ArchivesofCardiovascularDisease(2015)108,39—49
Availableonlineat
ScienceDirect
www.sciencedirect.com
CLINICAL
RESEARCH
Ischaemic
postconditioning
reduces
infarct
size:
Systematic
review
and
meta-analysis
of
randomized
controlled
trials
Réduction
de
la
taille
d’infarctus
du
myocarde
par
le
postconditionnement
ischémique
:
revue
systématique
et
méta-analyse
des
essais
thérapeutiques
contrôlés
randomisés
Caroline
Touboul
a,
Denis
Angoulvant
a,b,∗,
Nathan
Mewton
c,
Fabrice
Ivanes
a,b,
Danina
Muntean
d,
Fabrice
Prunier
e,
Michel
Ovize
c,
Theodora
Bejan-Angoulvant
f,g,haCHRUdeTours,ICCU&Cardiologydepartment,TrousseauHospital,37000Tours,France
bUniversitéFranc¸oisRabelais,EA4245CellulesDendritiquesImmunomodulationetGreffes,
FHU‘‘SUPORT’’,37000Tours,France
cInsermU1060-CarMeN,serviced’explorationsfonctionnellescardiovasculaires,centre
d’investigationclinique,1407,universitéClaude-BernardLyon1,Louis-PradelHospital,CHU
deLyon,Lyon,France
dDepartmentofPathophysiology,‘‘VictorBabes’’UniversityofMedicineandPharmacy,
Timisoara,Romania
eEA3860cardioprotectionremodelageetthrombose,CardiologyDepartment,université
d’Angers,CHUd’Angers,Angers,France
fCHRUdeTours,departmentofPharmacology,Tours,France
gCNRSUMR7292,Tours,France
hUniversitéFranc¸oisRabelais,GICC,Tours,France
Received3June2014;receivedinrevisedform29July2014;accepted28August2014 Availableonline13November2014
Abbreviations: AUC,areaunderthecurve;CI,confidenceinterval;CK,creatinekinase;CKMB,creatinekinasemyocardialband;CMR, cardiacmagneticresonance;CMR-IS,estimationofISbyCMR;cSTR,completeST-segmentresolution;IPost,ischaemicpostconditioning;IS, infarctsize;ITT,intention-to-treat;LVEF,leftventricularejectionfraction;PPCI,primarypercutaneouscoronaryintervention;RR,relative risk;SMD,standardmeandifference;SPECT,single-photonemissioncomputedtomography;SPECT-IS,directmeasurementofISbySPECT; STEMI,ST-segmentelevationmyocardialinfarction;Tropo,troponinTorI.
∗Correspondingauthor.ICCU&CardiologyDepartment,TrousseauHospital,CHRUdeTours,37044Tourscedex9,France.
E-mailaddress:[email protected](D.Angoulvant). http://dx.doi.org/10.1016/j.acvd.2014.08.004
KEYWORDS Ischaemic postconditioning; Infarctsize reduction; Meta-analysis; Randomized controlledtrials Summary
Background.—Infarct size (IS) is a major determinant ofpatient outcome after acute
ST-segmentelevationmyocardialinfarction(STEMI).Interventionsaimedatreducingreperfusion injury,such ascardiacischaemicpostconditioning (IPost),may reduceISandimprove clini-caloutcomes.IPosthasbeenshowntobefeasibleinpatientswithSTEMItreatedbyprimary percutaneouscoronaryintervention(PPCI).
Aims.—ToprovideanupdatedsummaryoftheefficacyofIPost,assessedbyanalysingaccurate
surrogatemarkersofIS.
Methods.—Weperformedameta-analysisofrandomizedcontrolledtrialsthatevaluatedthe
efficacy ofIPostinSTEMIpatients undergoingPPCI. Themain outcomewas area underthe curveofserum creatinekinaserelease(CK-AUC).Secondaryoutcomeswereothersurrogate biomarkersofIS,completeST-segmentresolution,directmeasurementofISbysingle-photon emissioncomputedtomographyandestimationofISbycardiacmagneticresonance(CMR-IS).
Results.—Elevenstudieswereretrieved,including1313STEMIpatientsundergoingPPCIwithor
withoutIPost.Comparedwithcontrols,weobservedasignificantreductioninCK-AUC(standard meandifference[SMD]—2.84IU/L,95%CI—5.43to—0.25IU/L;P=0.03).Othersurrogate mark-ers,such asCMR-IS(SMD—0.36,95%CI—0.88to0.15;P=0.16),showed anon-significantIS reductionintheIPostgroup.
