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Aspirinforprimarypreventionofvasculardiseaseinpeoplewithdiabetes|TheBMJ

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Editorials

Aspirinforprimarypreventionofvasculardiseasein
peoplewithdiabetes
BMJ2009339doi:http://dx.doi.org/10.1136/bmj.b4596(Published06November2009)Citethisas:BMJ
2009339:b4596
RichardHaynes,clinicalresearchfellow,LouiseBowman,clinicalresearchfellow,JaneArmitage,
professorofclinicaltrialsandepidemiology
1

ClinicalTrialServiceUnit,RichardDollBuilding,OldRoadCampus,OxfordOX37LF

louise.bowman@ctsu.ox.ac.uk

Balanceofbenefitsversusrisksiscurrentlyunclear
Diabetesisamajorglobalpublichealthproblemby2025anestimated300millionpeopleworldwidewillbe
affected.1Withtheassociatedtwofoldtofourfoldincreasedriskofcardiovasculardisease,morethanhalfof
thesepeoplewilldieprematurelyfromvascularevents.2Treatmentsthatlowerlipids,bloodpressure,and
glucoseallreducetheriskofcardiovasculardiseasesafely(preventingfirstandsubsequentevents),buteven
witheffectivetreatmentpatientswithdiabetesareathighrisk.345Furthertreatmentsarethereforeneededto
reducethisrisk.Inthelinkedmetaanalysis(doi:10.1136/bmj.b4531),DeBerardisandcolleaguesassessthe
benefitsandharmsoflowdoseaspirininpeoplewithdiabetesandnocardiovasculardisease.6
Becausemostpeoplewithdiabetesliveinlowandmiddleincomecountries,suchtreatmentsshouldideallybe
inexpensiveaswellassafeandeffective.Aspirinischeap,widelyavailable,andrecommended(andtaken)to
reducetheriskofrecurrenteventsforpeople(includingthosewithdiabetes)whohavesurvivedavascular
eventorhaveclinicalevidenceofvasculardisease.7Metaanalysesofsuchpeoplehaveshownthatthe
roughlyonequarterreductioninrelativeriskofvasculardiseasetranslatesintosignificantnetbenefits,despite
anincreasedriskofbleedingwithaspirin.8
Incontrast,aspirinisnotgenerallyrecommendedforhealthypeoplewhoareatlowriskofvascularevents
becauseitisnotclearthatthesmallreductioninocclusiveeventsisoutweighedbytheriskofbleeding.9
Patientswithdiabeteswhodonothavesymptomaticvasculardiseaseareatintermediateriskofvascular
disease,anditisunclearwhetherornotaspirinshouldberoutinelyprescribed.
ThemetaanalysisbyDeBerardisandcolleagueshighlightsthiscontinuinguncertainty.6However,ratherthan
reporttheirresultsinthecontextofalltheevidenceonprimaryprevention(withwhichitisentirelyconsistent),
DeBerardisandcolleaguesimplythataspirinmightnotworkinthisgroup.Giventhesubstantialevidencefor
thebenefitsofaspirininsecondarypreventionindiabetes,thisinterpretationmaybemisleading.
DeBerardisandcolleaguesreportthataspirinwasnotassociatedwithaclearbenefitonvascularevents.
However,thenonsignificant10%reductioninmajorcardiovascularevents(myocardialinfarction,stroke,or
cardiovasculardeath)(relativerisk0.9095%confidenceinterval0.81to1.00)isentirelyconsistentwiththe
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significant12%(6%to18%)proportionalreductioninseriousvasculareventsseeninthemetaanalysisof
combineddatafromindividualpatientsfromsixprimarypreventiontrialsof95000patients(Antithrombotic
TreatmentTrialistsCollaborationATTC).9About4000ofthesepatientsreporteddiabetesatbaseline,andthe
proportionalbenefitinthosetakingaspirinwasalso12%(relativerisk0.88,0.67to1.15),withnodifferencein
theeffectbetweenthosewithorwithoutdiabetes.However,giventheratesofseriousvasculareventsinthese
patients(1.63%ayearinthosetakingaspirinv1.87%ayearincontrols)thiswouldtranslateintoonlytwoor
threeseriousvasculareventsavoidedper1000patientstreatedeachyear.Sothecombineddatasuggesta
modestbutconsistentreductionintheriskofvasculareventswithaspirin,butwouldbenefitsofthissizebe
clinicallyworthwhileandclearlyoutweightheriskofbleeding?
Aspirintypicallyincreasestheriskofmajorbleedingbyaboutahalf(fromATTCprimarypreventiontrials:
relativerisk1.54,1.30to1.82).9DeBerardisandcolleaguesanalysiswaslimitedbythenumberoftrialsthat
reportedclinicallysignificantbleeding,buttheincreasedriskofbleedingwithaspirin(2.50,0.76to8.21)
althoughnotsignificantisconsistentwithotherdata.However,datafromtheATTCandobservationalstudies
showthatapersonsriskofbleedingcorrelateswiththeirriskfactorsforvasculardisease.910Consequently,
beingmale,havingdiabetes,beingolder,beingasmoker,andbeingmoreoverweightareassociatedwithan
increasedriskofbleedingandthereforeincreasetheadverseeffectofaspirin.Alternatively,aspirinmightbe
morebeneficialinpatientswiththeseattributesbecauseofthehigherriskofvasculardisease.Direct
randomisedevidenceistheonlywaytoassessthebalanceofthesepossiblebenefitsandrisks.Asshownby
DeBerardisandcolleagues,theavailabletrialswerelimitedintheirabilitytodothis,andmoretrialsare
urgentlyneededinthislargegroupofpatients.
Whatshouldcliniciansdointhefaceofongoinguncertainty?Ifpossible,theyshouldoffertheirpatientsthe
opportunitytoparticipateinoneoftheongoingtrialsinthisarea,whichwillincreasetheavailabledataand
potentiallyprovideacleareranswer.1112Untilthatinformationisavailable,alternativeapproachesareto
ensuremaximaluseofapproachesknowntominimisecardiovascularrisk(suchasavoidanceofsmoking,
statins,angiotensinconvertingenzymeinhibitors,andgoodglucosecontrol)beforethinkingaboutadding
aspirin.Guidelinesneedtoacknowledgethecurrentequipoiseandnotrecommendatreatmentwithout
supportingevidence,sothatcliniciansandtheirpatientsarefullyawareoftheevidencewhenmakinga
decision.

