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Atherosclerosis
j ou rn a l h o m e pa g e:w w w . e l s e v i e r . c o m / l o c a t e / a t h e r o s c l e r o s i s
Review
Adenosine
improves
post-procedural
coronary
flow
but
not
clinical
outcomes
in
patients
with
acute
coronary
syndrome:
A
meta-analysis
of
randomized
trials
Eliano
Pio
Navarese
a,d,∗,
Antonino
Buffon
b,
Felicita
Andreotti
b,
Paul
Alfred
Gurbel
c,
Marek
Kozinski
a,
Aldona
Kubica
e,
Giuseppe
Musumeci
f,
Alberto
Cremonesi
a,
Luigi
Tavazzi
a,
Jacek
Kubica
d,
Fausto
Castriota
aaInterventionalCardio-AngiologyUnit,GVMCareandResearch,Cotignola,RA,Italy bDepartmentofCardiovascularMedicine,CatholicUniversityoftheSacredHeart,Rome,Italy cSinaiCenterforThrombosisResearch,SinaiHospitalofBaltimore,Baltimore,MD,USA
dDepartmentofCardiologyandInternalMedicine,LudwikRydygierCollegiumMedicum,NicolausCopernicusUniversity,Bydgoszcz,Poland eDepartmentofHealthPromotion,CollegiumMedicum,NicolausCopernicusUniversity,Bydgoszcz,Poland
fDepartmentofCardiovascularMedicine,OspedaliRiuniti,Bergamo,Italy
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received26September2011
Receivedinrevisedform1November2011 Accepted2November2011
Available online 9 November 2011 Keywords:
Adenosine
Acutecoronarysyndrome Clinicaloutcome
a
b
s
t
r
a
c
t
Aims:Adjunctivetherapywithadenosinehasbeenshowntoimprovecoronaryflowinpatientswithacute coronarysyndromes(ACS);itisunclear,however,whetheradenosinecaneffectivelyreduceadverse clinicalevents.Theaimofourstudywastoperformameta-analysisofallrandomizedcontrolledtrials (RCTs)investigatingangiographicandclinicaloutcomesinACSpatientsundergoingPCIorthrombolysis andreceivingadjunctiveadenosinetherapyvs.placebo.
Methods:Medline/CENTRAL/EMBASEand GoogleScholardatabasewerescanned.Themeta-analysis includedtenRCTs(N=3821).All-causemortalitywaschosenasprimaryendpoint.Secondaryendpoints werere-infarction(MI),heartfailure(HF)symptoms(NYHAclassIII/IV),no-reflow(definedasTIMI0 flow)and>50%ST-resolution.
Results:Adenosinecomparedtoplacebowasassociatedwithasignificantreductionofpost-procedural no-reflow(OR[95%CI]=0.25[0.08–0.73],p=0.01);however,atamedianfollow-upof6months,prior treatmentwithadenosinedidnotconfersignificantbenefitsintermsofreductionofmortality(ORFixed [95%CI]=0.87[0.69–1.09],p=0.23),aswellasre-MI(p=0.80),HFsymptoms(p=0.44)andST-resolution (p=0.09).SeparateanalysesconductedinthesubgroupsofST-elevationMIpatientstreatedwitheither PCIorthrombolysisconfirmedthefindingsfoundintheoverallpopulation.
Conclusions:Thismeta-analysisshowsthatadenosineadjunctivetherapydoesnotimprovesurvivalnor reducetheratesofre-MIandHFsymptomsinpatientswithACStreatedwithPCIorthrombolysis.The beneficialeffectonpost-proceduralcoronaryflowwasnotassociatedwithconsistentadvantageson clinicaloutcomes.
© 2011 Elsevier Ireland Ltd. All rights reserved.
Contents 1. Introduction... 2 2. Methods... 2 2.1. Searchstrategy... 2 2.2. Selectioncriteria ... 2 2.3. Studyendpoints... 2 2.4. Statisticalanalyses... 2
Abbreviations: ACS,Acutecoronarysyndromes;CI,confidenceinterval;IC,intracoronaryadenosine;IV,intravenousadenosine;h,hours;HF,heartfailure;na,not available;OR,oddsratio;PCI,percutaneouscoronaryintervention;pts,patients;RCTs,randomizedcontrolledtrials;STEMI,ST-elevationmyocardialinfarction;TIMI, Thrombolysisinmyocardialinfarction.
∗ Correspondingauthorat:InterventionalCardio-AngiologyUnit,GVMCareandResearch,MariaCeciliaHospital,Cotignola,RA,Italy.Tel.:+393393342594725; fax:+390545217318.