Conclusions.—Thismeta-analysis,dealingwithaccuratesurrogatemarkersofIS,suggeststhat
IPostreduces IS.However, resultsshouldbeinterpreted cautiously becauseoflimited sam-plesizesandsignificantheterogeneity.Whetherthistranslatesinto improvementsincardiac functionandpatientprognosisstillneedstobedemonstratedinlargerprospectiverandomized controlledstudiesthatarepoweredsufficiently.
©2014ElsevierMassonSAS.Allrightsreserved.
MOTSCLÉS Postconditionnement ischémique; Réductiondetaille d’infarctus; Méta-analyse; Essaithérapeutique contrôlérandomisé Résumé
Objectifs.—Synthétiserlesdonnéesactuellesdelascienceconcernantl’efficacitédu
postcon-ditionnementischémiquesurlaréductiondetailled’infarctusdumyocarde(IDM).
Pré-requis.—Latailled’IDMestundéterminantmajeurdupronosticdespatientsaudécours
d’unSTEMI.Lesinterventionsvisantàprotégerdeslésionsdereperfusioncommele postcondi-tionnementischémiquepourraientréduirelatailled’IDMetaméliorerlepronostic.Desessais cliniquesontmontréquelepostconditionnementischémiqueétaitréalisablechezlespatients revascularisésparangioplastieprimaireàlaphaseaiguëd’unSTEMI.
Méthodes.—Nousavonsréaliséuneméta-analysedesessaisthérapeutiquesrandomiséset
con-trôlésévaluant l’efficacitédupostconditionnementischémiqueàla phaseaiguëd’unSTEMI revasculariséparangioplastieprimaire.Lecritèremajeurétaitl’airesouslacourbe(AUC)des CPK.Lescritèressecondairesétaientd’autresbiomarqueursdetailled’IDM,larésolutiondu segmentST,etlatailled’IDMestiméeparscintigraphieouIRMmyocardique.
Résultats.—Onzeétudesincluant1313patientsontétéretenues.Notreanalyseobjectiveune
réductionsignificativedel’AUCdesCPK(SMD−2,84,95%CI−5,43,−0,25IU/L,p=0,03)dans legroupeactif.Ellemontreunetendancenonsignificativeenfaveurdecettemêmeréduction danslegroupeactifsurlesautresmarqueursdesubstitutioncommel’IRM(SMD−0,36,95%CI −0,88,0,15,p=0,16).
Conclusions.—Nosrésultatssuggèrentquelepostconditionnementischémiqueréalisélorsdela
revascularisationd’unSTEMIparangioplastieprimairepermetd’obteniruneréductiondetaille d’IDM.Cesrésultatssontàinterpréteravecprudenceenraisondelapetitetailledeseffectifs etd’unehétérogénéitésignificative.Desessaisthérapeutiquescontrôléssurdelargeseffectifs sontnécessairespourdémontrerl’efficacitédecetteréductionsurdescritèrescliniquesetsur lepronosticdespatients.
©2014ElsevierMassonSAS.Tousdroitsréservés.
Background
Despitecurrentoptimaltreatment,coronaryheartdisease morbidityandmortalityremainsignificant,pavingtheway forthedevelopmentofnewcardioprotectivetherapies[1].
Timelyreperfusionisthemosteffectivetreatmenttoreduce thesizeofaninfarctresultingfrommyocardialischaemia. However,reperfusionhasthepotentialtoinduceadditional lethal injury, identified as reperfusion injury, which can be responsiblefor up to40% of thefinal infarct size (IS).
Meta-analysisofischaemicpostconditioning 41 BecauseISis knowntobeamajordeterminantofpatient
prognosis, any intervention that reduces its extent may resultinaclinicalbenefit[2].
Ischaemic preconditioning and postconditioning are interventions with multiple and interacting components marshalledagainstmyocardialreperfusioninjuryby endoge-nous cardioprotective mechanisms [3]. Cardiac ischaemic postconditioning (IPost) is defined as rapid intermittent interruptionsofbloodflowintheearlyphaseofmyocardial reperfusion,feasibleinpatientswithST-segmentelevation myocardialinfarction(STEMI)revascularizedbyprimary per-cutaneouscoronaryintervention(PPCI)[3].
Mostclinical trialsevaluatingthebenefitof IPostwere smallsingle-centrestudiesthatreportedconflictingresults regarding IS reduction [4,5]. Three meta-analyses inves-tigating the effect of IPost have already been published
[6—8].These meta-analyseseither usedsuboptimal surro-gatemarkersofmyocardialIS,suchaspeaknecrosismarker levels,or combineddifferent markers in the same analy-sis.MoreevidenceisneededbeforerecommendingIPostin routineclinicalpractice.
Theaimofthissystematicreviewandmeta-analysiswas toprovideanupdatedsummaryofpublishedrandomized tri-alsinvestigatingtheefficacyofIPostusingreliablesurrogate markersofISreduction.
