardialblush(beyondTIMI3flow)

InpatientswithTIMIblushGrade3,themyocardialblushclears

withinthreecardiaccyclesofwashout.AmongpatientswithTIMI

IIIflow,theassessmentofmyocardialblushthuspermitsfurther

riskstratification;onlypatientswithnormalepicardialflowand

normaltissue-levelperfusionhaveanextremelylowriskofdying

ApoorTIMIperfusiongradeisamarkerofpoorprognosisafter

primaryangioplasty

17.13.Coronarydopplerimaginginno-reflow

Theno-reflowphenomenonhasacharacteristiccoronaryblood

flowpatternwiththreemaincomponents:systolicflowreversal;

reducedantegradesystolicflow;andforwarddiastolicflowwitha

rapid deceleration slope This to-and-fro nature of blood flow

causescoronaryforwardflowtobereduced.IfTIMIIIflowisnoted

afterPCI,theto-and-froflowvelocitypatternimpliesno-reflow,

andfurtherstentingwillnothelp.51

Thecoronarybloodflowvelocitypatternhelpstodifferentiate

between individuals with micro-emboli and those without

Patientswithcoronarymicro-embolihaveaslowforwardflow,

an increase in diastolic-to-systolic flow ratio and an increased

coronaryarterialresistance.52

17.14.Otherimagingmodalities

Nuclearimaging,single-photonemissionCT,theuseofthallium

ortechnetium-99m,andPEThavebeenusedtostudyno-reflow

Contrast-enhanced MRI can alsobe used The firstpass of the

contrastagentand delayed contrast-enhancedMRI20minafter

contrastinjectioncanbeusedtodetectmyocardialnecrosis.53,54

Thrombus aspiration to prevent no-reflow: the role of

mechanicalthrombectomyandaspirationthrombectomy

Itisbelievedthatthemechanicalremovalofthethrombusor

the performance of aspiration thrombectomy will prevent

no-reflow We generally perform aspiration thrombectomy with a

Pronto V4 catheter or a Nipro TVAC catheter Although the

guidelines say not to perform aspiration thrombectomy, we

obtainedgood results Our institutional policy is if thepatient

hasatotallyoccludedcoronaryarteryafterpassingaguide-wire

wedo2or3runsofaspirationthrombectomy.Wehavenothadany

caseofstrokeinthelast3years.Priortothiswehad3strokes.We

arethereforecarefulin

1)makingsureweopentheaspirationcatheteronlyintheareaof

theblockedvessel;

2)closingtheaspirationcatheter(whichisconnectedtoasyringe

thatiskeptatnegativepressure)beforeenteringthepreviously

normal partof thevessel, and we especially close it before

withdrawingthe catheter neara large branch(say near the

mouthofthecircumflexcoronaryartery)toprevent

emboliza-tiontonormalvessels;

3)removingtheaspiration cathetercompletelyfromtheartery

and guide, even in a radial route before giving any check

injectionandallowingabackbleed;

4)performing injections after just withdrawing the aspiration

catheterorballoonintotheaortaintheguidecatheter,which

cancauseembolizationintothecerebralvessels;

5)withdrawingballoons,andnotperforminganinjectionwiththe

balloonintheguidecatheter(especiallyinradialangioplasty)

Ideally,theguidecathetershouldbesteadyandengagedwhile

withdrawingtheaspirationcatheter,againtoprevent emboli-zation

TheTapastrialwasapositivetrialthatshowedthataspiration thrombectomy reduces mortalityduring primary angioplasty.55 However,theTotaltrialandtheTastetrialbothshowedthatthere weremorestrokesinthecontrolarm.56,57Jollyetal.evaluatedthe benefitsofthrombusaspirationin STEMIpatientsataone-year follow-up.Itwasfoundthatroutinethrombusaspirationdidnot reducelonger-termclinicaloutcomesinSTEMIpatientswithinone year, and the mortality was 4 percent in both of the groups Thrombusaspirationmayalsoleadtoembolicstroke

Finally,theACCandESCguidelineshavealsodowngradedtheir recommendationforthrombusaspiration

17.15.Thetreatmentofno-reflow Since no-reflow has been associated with coronary spasm, calciumchannelantagonists,suchasverapamil,havebeenshown

toimproveno-reflow.18Sinceno-reflowhasbeenassociatedwith increasedcoronaryresistance,itispossiblethatthisishowboth sodiumnitroprussideandintracoronarynitroglycerinacttoreduce coronaryresistance

Embryonichaemangioblastshavebeenusedexperimentally.58

Bone marrowderived angioblasts prevent theapoptosis of the myocytesandimprovecardiacfunction

Intracoronarybutnotintravenousadenosinehasbeenshownto improveno-reflow.5

Intracoronaryadrenalinehasalsobeenshowntobeusefulin no-reflow59Authorshavereportedthatthelocalizedinstallationof adenosinethroughcustommadeballoonscansuccessfullyreduce no-reflow.60

Glycoprotein2b/3a inhibitorsappear tohelp in some cases However,neitherdistalprotectionorproximalprotectiondevices help.61,62

17.16.Preventionofno-reflow Thepreventionofno-reflowwouldimprovecardiacmortality afterprimaryangioplasty.Thrombusaspirationfollowedbydirect stenting,toenablethepreventionofembolizationofthethrombus debris,isbelievedtobehelpful

17.17.Howdoesadenosinehelp?