E-mailaddress:eliano.navarese@alice.it(E.P.Navarese).
0021-9150/$–seefrontmatter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2011.11.001
2 E.P.Navareseetal./Atherosclerosis222 (2012) 1–7 3. Results... 2 3.1. Eligiblestudies... 2 3.2. Mortality... 4 3.3. Secondaryendpoints... 4 3.3.1. No-reflow... 4 3.3.2. Re-infarction... 5 3.3.3. Heartfailure... 5 3.3.4. ST-segmentresolution ... 6 3.4. Sensitivityanalyses... 6 4. Discussion... 6 5. Conclusions... 7 6. Limitations... 7 References... 7 1. Introduction
The cornerstone of treatment of patients with acute coro-narysyndrome(ACS),especiallythosewithST-segmentelevation myocardialinfarction(STEMI),istopromptlyrestoremyocardial blood flow and thus limit infarct size.Reperfusion is generally achievedpharmacologically bythrombolysisormechanicallyby percutaneouscoronaryintervention(PCI).Althoughmostpatients treatedwithPCIorthrombolysisachieveepicardialcoronaryartery patency,effectivemyocardialreperfusion maynotoccurdueto amyocardialinjuryphenomenonknownasno-reflow[1].Small studies in STEMI patients[2,3] have suggested that adenosine improvedmicrovascularfunction,reducingtheoccurrenceofno re-flow.Severalrecentrandomizedstudies,investigatingwhether adenosinemightreducetheincidenceofadverseclinicaloutcomes amongACSpatients,haveyieldedconflictingresults.Theaimofthe currentstudywastoperformameta-analysisofallavailable ran-domizedcontrolledtrials(RCTs)comparingtheeffectofadenosine vs.placeboonclinicaloutcomesinACSpatientstreatedwithPCIor thrombolysis.
2. Methods
Thepresentmeta-analysiswasperformedaccordingto estab-lishedmethodsoftheCochraneguidelines[4]andincompliance withthePRISMAstatementforreportingsystematicreviewsand meta-analysesinhealthcareinterventions[5].
2.1. Searchstrategy
A search covering the period from January 1993 to August 2011 was conducted by two independent investigators using MEDLINE, CENTRAL, EMBASE and Google Scholar databases. Proceedings from the Scientific Sessions of the Ameri-can College of Cardiology [http://www.acc.org], American Heart Association [http://www.aha.org], European Society of Cardiology [http://www.escardio.org], Transcatheter Cardio-vascular Therapeutics [http://www.tctmd.com] and EuroPCR [http://www.europcr.com] were also considered. The following keywordswereapplied:“adenosine”;“acutecoronarysyndrome”; “ST-elevationmyocardialinfarction(STEMI)”;“randomized”. Ref-erencesofretrievedstudiesweresearchedmanuallyforadditional trials.Nolanguagerestrictionswereapplied.
2.2. Selectioncriteria
Citations werescreened at title/abstract level and retrieved as full reports. Inclusion criteria were: (1) human studies; (2) randomized administration of adenosine vs. placebo; (3) ACS
treated with PCI or thrombolysis; (4) systematic reporting of clinicaloutcomes.Exclusion criteria were:– studies comparing adenosinevs.placeboduringelectivePCIorinthesettingofbypass surgery; – observational studies; – studies comparingthe use ofacompoundsimilartoadenosinebutwithdifferentchemical properties; – lack of placebo arm; – RCTs not reporting clini-caloutcomes.Theinternalvalidityofeach studywasappraised by two unblinded investigators according to proper allocation sequence/concealment, patient blinding, investigator blinding, and completeness of outcome data/full reporting. Prespecified abstracted datawere: study/trial name, journal (year), number ofadenosine-andplacebo-treatedpatients,maximumfollow-up timeavailable,clinicalsetting,routeanddoseofadenosine admin-istration,treatmentstrategy,andischaemictime,definedastime fromsymptomonsettostartoftreatment(PCIorthrombolysis). 2.3. Studyendpoints
The primary chosen endpoint was all-cause mortality. Sec-ondary endpoints were the incidence of no-reflow (defined as TIMI 0flow accordingtotheTIMI definition), re-MI,heart fail-uresymptoms(NYHAclassIII–IV),andST-resolution,definedas post-proceduralresolution≥50%.