Methods
This review wasconducted andreportedaccording tothe PreferredReportingItemsforSystematicreviewsand Meta-Analyses(PRISMA)criteria[9].
Information
sources
and
search
strategy
Wesearchedelectronicdatabases(PubMed,Cochrane)for studiespublishedbeforeDecember2013.Inordertohave comparableinformationfromeligiblestudies,wecollected additionaldatabycommunicatingdirectlywiththeauthors. Thefollowingkeywordswereused:‘‘ischaemic postcon-ditioning’’;‘‘myocardialinfarction’’;and‘‘acutecoronary syndrome’’. Our search was restricted to human and randomized controlled studies, without any language restriction.Wealsoreviewedthereferencelistsofpublished meta-analysesandselectedstudies.Eligibility
criteria
and
study
selection
The selection of eligiblestudies wasdone by twoauthors (C.T., D.A.), with disagreements resolved by consensus betweenthesetwoauthors.
Inclusion criteria were randomized controlled trials enrollingSTEMIpatientsadmittedduringtheacutephasefor PPCI,comparingIPost(activegroup)witharoutine interven-tion(controlgroup),andevaluatingoneormoresurrogate markersof IS.Wedecidedaprioritoexcludestudies that systematicallyusedintracoronaryadenosineinjectionatthe timeofreperfusion,becauseadenosineisaknownactivator ofcardioprotectivesignallingpathways,inducingpotential pharmacologicalconditioning,whichmaydilutetheeffect ofIPostonISreduction[3].
The following surrogate markers of IS were consid-ered: area under the curve (AUC) of serum creatine kinase (CK) release (CK-AUC); AUC of CK myocardial band release (CKMB-AUC); AUC of troponin (T or I isoforms)release(Tropo-AUC);complete ST-segment reso-lution(cSTR),definedasSTR>70%afterreperfusion;direct measurement of IS by single-photon emission computed tomography(SPECT);orestimationofISasapercentageof theareaatriskbycardiacmagneticresonance(CMR).
Risk
of
bias
in
individual
studies
Oneauthor(C.T.)assessedthemethodologicalqualityofthe selectedtrialsaccordingtotheCochraneriskofbias crite-ria.Weconsideredthefollowingdomains:randomsequence generation and allocation concealment (selection bias); blindingofparticipantsandpersonnel(performancebias); blindingofoutcomeassessment(detectionbias);and com-pletenessofthefollow-up,intention-to-treat(ITT)analysis anddropouts(attritionbias).
Based onthe abovecriteria, studies were dividedinto threecategories:low(allcriteriawereatlowriskofbias); high (at least one criterion was at high risk of bias); or unclearifotherwise.
Outcomes
and
comparisons
OurmainoutcomewastheeffectofIPostonCK-AUC. Sec-ondaryoutcomeswere:otherbiologicalsurrogatemarkers (CKMB-AUC,Tropo-AUC);cSTRasaclinicalsurrogatemarker ofischaemiaresolution;andimagingsurrogatemarkersof IS,measuredbySPECT(SPECT-IS)orestimatedbyCMR (CMR-IS).
Data
extraction
process
Datafromeligibletrialswereextractedbyoneauthor(C.T.). Wecontacted authorsbye-mail wheneveradditionaldata wereneeded.
Statistical
analysis
Weextractedaggregatedatafrompublishedreports. Sum-marymeasures are reportedasstandard mean difference (SMD)±standard deviation for continuous variables (CK-AUC,CKMB-AUC,Tropo-AUC,SPECT-ISandCMR-IS)asstudies assessed the same outcome but measured it in a variety ofways.Summaryrisk ratios(RRs)arereportedfor binary variables(cSTR)with95%confidenceintervals(CIs).Weused afixed-effects model,andifsignificantheterogeneity was observed,a random-effects modelwasperformed. If het-erogeneity persisted after using a random-effects model, wethenperformedasensitivityanalysis,byexcludingone trialatatime.Wetriedtoexploreheterogeneityfurtherby consideringcharacteristicsatbothtrialandpatientlevels. Aninverse-variancemodelwasusedtopoolthedata. Sta-tisticalheterogeneityacrosstrialswasassessedwithChi2,I2 andTau2statistics.Heterogeneitywasconsideredsignificant iftheP valuewas<0.1 andheterogeneity wasconsidered highifI2was>50%.Riskofbiasassessmentbyvisual inspec-tionoffunnelplotwasnotrelevantduetothesmallnumber
Figure1. Flowdiagramofstudyselection.
of included studies. Statistical analyses were performed usingRevMansoftware(version5.1).
