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Benefitsandrisksofaspirininsecondaryandprimarypreventionofcardiovasculardisease

OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate

Benefitsandrisksofaspirininsecondaryandprimarypreventionofcardiovasculardisease
Author
CharlesHHennekens,MD,DrPH

SectionEditors
DeputyEditor
FreekVerheugt,MD,FACC,FESC GordonMSaperia,MD,FACC
ChristopherPCannon,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Jul28,2014.
INTRODUCTIONCardiovasculardisease(CVD),whichincludescoronaryheartdisease,cerebrovascular
disease,andperipheralarterydisease,isfarandawaytheleadingthecauseofdeathintheUnitedStates
(US)andmostdevelopedcountriesandisrapidlybecomingtheleadingcauseofdeathintheworld.In2014,in
theUSalone,CVDaccountsformorethan900,000deaths.Thetotalityofevidencefrombasicresearch,
clinicalinvestigations,observationalepidemiologicstudies,andrandomizedtrialshasprovidedstrongsupport
forthenetbenefitsofaspirinindecreasingtheriskofCVDeventsinawiderangeofpatientsatsufficientrisk
[1]:
Inacuteischemicsyndromessuchasacutemyocardialinfarction(MI)andunstableangina,andlong
termtoreducerisksofrecurrentMI,stroke,andvasculardeath.
InacuteocclusivestrokeandlongtermtoreducerisksofMI,recurrentstroke,andvasculardeath
InsecondarypreventionofCVDafteracuteMI,occlusivestroke,transientischemicattack,stable
angina,andcoronaryarterybypasssurgerytoreducerisksofMI,stroke,andvasculardeath.
InprimarypreventionofafirstMIasanindividualclinicaljudgmentforapparentlyhealthymenand
womenatsufficientrisk.
TheevidencesupportingtheefficacyofaspirinforawiderangeofpatientsathighormoderateriskofCVD,
includingoptimaldosing,andtherelativeandabsoluterisksofsideeffectswillbereviewedhere.Theuseof
aspirininprimarypreventionofCVDaswellascancerisalsoreviewedelsewhere.(See"Aspirinintheprimary
preventionofcardiovasculardiseaseandcancer".)
Severallargerandomizedtrials,aswellastheirmetaanalyses,havedemonstratedstatisticallysignificantand
clinicallyimportantnetbenefitsoftheearlyinitiationofaspirininpatientswithacutecoronarysyndromes.This
issueisdiscussedseparately.(See"AntiplateletagentsinacutenonSTelevationacutecoronarysyndromes"
and"AntiplateletagentsinacuteSTelevationmyocardialinfarction".)
Thenetbenefitsofaspirinasadjunctivetherapyafterpercutaneouscoronaryinterventionorcoronaryartery
bypassgraftsurgeryandassecondarypreventionafterstrokeorduringthetreatmentofacuteischemicstroke
arediscussedseparately.(See"Antithrombotictherapyforelectivepercutaneouscoronaryintervention:
Generaluse"and"Coronaryarterystentthrombosis:Incidenceandriskfactors"and"Coronaryarterybypass
graftsurgery:Causesandratesofgraftfailure"and"Antiplatelettherapyforsecondarypreventionofstroke"
and"Antithrombotictreatmentofacuteischemicstrokeandtransientischemicattack",sectionon'Aspirin'.)
MECHANISMSOFACTIONPlatelets,plateletproducts,andclottingfactorsallplayimportantand
proximatecausalrolesintheoccurrenceofvirtuallyallocclusivevascularevents,includingMIandischemic
stroke.Thedisruptionofplateletandfibrinrichatheroscleroticplaquesmayleadtoenhancedplatelet
deposition,andultimatelytheformationofathrombusthatcanprecipitateanacuteclinicalcardiovascular
event[2].(See"Plateletbiology"and"Theroleofplateletsincoronaryheartdisease"and"Theroleofthe
vulnerableplaqueinacutecoronarysyndromes".)
Inadditiontoitswelldocumentedandclinicallyimportantantiplateleteffects,aspirinhasbeenpostulatedto
haveotherbiologicmechanismsthatmayplayaroleindecreasingrisksofcardiovasculardisease[3].One
suchmechanismmaybeviaincreasednitricoxideformation[4],andanothermaybeapositiveeffecton
elevatedlevelsofcertaininflammatorymarkers,includingproinflammatorycytokinesandCreactiveprotein.
TherelationshipbetweenCRPandaspirinuseisdiscussedelsewhere.(See"Creactiveproteinin
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cardiovasculardisease".)
ASPIRINNONRESPONSEANDRESISTANCETheterm"aspirinresistance"hasbeenusedtodescribe
theoccurrenceofcardiovasculareventsdespiteregularaspirinintakeatrecommendeddoses.Suchtreatment
failuresresemblethosewithotherdrugs,includingstatins,betablockers,andangiotensinconvertingenzyme
inhibitors,allofwhichareofprovenbenefitinthetreatmentofcardiovasculardisease(CVD).Whenusedfor
secondaryprevention,allofthesedrugsreducenonfatalCVDbyaboutonefourthandfataleventsbyabout
onesixth.Thus,threefourthsofnonfatalandfivesixthsoffataleventsarenotpreventedbyallthesedrugs,
butthesecircumstancesdonotnecessarilyimplythepresenceof"resistance."
Thecurrentlackofcogentevidencetosupporttheclinicalrelevanceofaspirin"resistance"intheCVDevents
thatcontinuetooccurisdiscussedindetailseparately.(See"Nonresponseandresistancetoaspirin".)
ASPIRINSENSITIVITYAminorityofpatientsareunabletotolerateaspirinbecauseofhypersensitivity,
whichismostoftenmanifestedclinicallyasrespiratorytractdisease(rhinitisandasthma,10percent,rarely
withsystemicsymptoms)orurticaria/angioedema(0.07to0.2percent)[57].Withsomeformsofaspirin
sensitivity,crossreactionsoccurwithothernonsteroidalantiinflammatorydrugs.(See"NSAIDs(including
aspirin):Allergicandpseudoallergicreactions".)
TheclearbenefitsofaspirininreducingrisksofCVDraiseclinicalchallengesforhighriskpatientswhorequire
aspirinandhavesuchsensitivities[8].
Formostpatientswithstablecoronarydisease,aspirindesensitizationcanbeattempted,althoughthis
techniquemaynotbeeffectiveinpatientswithunderlyingchronicurticaria.(See"Diagnosticchallenge
anddesensitizationprotocolsforNSAIDreactions".)
Forpatientswithanacutecoronarysyndromeorforthosewhocannotundergoaspirindesensitization,
clopidogrelmaybeaneffectivealternative.Dependingupontheclinicalpresentationandtheneedfor
percutaneouscoronaryintervention,otherantithrombotictherapymaybeaddedorsubstituted.
Randomizeddataarelackingontheoptimalstrategy.
BLEEDINGRISKThemainadverseeffectofaspirinisanincreasedriskofbleeding,chieflyfromthe
gastrointestinal(GI)tractbutalsoveryrarelyfromintracranialvessels.Metaanalysesofrandomizedtrials
havedemonstratedthatfiveyearsoftreatmentwith325mgaspirindailyproducesaboutaonepercent
absoluteincreaseinriskofGIbleedingcomparedtoplacebo(2.47versus1.42percentwithplaceboatan
averageof28monthsand1.3versus0.5percentatvariablefollowup)[9,10].Anonsignificantincreaseinthe
riskofhemorrhagicstrokeofaboutonethirdhasbeenobservedinthemetaanalysesoftheprimaryprevention
trials.Thisrelativeincreasecorrespondstoaverysmallabsoluteannualincreaseofaroundtwohemorrhagic
strokesper10,000allocatedtoaspirin.(See"Spontaneousintracerebralhemorrhage:Pathogenesis,clinical
features,anddiagnosis",sectionon'Riskfactors'.)
Theincidenceofmajorbleeding,aswellasocclusivevascularevents,arelikelytobehigherinthegeneral
populationthanamongwillingandeligibleparticipantsinrandomizedtrials.Inapopulationbasedstudy,
186,425Italiancitizenswithanewprescriptionforlowdose(300mg)aspirinwerecomparedwithanequal
numbernotprescribedaspirin[11].TheprimaryoutcomewashospitalizationformajorGIbleedingandor
cerebralhemorrhage.Afteramedianfollowupof5.7years,thefollowingfindingswerenoted:
Thosewhoselfselectedforaspirinusehadahigheroverallincidenceofhemorrhagicevents(5.58versus
3.60per1000personyearsincidencerateratio1.55,95%CI1.481.63).Subjectswhoselfselectedfor