Adenosinelowerstheneutrophilcountsintheinfarctzones, maintainsendothelialintegrityandmayexertacardioprotective effect.InpatientswithacuteMI,intracoronaryadministrationof

24–48mgofadenosinereducesno-reflowafterPCI.63

Nicorandil is a hybrid between a mitochondrial potassium-channel opener and NO, and has shown promising results in patientswithacuteMIwhengivenbeforereperfusion.Thisdrug reducespreloadandafterload,dilatescoronaryresistancevessels, reducestheCa2+overloadofmyocytes,andattenuatesneutrophil activation.64,65Theseactionsareapparentevenwhennicorandilis givenintravenously

Treatmentwithintracoronarynitroprussideorverapamilwas associatedwithasignificantimprovementincoronaryflowandan increaseinTIMIflowgrade.66

Sodium–hydrogenpumpinhibitorshavethepotentialtoreduce reperfusioninjurybyattenuatingintracellularCa2+overload.Inan experimentalstudy,theuseofsuchanagentimproved microvas-cularfunctionandmyocardialbloodflow,andreducedinfarctsize Large-scale multicentre trials did not show any benefit of cariporide or eniporide on functional and clinical outcomes in patientswithawiderangeofischemicrisks.67–69

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Other adjunctive agents, including monoclonal antibodies

against leukocytes, complement receptor inhibitors, adhesion

molecule antibodies, endothelin-A selective antagonists, and

erythropoietinhavebeentried

Post-conditioning has been associated with reduced

no-reflow.70Themechanismofprotectioninvolvestheactivationof

extracellular-signal-regulated kinase, the production of nitric

oxide, the opening of mitochondrial potassium channels, and

theinhibition oftheopeningof themitochondrial permeability

transitionpore.Staatetal.71performedpost-conditioningduring

PCIforacuteMIinhumans,startingwithin1minofreflow,and

achieved reflow by inflating an angioplasty balloon for 1min

followedbydeflationfor1min4times.71

17.18.Predictorsofno-reflowinotherstudies

Studies have been undertaken to identify clinical factors,

angiographicfindingsandproceduralfeaturesthatcanpredictthe

no-reflowphenomenoninpatientswithAMIafterprimaryPCI

InthestudyconductedbyHuaZhouetal.72in312consecutive

patientswithAMIwhohad beentreatedfromJanuary2008 to

December2010 atthe CardiologyDepartmentof EastHospital,

Tongji University School of Medicine, fifty-four (17.3%) of the

patientsdevelopedNRphenomenonafterprimaryPCI

Univariate analysis showed that age, time from onset to

reperfusion, systolic blood pressure (SBP) on admission, Killip

classofmyocardialinfarction,intra-aorticballoonpump(IABP)use

beforeprimaryPCI,TIMIflowgradebeforeprimaryPCI, typeof

occlusion,thrombusburdenonbaselineangiography,targetlesion

length,reference luminal diameter and method of reperfusion

werecorrelatedwithno-reflow(p<0.05forall).Multiplelogistic

regressionanalysisidentifiedthatage>65years(OR=1.470,95%

confidenceinterval(CI)1.460–1.490,p=0.007),>6hfromthetime

ofonsettoreperfusion(OR=1.270,95%CI1.160–1.400,p=0.001),

low SBP on admission (<100mmHg, OR=1.910, 95%CI 1.018–

3.896,p=0.004),IABP usebeforePCI (OR=1.949,95%CI 1.168–

3.253, p=0.011), low (1) TIMI flow grade before primary PCI

(OR=1.100,95%CI1.080–1.250,p<0.001),highthrombusburden

(OR=1.600,95%CI 1.470–2.760,p=0.030),andlongtargetlesion

(OR=1.948, 95%CI 1.908–1.990, p=0.019) on angiography were

independentpredictorsofno-reflow

17.19.Delayintreatmentandno-reflow

Delayedpresentationtothehospitalcausesdelayedtreatment

Thisisdirectlyrelatedtoanincreaseinno-reflowandmortality

Widecampaignstobring thepatienttothehospitalearlierwill

preventno-reflow

Delayedreperfusion(alongdurationfromonsettoreperfusion)