Results
Included
studies
Thenumbersofstudiesidentifiedateachstageofthe sys-temicreviewareshowninFig.1.Afterremovingduplicate references,the searches identified595 records.Based on titleand/or abstract,37 relevant articles were retrieved for full-textreading. We excluded 22 articlesfor the fol-lowingreasons:16 werenotrandomizedcontrolledtrials; threewere meta-analyses; one did not report any surro-gatemarkerofIS;andtwodealtwiththesamedatabaseas eligiblestudies.Weexcludedafurthertwotrialsthat sys-tematically usedintracoronary adenosine injection at the time of reperfusion and two trials published in Chinese
[10,11],aswe didnotsucceedinobtaining datafromthe authors.Elevenstudies[4,5,12—22]werefinallyincludedin thisreview,correspondingto1313patients(646randomized totheIPostgroupand667tothecontrolgroup)(Table1). Additionaldatawereobtainedbycontactingtheauthorsof threestudies[4,17,18].ThestudiesbyLonborgetal.[14,15]
andThunyetal./Mewtonetal.[17,20]werereportedintwo
publicationseach,soweincludedthedataasonestudyonly foreachgroup.
Patientshad a mean age of 60.4 years and were pre-dominantlymen(Table1).Patientexclusioncriteriainthe includedstudieswerehomogenous:cardiacarrest; cardio-genicshock; leftmain coronaryarteryocclusionor severe stenosis; bloodflow inthe infarct-relatedartery> throm-bolysisinmyocardialinfarction(TIMI)grade1atthetimeof the diagnosis coronaryangiography;obvious coronary col-lateralstotheriskregion;previousmyocardialinfarctionor preinfarctionanginawithin48hours;priorcoronarybypass surgery or PCI; and left bundle branch block. IPost pro-tocols were different in the various studies but were all performed within1minute of reflowwith balloon reinfla-tionat4to6atm(Fig.2).Threestudies[5,17,19,20]came fromthesameresearchgroupandusedthesameIPost pro-tocol, with four cycles of 1minute of balloon reinflation abovetheindexlesionfollowedby1minuteofreperfusion immediatelyafterdirectstenting.IPostprotocolswere sim-ilarinthreeotherstudies[4,13,18],butballoonreinflation wasperformedatthesamelocationasthePPCIinsidethe implantedstent.Inthefiveotherstudies,theIPostprotocol wasperformedbeforestentimplantation,justafterballoon angioplasty:fourcyclesof1minuteofinflationand1minute ofdeflation[21]orfourcyclesof30secondsofinflationand 30secondsofdeflation[14,15]withstentimplantationleft
Meta-analysis
of
ischaemic
postconditioning
43
Table1 Mainstudycharacteristics.
Studies Numberofpatients Meanage
(years) Men/women (n/n) Ischaemia duration(hours) IPost protocol
Culpritarterya Summary
riskofbias
Outcomes reported
IPost Control IPost Control
Yangetal.,2007[22] 23 18 61 31/10 5.2 4.4 30s×3 LAD>RCA>LCX U CK-AUC;cSTR;
SPECT-IS
Maetal.,2006[16] 47 47 64 64/30 6.6 7.1 30s×3 LAD>RCA>LCX H
Staatetal.,2005[5] 16 14 57 25/5 5.3 5.5 60s×4 RCA>LAD U CK-AUC
Thibaultetal.,2008[19] 17 21 56 25/13 4.7 4.9 60s×4 LAD>RAD L CK-AUC;
Tropo-AUC; SPECT-IS
Lonborgetal.,2010[14,15] 59b 59b 62 92/26 4.0 4.3 30s×4 RCA>LAD>LCX U cSTR;CMR-IS
Sorenssonetal.,2010[18] 45b 45b 63 65/25 2.8 3.1 60s×4 RCA>LAD>LCX U CKMB-AUC;
Tropo-AUC; CMR-IS
Freixaetal.,2012[4] 39b 40b 60 62/17 5.4 5.0 60s×4 LAD>RCA L cSTRc;CMR-IS
Fanetal.,2011[12] 22 28 66 31/19 MD MD 30s×3 MD U
Thunyetal.,2012[17,20] 25 25 57 37/13 4.8 3.6 60s×4 LAD>RCA>LCX U CMR-IS
Xueetal.,2010[21] 23 20 58 41/2 4.1 5.4 60s×4 LAD>RCA U CKMB-AUC;
cSTR; SPECT-ISd
Hahnetal.,2013[13] 350 350 60 537/163 3.3 3.2 60s×4 LAD>RCA>LCX L cSTR
Total 646 667 60.4
AUC:areaunderthecurve;CK:creatinekinase;CKMB:creatinekinasemyocardialband;CMR:cardiacmagneticresonance;cSTR:completeST-segmentresolution;H:highriskofbias; IPost:ischaemicpostconditioning;IS:infarctsize;L:lowriskofbias;LAD:leftanteriordescendingartery;LCX:leftcircumflexartery;MD:missingdata;RCA:rightcoronaryartery; SPECT:single-photonemissioncomputedtomography;U:unclearriskofbias.