aspirinhadanincreasein20majorbleedingeventsforevery10,000treatedpatients.Theincidencerate
ratiosweresimilarfortherelativelycommongastrointestinalbleedsandtherareintracranialbleeds.
Insubgroupanalysesofpatientswithdiabetes,thosewhoselfselectedforaspirinusedidnothavea
significantincreaseinhemorrhagicevents(incidenceriskratio1.09,95%CI0.971.22).(See'Impactof
diabetes'below.)
DosingandbleedingriskInindirectcomparisonsintheworldwidemetaanalysisconductedbythe
AntithromboticTrialists'Collaboration,therewerenosignificantdifferencesbetween75and325mgaspirinand
risksofmajorextracranialbleedingbasedondatafromthreeindividualrandomizedtrials[12].
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InnonrandomizedposthocsubgroupanalysesfromtheCUREandBRAVOtrials,whichareusefulto
formulatebutnottesthypotheses,therewasanincreaseinbleedingriskathigherdoseswithinthelowdose
range[13,14]butconfoundingbyindicationwasaplausiblealternativeexplanation.
Ina2006systematicreviewof22randomizedtrialsoflowdoseaspirin(75to325mg/day)andclopidogrelfor
adverseeffects,thefollowingfindingswerenotedforaspirin[15]:
Lowdoseaspirinincreasedtheriskofanymajorbleeding,majorGIbleeding,andintracranialbleeding1.7
to2.1timescomparedtoplacebo.Theabsoluteannualincreaseinriskwas1.3per1000patientsforall
majorbleedingepisodes(mostlyGI)and3per10,000forintracranialbleeding.
Therewasnodifferenceinbleedingriskataspirindosesof>162to325mg/daycomparedto75to162
mg/day.
Inanonrandomized,posthocsubgroupanalysisfromtheCHARISMAtrialofpatientswitheitherestablished
cardiovasculardisease(about12,000)orathighrisk(about4000)whowererandomlyassignedtoclopidogrel
75mgdailyorplacebo[16],allweregivenconcurrentaspirininadailydoseatthediscretionofthe
investigators.(See"Secondarypreventionofcardiovasculardisease",sectionon'Antithrombotictherapy'.)
Theincidenceofsevereorlifethreateningbleeding(primarysafetyendpoint)wasevaluatedatamedianof28
monthsinrelationtothedoseofaspirin(<100mg,100mg,or>100mgdaily)andwhetherornotthepatient
receivedclopidogrel.Therewerenosignificantdifferencesbetweenthedifferentaspirindosegroupsinthe
adjustedhazardratiofortheincidenceofsevereorlifethreateningbleeding.Inaddition,therewasnoeffect
modificationbyclopidogrel.
Ina2011metaanalysisofrandomizedtrials,lowdosesofaspirinalonedecreasedtheriskforallcause
mortalityandincreasedtheriskforGIbleeding,whichfurtherincreasedwithconcomitantuseofclopidogrel
andanticoagulanttherapies,butdecreasedinpatientswhotookprotonpumpinhibitors[17].
RiskfactorsRiskfactorsforaspirinassociatedGIbleedinghavebeenidentifiedandarediscussed
separately.(See"NSAIDs(includingaspirin):Primarypreventionofgastroduodenaltoxicity",sectionon'Risk
factors'.)
IntheUnitedStatesPreventiveServicesTaskForcereportontheuseofaspirinfortheprimarypreventionof
cardiovasculardisease,themagnitudeofincreaseinriskwasestimatedtobeapproximatelytwotothreetimes
higherinpatientswithahistoryofGIulcer,andtwiceashighformenaswomen[18].(See"NSAIDs(including
aspirin):Primarypreventionofgastroduodenaltoxicity",sectionon'Lowdoseaspirinforcardiovascular
protection'and"NSAIDs(includingaspirin):Primarypreventionofgastroduodenaltoxicity",sectionon'Risk
factors'.)
PrimarypreventionofaspirininducedGIbleedingIssuesrelatedtotheprimarypreventionofGItoxicity
fromnonsteroidalantiinflammatorydrugsarediscussedindetailelsewhere.(See"NSAIDs(includingaspirin):
Primarypreventionofgastroduodenaltoxicity",sectionon'Preventionstrategies'.)
Manypatientstakingaspirin,suchasthosewithacutecoronarysyndromesorplacementofanintracoronary
stent,arealsoonclopidogrel.In2008,thepossibilitywasraisedthatprotonpumpinhibitors(PPIs)can
interferewithclopidogrel'sabilitytoimpairplateletfunction.ThisissueandourrecommendationsforPPIusein
patientstakinglongtermdualantiplatelettherapywithaspirinandclopidogrelarefoundelsewhere.(See
"Periproceduralandlongtermgastrointestinalbleedinginpatientsundergoingpercutaneouscoronary
intervention",sectionon'Prevention'and"Clopidogrelresistanceandclopidogreltreatmentfailure",sectionon
'Interactionwithotherdrugs'.)
SecondarypreventionofGIbleedingTheriskassociatedwithrestartingantiplatelettherapyinpatients
whosemeanagewas70to72andwhohavehadanulcercomplication,mostlyGIbleeding,hasbeen
evaluatedintworandomizedtrialsinwhichpatientswerefirsttreatedforeradicationofHelicobacterpyloriand
therapywasrestartedonlyiferadicationofH.pyloriandhealingoftheulcerweredocumented[19,20].(See
"NSAIDs(includingaspirin):Secondarypreventionofgastroduodenaltoxicity",sectionon'Withcontinuedlow
doseaspirin'.)
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Thefollowingrisksofrecurrentbleedingwerenotedatoneyear:
Restartinglowdoseaspirin(100mg/day)14.8percent
Substitutingclopidogrel(75mg/day)forlowdoseaspirin8.6percent
Restartinglowdoseaspirin(80to100mg/day)withaPPI0.7to1.6percent
Notsurprisingly,aPPIdidnotprotectagainstlowerGIbleeding(4.6percentatoneyearinbothgroups)[20].
TheefficacyofaddingaPPIinpatientstreatedwithclopidogrelwasnotevaluated.
Thehighbleedingriskwithclopidogrelwasobserveddespitethefactthattheulcerriskwithaspirinandother
nonsteroidalantiinflammatorydrugsisthoughttobemediatedprimarilybyinhibitionofcyclooxygenase,which
isnotaffectedbyclopidogrel.Oneplausiblemechanismisimpairedhealingofspontaneousasymptomatic
ulcersthatformatarateofupto2percentpermonth[21].(See"NSAIDs(includingaspirin):Pathogenesisof
gastroduodenaltoxicity".)
Insummary,furtherresearchisneededtodeterminetheoptimalregimenamongpatientswhohavehadaGI
bleedonlowdoseaspirin.Baseduponthecurrentlyavailableevidence,aspirinmaybegivenwithaPPIifthe
estimatedcardiovascularriskofthepatientwarrantscontinuedtherapy.Inametaanalysisofsixsecondary
preventiontrials,itwasestimatedthat1.5deathscouldbepreventedforeveryepisodeofnonfatalGIbleeding
[10].(See"NSAIDs(includingaspirin):Secondarypreventionofgastroduodenaltoxicity",sectionon'With
continuedlowdoseaspirin'.)
NONASPIRINNSAIDSOneconcernwiththeconcurrentadministrationofnonsteroidalantiinflammatory
drugs(NSAIDs)isapossiblereductionofthecardioprotectiveeffectofaspirin.Baseduponthelimited
evidenceavailable,ibuprofenandprobablyothernonselectiveNSAIDsmayhaveadeleteriousinteractionwith
aspirinthatmayhaveclinicalrelevance[22,23].Itispossiblethatthisdeleteriousinteraction,ifreal,is
mitigatedbyadministeringaspirinatleasttwohoursbeforetheNSAID[22].
TheseissuesaswellastheeffectofNSAIDtherapy(bothnonselectiveandCOX2selective)on
cardiovascularriskinpatientsnottakingaspirinarediscussedindetailseparately.(See"COX2selective
inhibitors:Adversecardiovasculareffects"and"NonselectiveNSAIDs:Adversecardiovasculareffects",
sectionon'Patientstakingaspirinforprevention'.)
SECONDARYPREVENTIONOFCVD
EfficacyAspirinproducesstatisticallysignificantandclinicallyimportantreductionsintheriskof
subsequentmyocardialinfarction(MI),stroke,andvasculardeathamongawiderangeofpatientswhohave
survivedanocclusivecardiovasculardiseaseevent[12,24].
TheconclusivebenefitsoflongtermaspirintherapywerebestdemonstratedbytheAntithromboticTrialists'
Collaborationsmetaanalysesof195randomizedtrialsofantiplatelettherapy,principallywithaspirin,among
