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12/9/2016

Antihypertensive therapy to prevent recurrent stroke or transient ischemic attack


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Antihypertensivetherapytopreventrecurrentstrokeortransientischemicattack
Authors
NormanMKaplan,MD
RaymondRTownsend,MD

SectionEditors
GeorgeLBakris,MD
ScottEKasner,MD

DeputyEditors
JohnPForman,MD,MSc
JohnFDashe,MD,PhD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2016.|Thistopiclastupdated:Mar21,2016.
INTRODUCTIONHypertensionisamajorriskfactorforstrokeandtransientischemicattack(TIA),withtherisk
increasingwitheveryriseinsystolicbloodpressure[1].Thecardiovascularriskcanbeminimizedbypersistent
correctionofthehypertension[2].(See"Overviewofprimarypreventionofcoronaryheartdiseaseandstroke",section
on'Hypertensioncontrol'and"Hypertension:Whoshouldbetreated?",sectionon'Decreasedcardiovascularriskwith
therapy'.)
Oncethestrokehasstabilized,antihypertensivetherapycanreducetherateofrecurrentstroke,independentofthe
baselinebloodpressure.(See'Trialsoflongtermantihypertensivetherapy'below.)
Thistopicwillreviewthelongtermroleofantihypertensivetherapyforpreventionofarecurrentstroke.Themajor
randomizedtrialswillbereviewedfollowedbydiscussionsofspecificissues,suchaswhentolowerthebloodpressure,
thechoiceofantihypertensivedrugs,thebloodpressuregoalinrelationtothepresenceorabsenceoflargeartery
stenosis,andtherateofbloodpressurereduction.
Theapproachisdeterminedbythedegreeofhypertensionandbythetypeofstrokethatispresent:thromboembolic
strokeorintracerebralorsubarachnoidhemorrhage.Thediagnosisofstrokesubtypesandriskfactorreductionforthe
secondarypreventionofstrokeotherthanbloodpressurecontrolarediscussedseparately.(See"Clinicaldiagnosisof
strokesubtypes"and"Overviewofsecondarypreventionofischemicstroke".)
AcutestrokeTreatmentofhypertensionmaybeanimmediateconcerninpatientswithanacuteischemicstrokeand
thosewithasubarachnoidorintracerebralhemorrhage.Bloodpressuremanagementintheacutephaseofstrokeis
differentfromchronictherapyandisdiscussedindetailelsewhere.(See"Initialassessmentandmanagementofacute
stroke",sectionon'Bloodpressuremanagement'and"Spontaneousintracerebralhemorrhage:Treatmentand
prognosis",sectionon'Bloodpressure'and"Treatmentofaneurysmalsubarachnoidhemorrhage",sectionon
'Intracranialpressure'.)
TRIALSOFLONGTERMANTIHYPERTENSIVETHERAPYTheefficacyoflongtermantihypertensivetherapyto
preventrecurrentstrokeaswellasothercardiovascularcomplicationshasbeenevaluatedinanumberofrandomized,
placebocontrolledtrials[36].Thissectionwillreviewthefindingsinthethreelargestplacebocontrolledtrialsandin
metaanalyses.Trialscomparingtheefficacyofdifferentantihypertensivedrugsarediscussedbelow.(See'Which
antihypertensivedrugsshouldbeused?'below.)
PROGRESStrialThePROGRESStrialincludedover6100patients(meanageof64years)withanischemicor,less
often,hemorrhagicstrokeortransientischemicattack(TIA)withinthepreviousfiveyears(medianofeightmonths)[4].
Thepatientswererandomlyassignedtoperindoprilorplacebothediureticindapamidewasaddedasnecessaryinthe
perindoprilgroup.Themeanbaselinebloodpressurewas147/86mmHgapproximatelyonehalfofpatientswere
hypertensive(meanof159/94mmHg),whileremainingpatientshadhighnormalvalues(meanof136/79mmHg).
Thefollowingfindingswerenoted[4,7]:
Areductioninbloodpressureof9/4mmHgintheperindoprilgroupcomparedwithplacebodecreasedtherateof
theprimaryendpointoffatalornonfatalstroke(10versus14percentwithplacebo,relativeriskreduction28
percent,95%confidenceinterval[CI]17to38percent).Activetherapyalsoreducedtheriskofallcardiovascular
eventsby26percentand,althoughthenumberofeventswassmall,significantlyreducedtherateofintracerebral
hemorrhageby50percent(1.2versus2.4percent).