2.4. Statisticalanalyses
Oddsratio(OR)and95%confidenceintervals(95%CI)wereused assummarystatistics.HeterogeneitywasassessedbyCochran’sQ test,witha2-tailedp=0.1,asconventionallyrecommended[6]. Statisticalinconsistency test (I2) [(Q−df)/Q]×100%, where Q is thechi-squaredstatisticanddfisitsdegreesoffreedom,wasalso employedtoovercomethelowstatisticalpowerofCochran’sQtest [7].ThepooledORwascalculatedusingafixed-effectmodelwith theMantel–Haenszelmethod.TheDerSimonianandLairdrandom effectsmodelwasusedincaseofsignificantheterogeneityand/or moderateorsignificantinconsistency(>50%)acrossstudies. Poten-tialpublicationbiaswasexaminedbyconstructinga‘funnelplot’, inwhichthestandarderror(SE)ofthelnORwasplottedagainst theOR(formortalityorre-MIorre-PCI)[8].Inaddition,a mathe-maticalestimateoftheasymmetryofthisplotwasprovidedbya linearregressionapproach[9].Allanalyseswereperformed accord-ingtotheintention-to-treatprinciple.A2-tailedpvalue<0.05was consideredsignificant.
3. Results 3.1. Eligiblestudies
Ten RCTs[10–15,3,16–18], involving3821 patients, metthe inclusioncriteriaandwereincludedinthemeta-analysis(Fig.1).
Fig.1.Flowchartofthemeta-analysisaccordingtothePRISMAstatement.
ThemainstudycharacteristicsarelistedinTable1.Alleligible tri-alsinvestigatedtheuseofadenosineinSTEMIpatients,exceptfor one[19]whichincludedamixedpatientpopulation(non-STEMI andSTEMI). Themedianfollow-upwas6months.Inthe AMIS-TAD(AcuteMyocardialInfarctionSTudyofADenosine)IandIIand intheATTACC(ATTenuationbyAdenosineofCardiacComplications)
trials,adenosinewasadministeredafterthrombolysisthroughthe intravenous route; in theremaining seven trials, intracoronary (IC)adenosinewasgivenduringPCI.Thepatientsfromthe AMIS-TADIItrialincludedinthemeta-analysiswerethosetreatedwith thehighestdoseofadenosine(70g/kg/min),comparedtothose receivingplacebo.
Table1
Summaryofrandomizedstudiescomparingadenosinevs.placeboinpatientswithacutecoronarysyndrome;h=hours;IC=intracoronaryadenosine;IV=intravenous adenosine;na=notavailable;NSTEMI=nonST-segmentelevationmyocardialinfarction;STEMI=ST-segmentelevationmyocardialinfarction;PCI=percutaneouscoronary intervention;pts=patients.
Study Journal(year) Adenosine+
placebopts Follow-up time (months) Setting Routeof adenosine
Doseofadenosine Treatment
strategy
Ischemictime beforetreatment (min)
AMISTAD-I[10] JACC(1999) 236 1.4 STEMI IV 70g/kg/minfor
3h
Thrombolysis 111
AMISTAD-II[11] JACC(2005) 2117 6 STEMI IV 70g/kg/minfor
3h
Thrombolysis 195 ATTACC[12] EurJClin
Pharmacol (2003)
608 12 STEMI IC 10g/kg/minfor
6h
Thrombolysis 208
Desmet[13] EurHeartJ (2011)
112 1.12 STEMI IC 4mgquickly
administered
PCI 215
Fokkema[14] CircCardiov Intervent (2009) 448 1 STEMI IC 2×120gin20mL 0.9%NaCl PCI 180 Grygier[15] AmJCardiol (2011)
70 1 STEMI IC 2mgtotheleft
artery,1mgtothe rightarteryin ∼1min PCI 270 Marzilli[16] Circulation (2000)
54 In-hospital STEMI IC 4mgin∼1min PCI 106
Stoel[3] Catheter
Cardiovasc Interv(2008)
49 12 STEMI IC 60mgin5–10min PCI 196
Tian[17] Chiense
MedicalJ (2008)
26 1 STEMI IC 2mg/minfor
10min
PCI na
Vijayalakshmi[18] Heart(2006) 101 6 NSTEMI,
STEMI
IC 30gin10mlof heparinisedsaline
4 E.P.Navareseetal./Atherosclerosis222 (2012) 1–7
Fig.2. Funnelplotforthemortalityoutcome.Thesamplesizeofeachstudy (mea-suredasstandarderrorofthetreatmenteffect)wasplottedagainsttheoddsratio foroverallmortality.Onestudy(Tian)didnotreportmortalitydata;inanother (Grygier),theoddsratiowasnotestimableforlackofevents.