morethan135,000highriskpatientswithpriorevidenceofcardiovasculardisease,includingpriororacuteMI,
priororacutestrokeortransientischemiaattacks(TIA),andotherhighriskgroupssuchasunstableangina,
stableangina,peripheralarterydisease,coronaryarterybypassgraftsurgery,percutaneouscoronary
intervention,atrialfibrillation,andvalvulardisease[12].
Themajorfirmconclusionswereasfollows(table1):
Antiplatelettherapy,primarilywithaspirin,significantlyreducedtherelativeriskofsubsequentvascular
events(nonfatalMI,nonfatalstroke,andvasculardeath)byapproximately22percent.
Inabsoluteterms,antiplatelettherapyledtoavoidanceofapproximately36vasculareventsper1000
patientswithapriorMItreatedforameanof27months38eventsper1000patientswithanacuteMI
treatedforonemonth,36eventsper1000patientswithapreviousstrokeorTIAtreatedfor29months,
nineeventsper1000patientswithanacutestroketreatedfor0.7months,and22eventsper1000
patientswithotherhighriskfeaturestreatedfor22months.
Therewerenodifferencesinefficacyorsafetybetweendosesof75to150mg/day(calledlowdose
aspirin)and160to325mg/day(calledmediumdoseaspirin).
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UseinheartfailureTheuseofaspirininpatientswithheartfailurewithorwithoutvasculardisease
(includingcoronarydisease)isdiscussedseparately.(See"Drugsthatshouldbeavoidedorusedwithcaution
inpatientswithheartfailure",sectionon'Aspirin'.)
ComparisontothienopyridinesSeveralrandomizedtrialsofsecondarypreventiondidnottestwhether
thienopyridinesaddedtotheclinicalbenefitsofaspirin,butinsteadcomparedaspirinwithclopidogrelor
ticlopidine[2528].TheCAPRIEtrial,forexample,foundthatclopidogrelhadamodest,andmarginally
significantadvantageoveraspirinforthepreventionofstroke,MI,andvasculardiseasein19,185patientswith
arecentstroke,MI,orperipheralarterydisease(annualeventrate5.3versus5.8percent)[25].
Asmallbutsignificantreductioninseriouscardiovasculareventswasalsonotedwithclopidogrelcomparedto
aspirinintheAntithromboticTrialists'Collaborationreport(10.1versus11.1percent)[12]andwithticlopidineor
clopidogrelcomparedtoaspirininametaanalysisoffourtrialswith22,656patientsathighriskforvascular
disease(12versus13percentatapproximatelytwoyears,oddsratio0.91)[29].
Inthelatterreport,ticlopidineandclopidogrelwereassociatedwithlowerincidencesofgastrointestinal
hemorrhageanduppergastrointestinalupset,butahigherincidencesofrash,diarrhea,and,withticlopidine,
neutropenia[29].Clopidogrelispreferredtoticlopidinebecauseitissafer.Anyminimalimprovementinefficacy
withclopidogrelorticlopidinecomparedtoaspirinmustbeweighedagainsttheirsideeffectsandmuchhigher
costs.
CessationofaspirinThebenefitsofaspirinareacuteandlikelyresultfromantiplateleteffectsforthelifeof
theplateletwhosehalflifeisabouteightdays.Thus,cessationofaspirinmayincreaserisksofcomplications
suchasMI,stroke,orstentthrombosis.Themajorreasonsforphysiciandirectedcessationofaspirintherapy
indescriptionsofcomplicationshavebeenminorsurgery,endoscopy,anddentaltreatment.However,with
respecttosurgery,thereisincreasingevidencethataspirinshouldbecontinuedinpatientsathighriskfor
perioperativeocclusivevascularcomplications(eg,thoseundergoingcoronaryarterybypassgraftorperipheral
arterialsurgery).(See"Antiplatelettherapyaftercoronaryarterystenting"and"Perioperativemedication
management",sectionon'Aspirin'.)
ConcomitantuseofACEinhibitorsAngiotensinconvertingenzyme(ACE)inhibitorsarestandardtherapy
inpatientswithheartfailureaswellasmostwithpriorMIordiabeticpatients,especiallythosenotatgoal
bloodpressure.Posthocsubgroupanalysesofcompletedrandomizedtrialshaderroneouslyraisedthe
possibilitythataspirinmightpartiallyattenuatethebenefitfromACEinhibitors.Thetotalityoftheevidence,
however,supportsnodeleteriousinteractionbetweenACEinhibitorsandaspirin[3032].(See"Angiotensin
convertingenzymeinhibitorsandreceptorblockersinacutemyocardialinfarction:Recommendationsforuse"
and"ACEinhibitorsinheartfailureduetosystolicdysfunction:Therapeuticuse".)
AsystematicreviewoftheeffectsoflongtermtreatmentwithACEinhibitorsinthepresenceorabsenceof
aspirinwasperformedondatafromsixmajortrialsof22,060patientswithcardiovasculardisease(eg,heart
failure,leftventriculardysfunction,orMI)[32].TheoverallbenefitsofACEinhibitorsonmajorcardiovascular
outcomes(eg,death,stroke,andallmajorvascularevents)weregreaterinpatientswhoalsoweregiven
aspirin,exceptforthesubgroupofMI,whichmayhavebeenduetotheplayofchance.
Intheabsenceofacontraindication,aspirinandACEinhibitorscanbeusedsafelyinpatientsathighriskfor
majorvascularevents.Asdescribedinthenextsection,itmaybeprudenttouseamaintenanceaspirindose
of75to325mg/dayinsuchpatients.
RecommendationsofothersInthe1980s,theUnitedStatesFoodandDrugAdministration(FDA)
approvedprofessionallabelingindicationsforaspirininpatientswithpriorMIorunstableangina[33]andfor
menwithpriorTIAs[34].InJanuary1997,atajointmeetingoftheFDA'sNonprescriptionDrugsand
CardiovascularandRenalDrugsAdvisoryCommittees,expansionoftheprofessionallabelingindicationwas
recommendedtoincludewomenaswellasmenwithpriorTIAs,priorocclusivestroke,orchronicstable
angina,andthosewhohaveundergonearterialrevascularizationprocedures(eithercoronaryarterybypass
graftorpercutaneouscoronaryintervention).
The2012AmericanCollegeofChestPhysiciansAntithromboticTherapyandPreventionofThrombosis
guidelineontheprimaryandsecondarypreventionofcardiovasculardiseasemakesastrongrecommendation
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foreitheraspirinorclopidogrelforpatientswithestablishedcoronaryarterydisease[35].
DosingandcardiovascularbenefitThemostwidelytestedregimeninthesecondarypreventiontrials
intheAntithromboticTrialists'Collaborationwasaspirinatadoseof75to325mg/day[12].
Indirectandnonrandomizedcomparisons,includingaposthocsubsetanalysisfromthelargeCHARISMAtrial
[16],showednodifferenceinefficacybetweendosesof75to150mg/day(calledlowdoseaspirin)and160to
325mg/day(calledmediumdoseaspirin),astheproportionalreductionineventswas32and26percent,
respectively,orhigherdosesupto1500mg/day.Insuchcomparisons,thereisconfoundingbyindication,as
mostpatientsassignedtohigherdosesenteredwithcerebrovasculardiseaseandmostassignedtolowdoses
hadpriorcardiacevents[3,12,36,37].
Ithasbeensuggestedthataspirindosesbelow75mg/daymightbemoreeffectivethanhigherdosesbecause
suchlowdosesarereportedto"spare"prostacyclin(aplateletantiaggregantandvasodilator)andcauseless
bleeding.Theclinicalrelevanceofprostacyclinsparing,however,hasneverbeendemonstrated.Withrespect
toefficacy,basedonsmallnumbersofeventsinonlythreerandomizedtrials,dosesbelow75mgdaily
showedanonsignificantbenefitofabout13percent,whichwasaboutonehalfthesignificantoverallbenefitof
about25percentseenwithhigherdosesupto1500mg/day[12].
Atpresent,theUnitedStatesFoodandDrugAdministrationrecommendsdailydosesof75to325mg,while
the2006AmericanCollegeofCardiology/AmericanHeartAssociationguidelinesonsecondaryprevention
recommendsdailydosesof75to162mgforsecondaryprevention[38].TheAmericanCollegeofChest
Physiciansrecommendsadailydoseof75to100mg[35].
Webelievethetotalityofevidencesuggeststhatdosesofaspirinfrom75to325mgdailyareassociatedwith
thebestrisk/benefitratio,whilesomeexpertsrecommendthe75to162mgperdayrange.