aCulpritartery:referstothemostfrequentlocation(inpercentages)ofthearteryresponsibleforST-segmentelevationmyocardialinfarctionineacharticle. b Notintention-to-treat.
c ResultswerereportedasaverageSTRineachgroup(insteadofcSTRdefinedbySTR>70%)andhencecouldnotbeusedforthequantitativemeta-analysis. d Resultswerereportedintheformofascore(semi-quantitativemethod)andhencecouldnotbeusedforthequantitativemeta-analysis.
Figure2. Differentischaemicpostconditioning(IPost)protocols performed in studies included in the qualitative analysis. Stent implantationwasperformedusingdirectstentingorafterfirst bal-looninflationorafterIPostsequences.Bracketsindicatethatstent implantationwasnotpartoftheprotocoland wasthereforeleft totheoperator’spreference. Blacksquares represent intracoro-naryballoonreinflation(at4to6atm)afterrevascularizationand localizationinsidetheinfarct-relatedartery.
tothediscretionoftheoperator;threecyclesof30seconds ofinflationand30secondsofdeflationfollowedbystenting [12,22]orwithoutstenting[16].
Onlythreestudies[4,13,19]wereatlowriskofbiasfor allconsideredcriteria,andone[16]wasconsideredathigh riskofbiasbecauseofarandomizationmethodbasedonthe dateofadmission.Theothersevenstudieswereconsidered ashavinganunclearriskofbias(Table1).
Eight studiesprovidedatleast partialdataonIS surro-gates(Table 1) andcould beincluded in thequantitative analysis.Three studies provideddata on CK-AUC, two on CKMB-AUC, two on Tropo-AUC, four on cSTR, three on SPECT-IS(althoughone[21]presentedresultsinawaythat preventedcomparisonwiththeresultsfromthetwoother studies)andfouronCMR-IS.
Surrogates
biomarkers
of
infarct
size:
CK-AUC,
CKMB-AUC
and
Tropo-AUC
IPostwasassociatedwithasignificantreductioninCK-AUC (SMD—2.84IU/L,95% CI—5.43to—0.25IU/L;P=0.03)in three studies [5,19,22] (Fig. 3), but withsignificant het-erogeneity (Chi2=47.1, P<0.001; I2=96%; Tau2=4.88). In
thesensitivityanalysis,heterogeneitydisappearedwiththe exclusionofthestudybyYangetal.[22];thisstudywas dif-ferentfromthetwootherstudies[5,19]regardingpatient profiles(morehypertensionanddiabetes)andpatient selec-tion(noagelimitation,nospecificationfor thetimefrom chestpain onsettoPPCI).Of note,the twoother studies
were performed by the same research group. CK dosage methods weredifferentin thestudyby Yangetal. (auto-matedanalyserSynchronLX20;BeckmanCoulter,Brea,CA, USA)comparedwiththeothertwostudies(CKKit;Beckman Coulter).Inaddition,theIPostprotocolwasdifferentinthe study byYangetal.comparedwiththeother twostudies (Fig.2).
IPostwasnotassociated witha significant reductionin CKMB-AUC (SMD —0.35 IU/L, 95% CI —0.96 to 0.26 IU/L;
P=0.27) in two studies [18,21] (Fig. 3), with moderate heterogeneity (Chi2=2.58; P=0.11; I2=61%; Tau2=0.12).
Heterogeneitybetweenthetwostudiescouldbeexplained bytheuseofdifferentdosagemethodsforbloodanalysisand byfewerbloodsamplingsinthestudybyXueetal.[21].
IPostwasnotassociated witha significant reductionin Tropo-AUC (SMD —0.28 IU/L, 95% CI —1.04 to 0.48 IU/L;
P=0.48)intwostudies[18,19](Fig.3),withsignificant het-erogeneity between studies (Chi2=3.67; P=0.06; I2=73%;
Tau2=0.22).Heterogeneitybetweenthetwostudiescould
beexplainedbytheuseofdifferenttroponinisoforms (iso-formIinthestudybyThibaultetal.[19]versusisoformT inthestudybySorenssonetal.[18])anddifferentdosage methods.
Clinical
surrogate
of
ischaemia
resolution:
cSTR
IPostwasnotassociatedwithasignificantlyimprovedcSTR, withonly10%patientsexperiencingSTR>70%afterIPostin four studies[13—15,21,22] (RR1.10, 95% CI0.95 to1.27;
P=0.20), with significant heterogeneity between studies (Chi2=6.56;P=0.09;I2=54%)(Fig.4).