Thestrokepreventionbenefitwasrelatedtothedegreeofbloodpressurereduction,beingmostprominent
(relativeriskreduction43percent)andstatisticallysignificantinpatientstreatedwithcombinationtherapy
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(perindoprilplusindapamide)whohada12/5mmHgmeanreductioninbloodpressurecomparedwithplacebo.By
comparison,patientstreatedwithperindoprilalonehadonlya5/3mmHgmeanreductioninbloodpressureanda
smallandnotsignificantbenefit(relativeriskreduction5percent).Thereductionsinbloodpressureweresimilarin
thehypertensiveandhighnormalbloodpressuregroups.
Thereductioninrecurrentstrokewithantihypertensivetherapywasseeninbothhypertensive(11.1versus16.2
percent,relativeriskreduction32percent)andnonhypertensivepatients(9.1versus11.5percent,relativerisk
reduction21percent).Thus,boththeriskofstrokeandtheabsolutebenefitfromantihypertensivetherapywere
greaterinthehypertensivepatients.Similarfindingswerenotedwhenallmajorvasculareventswereevaluated.
AposthocanalysisfromPROGRESSaddressedtheissueofwhetherthebaselinebloodpressureaffectedthe
responsetoantihypertensivetherapy,includingthepossibilitythatpatientswithnormalbloodpressure(<120mmHg
systolic)atbaselinemightbeharmedfromsuchtherapy[8].Amongpatientsinthecombinationtherapyarm,therelative
riskreductioninstrokewassimilaratalllevelsofbaselinesystolicpressure(rangingfrom<120to160mmHg).
Althoughthissuggestsnoharmfromtherapyinpatientswithlowbaselinepressures,thereweresofewevents(six)in
thesubgroupof146patientswithasystolicpressureof<120mmHgatbaselinethatonecannothaveconfidenceinthe
results.
Therewasalsoasuggestionthattheriskofrecurrentstrokewaslowestinpatientsinthelowestquartileofattained
bloodpressure(medianof112/72mmHg)andprogressivelyhigherathigherbloodpressures[8].However,thetrialwas
notdesignedtoevaluatedifferentbloodpressuregoals.(See'Whatisthegoalbloodpressure?'below.)
ThevalueofperindoprilbasedtherapyinthesubsetofpatientsinPROGRESSwhohadatrialfibrillationisdiscussed
separately.(See"Strokeinpatientswithatrialfibrillation",sectionon'Controlofhypertension'.)
PRoFESStrialThePreventionRegimenforEffectivelyAvoidingSecondStrokes(PRoFESS)trialrandomlyassigned
20,332patientswithnoncardioembolicischemicstroketoreceiveeitherfixeddosetelmisartan(80mgdaily)orplacebo
[5].Allotherantihypertensivedrugs,exceptforangiotensinreceptorblockers(ARBs),werepermittedasaddontherapy.
Approximatelythreequartersofpatientshadapriorhistoryofhypertension,andtheaveragebloodpressurewas
144/84mmHginbothgroupsatbaseline.
Atanaveragefollowupof2.5years,therewasnosignificantdifferencebetweenthetelmisartanandplacebogroupsin
theprimaryoutcomeofrecurrentstroke(8.7versus9.2percent,hazardratio[HR]0.95,95%CI0.861.04),orin
secondaryoutcomesincludingmajorcardiovascularevents(13.5versus14.4percent,HR0.94,95%CI0.871.01).
However,significantbenefitcomparedwithplacebowouldnothavebeenexpected,sincetelmisartantherapyonly
reducedthebloodpressurebyanaverageof3.8/2.0mmHgmorethanplacebo.Thisfindingissimilartothelackor
benefitwithperindoprilmonotherapyinthePROGRESStrial,inwhichinthemeandifferenceinattainedbloodpressure
wasonly5/3mmHgcomparedwithplacebo.(See'PROGRESStrial'above.)
Inadditiontothefixedtelmisartandoseandthefactthatmostpatientsintheplacebogroupreceivedantihypertensive
therapy,otherfactorsthatcouldhavecontributedtothesmalldifferenceinattainedbloodpressuresinthetwogroups
includecessationoftherapybecauseofsideeffectsinsomepatientstreatedwithtelmisartanaswellastheinitiationof
antihypertensivetherapyinsomepatientsintheplacebogroupbecauseofthedevelopmentofhypertension[5].