Inpatientswithacuteocclusiveevents,aloadingdoseofatleast162mgaspirinandpreferably325mgshould
begiventoachievearapidclinicalantithromboticeffect.Thisissueisdiscussedindetailseparately.(See
"AntiplateletagentsinacutenonSTelevationacutecoronarysyndromes"and"AntiplateletagentsinacuteST
elevationmyocardialinfarction".)
AspirinformulationTheformulationofaspirin(regular,buffered,orentericcoated)shouldbeanindividual
clinicaldecisionmadewiththepatient.Entericcoatedaspirinisdesignedtoresistdisintegrationinthe
stomachthus,healthcareprovidersandtheirpatientsmaybelievethistobeanattractivealternativeto
conventionalaspirin.Althoughthispreparationmayreduceerosionsonendoscopy,entericcoatingdoesnot
appeartoprotectagainsttheclinicallyrelevantendpointofgastrointestinalbleeding[39].Thisfindingisnot
surprising,sinceinjurysevereenoughtoinducebleedingisthoughttoreflectthesystemicratherthanjustthe
localeffectsofaspirin.(See"NSAIDs(includingaspirin):Primarypreventionofgastroduodenaltoxicity",
sectionon'Entericcoatedandbufferedaspirin'and"NSAIDs(includingaspirin):Pathogenesisof
gastroduodenaltoxicity",sectionon'Systemicversustopicaleffects'.)
Insome[40]butnotall[41,42]studies,equivalentdosesofentericcoatedaspirinarenotaseffectiveasplain
aspirin.LowerbioavailabilityofthesepreparationsandpoorabsorptionfromthehigherpHenvironmentofthe
smallintestinemayresultininadequateplateletinhibition,particularlyinheaviersubjects.Thesedata
contributetotheformulationofthehypothesisthatlowdoseentericcoatedaspirindoesnotproduceadequate
plateletinhibition.
Inacuteocclusivevascularevents(eg,acutecoronarysyndrome),thenecessitytoachievearapidclinical
antithromboticeffectprecludestherecommendationofentericcoatedaspirinbecauseofitsdelayed
absorption.Iftheonlyavailablepreparationisentericcoated,thesingletabletormultipletabletsnecessaryto
achievetherecommendeddoseof325mgshouldbecrushedorchewed.
PRIMARYPREVENTIONOFCVDThissectionpresentsanindepthreviewoftheevidenceonaspirinin
theprimarypreventionofcardiovascularevents.Theevidenceonaspirinintheprimarypreventionofcanceris
presentedseparately.(See"Aspirinintheprimarypreventionofcardiovasculardiseaseandcancer".)
Basedonevidencefromninelargescaleprimarypreventiontrialsofmenandwomenwithoutestablished
cardiovasculardisease(CVD),aspirinproducesastatisticallysignificantandclinicallyimportantreductionin
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theriskofafirstmyocardialinfarction(MI),butnotstrokeorcardiovasculardeath.
WebelievethatanydecisiontoprescribeaspirinforprimarypreventionofCVDshouldbeanindividualclinical
judgmentthatweighstheabsolutebenefitinreducingtheriskofafirstMIagainsttheabsoluteriskofmajor
bleedingwithlongtermadministration.Thehighertheriskofcardiovascularevents,thegreaterthelikely
benefitfromaspirin.(See'Estimatingthebenefittoriskratio'below.)
MetaanalysesAcomprehensive2009metaanalysisofsixtrialsthatincludedindividualpatientleveldata
amongover95,000menandwomenwhowererandomlyassignedtoeitheraspirin(atdosebetween75and
500mgperday)orplaceboshowedthefollowing[43]:
Aspirinsignificantlyreducedtheincidenceofseriousvascularevents,definedasaprespecifiedcombined
endpointofMI,deathfromavascularcause(includingsuddendeath,pulmonaryembolism,hemorrhage),
orstroke(0.51versus0.57percentperyear).Thissignificantreductionwasattributableprincipallytoa
significantreductioninfirstnonfatalMI(0.18versus0.23percentperyear).
Aspirinsignificantlyincreasedtherateofmajorgastrointestinal(GI)andextracranialbleeds(0.10versus
0.07percentperyear).
Theproportionalreductionsweresimilarforwomenandmen
Threemetaanalyses,publishedin2011and2012addedapproximately6000additionalpatientsfromthree
trials[4446]tothecomprehensivemetaanalysisofover95,000patientspublishedin2009[4749].Not
surprisingly,thesemetaanalysescametosimilarconclusionstothe2009study.Inthe2012metaanalysis,
netcardiovascularbenefitexceededthebleedingriskathigherbaselineCVDeventsrates[49].
IndividualtrialsThefollowingaretheninerandomizedtrialscomparingaspirintoplacebothatareincluded
intheabovemetaanalyses.Nearly80percentofpatientswhoreceivedaspirincamefromthePhysicians
HealthStudy,theWomensHealthStudy,andtheHypertensionOptimalTreatmentTrial,sothe10yearriskof
afirsteventinthesepatientsisfarlowerthanthe10percent,whichindicatesmoderaterisk.
PhysiciansHealthStudyTheUnitedStatesPhysician'sHealthStudywasthefirsttodemonstratethat
aspirinreducestheriskofafirstMI[50].Aspirinwasgivenatadoseof325mgdailyeveryotherday.
BritishDoctorsTrialIntheBritishDoctor'sTrial,aspirinwasgivenatadoseof500mgdaily[51].
ThrombosisPreventionTrialTherelativebenefitoflowdose(75mg)aspirinandwarfarintherapy
(internationalnormalizedratio[INR]goalof1.5)inpatientsathighriskwasaddressedintheThrombosis
PreventionTrial[52].Thistrialuseda2by2factorialdesigntoevaluatelowdoseaspirin(75mg/day)
and/orwarfarin(targetINR1.5).
HypertensionOptimalTreatmentTrialIntheHypertensionOptimalTreatmentTrial,aspirinwasgivenat
adoseof75mgdaily[53].
PrimaryPreventionProjectInthePrimaryPreventionProject,entericcoatedaspirinwasgivenata
doseof100mgdaily[54].
WomensHealthStudyIntheWomen'sHealthStudy,aspirinwasgivenatadoseof100mgon
alternatedaysforameanof10.1years[55].
AspirinforAsymptomaticAtherosclerosistrialIntheAspirinforAsymptomaticAtherosclerosistrial,
aspirinwasgivenatadoseof100mgdaily[44].
JapanesePrimaryPreventionofAtherosclerosisWithAspirinforDiabetestrialIntheJapanesePrimary
PreventionofAtherosclerosisWithAspirinforDiabetestrial,aspirinwasgivenatadoseof81to100mg
dailytopatientswithdiabetes[46].
PreventionofProgressionofArterialDiseaseandDiabetestrialInthePreventionofProgressionof
ArterialDiseaseandDiabetestrial,aspirinwasgivenatadoseof100mgdailytopatientswithdiabetes
[45].
EstimatingthebenefittoriskratioIndividualclinicaldecisionmakingforaspirinintheprimaryprevention
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ofCVDisfarmorecomplexthanthatforsecondaryprevention.Insecondaryprevention,therandomized
evidencehasfarmorestrokeandCVDdeathendpointsandshowsconclusivebenefitsonMI,stroke,and
CVDdeath.Whenaspirinisusedforsecondaryprevention,thebenefitoftherapy(atleasta20percentrelative
riskreductioninapopulationwhose10yearriskisgreaterthan20percent)almostalwaysexceedsthe
absoluterisk(rangingfromabout1percentinyoungtoabout4percentinolderindividuals)ofmajor
extracranialbleedingaswellastheveryseriousbutveryrareriskofhemorrhagicstroke.
Inprimaryprevention,therandomizedevidenceshowsconclusivebenefitsonfirstMI,butthedataonstroke
andCVDdeathremaininconclusive.Inaddition,theabsoluteriskreductionisfarlowerforprimaryprevention
intheprimarypreventiontrials,theaverageabsoluteriskwaslessthan5percent(a20percentrelativerisk
reductioninapatientwitha10yearriskof5percentisabout1percenta10percentrelativeriskreductionina
patientwitha10yearriskof5percentisabout0.5percent).Further,ifoneassumesthattheriskofableeding
eventisthesameasdescribedforsecondaryprevention,thebenefitsoutweightherisksonlywhentheriskof
acardiovasculareventbeginstoexceed6to10percentin10years(table2C).
Inaddition,however,ageisariskfactorforbleedingaswellasocclusion.Further,notallpatientsareatequal
riskforthedevelopmentofmajorbleeding.PatientswithahistoryofGIbleed,thoseonchronicnonsteroidal