InadditiontothedifferentIPostprotocolsacrossstudies (Table1andFig.2),heterogeneitymayalsobeexplainedby thedifferenttimingsforST-segmentresolutionevaluation: 120minutesforXueetal.andYangetal.[21,22],90minutes forLonborgetal.[14,15]and30minutesforHahnetal.[13]. Ofnote,differentmethodswereusedforelectrocardiogram analysis:atrainedtechnicianforXueetal.[21],dedicated software(LIFENET)forLonborgetal.[14,15],acardiologist forYangetal.[22]andanindependentlaboratoryforHahn etal.[13].
Imaging
surrogates
of
infarct
size:
SPECT-IS
(%
of
the
LV)
and
CMR-IS
(%
of
the
LV)
IPost was not associated with a significant reduction in SPECT-IS(SMD—0.42,95%CI—0.88to0.03;P=0.06)intwo studies [19,22] (Fig.5), without significant heterogeneity betweenstudies(Chi2=0.68;P=0.41;I2=0%).
IPost was not associated with significant reduction in CMR-IS(SMD—0.36,95%CI—0.88to0.15;P=0.16)infour studies [4,14,15,17,18,20] (Fig. 5), with significant het-erogeneitybetweenstudies(Chi2=13.6;P=0.004;I2=78%;
Tau2=0.21).Sensitivity analyses did notidentify one
spe-cificstudyresponsibleforheterogeneity.Forestplotvisual inspection indicates that twostudies (Lonborg et al. and Thunyetal./Mewtonetal.[14,15,17,20])showedsignificant reductionsinCMR-IS,whilethetwoothers(Freixaetal.and Sorensson etal.[4,18])showednoreduction.This finding couldbepartiallyexplainedbydifferencesintimingofCMR
Meta-analysisofischaemicpostconditioning 45
Figure3. Forestplotsofbiologicalsurrogatemarkersofinfarctsize.Resultsarepresentedasthestandard(Std.)meandifference.A random-effectsmodelwasperformed.AUC:areaunderthecurve;CI:confidenceinterval;CK:creatinekinase;CKMB:creatinekinase myocardialband;IPost:ischaemicpostconditioning;IV:inverse-variance;SD:standarddeviation;Tropo:troponinTorI.
Figure4. ForestplotofcompleteST-segmentresolution(cSTR).cSTRwasdefinedasthedifferenceinST-segmentelevationbetween thebaselineelectrocardiogram(ECG)andtheECGrecordedafterreperfusion,dividedbytheST-segmentelevationinbaselineECG>70%. Resultsarepresentedastheriskratio.Afixed-effectsmodelwasperformed.CI:confidenceinterval;IPost:ischaemicpostconditioning;IV: inverse-variance.
Figure5. Forestplotsofimagingsurrogatemarkersofinfarctsize(IS).Resultsarepresentedasthestandard(Std.)meandifference. Afixed-effectsmodelwasperformedforSPECT-ISandarandom-effectsmodelwasperformedforCMR-IS.CI:confidenceinterval;CMR: cardiacmagneticresonance;IPost:ischaemicpostconditioning;IV:inverse-variance;SD:standarddeviation;SPECT:single-photonemission computedtomography.
analysis.CMRwasperformed2daysafteradmissioninthe studyby Thunyetal./Mewtonetal. [17,20],7daysafter admissioninthestudiesbySorenssonetal.andFreixaetal.
[4,18]and3monthsafteradmissioninthestudybyLonborg etal.[14,15].
Left ventricular ejection fraction (LVEF), measured by either transthoracicechocardiographyor CMR, showed no significantdifferencesbetweengroupsatshort(7-day)and long(6-month)follow-up(datanotshown).
Discussion
Ourstudyisthefirstmeta-analysisanalysingtheeffectsof IPostonthefollowingsurrogatesofIS:CK-AUC,CKMB-AUC andTropo-AUC.Ourresultssuggest thatIPostsignificantly decreases CK-AUC. Although not statistically significant, resultsforCKMB-AUC,Tropo-AUC,cSTR,SPECT-ISand CMR-IS showed a trend towards a beneficial effect of IPost. RegardingCMR analysis,thismay berelatedtosignificant discrepancy between studies regarding CMR timing after myocardialinfarction.Inaddition,CMRdeterminationofthe areaat risk has recently been the subjectof controversy because of other potential causes of myocardial oedema [23].