PATStrialThePoststrokeAntihypertensiveTreatmentStudy(PATS)trialrandomlyassigned5665Chinesepatients
withahistoryofstroke(mostlyischemic)orTIAtotreatmentwithindapamide(2.5mgdaily)orplacebo[6].Theaverage
intervalfromstroketorandomizationwas31months,andtheaveragebloodpressureatrandomizationwas154/93
mmHg.Atamedianfollowupoftwoyears,activetreatmentreducedbloodpressurebyameanof6.8/3.3mmHg.There
weresignificantlyfewerstrokesintheactivetreatmentcomparedwiththeplacebogroup(143versus219,HR0.69,
95%CI0.540.89).Inaddition,indapamidetreatmentreducedtherateofcardiovascularevents(HR0.75,95%CI0.89
0.62).Limitationsofthistrialincludeprematureterminationandahighdropoutrate(28percent).
MetaanalysesThelimitedbloodpressurereductionandlackofsignificantbenefitinPRoFESSisimportantwhen
consideringtheresultsofmetaanalysessincePRoFESSwas,byfar,thelargeststudyandaccountedformorethan
onehalfofpatientsinthetrialsofsecondarystrokeprevention.Asillustratedbythefollowingobservations,thebenefit
ofantihypertensivetherapyincreasedprogressivelyastheproportionofpatientsfromPRoFESSbecamesmaller:

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Ametaanalysisofeightplacebocontrolledtrialsofangiotensininhibitionincludedalmost30,000patients,mostof
whomcamefromthePRoFESStrial[9].Antihypertensivetherapy(mostoftheincludedtrialsinthismetaanalysis
comparedangiotensininhibitorswithplacebo)resultedinasignificantreductioninmajorcardiovascularevents
(13.1versus14.7percent,riskratio0.92,95%CI0.860.98)andanalmostsignificantreductioninrecurrentstroke
(9.0versus9.6percent,riskratio0.94,95%CI0.871.01).
Thesecondmetaanalysiswaspublishedin2011andincluded40,300patientsfrom16randomizedtrialsof
antihypertensivetherapyinpatientswithapriorstroke,approximatelyonehalfofwhomcamefromPRoFESS[7].
Antihypertensivetherapywasassociatedwithasignificantreductioninrecurrentstroke(relativerisk0.81,95%CI
0.730.91).
APPROACHTOANTIHYPERTENSIVETHERAPYAvarietyofquestionsmustbeaddressedwhenconsideringthe
roleofantihypertensivetherapyinpatientswhohavehadastrokeortransientischemicattack(TIA):

Whichpatientsshouldbetreated?
Whenshouldtherapybeinitiated?
Whichantihypertensivedrugsshouldbeused?
Whatisthegoalbloodpressure?

Regardlessoftheregimen,bloodpressurereductionshouldbegradual.(See'Gradualbloodpressurereduction'below.)
Whichpatientsshouldbetreated?InaccordwithAmericanHeartAssociationandAmericanStrokeAssociation
(AHA/ASA)guidelines,werecommendresumptionofantihypertensivetherapyforpreviouslytreatedpatientswith
knownhypertensionforbothpreventionofrecurrentstrokeandpreventionofothervascularevents[10].Inaddition,we
recommendinitiationofantihypertensivetherapyforpreviouslyuntreatedpatientswithanytypeofischemicstrokeor
TIAwhohaveanestablishedbloodpressureof140mmHgsystolicor90mmHgdiastolic.(See'AHA/ASAguidelines
forthepreventionofrecurrentstroke'below.)
Unlikethe2014AHA/ASAguidelines,wesuggest(aweakerrecommendation)initiationofantihypertensivetherapyfor
previouslyuntreatedpatientswithischemicstrokeorTIAofatherothrombotic,lacunar(smallvesselocclusive),or
cryptogenictype,whosebaselinebloodpressureis>120mmHgsystolicor>70mmHgdiastolic.Thisrecommendation
isbaseduponobservationsinrandomizedtrials,suchasPROGRESS,thattherelativeriskreductioninstrokewith
antihypertensivetherapywassimilaratalllevelsofbaselinesystolicpressure(rangingfrom<120to160mmHg)[8].
Wedonotsuggestantihypertensivetherapyinthefollowingsettings:
Nonhypertensivepatients(ie,bloodpressureof<140/90mmHg)whohavehadastrokeorTIAduetoa
cardioembolicphenomenon(eg,atrialfibrillation)orparadoxicalembolus.