antiinflammatorytherapy,andthosewithGIsymptomsattributableto(orhistoryof)ulcerdisease,gastritis,or
gastroesophagealrefluxdiseaseareatincreasedrisk.
(See'Bleedingrisk'aboveand"NSAIDs(includingaspirin):Primarypreventionofgastroduodenaltoxicity",
sectionon'Riskfactors'.)
Wesuggestassessingthenetbenefit(reductionincoronaryheartdisease[CHD]eventsminusanincreasein
theriskofmajorbleeding)ofaspirinusingthefollowingguidelinesfromtheUnitedStatesPreventiveServices
TaskForce(USPSTF):
Theindividualpatient'sriskofafirstcardiovasculareventshouldbecalculated.Wesuggestusinga
calculatorthatusesamultivariableriskfunctionderivedfromdataintheFraminghamHeart
Study(calculator1andcalculator2).(See"Estimationofcardiovascularriskinanindividualpatient
withoutknowncardiovasculardisease".)
ThemagnitudeofthebenefitandriskcanbeestimatedfromexistingtablesprovidedbytheUSPSTF
(table2AC).
Aspirinshouldbeprescribedbasedonanindividualclinicaljudgmentwhenthemagnitudeoftheabsolute
benefitexceedsthemagnitudeoftheabsoluteharm(table2C).Whenthemagnitudeofbenefitissimilar
tothatofrisk,patientpreferencemaybeconsidered(USPSTF).Forinstance,anindividualwhofeelsthat
thepreventionofanMIorstrokeismoreimportantthanthedevelopmentofaGIbleedmaystateaclear
preferenceforaspirinuse.
ThisgeneralapproachmaynotbeusefulinpatientswithriskfactorsforbleedingsuchashistoryofGI
bleedingorulcers,nonsteroidalantiinflammatorydruguse,orupperGItractpain,astheirriskofGI
bleedingismuchhigher.(See"NSAIDs(includingaspirin):Primarypreventionofgastroduodenaltoxicity",
sectionon'Riskfactors'.)
WhiletheFraminghamriskcalculatorhasalargebodyofevidencetosupportitsvalidityinriskstratification,
onecohortstudysuggestedthatmeasuringcoronaryarterycalcification(CAC)maybeareasonablealternative
approach.(See"Diagnosticandprognosticimplicationsofcoronaryarterycalcificationdetectedbycomputed
tomography",sectionon'CACandprognosisinasymptomaticpatients'.)Usingdatafrom4229patientsinthe
MultiEthnicStudyofAtherosclerosis(MESA),participantswithCAC100hadfavorablerisktobenefit
estimationsforaspirinuseandthosewithascoreofzerowereestimatedtoreceivenetharm[56].Atpresent,
webelievethatfurtherresearchisnecessarytosupporttheuseofCACscoring.
Somepatientsareatparticularlyhighrisk,suchasthoseoverage40withmetabolicsyndromewhose10year
risksofafirstCHDeventare16to18percent.Assuch,itmaybeprudenttoconsideraspirinasanadjunctto
statinsforprimaryprevention.Thedecisionshouldalsobeanindividualclinicaljudgmentthatweighsthe
magnitudeoftheabsolutebenefitonfirstMIagainstthemagnitudeoftheabsoluterisk,chieflymajorbleeding.
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Webelievethatanygeneralguidelinesforaspirininprimarypreventionshouldincludetheresultsofongoing
randomizedtrialsofaspirininmoderatetohighriskprimarypreventionsubjects.
ImpactofageThesixlargescalerandomizedtrialsofaspirininprimarypreventionincludeover90,000
subjectsfromage40to89,buttheiraverage10yearriskofafirstCHDeventislessthan5percent.Further
randomizedevidenceisaccumulatinginseverallargescalerandomizedtrials,inparticularARRIVEand
ASPREE,whichtargetpatientsatmoderatetohighriskwithanaverageriskofafirstCHDeventof10to19
percent.SinceriskofafirstCHDeventincreaseswithageinmenandwomen,thesetrialswillincludea
greaterpreponderanceofoldersubjects.Suchdatashouldformarationalbasisforguidelinesforprimary
preventioninmoderatetohighriskmenandwomen.
ImpactofgenderThetotalityofrandomizedevidencesuggestsnodifferencesinresponsetoaspirin
betweenmenandwomen[57].A2009metaanalysisoftheresultsfrom22trialsofprimaryandsecondary
prevention,includingabout135,000patients,showednodifferenceintheresponsetoaspirinbetweenmenand
women[43].A2002metaanalysisofthetrialsofsecondarypreventioncametoasimilarconclusion[12].
IntheWomensHealthStudy(WHS),aspirinshowedasignificantbenefitonriskofafirststrokebutnotafirst
MI[55].Since90percentofthesubjectswereunder65,thepredominantocclusivevasculareventinsuch
womenisstroke,notMI.Inthe10percentofwomenaged65andoverwhoaccrued30percentoftheend
points,MIwasfarmorecommon,andaspirinreducedtheriskofafirstMItothesamedegreeasinthe
previoustrialsofprimarypreventionpredominantlyinmen.
Thishypothesisofpossiblegenderdifferenceshadbeenformulatedfroma2006genderspecificmetaanalysis
ofrandomizedtrialsrestrictedtoaspirinintheprimarypreventionofCVDsuggestedagenderdifference[58].
Inthismetaanalysisofover51,000women,about80percentofwomenwerefromtheWHSdiscussedabove.
Aspirinwasassociatedwithasignificant12percentreductioninthecombinedcardiovascularoutcomeof
nonfatalMI,nonfatalstroke,andcardiovascularmortality(oddsratio0.8895%confidenceinterval0.790.99),
attributableprincipallytoasignificant33percentMIreductioninmenand17percentstrokereductionin
women.
ImpactofdiabetesInthe2002versionoftheNationalCholesterolEducationProgramAdultTreatment
PanelIII,diabeteswaselevatedfromamajorriskfactortoaCHDriskequivalent[59].Therationaleforthis
changederives,inpart,fromearlierobservationsthatpatientswithdiabeteshaveseveralfoldincreasedrisks
ofCHD,whichareevengreaterinwomenthanmen.Thisissueisdiscussedindetailelsewhere.(See
"Overviewoftheriskequivalentsandestablishedriskfactorsforcardiovasculardisease",sectionon'Diabetes
mellitus'.)
WithrespecttotheuseofaspirinfortheprimarypreventionofCVDamongpatientswithdiabetesbutnoother
riskfactors,evidenceofbenefitisconflicting.Furtherrandomizedevidenceisnecessaryandwillemergeover
thenextseveralyears[60].(See"Overviewofmedicalcareinadultswithdiabetesmellitus",sectionon
'Aspirin'.)
Basedontheavailableevidence,a2010expertconsensusdocumentwrittenjointlybytheAmericanDiabetes
Association,AmericanHeartAssociation,andtheAmericanCollegeofCardiologyFoundationmadethe
followingrecommendationsfortheuseoflowdoseaspirin(75to162mgdaily)inadultswithdiabetesbutno
historyofCVD[61]:
Aspirinmaybeconsideredforthosewhose10yearriskofCVDeventsisgreaterthanorequalto10
percentandinwhomtheriskofbleedingisnotincreased.
Aweakerrecommendation,basedonweakevidence,wasmadeforpatientswhose10yearriskofCVD
eventsisbetween5and10percent.
Theserecommendationsdonotdifferinsubstancefromourrecommendationsforprimaryprevention.(See
'Summaryandrecommendations'below.)
Theviewpointofthisconsensusdocument,aswellasthe2012AmericanCollegeofChestPhysicians
AntithromboticTherapyandPreventionofThrombosisguidelineonthePrimaryandsecondarypreventionof
cardiovasculardisease,isthatdiabetesshouldbeconsideredariskfactor,asopposedtoaCHDequivalent
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[35].
The2012EuropeanGuidelinesonCardiovascularDiseasePreventioninClinicalPracticemakeastrong
recommendationtonotprescribeaspirinforpatientswithdiabetesifCVDisnotpresent[62].
PossiblebenefitforthepreventionofcancerrelatedeventsTheuseofaspirinforprimarypreventionof
CVDaswellascancerisreviewedelsewhere.(See"Aspirinintheprimarypreventionofcardiovascular
diseaseandcancer".)
RecommendationsofothersThe2009USPSTFstatementontheuseofaspirinforthepreventionofCVD
makesstrongbutseparaterecommendationsforwomenandmen,basedontheirinterpretationoftheabove
trials[18,63]:
Inwomenaged55to79years,whenthepotentialbenefitofareductioninischemicstrokeoutweighsthe