3.2. Mortality
As shown in Fig. 2, no publication bias was found, and this was confirmed by Egger’s test which was non significant.
Nine randomized studies, involving a total of 3793 patients, reported the incidence of death in those allocated to adeno-sine (N=2257) or placebo (N=1536). There were a total of 335deaths.The incidenceofdeathwas8.7% (196/2257)inthe adenosine group and 9.0% (139/1536) in the placebo group. The overall results showed no significant benefit with adeno-sine therapy as compared to placebo in reducing mortality
(ORFixed [95% CI]=0.87 [0.69–1.09], p=0.23; p
heterogene-ity=0.55;Fig.3).Theseresultswereconfirmedwhenanalyzing the STEMI population only: ORFixed [95% CI]=0.89 [0.72–1.09], p=0.25.
3.3. Secondaryendpoints 3.3.1. No-reflow
Therewas no evidence of publication bias, witha non sig-nificantEgger’stest. Fiverandomizedstudies(N=865)reported the rates of no-reflow after administration of adenosine or placebo. Adenosine markedly reduced the incidence of post-proceduralno-reflowascomparedtoplacebo(0.7%vs.3.5%; OR Fixed [95%CI]=0.23 [0.08–0.70], p=0.01; p heterogeneity=0.24;
Fig.4).
Asignificantreduction ofnoreflowwasalsoobservedwhen consideringthe STEMIpopulation only: ORFixed [95%CI]=0.22 [0.07–0.72],p=0.01.
Fig.3.Forestplotofadenosinevs.placeboforall-causemortality;overallandindividualoddsratiosand95%confidenceintervals(CI)arereported.Thesizeofthedata markers(squares)isproportionaltothestatisticalweightofeachtrial.
Fig.4.Forestplotofadenosinevs.placeboforno-reflow;overallandindividualoddsratiosand95%confidenceintervals(CI)arereported.Thesizeofthedatamarkers (squares)isproportionaltothestatisticalweightofeachtrial.
Fig.5. Forestplotofadenosinevs.placeboforre-infarction;overallandindividualoddsratiosand95%confidenceintervals(CI)arereported.Thesizeofthedatamarkers (squares)isproportionaltothestatisticalweightofeachtrial.
Fig.6. Forestplotofadenosinevs.placeboforheartfailuresymptoms(NYHAclassIII-IV);overallandindividualoddsratiosand95%confidenceintervals(CI)arereported. Thesizeofthedatamarkers(squares)isproportionaltothestatisticalweightofeachtrial.
3.3.2. Re-infarction
Among1372patients,therewere94re-MIsoverthelong-term followup.TheincidenceofMIwas6.9%(48outof686patients)in theadenosinegroupand7.0%(46outof686)intheplacebogroup (ORFixed[95%CI]=1.06[0.69–1.62],p=0.80;pheterogeneity=0.50;
Fig.5).
3.3.3. Heartfailure
AsshowninFig.6,theratesofheartfailuresymptoms(NYHA classIII–IV)werehighlycomparablebetweentheadenosineand placeboarms,withoutanysignificantbenefitinsymptomrelief byadenosinetreatment:4.8%(81/1688)vs.4.3%(42/970):ORFixed [95%CI]=1.26[0.85–1.87],p=0.24;pheterogeneity=0.31).
Fig.7. Forestplotofadenosinevs.placeboforST-segmentresolution;overallandindividualoddsratiosand95%confidenceintervals(CI)arereported.Thesizeofthedata markers(squares)isproportionaltothestatisticalweightofeachtrial.
6 E.P.Navareseetal./Atherosclerosis222 (2012) 1–7
Fig.8. Forestplotofadenosinevsplaceboforoverallmortalityin3predefinedsubgroups:treatmentwithPCIvs.thrombolysis,follow-up<vs.>6months,numberofenrolled patients≤101vs.>101patients.Individualoddsratioswith95%confidenceintervals(CI)arereported,withtherelatedpvaluefortheirinteraction.