Untreatedpatientswhosebaselinebloodpressureis<120/<70mmHg.Thesepatientshaveanincreasedriskof
recurrentstrokeiftheirbloodpressureisfurtherreducedcomparedwithpatientswhohavehigherbloodpressures.
(See'Datafromrandomizedtrials'below.)
Whenshouldtherapybeinitiated?Thetimingofinhospitalinitiationorresumptionofantihypertensivetherapy
duringtheacutephaseofstrokeisdiscussedindetailelsewhere.(See"Initialassessmentandmanagementofacute
stroke",sectionon'Bloodpressuremanagement'.)
Forpatientswhohavenotbeentreatedinthehospital,antihypertensivetherapyshouldbeinitiatedorreinitiatedasan
outpatientinallappropriatepatients,asnotedintheprecedingsection.(See'Whichpatientsshouldbetreated?'above.)
Whichantihypertensivedrugsshouldbeused?Ourpreferencesforantihypertensivetherapyinpatientswho
havehadastrokeorTIAdifferaccordingtowhethermonotherapyorcombinationantihypertensivetherapyisrequiredto
achieveanadequatereductioninbloodpressure.
MonotherapyThereisnocompellingevidencefavoringoneclassofantihypertensivedrugsoveranotheras
monotherapyforsecondarypreventioninpatientswhohavehadastroke[11].Inametaanalysisofsevenrandomized
trialsofalmost30,000patientswithapriorhistoryofstroke,therapywithangiotensininhibitors(angiotensinconverting
enzyme[ACE]inhibitorsorangiotensinreceptorblockers[ARBs])significantly,butmodestly,reducedtheriskof
recurrentstroke(9.0versus9.7percent)andmajorvascularevents(14.3versus15.7percent)comparedwithplacebo
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[9].Bycontrast,therewasnosignificantbenefitofangiotensininhibitorsinthethreetrialsthatcomparedtheseagents
withcalciumchannelblockers.Inaddition,calciumchannelblockersmaybesuperiortoangiotensininhibitorsforthe
primarypreventionofstroke[12].Finally,theresultsofthePoststrokeAntihypertensiveTreatmentStudy(PATS)trial
(see'PATStrial'above)suggestthatdiureticsareeffectiveforsecondarystrokeriskreduction.
Basedupontheseobservations,angiotensininhibitors(mosttrialshaveusedACEinhibitors),calciumchannelblockers,
anddiureticsarereasonableoptionsforinitialantihypertensivemonotherapyinpatientswhohavehadastroke.Thereis
someevidencefromclinicaltrialsthatbetablockersmaynotreducestrokeriskcomparedwithangiotensininhibitors,
calciumchannelblockers,and,insometrials,placebo[1315].Thus,unlessthereisacompellingindicationfortheir
use,betablockersshouldnotbeusedforpreventionofrecurrentstroke.
CombinationtherapyAseparateissueisthechoiceofdrugswhencombinationtherapyisnecessary.We
recommendthecombinationofanangiotensininhibitorplusalongactingdihydropyridinecalciumchannelblocker.This
recommendationcontrastswiththe2014AHA/ASAguidelinesthatrecommendanACEinhibitorplusadiuretic[10].
(See'AHA/ASAguidelinesforthepreventionofrecurrentstroke'below.)
However,theAHA/ASAguidelinesdidnotmentiontheACCOMPLISHtrialofcombinationantihypertensivetherapyin
hypertensivepatientswhorequiredtwodrugsandwereathighriskforacardiovascularevent(definedasahistoryof
coronarydisease,stroke,peripheralarterialdisease,ordiabetes,orthepresenceofleftventricularhypertrophyor
impairedrenalfunction)[16].PatientsinACCOMPLISHweretreatedwithcombinedtherapywithbenazeprilpluseither
amlodipineorhydrochlorothiazide,andtheattainedbloodpressuresweresimilarinthetwogroups.Historyofaprior
strokewaspresentin13percent.Thetrialwasterminatedearlyat36monthsbecauseofworseoutcomesinthe
hydrochlorothiazidegroupthatexceededaprespecifiedstoppingrule.Benazeprilplusamlodipine,comparedwith
benazeprilplushydrochlorothiazide,significantlyreducedtheincidenceoftheprimaryendpointofcardiovasculardeath
orcardiovascularcomplications(9.6versus11.8percent,HR0.80,95%CI0.720.90)andthesecondaryendpointof
cardiovasculardeathornonfatalmyocardialinfarctionorstroke(5.0versus6.3percent,HR0.79,95%CI0.670.92).