riskofanincreaseingastrointestinalhemorrhage.
Inmenaged45to79,whenthepotentialbenefitfromareductionintherateofMIoutweighstheriskof
anincreaseinGIhemorrhage.
The2012AmericanCollegeofChestPhysiciansAntithromboticTherapyandPreventionofThrombosis
guidelineonthePrimaryandsecondarypreventionofcardiovasculardiseasemakesaweakrecommendation
forlowdoseaspirin(asopposedtonoaspirin)forprimarypreventioninallpersonsovertheageof50years.
Thedocumentacknowledgestheimportanceofindividualclinicaljudgement,whichshouldincludean
assessmentoftheabsolutebenefitsandrisks.(See"Estimationofcardiovascularriskinanindividualpatient
withoutknowncardiovasculardisease".)
In2014,theUnitedStatesFoodandDrugAdministrationissuedastatement,consistentwithourposition,that
anydecisiontouseaspirininprimarypreventionofCVDshouldbeanindividualclinicaljudgmentbetweenthe
healthcareproviderandeachofhisorherpatientsthatweighstheabsolutebenefitsonocclusionagainstthe
absoluterisksofbleeding[64].Randomizedtrialsofsuchsubjectsareongoingandwillprovidedirectdataon
thisissue.
OurapproachTheapproachsummarizedbelowtakesintoaccountonlythepreventionofCVDevents.As
mentionedatthebeginningofthesection,thereisreportedevidencethatadecisiontoprescribeaspirinmay
needtotakeintoaccounttheprimarypreventionofcancer.Thisapproachisdiscussedindetailseparately.
(See"Aspirinintheprimarypreventionofcardiovasculardiseaseandcancer".)
Thedatafortheuseofaspirininprimarypreventionofcardiovasculardiseasehavefarmoreuncertaintiesthan
forsecondaryprevention.Webelievethathealthcareprovidersshouldmakeindividualclinicaljudgmentsabout
theuseofaspirinforprimarypreventioninthoseapparentlyhealthymenandwomenwhoseabsolutebenefiton
reducingcardiovasculareventswilloutweightheirrisksofmajorbleeding.(See'PrimarypreventionofCVD'
above.)
Atpresent,judgmentsaboutprescribinglongtermaspirintherapyforapparentlyhealthyindividualsat
intermediatecardiovascularriskshouldcontinuetobemadeonacasebycasebasis.Suchdecisionsshould
bebasedonindividualclinicaljudgmentsbetweenthehealthcareproviderandeachofhisorherpatients.The
decisionshouldinvolvetheabsoluteriskofanimportantvasculareventaswellastheabsoluteriskofamajor
extracranialbleed.(See'Efficacy'aboveand'Estimatingthebenefittoriskratio'above.)
Thefollowingpointsmaybeconsidereddecisionmaking:
Forlowriskpatients(ie,menandwomenwhose10yearriskofafirstCHDeventislessthan10
percent),theabsolutebenefitonocclusivevasculareventsmaybelessthantheabsoluteriskofmajor
bleeding.
Formoderateriskpatients(ie,menandwomenwhose10yearabsoluteriskofafirstCHDeventis10to
19percent),therandomizeddataonbenefitsandrisksaresparse,soclinicaldecisionmakingshouldbe
madeonanindividualbasisforthosemenandwomeninwhomthebenefitsofaspirintopreventafirst
MIarelikelytoexceedtheirriskofmajorextracranialbleeding.Inthesepatients,itshouldalsobenoted
thataggressiveriskpreventativestrategies,includingtheuseofstatins,willreducebothMIand
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occlusivestrokewithlittlehazard.Aninformedclinicaldecisionshouldincludewhethertouseaspirinas
anadjunct,notalternativetoothertherapeuticlifestylechangesandpharmacologicmeasures.
Webelievethatindividualclinicaljudgementshouldbeconsideredforthosesubjectswhose10yearrisk
ofafirsteventis10percentorgreaterwhileawaitingtheresultsoftheongoingrandomizedtrialsdirectly
testingthishypothesis.
Availabledatasuggestthatdailydosesofaspirinbetween75and325mgareequallysafeandeffective.
(See'Efficacy'aboveand'PrimarypreventionofCVD'above.)
UNDERUTILIZATIONOFASPIRINDespitetheestablishedbenefitofaspirininpatientswithawiderange
ofpriorocclusivevasculardiseases,itsuseremainssuboptimal.Inaddition,aspirinremainsanunderutilized
treatmentforacutemyocardialinfarction(MI).Inanationalregistryofmorethan1000largerUnitedStates
hospitals,only77percentofacuteMIpatientsreceivedaspirinin1993[65].Similarfindingswerenotedina
1992to1993studyofpatients65yearsofageandolder:Only61percentwerereceivingaspirinwithintwo
daysofhospitalization[66].IncreasingtheuseofaspirintovirtuallyallacuteMIpatientswouldsavean
additional5000to10,000livesintheUnitedStateseachyear[67].
AspirinutilizationinpatientswithanacuteMIintheUnitedStatesappearstobeimprovingovertime.Thiswas
illustratedinareportinwhichacohortofMedicarepatientshospitalizedwithacuteMI(bothSTelevationand
nonSTelevationMI)between1994and1995(over230,000patients)wascomparedwithacohorthospitalized
between1998and1999(over35,000patients)[68].Theuseofseveralrecommendedtherapiesincreasedover
time,includingearlyaspirin(76to83percent)andaspirinatdischarge(77to83percent).
While60to84percentofpatientsintheUnitedStateshospitalizedforunstableanginaoranMIreceive
aspirin,itislessfrequentlyusedinoutpatientswithcoronaryarterydiseaseordiabetes[6971].Onestudyof
10,942visitstocardiologistsorprimarycarephysiciansbypatientswithcoronarydiseasefoundthatforthe
periodof1993to1996,aspirinusewas26percent[70].Aspirinusewasmorefrequentlyreportedby
cardiologiststhaninternists,familypractitioners,orgeneralpractitioners(37versus20,18,and11percent,
respectively).
ANTICOAGULATEDPATIENTSDespitetheevidencepresentedabove,whichshowsthataspirinreduces
therateofadversecardiovasculareventsinmostpatientswithestablisheddiseaseandmanyathighrisk,the
additionofaspirin(orotherantiplateletagent)towarfarininpatientswithanindicationforthelatterhasnot
beenshowntoimproveoutcomes.Thissectionwilloutlinetherationalefornotrecommendingaspirinfor
anticoagulatedpatientswhowouldotherwiseseemtobenefit.
Patientswhopotentiallycouldbenefitfrombothantiplateletandanticoagulanttherapyarecommon.For
example,itisestimatedthatbetween5and10percentofpatientsscheduledforpercutaneouscoronary
interventionaretakingoralanticoagulation.(See"Atrialfibrillation:Anticoagulanttherapytoprevent
embolization"and"Tripleantithrombotictherapyinpatientswithcardiovasculardisease",sectionon
'Introduction'.)
Forpatientswithcardiovasculardiseasewhomustbeanticoagulated,itisimportanttoknowwhetherthe
additionofaspirinsignificantlyimprovesoutcomes(reductionintheriskofadverseischemiccardiovascular
events)sincetheriskofmajorbleedingincreasessignificantlywhenbothagentsareusedcomparedto
warfarinalone.(See"Tripleantithrombotictherapyinpatientswithcardiovasculardisease",sectionon'Rates'.)
Thefirststepinsupportingarecommendationtonotaddaspirintowarfarinistodemonstratethat
anticoagulanttherapylowerstherateofischemicheartdiseaseeventsinpatientsnottakingaspirin.The
followingtwostudiesarerelevant:
A2003metaanalysisidentifiedthreetrialsofnearly1000patientswithestablishedcardiovascular
diseasethatcomparedmoderateintensitywarfarintherapy(internationalnormalizedratio[INR]2to3)to
placebo[72].(See"Chronicanticoagulationafteracutecoronarysyndromes",sectionon'Randomized
trials'.)Anticoagulationwasassociatedwithanonsignificant16percent(95%confidenceinterval[CI]11
to37)reductionintheriskofcardiovasculardeath,myocardialinfarction(MI),orstroke.In13trials(8140
patients)thatcomparedhighintensitywarfarin(INR>2.8)toplacebo,warfarinsignificantlyreducedthe
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rateofthisoutcomecomparedtoplacebo(2.3versus30.3percent).
TheThrombosisPreventiontrial(notincludedinthemetaanalysis)randomlyassignednearly5000men