ReducingISthroughthepreventionofreperfusioninjuries isanewfrontierinmyocardialinfarctiontherapy.Apartfrom IPost,otherprocedureshaveproducedencouragingresults: injectionof cardioprotective agents,such ascyclosporine
or metoprolol [24,25];and remoteischaemic conditioning
[26,27].Sofar,nolargeprospectiverandomizedclinical tri-alswithhardclinicalendpointsevaluatingtheseprocedures have been published;theyarethereforestillin transition frombenchtobedside.Performingmeta-analyses combin-ing datafromsmallclinical trials mayprovide interesting insights for both researchers and clinicians regarding the benefitoftheseprocedures.
Wecansummarizetheresultsofthethreemeta-analyses already published [6—8] asfollows. The meta-analysis by Hansen et al. [6] published in 2010 included six studies (244patients) and showed a significant decrease in peak CK and an increase in LVEF in IPost patients compared withusualcare.Tworecentmeta-analyses[7,8]published in 2012 had differentinclusion/exclusion criteria, leading todifferencesinincluded studiesandreportedoutcomes. The meta-analysis by Wei et al. [7] included 13 studies (673patients)andshowed:asignificantdecreaseinpeakCK; asignificantdecreaseinpeakCKMB;asignificantreduction inSPECT-IS;nosignificantimprovementincSTR;and signif-icantimprovementinlong-termLVEF.Themeta-analysisby Zhouetal.[8]included10studies(560patients)andshowed asignificantreductioninnecrosisbiomarkersandsignificant improvementinLVEF.
Thenoveltyofourmeta-analysiscomesfromthe inclu-sionofthelatestandlargestpublishedclinicaltrialbyHahn etal. [13], theanalysis of differentsurrogate markers of ISandthemethodology.Comparedwiththemeta-analyses byHansenetal.andWeietal.[6,7],weusedAUCandnot
Meta-analysisofischaemicpostconditioning 47 peakofbiomarkersasasurrogatemarkerforIS.According
toGibbonsetal.[28],peakCKMBcanbeusedasasubstitute forAUCifasufficientnumberofsamplesaremeasuredto detecttruepeakvalues.Tureretal.[29]showedthatpeak CK, peak CKMB and AUC calculations had significant cor-relationwithfunctionaloutcomes(LVEFandSPECT-IS)and deathinthesettingofSTEMI.Lopesetal.[30]showedthat theobservedCKMBmeasures(AUCandpeak)andmeasures obtainedfromsophisticatedcurvefittingalsohadsignificant correlationswith clinicalendpoints, suchas90-day death andheartfailure.However,thismaynotbetrueinstudies inwhichCKMBvaluesaremeasuredlessfrequently.Atleast, fiveCKMBmeasurementsarenecessary tofit alog-normal model to the CKMB curve. It is stillpossible tocalculate observed CKMB-AUCusing fewer than fivemeasurements, butthevalidityisquestionable[30].Inlinewiththearticle byGibbonsetal.[28],wefavouredAUCratherthanpeak values.Besides,weanalysedISasapercentageofthearea atrisk,estimatedbyCMR(CMR-IS)infourstudies,whereas Hansenetal.[6]didnotconsiderCMR-ISandWeietal.[7]
onlyanalysedCMR-ISfortwostudies.
Comparedwiththemeta-analysisbyZhouetal.[8],we followedadifferentmethodology:each myocardial necro-sis biomarker was analysed separately, while Zhou et al. aggregatedallbiomarkers(i.e.themorerelevantavailable marker was chosen for each study, resulting in a non-homogeneouscomparisonsofISsurrogates).
Preclinical studies have suggested that only the first fewminutesofmyocardial reperfusionfollowingtheindex ischaemicperiodofferawindowforIPostprotectionagainst ischaemiareperfusioninjuries.Emergingevidencesuggests thatseveral signallingpathways arerecruitedat thetime ofmyocardialreperfusion,includingcell-surfacereceptors, a diverse array of protein kinase cascades, including the reperfusion injury salvage kinase (RISK) pathway and the survivor activating factor enhancement (SAFE) pathway, redoxsignallingandthemitochondrialpermeability transi-tionpore(mPTP)[3,31].Inaddition,significantmyocardial ischaemicinjuryisneededtogainanysignificantIS reduc-tionfromprocedurespreventingreperfusioninjuries.Miura etal.[32]suggestedthattheinterventionwouldneedtobe potentenoughtolimitthefractionoftheriskzoneinfarcting from75%intheuntreatedpatientto≤40%inpatientswith an areaat risk thatis>20%ofthe leftventricle.Ofnote, mostoftheclinicaltrialsincludedinourmeta-analysisdid notgiveanydetailsregardingtheareaatrisk.