isrelatedtono-reflow.Theabovestudyshowedthatpatientswith

a long duration before reperfusion (>6h) had a significantly

greaterthrombusburdenanda1.3-foldincreaseintheno-reflow

ratethanpatientswithashortdurationofreperfusion.73

Yipetal.70demonstratedthatinpatientswithAMIwhohada

highthrombusburden,therateofno-reflow waslowerthanin

thosewithreperfusioninlessthan4h.Thisindicatesthepossible

correlationof athrombusburdenwiththedurationof

reperfu-sion.70

PatientswhohadalowTIMIflowintheIRApriortoPCIhada

higherrate of no-reflow than thosewith a good (2) TIMI flow

accordingtobaselineangiography.DeLucaetal.foundthata

pre-PCIgoodTIMI flow wasstronglyrelated tothepost-procedural

TIMI 3 flow, myocardial blush grade 2–3 and lower enzymatic

infarctsize.71AgoodpatencyoftheIRApriortoPCIsuggestsa

lowerthrombusburden,a spontaneousendogenouslysisofthe

thrombus,theresolutionofvasospasmandasmallerinfarctsize

AnIVUSsub-studyofno-reflowhasshownthatasoftlipidrich plaque is associated with no-reflow more so than a hard atheroscleroticplaque.72

Tanakaetal.usedIVUStoexamineplaqueburdenandidentified thatahigherlipidcontentintheinnerplaquecoreandthewidthof theexternalelasticmembranewereindependentmarkersforthe no-reflowphenomenon.73

Our study demonstrates that the presenceof large lesioned vessels,especiallythosewithanIRAdiameterabove4mm,was associatedwiththeoccurrenceofno-reflow.Patientswithlesions thatwerelargerthan20mminsizeweremorelikelytodevelop no-reflow after primary PCI than those withlesions that were smallerthan20mminsize.Largevesselsareabletocontainlarge amountsofplaquelipidorthrombi.Thelargerthelesionedvessels, theslowertheflowvelocity.Thelongerthetargetlesion,thelarger theamountofthrombusandplaqueburden.Thiswouldexplain the high risk for slow/no-reflow that was observed in these patientsafterprimaryPCI.74,75

Kirmaetal.reportedtheirfindingsinaseriesof382consecutive patients withAMI who underwent primary PCI within 12hof symptom onset.46 Patients with ischemic symptoms that had persisted for more than 12h were also included Clinical, angiographicandproceduraldatawerecollectedforeachsubject Ninety-three (24.3%) of the patients developed no-reflow, and their findings were compared withthose of the reflow group Univariateanalysisshowedthatadvancedage(>60years),delayed reperfusion(4h),low(1)TIMIflowpriortoPCI,cut-offtype total occlusion, high thrombus burden according to baseline angiography,thepresenceofalongtargetlesion(>13.5mm)and largevesseldiameterallcorrelatedwithno-reflow(p<0.05for all).Multiplelogisticregressionanalysisidentifiedthatadvanced age(oddsratio(OR)1.04,p=0.001),delayedreperfusion(OR1.4,

p=0.0004),lowTIMIflowbeforeprimaryPCI(OR1.1,p=0.0002), targetlesionlength(OR5.1,p=0.0003)andhighthrombusburden (OR1.6,p=0.03)onangiographyasindependentpredictorsofthe no-reflowphenomenon.76

18.Limitationsofthisstudy

 Asmallsample size.Weonlyincluded181patientsinthis 6-monthperiodasthiswasapost-graduatethesisthatcouldbe startedonlyafterclearancefromtheethicalcommitteeandthe researchcommittee.Furthermore,wehadonlyone catheteriza-tionlab at thetime of the study (presently we have almost finishedinstallingasecondcatheterizationlabsowewillsoonbe abletoevaluatemorepatients.Inaddition,veryoftenwhena patientwithprimaryangioplastyarrivedatthelab,theywould exhibit CTO (chronic total occlusion) We did not make the patient wait, we generally asked for thrombolysis with streptokinase

 Wehavenotanalysedthemicrovascularfunctionandno-reflow usingmyocardialcontrastechocardiographyornuclear scintig-raphy

 Thisisanobservationalstudyandnotaprospectiverandomized trial.Thehighernumberofpatientsintheno-reflowgroupwho received GpIIb/IIIa inhibitors and who underwent thrombus aspirationwasmostlikelyrelatedtotheirinitiallargethrombus burden

 Weappeartohavearelativelyhigherrateofno-reflow.Thisis probablybecauseofthereasonsgivenbelow

 Recentlywehavechanged totreating loadingprimary angio-plastypatientswithTicagrelor.Since thenweappear tohave fewer no-reflow patients in spite of some of the patients presentingafterninehours.Soitispossiblethatsincewewere usingclopidogreltherewasahigherrateofno-reflow.Ofcourse

wenowaggressivelygiveintracoronaryadenosinetwoorthree

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