3.3.4. ST-segmentresolution
Fourstudiesreportedtheincidenceof≥50%ST-segment reso-lutionafterintracoronaryadenosinevs.placebo.Patientstreated with intracoronary adenosine showed a non-significant trend towardsgreaterST-segmentresolutioncomparedtothepatientsin theplacebogroup:62.5%(215/344)vs.52.9%(186/333),ORRandom [95%CI]=0.54[0.26–1.10],p=0.09;pheterogeneity=0.03;Fig.7). 3.4. Sensitivityanalyses
Severalsensitivityanalyseswereconductedtoformallyexplore therobustnessoftheresults.Thesensitivityanalysisperformed byremovingeach ofthestudiesone ata time didnot demon-strateany single study to influencethe overall results for any ofthechosenoutcomes.Stratifiedanalysisshowednosignificant differencesinmortalityrates between:(1)studiesinwhichthe treatmentstrategywasPCI(whereICadenosinewasgiven)and studiesinwhich thrombolysis wasused(where adenosinewas administeredintravenously;pforinteraction=0.62); (2)studies reportingafollow-up<or>6months(pforinteraction=0.79);(3) studiesenrollingatotalnumberofpatients>101or>101patients (pinteraction=0.21)(Fig. 8).Sensitivity analysis,performed by includingeachofthestudiesoneatatimeaccordingtoincreasing doseofICadenosine,fromthelowesttothehighest(upto60mg), showedthatdifferentdosesdidnotinfluenceanyoftheclinical out-comesinvestigated,aswell.Thedifferentburdenofischaemictime acrossthevariousstudiesdidnotinfluencetheresults,asshown inthesensitivityanalyseswheretheinclusionofstudieswith vari-ableischaemictimefromthelowesttothehighestdidnotchange themagnitudeanddirectionoftheoverallresultsforallthe out-comeschosen.Finally,theanalysesconductedonlyintheSTEMI population,byremovingthestudyinwhichamixedpopulation (non-STEMIandSTEMI)wasenrolled,confirmedtheresultsfound intheoverallpopulationforalloftheoutcomes.
4. Discussion
Cardiovasculardiseaseremainsthebiggestkillerinthe devel-oped world, with the majority of morbidity and mortality attributabletotheeffects ofACS. Thelack ofeffective reperfu-sionofthemyocardiumafterprolongedischaemia,thatmayoccur despiteopeningoftheepicardialinfarct-relatedartery,hasbeen attributedtothereperfusioninjurytermed“no-reflow”.Adenosine
hasbeenshown inanimalmodelstopotentiallyprevent reper-fusion injury and theno-reflow phenomenon [19–21].In vitro, adenosineexhibitsenergy-saving,antiplatelet,vasodilatory, anti-inflammatory,antioxidant,aswellasantiarrhythmiceffects[22]. ClinicalstudieswithadenosineinACShaveyieldedmixedresults. AMISTADwasoneofthefirsthumanstudiesinacutemyocardial infarction[10].Itshowedin236patientsthatadenosine,givenasa 3-hintravenousinfusion(10g/kg/minincreasingto70g/kg/min astolerated)andcommencedpriortothrombolysiswith streptok-inaseoralteplase,didnotreducethecompositeclinicalendpoint (death,reinfarction,shock,congestiveheartfailureorstroke).In thestudybyMarzillietal.,ICadenosine(4mg),givenasaslow hand-injectioninpatientsundergoingemergentrevascularization foracuteMI withballoonangioplasty(andstentingfor subopti-malballooninflations), resultedin adecreasedincidenceofthe no-reflowphenomenon,withimprovedmyocardialperfusionand amorefavourableclinicalcourse,intermsofcombinedclinical end-points[16];theseresults,ontheotherhand,werenotconfirmedin amorerecentstudy,evenwhenadministeringhigherICadenosine doses[14].Becausenoneofthesetrialswereindividuallypowered toassessdifferencesinclinicaloutcomes,adefinitiveconclusion onthepotentialclinicalbenefitsofadenosinetreatmentcouldnot bedrawn.
Thisisthefirstmeta-analysiscomparingtheangiographicand clinicaleffectsofadenosineadjunctivetherapyintheACS popula-tion.Despiteamarkedfallintheincidenceofno-reflowafterPCI, thismeta-analysisdidnotshowanyclearadvantagewith adeno-sineontherates ofall-causemortality,re-MIorHFsymptoms; these resultswere confirmed in sensitivity analysesconducted inthesubgroupsofSTEMIpatientstreatedwitheitherprimary PCIorthrombolysis.CurrentESCguidelinesforthemanagement of patients with acute STEMI allow the option of an IV infu-sion of 70g/kg/min over 3h during and after PCI (class IIb; levelofevidenceB)oranICbolusof30–60gadenosineduring PCI(classIIb; levelofevidenceC)for theprevention-treatment ofno-reflow[23].Theresultsofthepresentmeta-analysis sug-gest that the improvement of coronary flow velocities shown in observationalstudies, aswell asthe significantreduction of no-reflow[2,24],maybetransientvascular/rheologicaleffectsof adenosine,thatdonottranslateintolong-lastingrelevantclinical benefits.