Basedupontheseobservations,werecommendthecombinationofanangiotensininhibitorplusalongacting
dihydropyridinecalciumchannelblockerratherthanadiureticasthecombinationantihypertensiveregimenof
choiceinthetreatmentofpatientswhohavehadastroke.Thisrecommendationassumesthatthepatientcantolerate
anddoesnothaveacontraindicationtotheuseofeitherdrugclassanddoesnothaveaspecificindicationfortheuse
ofanotherclassofantihypertensivedrugs.(See"Choiceofdrugtherapyinprimary(essential)hypertension",sectionon
'Indicationsforspecificdrugs'.)
Whatisthegoalbloodpressure?Issuesrelatedtogoalbloodpressure,bothingeneralandspecificallyinpatients
withatheroscleroticcardiovasculardisease,arediscussedindetailelsewhere.(See"Whatisgoalbloodpressureinthe
treatmentofhypertension?"and"Goalbloodpressureinpatientswithcardiovasculardiseaseorathighrisk",sectionon
'Goalbloodpressure'.)
ThissectionwillreviewgoalbloodpressureinpatientswhohavehadastrokeorTIA.Aswillbediscussedingreater
detailbelow,therecommendationsdependuponwhetherornottheeventwasduetoahemodynamicallysignificant
stenosisinalargecervicocephalicartery(ie,internalcarotid,middlecerebral,vertebral,orbasilarartery):
Inpatientswithhemodynamicallysignificantlargearterydisease,wesuggestcautiousbloodpressureloweringas
tolerated,butwithoutaspecificbloodpressuregoalotherthanaminimumreductionof10/5mmHg.However,in
suchpatientswhoseinitialbloodpressureislessthan120/70mmHg,wedonotgiveantihypertensivetherapy.
Inpatientswithouthemodynamicallysignificantlargearterystenosis,wetakethefollowingapproach:
Werecommendloweringthebloodpressureaminimumof10/5mmHginnearlyallpatients.However,in
suchpatientswhoseinitialbloodpressureislessthan120/70mmHg,wedonotgiveantihypertensive
therapy.(See'Whichpatientsshouldbetreated?'aboveand'AHA/ASAguidelinesforthepreventionof
recurrentstroke'below.)
Inpatientswithunderlyinghypertension,werecommendagoalbloodpressureoflessthan140/90mmHg
comparedwithhigherpressures,andwesuggest(aweakerrecommendation)loweringthesystolicpressure
below130to135mmHgifitcanbeachievedwithoutproducingsignificantsideeffects.Theevidence
supportingthisapproachinpatientswithatheroscleroticcardiovasculardiseaseingeneralisdiscussedin
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detailelsewhere.(See"Goalbloodpressureinpatientswithcardiovasculardiseaseorathighrisk",section
on'Goalbloodpressure'.)
Forpatientswithrecentsmallvessel(ie,lacunar)ischemicstroke,wesuggest(aweakrecommendation)
loweringthesystolicbloodpressurebelow130mmHg.
DatafromrandomizedtrialsAnumberoftrials,someofwhichhavebeencitedabove,evaluatedthe
relationshipbetweenbloodpressureandcardiovascularoutcomesinpatientswithapriorstroke.Thefindingshave
addressedboththedegreeofbloodpressurereductionfrombaselineandtheabsolutelevelofbloodpressureattained,
withsomedifferingresults.
ThemaintrialevaluatingspecificbloodpressuretargetsinpatientswithischemicstrokewasSPS3,whichrandomly
assigned3020patients(meanageof63years)withrecentlacunar(ie,smallvessel)infarctiontoasystolicblood
pressuretargetofeither130to149mmHgorlessthan130mmHg[17].Threequartersofthepatientswere
hypertensiveatstudyentry.Treatmentwasopenlabel,usingdrugsfromeachofthemajorclassesofantihypertensive
medicationsprescribedbythelocalclinician.Atoneyear,theachievedaveragesystolicbloodpressuresforthehigher
andlowertargetgroupswere138and127mmHg,respectively,andthemean11mmHgdifferencebetweenthegroups
wassustainedforthedurationofthestudy.Patientsassignedtothelowerbloodpressuretargetgroupweretreatedwith
agreaternumberofantihypertensivemedicationscomparedwiththehighertargetgroup(meanof2.4versus1.8).The
followingoutcomeswerereported[17]:
Atstudyend,withameanfollowupof3.7years,therewere277firstrecurrentstrokestheannualizedrateofall
recurrentstrokewasnonsignificantlyreducedinthelowertargetcomparedwiththehighertargetbloodpressure
group(2.25versus2.77percent,HR0.81,95%CI0.641.03).Similarly,therateofacompositeoutcomeof
myocardialinfarctionorvasculardeathwasnonsignificantlyreducedinthelowerbloodpressuregroup.