As depicted in our work, the IPost protocols dif-fered between studies. This mayhave induced variability regarding the efficacy of IS reduction. Four studies used directstenting, fourothers implantedthe stentafter the IPost protocol and four studies only allowed the use of thrombusaspirationbeforestenting[4,13—15,17,20].This isimportant,becausethrombusaspirationmayreducepost PCI distal embolization that may play an important role in the ‘‘no-reflow’’ phenomenon. A recent clinical trial showednoclinicalbenefitofsystematicthrombusaspiration inSTEMIpatients[33].Somestudiesdidnotspecifically men-tionintheirprotocolthatballoonreinflationwasperformed afterretractionabovetheimplantedstent.Balloon reinfla-tioninsidetheimplantedstentmayhavetriggeredthrombus fragmentationanddistalembolization,leadingto microvas-cular occlusion, jeopardizingmyocardial revascularization
andpotential IPostefficacy[4]. Ourdata donot allowus todrawanyconclusionregardingthebestIPostprotocolto protectthemyocardiumagainstreperfusioninjuriesatthe timeofPPCI.Ofnote,animalmodelsusedtoestablishIPost efficacy and mechanisms could not address this concern either.Inanimalmodels,myocardialischaemiaisprovoked byexperimental non-atherothrombotic coronaryocclusion subsequentlyrevascularizedwithoutcoronarystenting.
As mentioned above, our meta-analysis included the recentpublicationbyHahnetal.[13]reportingthelargest clinical trial comparing IPostwith control in 700 patients undergoingPPCIfor STEMI.In thisstudy,theprimary end-point(percentageofST-segmentresolution>70%measured 30minutesafter PPCI)wasnot differentbetween treated and control groups. The weight of this study was impor-tant; its integration in our analysis turned the effect of IPost on cSTR reduction to statistically non-significant. However, some limitations of this study that may have jeopardized the potential beneficial effect of IPost need to be acknowledged: balloon reinflation within the stent at the location of the culprit lesion; and a large num-ber of infarct-related artery predilatations and thrombus aspirations before stenting, which may have delayed the subsequent IPost procedure. These limitations have been discussedextensivelyinareportbyOvizeetal.[34].
Althoughourmeta-analysisproducedencouragingresults regardingISreduction,wemustacknowledgethatIPostmay notbe easy to translate into clinical practicebecause of theburdenofimmediateballoonreinflationaftercoronary revascularizationduring PPCI.Of note, preclinical studies havesuggestedthat IPostmaynotbeefficientinpatients withmetabolicdisorderssuchashyperlipidaemiaand dia-betes[35]. Other strategies, such asremote conditioning
[27]and/orpharmacologicalconditioning[25],maybe eas-iertotranslateintoclinicalpractice.
Study
limitations
Ourmeta-analysishasseverallimitations,mainlyduetothe characteristics of the studies. Included studies had small numbers of patients and poorly reported methodological aspects, such as random sequence generation, allocation concealmentandperformance bias.Ofnote, threeofthe included studiesdid nothave an intention-to-treat analy-sis[4,14,15,18].Severaloutcomes(CK-AUC,Tropo-AUCand CMR-IS) were heterogeneously reported. Methods used to measureCK-AUCorcSTRwerealsoheterogeneous.Thisled ustopresent severalForestplots witha smallnumberof studiesfor eachendpoint. Inaddition,high heterogeneity (I2>50%) was observed for almost all analysed outcomes.
Wediscussed severalpossible causesofheterogeneity,but couldnotidentifyamajorcause.Therelevanceof perform-ingameta-analysismaybequestionableincaseofpersisting heterogeneity,despitethe useof arandom-effects model or subgroup analysis. On the other hand, performing a meta-analysisallowedusto providegraphical representa-tionofthesummaryofevidenceregardingIPost-relatedIS reduction;italsoprovidedquantitativeestimatesofsucha reductiononvariousoutcomes,whichcouldbetakeninto accountwhen designing future clinical trials. Our results suggestasmallbenefitofIPostonsurrogatemarkersofIS, withnodataregardingclinicaloutcomes.BothISreduction
and clinical outcomes remain to be investigated in large clinicaltrials.
Conclusions
UsingCK-AUC asa surrogatemarker,ourresults suggesta smallbenefitofIPostonIS,whichisamajordeterminantof apatient’sclinicaloutcomeafteracutemyocardial infarc-tion;hence,thisreductioncouldsignificantlyimprovepost myocardialinfarctioncardiacfunctionandpatient progno-sis.Published clinical trials evaluating IPost were neither tailorednorconceivedtodetectclinicalbenefitsonmajor adversecardiacevents, suchasheart failureormortality. Thereisaneedforlargeprospectiverandomizedcontrolled studieswithintention-to-treatanalysis,usinghardclinical endpoints.
Disclosure
of
interest
Theauthorsdeclarethattheyhavenoconflictsofinterest concerningthisarticle.
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