(withoutcardiovasculardiseasebutathighrisk)ina2x2factorialdesigntoeithertolowdoseaspirin(75
mgdaily)orplaceboandtolowdosewarfarin(INRtargetof1.5)orplacebo[52].(See'Individualtrials'
above.)Lowdosewarfarinsignificantlyreducedtherateofischemicheartdiseaseeventscomparedto
placebo(10.3versus13.3percent).AnimportantlimitationofthisstudyisthelowINRachieved.
Thesecondstepistoshowthatanticoagulantplusaspirinisnotsignificantlybetterthanwarfarinalone,given
theknownincreaseinmajorbleedingassociatedwiththeconcomitantuseofbothagents:
Inthemetaanalysisdiscussedabove,threetrials(over3000patients)comparedmoderatetohigh
intensitywarfarin(INR>2)plusaspirintowarfarinalone.Combinedtherapywasassociatedwithanon
significantloweringoftherateofcardiovasculardeath,MI,andstroke(12.5versus14.3percent,
respectivelyoddratio0.86,95%CI0.701.06).Theresultsofthisanalysisshouldbeinterpretedwith
somecaution,astheachievedINRtargetwassomewhatlowerthanthatfelttobeideal(2.5).
IntheThrombosisPreventiontrialdiscussedabove,combinationwarfarinplusaspirinreducedtherateof
ischemicheartdisease(8.7versus10.3percent),butthestatisticalsignificancewasnotreported.
TheSPORTIFtrials(IIIandIV)evaluatedtherelativeefficacyofwarfarin(INR2to3)toximelagatranin
patientswithatrialfibrillationandincludedahighpercentageofpatientswithstablecardiovascular
diseaseorathighrisk.(See"Atrialfibrillation:Anticoagulanttherapytopreventembolization",sectionon
'Clinicaluseofanticoagulants'.)
Aposthocanalysiscomparedoutcomesinthe14percentofpatientswhoreceivedaspirintothosewho
didnot[73].TherateofMIwithaspirinpluswarfarin(0.6percentperyear)wasnotsignificantlydifferent
fromthatwithwarfarinalone(1.0percentperyear).Inaddition,combinationtherapywasassociatedwith
asignificantincreaseintheriskofmajorbleedingcomparedtowarfarinalone(3.9versus2.3percent).
Basedonlimitedevidence,wedonotrecommendroutinelyaddingaspirin(orotherantiplateletagent)to
warfarin(orotheranticoagulant)toreducetheriskofischemiccardiovasculardiseaseeventsinpatientswithor
athighriskforcardiovasculardisease.Thereisnoconvincingevidenceofbenefitandtheriskofmajor
bleedingwithcombinedtherapyishigher.Thisrecommendationisconsistentwiththatmadeinthe2012
AmericanCollegeofChestPhysiciansAntithromboticTherapyandPreventionofThrombosisguidelineon
Antithrombotictherapyforatrialfibrillation[74].
Theuseofdualantiplatelettherapy(aspirinplusaplateletP2Y12receptorblocker)plusoralanticoagulantin
patientswithrecentacutecoronarysyndromeorstentplacementisdiscussedindetailelsewhere.(See
"Chronicanticoagulationafteracutecoronarysyndromes",sectionon'Patientswithindicationsforchronic
anticoagulation'and"Tripleantithrombotictherapyinpatientswithcardiovasculardisease",sectionon'TOAT
versusothertherapies'.)
Someofourauthorsandreviewersarecomfortablecontinuingaspirinandanticoagulanttherapy,especiallyin
patientswithpriorMIorlessthanayearafterstentingiftherehavebeennosignificantbleedingepisodesand
theriskoffuturebleedingislow.(See"TherapeuticuseofwarfarinandothervitaminKantagonists",section
on'Majorriskfactors'.)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasics
andBeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoread
materials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.
Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowantindepth
informationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
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patientinfoandthekeyword(s)ofinterest.)
BeyondtheBasicstopic(see"Patientinformation:Aspirinintheprimarypreventionofcardiovascular
diseaseandcancer(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
SecondarypreventionInsecondaryprevention,aspirindecreasestheriskofcardiovasculardisease(CVD)
eventsinawiderangeofpatientswithestablisheddisease.Althoughtherandomizeddataaresparse,aspirin
mayalsobeofnetbenefitinpatientswithacoronaryheartdiseaseequivalent(suchaspatientswithdiabetes).
(See'Efficacy'aboveand'PrimarypreventionofCVD'above.)
Inallpatients,theuseofaspirinisassociatedwithanincreaseintheriskofmajorbleeding,particularlyfrom
thegastrointestinaltract.(See'Bleedingrisk'above.)Insecondaryprevention,theabsolutebenefitislarge
comparedtotheabsoluteriskofmajorbleeding.Inprimaryprevention,theabsolutebenefitislowerandmust
beweightedonanindividualclinicalbasisagainsttheabsoluteriskofmajorbleeding.
Werecommendlongtermantiplatelettherapy(eitheraspirinorclopidogrel)forthesecondarypreventionof
cardiovasculareventsinmostpatientswithestablishedCVD,includingthosewithahistoryofgastrointestinal
bleeding(Grade1A).Inpatientswithahistoryofgastrointestinalbleeding,preventionwithaprotonpump
inhibitorshouldbeconsidered.(See'Efficacy'aboveand'PrimarypreventionofCVD'aboveand'Secondary
preventionofGIbleeding'above.)
Basedonoverallbenefittoriskandbenefittocostconsiderations,wesuggestaspirinratherthanclopidogrel
forsecondaryprevention(Grade2B).(See'Comparisontothienopyridines'above.)Patientsforwhomcostis
notanissuecouldreasonablychooseclopidogrelratherthanaspirin,givenclopidogrel'sslightlygreater
efficacy.
Theuseofaspirininpatientswithacutecoronarysyndromes,inpatientswhohaveundergone
revascularizationprocedures,orinpatientsafterstrokeisdiscussedseparately.(See"Antiplateletagentsin
acutenonSTelevationacutecoronarysyndromes"and"AntiplateletagentsinacuteSTelevationmyocardial
infarction"and"Antithrombotictherapyforelectivepercutaneouscoronaryintervention:Generaluse"and
"Coronaryarterystentthrombosis:Incidenceandriskfactors"and"Coronaryarterybypassgraftsurgery:
Causesandratesofgraftfailure"and"Antiplatelettherapyforsecondarypreventionofstroke"and
"Antithrombotictreatmentofacuteischemicstrokeandtransientischemicattack",sectionon'Aspirin'.)
PrimarypreventionThistopicpresentsanindepthreviewoftheevidencethatcanbeusedtoformulatean
approachtotheuseofaspirinfortheprimarypreventionofcardiovascularevents.(See'Ourapproach'above.)
WedonotfeelthatwecanmakeabroadrecommendationtouseaspirinfortheprimarypreventionofCVD
events.However,asthebenefitsofaspirinusemayextendtocancerprevention,itsroleinprimaryprevention
isbetterevaluatedwhenthepreventionofcancerisalsotakenintoaccount.Werecommendthisbroader
approach,whichisdiscussedindetailseparately.(See"Aspirinintheprimarypreventionofcardiovascular
diseaseandcancer".)
PatientstakingoralanticoagulanttherapyFormostpatientswitheitherestablishedCVDorathighrisk
whohaveanindicationforlongtermoralanticoagulanttherapy,wesuggestnotaddingaspirin(orother
antiplatelettherapy)solelyforthepurposeofreducingcardiovascularrisk(Grade2C).(See'Anticoagulated
patients'above.)
SomepatientswithCVD,suchasthosewithrecentacutecoronarysyndromeorstentplacement,requireboth
antiplateletandanticoagulanttherapyforadefinedperiodoftime.Thisissueisdiscussedelsewhere.(See
"Chronicanticoagulationafteracutecoronarysyndromes",sectionon'Patientswithindicationsforchronic
anticoagulation'and"Tripleantithrombotictherapyinpatientswithcardiovasculardisease",sectionon'TOAT
versusothertherapies'.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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GRAPHICS
Effectofantiplatelettherapyonvascularevents
Numberof
trialswith
data