Notes
Citethisas:BMJ2009339:b4596

Footnotes
Research,doi:10.1136/bmj.b4531
Competinginterests:TheClinicalTrialServiceUnitandEpidemiologicalStudiesUnit(CTSU)doesnot
accepthonorariumsorotherfeesfromdrugcompanies.JAandLBareprincipalinvestigatorsofthe
BritishHeartFoundationsupportedASCENDstudy.
Provenanceandpeerreview:Notcommissionedexternallypeerreviewed.

References
1.KingH,AubertRE,HermanWH.Globalburdenofdiabetes,19952025:prevalence,numericalestimates,and
projections.DiabetesCare199821:141431.
2.PyoralaK,LaaksoM,UusitupaM.Diabetesandatherosclerosis:anepidemiologicview.DiabetesMetab
Rev19873:463524.
http://www.bmj.com/content/339/bmj.b4596.full.print

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3.CholesterolTreatmentTrialists(CTTC)Collaboration.Efficacyandsafetyofcholesterolloweringtreatment:
prospectivemetaanalysisofdatafrom90056participantsin14randomisedtrialsofstatins.Lancet 2005366:1267
78.
4.TurnbullF.Effectsofdifferentbloodpressureloweringregimensonmajorcardiovascularevents:resultsof
prospectivelydesignedoverviewsofrandomisedtrials.Lancet 2003362:152735.
5.RayKK,SeshasaiSR,WijesuriyaS,SivakumaranR,NethercottS,PreissD,etal.Effectofintensivecontrolof
glucoseoncardiovascularoutcomesanddeathinpatientswithdiabetesmellitus:ametaanalysisofrandomised
controlledtrials.Lancet 2009373:176572.
6.DeBerardisG,SaccoM,StrippoliGFM,PellegriniF,GrazianoG,TognoniG,etal.Aspirinforprimarypreventionof
cardiovasculareventsinpeoplewithdiabetes:metaanalysisofrandomisedcontrolledtrials.BMJ2009339:b4531.
7.JBS2.JointBritishSocietiesguidelinesonpreventionofcardiovasculardiseaseinclinicalpractice.
Heart 200591(suppl5):152.
8.AntithromboticTrialistsCollaboration.Collaborativemetaanalysisofrandomisedtrialsofantiplatelettherapyfor
preventionofdeath,myocardialinfarction,andstrokeinhighriskpatients.BMJ2002324:7186.
9.AntithromboticTrialistsCollaboration.Aspirinintheprimaryandsecondarypreventionofvasculardisease:
collaborativemetaanalysisofindividualparticipantdatafromrandomisedtrials.Lancet 2009373:184960.
10.HernandezDiazS,GarciaRodriguezLA.Cardioprotectiveaspirinusersandtheirexcessriskofuppergastrointestinal
complications.BMCMed20064:22.
11.DeBerardisG,SaccoM,EvangelistaV,FilippiA,GiordaCB,TognoniG,etal.AspirinandSimvastatinCombination
forCardiovascularEventsPreventionTrialinDiabetes(ACCEPTD):designofarandomizedstudyoftheefficacyof
lowdoseaspirininthepreventionofcardiovasculareventsinsubjectswithdiabetesmellitustreatedwithstatins.
Trials20078:21.
12.ASCENDCollaborativeGroup.Astudyofcardiovasculareventsindiabetes.www.ctsu.ox.ac.uk/ascend.

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