Notably,thelackofbenefitonclinicaloutcomeswith adeno-sine treatment observed in our meta-analysis persisted in the
sensitivityanalysisbyremovingthestudiesaccordingto increas-ingIC doseof adenosine,fromthelowesttothehighest,upto 60mg. The lack of impact of increasingdoses of adenosine on outcomeisrelevant,promptingcautioninadministeringveryhigh ICdoses,asthiscautionmayreducethefrequencyand severity ofsideeffectsassociatedwiththedrug,suchasbradycardiaand hypotension,thataredose-dependent.
Apotentialreasonforthelackofpersistentbeneficialeffectsof adenosineinthesettingofACSisthatduringmyocardialischaemia thereisalreadyahugeproductionofendogenousadenosine; more-over,giventheextremelyshorthalf-lifeofthisactivemetabolite (intheorderofa few seconds)[25],exogenous adenosinemay notproducelastingeffectsbeyondthetimeofitsadministration. Indeed,thehalflifeofadenosineinhumanbloodmaybetooshortto protectfromoxygenfreeradicals,whichpeakat2–3minof reper-fusion,evenifreperfusionisstartedonly15–30safteradenosine administration[26].
Additionally,mechanisticevidencebasedonshortterm, surro-gateparameterssuchascoronaryTIMIflowmaybepoorpredictors ofpotentialprotectivepathways;moreover,shorttermeffectsmay beweakpredictorsoflongtermoutcomes,especiallysince extrap-olationproblemsincreasewithincreasingextrapolationtime(i.e., timedifferencebetweentheeffectplayedbyadenosineandthe clinicaloutcome).
Todatetheoptimalmanagementofreperfusion-relatedinjury inACSpatientsstillremainsachallengingquestion.Thepresent meta-analysisshowsthattheshort-termtreatmentwith adeno-sineascomparedtoplaceboisnoteffectiveinachievingsignificant lastingimprovementsintheclinicaloutcomes.FurtherRCTs test-ingdifferenttreatmentstrategiesarewarrantedtofindwaysto improvebothcoronaryflowandclinicaloutcomesinACSpatients. 5. Conclusions
Thismeta-analysisshowsthatadenosine,asadjunctivetherapy forACSpatients,doesnotimprovesurvival,norreducetherates ofMI andHFsymptoms.Thebeneficialeffectofadenosinewas confinedtotheimprovementofpost-proceduralcoronaryflowbut withoutconsistentadvantagesonclinicaloutcomes.Similarresults wereobservedintheSTEMIsubgroupstreatedwitheitherPCIor thrombolysis.
6. Limitations
Alimitationofthismeta-analysis,commontoallmeta-analyses basedonstudy-leveldata,isthelackofindividualpatientdatathat wouldhavefurtherimprovedtheresultsofthecurrentstudy.In particular,analysisofoutcomesbytimefromsymptomonsetto adenosine/placeboadministrationwasnotpossible.
Theheterogeneoussamplesizewithasmallnumberofpatients enrolledinsomestudies(<100)andtherelativelylowrateof clin-icaleventsaresomelimitationsinherenttotheincludedstudies; themeta-analysisthereforemighthavealowpowercomparedto alargerrandomizedtrial;thevarianceofsingleoddsratiosacross thestudiesalsosuggestscautionininterpreting theresults; on theotherhand,thestabilityoftheresultsafterperforming sen-sitivityanalysesforalltheoutcomeschosen(includingmortality astheprimaryendpoint)(cfrsensitivityanalysisparagraph)and thenarrowerCIsassociatedwiththeoverallestimatesthanwith thosepertainingtotheincludedstudiessupportthefindingsofthe meta-analysisandsuggestthattheoveralleffectisjustified.
Multiplecausesmightinfluencemortalityandotherendpoints infavourofoneoranotherinterventioninacomplexpopulation such as that of ACS patients; on the other hand, this meta-analysisisbasedonrandomizeddatawhichshouldovercomeorat
leastmitigateinthebestpossiblewaythisbias.Information regard-ingtheadministrationofconcomitantdrugs,suchasglycoprotein IIb/IIIainhibitors,wasavailableinonlyonestudy,thereforethe effectofconcomitantadjunctivetherapiescouldnotbeevaluated. References
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