Categoryof
trial

Anti
platelet,
percent*

Adjusted
controls,
percent*

Odds
reduction,
percent

PriorMI

12

13.5

17.0

254

AcuteMI

15

10.4

14.2

304

Priorstroke/TIA

21

17.8

21.4

224

Acutestroke

8.2

9.1

113

Otherhighrisk

140

8.0

10.2

263

Unstable
angina

12

8.0

13.3

467

Stable
angina/CHD

9.9

14.1

339

Peripheral
arterial
disease

42

5.8

7.1

238

Alltrials(high
orlowrisk)

195

10.7

13.2

222

Alllowrisk
(primary
prevention)

4.5

4.9

10

*Percentofpatientssufferingvasculareventswhoaretreatedwithantiplateletagentsorplacebo
thedurationoftreatmentwastwoyearswithapriorMIorstroke/TIA,30dayswithanacuteMI,
threeweekswithanacutestroke,andtwoyearsforotherhighriskpatients.
Oddsreductionofvasculareventsduetoantiplatelettherapy.
Datafrom:AntiplateletTrialists'Collaboration,BMJ1994308:81.
Graphic56243Version4.0

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Estimatedmyocardialinfarctions(MIs)preventedandestimated
harmsofusingaspirinfor10yearsinahypotheticalcohortof
1000men
Variable

EstimatedMIsprevented(per1000men),n

10yearCHDrisk,
percent

Age45to59
years

Age60to69
years

Age70to79
years

3.2

3.2

3.2

6.4

6.4

6.4

9.6

9.6

9.6

12.8

12.8

12.8

16

16

16

19.2

19.2

19.2

22.4

22.4

22.4

25.6

25.6

25.6

28.8

28.8

28.8

10

32

32

32

11

35.2

35.2

35.2

12

38.4

38.4

38.4

13

41.6

41.6

41.6

14

44.8

44.8

44.8

15

48

48

48

16

51.2

51.2

51.2

17

54.4

54.4

54.4

18

57.6

57.6

57.6

19

60.8

60.8

60.8

20

64

64

64

Typeofevent

Estimatedharms,n

GIbleeding

24

36

Hemorrhagicstroke

Asindicated,theestimatednumberofMIspreventedvarieswith10yearCHDrisk.The
estimatedharmsofusingaspirinvarywithage.Therefore,both10yearCHDriskandage
mustbeconsideredwhendeterminingwhetherthepotentialharmsofaspirinuseoutweigh
thepotentialbenefitintermsofMIsprevented.Theboldfacednumbersindicatethe
combinationsof10yearCHDriskandageforwhichthenumberofharms(GIbleedingand
hemorrhagicstroke)aregreaterthanorapproximatelyequaltothenumberofMIs
prevented.*
CHD:coronaryheartdiseaseGI:gastrointestinalMI:myocardialinfarction.
*Calculationsofestimatedbenefitsandharmsrelyonassumptionsandarebynaturesomewhat
imprecise.Estimatesofbenefitsandharms,especiallyatthebordersoftheboldfacedandnon
boldfacedareas,shouldbeconsideredinthefullcontextofclinicaldecisionmakingandusedto
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stimulateshareddecisionmaking.Thecalculationsinthetablearebasedonthefollowing
assumptions:thatthereisa32percentriskreductionofMIswithregularaspirinuseandthat
gastrointestinalbleedingincludesserioushemorrhage,perforation,orothercomplicationsleadingto
hospitalizationordeath.TheharmofGIbleedinginthetableassumesthattheriskforGIbleeding
increaseswithageandthatthemenarenottakingnonsteroidalantiinflammatorydrugs,donot
haveupperGIpain,ordonothaveahistoryofGIulcer.Estimatesarebasedonageand10year
CHDrisk.
Reproducedfrom:USPreventiveServicesTaskForce.AspirinforthePreventionofCardiovascular
Disease:RecommendationStatement.AHRQPublicationNo.0905129EF2,March2009.Agencyfor
HealthcareResearchandQuality,Rockville,MD.
http://www.ahrq.gov/clinic/uspstf09/aspirincvd/aspcvdrs.htm.
Graphic53748Version3.0

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10yearCHDrisklevelsatwhichthenumberofcardiovascular
diseaseeventspreventediscloselybalancedtothenumberof
seriousbleedingevents
Men
Age

10yearCHDrisk,percent

Women
Age

10yearstrokerisk,percent

4559y

5559y

6069y

6069y

7079y

12

7079y

11

Shareddecisionmakingisstronglyencouragedwithpersonswhoseriskiscloseto(either
aboveorbelow)theseestimatesof10yearrisklevels.Asthepotentialcardiovascular
diseasereductionbenefitincreasesaboveharms,therecommendationtotakeaspirin
shouldbecomestronger.
CHD:coronaryheartdisease.
Reproducedfrom:USPreventiveServicesTaskForce.AspirinforthePreventionofCardiovascular
Disease:RecommendationStatement.AHRQPublicationNo.0905129EF2,March2009.Agencyfor
HealthcareResearchandQuality,Rockville,MD.
http://www.ahrq.gov/clinic/uspstf09/aspirincvd/aspcvdrs.htm.
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Estimatednumberofstrokespreventedandestimatedharmsof
usingaspirinfor10yearsinahypotheticalcohortof1000women
onthebasisofageand10yearstrokerisk
Estimatedstrokesprevented(per1000
women),n

Variable
10yearstrokerisk,
percent

Age55to59
years

Age60to69
years

Age70to79
years

1.7

1.7

1.7

3.4

3.4

3.4

5.1

5.1

5.1

6.8

6.8

6.8

8.5

8.5

8.5

10.2

10.2

10.2

11.9

11.9

11.9

13.6

13.6

13.6

15.3

15.3

15.3

10

17

17

17

11

18.7

18.7

18.7

12

20.4

20.4

20.4

13

22.1

22.1

22.1

14

23.8

23.8

23.8

15

25.5

25.5

25.5

16

27.2

27.2

27.2

17

28.9

28.9

28.9

18

30.6

30.6

30.6

19

32.3

32.3

32.3

20

34

34

34

Typeofevent
GIbleeding

Estimatedharms,n
4

12

18

Asindicated,theestimatednumberofstrokesavoidedvarieswith10yearstrokerisk.The
estimatedharmsofusingaspirinvarywithage.Therefore,both10yearstrokeriskand
agemustbeconsideredwhendeterminingwhetherthepotentialharmsofaspirinuse
outweighthepotentialbenefitintermsofstrokesprevented.Theboldfacednumbers
indicatethecombinationsof10yearstrokeriskandageforwhichthenumberofharms
(GIbleeding)aregreaterthanthenumberofstrokesprevented.*
GI:gastrointestinal.
*Calculationsofestimatedbenefitsandharmsrelyonassumptionsandarebynaturesomewhat
imprecise.Estimatesofbenefitsandharms,especiallyatthebordersoftheboldfacedandnon
boldfacedareas,shouldbeconsideredinthefullcontextofclinicaldecisionmakingandusedto
stimulateshareddecisionmaking.Thecalculationsinthetablearebasedonthefollowing
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assumptions:thatthereisa17percentriskreductionofstrokeswithregularaspirinuseandthat
gastrointestinalbleedingincludesserioushemorrhage,perforation,orothercomplicationsleadingto
hospitalizationordeath.HarmofGIbleedinginthetableassumesthatriskforGIbleedingincreases
withageandthatthewomenarenottakingnonsteroidalantiinflammatorydrugs,donothaveupper
GIpain,ordonothaveahistoryofGIulcer."Strokesprevented"isthenetreductionofstrokes,
whichincludesadecreaseinischemicstrokesandasmallincreaseinhemorrhagicstrokes.
Reproducedfrom:USPreventiveServicesTaskForce.AspirinforthePreventionofCardiovascular
Disease:RecommendationStatement.AHRQPublicationNo.0905129EF2,March2009.Agencyfor
HealthcareResearchandQuality,Rockville,MD.
http://www.ahrq.gov/clinic/uspstf09/aspirincvd/aspcvdrs.htm.
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Benefitsandrisksofaspirininsecondaryandprimarypreventionofcardiovasculardisease

Disclosures

Disclosures:CharlesHHennekens,MD,DrPHDataandSafetyMonitoringBoards:Amgen[CVD(Evolocumab),Osteoporosis(Romosozuma
Simvastatin,Atenolol,Hydrochlorthiazide,Cholecaciferol)]CanadianInstitutesofHealthResearch[CVD(Rosuvastatin,Candesartan)]DalCor[
Verheugt,MD,FACC,FESCConsultant/AdvisoryBoards:AstraZeneca[thrombosis(ticagrelos)]BMS/Pfizer[thrombosis(apixaban)]Bayer[th
(apixaban)]BayerHealthcare[thrombosis(rivaroxaban)]EliLilly[thrombosis(prasugrel)]DaiichiSankyo[thrombosis(edoxaban)]Boehringer
BoehringerIngelheim(AF[Dabigatran])CSLBehring(Lipids)Essentialis(Lipids)GlaxoSmithKline(LipidsandDM)Janssen(AFandDM[Riva
andLipids[Apixaban,Etrugliflozin,Atorvastatin])Kowa(lipids).GordonMSaperia,MD,FACCNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately
referencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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