Therateofintracerebralhemorrhagewassignificantlyreducedinthelowertargetbloodpressuregroup,butthe
smallnumberofevents(n=22)limitsthestrengthofthisfinding.
Therewerefewseriousadverseeventsinthehigherandlowertargetgroups(annualizedrateof0.4versus0.3
percent),andthedifferencewasnotsignificant.
Thus,theSPS3resultssuggestbutdonotestablishthatasystolicbloodpressuretargetoflessthan130mmHgis
beneficialandsafeforpreventingrecurrentstrokeinpatientswithsmallvesselischemicstroke.
InadditiontoSPS3,findingsfromothertrialsalsosuggestthatlowerbloodpressuresareassociatedwithbetter
outcomes.Analysesaccordingtothepresenceorabsenceofalargecervicocephalicarterystenosiswerenot
performed:
ThePreventionAfterStrokeBloodPressure(PASTBP)trialassigned529patientswithahistoryofstrokeorTIA
andasystolicpressureofatleast125mmHgtointensivebloodpressurelowering(targetingasystolicpressureof
<130mmHg)orstandardbloodpressurelowering(targetingasystolicpressureof<140mmHg)[18].Thistrialhad
manylimitations,includinganearly30percentdropoutrate,alownumberofevents,andaminimalsystolic
pressureseparationbetweentheintensiveandstandardgroups(127versus129mmHg,respectively).However,
therateofmajorcardiovasculareventswasnonsignificantlylowerintheintensivetreatmentgroup(1versus5
events).
Ametaregressionanalysisofninerandomizedtrialsfoundthateach10mmHgreductioninsystolicpressurewas
associatedwitha33percent(95%CI9to51percent)reductionintheriskofrecurrentstroke,withthelowestrisk
occurringatanattainedsystolicpressurebelow120mmHg[7].
SimilarfindingswerenotedinareviewfromtheUnitedKingdomTransientIschemicAttack(UKTIA)trial:there
wasa28percentreductioninrecurrentstrokeforevery10mmHgreductioninsystolicpressureanda34percent
reductionforevery5mmHgreductionindiastolicpressure[19].
InthePROGRESStrial,theriskofrecurrentstrokewaslowestinpatientsinthelowestquartileofattainedblood
pressure(medianof112/72mmHg)andwasprogressivelyhigherathigherbloodpressures[8].(See'PROGRESS
trial'above.)

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Inametaanalysisof25randomizedtrialsofantihypertensivetherapyversusplaceboinpatientswithahistoryof
cardiovasculardiseasewithouthypertension,thetreatedpatientshadsignificantlybettercardiovascularoutcomes
includingreductionsincardiovascularevents(relativerisk0.77,95%CI0.610.98),cardiovascularmortality
(relativerisk0.83,95%CI0.690.99),andstroke(relativerisk0.80,95%CI0.690.93)[20].Theabsolutereduction
instrokeriskwas7.7per1000persons.
TheseobservationsareconsistentwiththefindingsintheActiontoControlCardiovascularRiskinDiabetesBlood
Pressure(ACCORDBP)trialof4733patientswithtype2diabetesplusothercardiovascularriskfactorspriorstroke
wasuncommon[21].Thepatientswererandomlyassignedtoagoalsystolicpressureoflessthan140orlessthan120
mmHg,andthemeanattainedsystolicpressureswere134and119mmHg,respectively.Atameanfollowupof4.7
years,therewasnooverallcardiovascularbenefitofloweringthesystolicpressurebelow120mmHg,but,onsubset
analysis,therewasasmallbutsignificantreductionintheannualrateofstroke(0.32versus0.53percent,HR0.59).
Moreaggressivetherapywasalsoassociatedwithasignificantlyhigherrateofseriousadverseeffectsattributableto
antihypertensivedrugs(3.3versus1.3percent).
Incontrasttotheseobservations,harmratherthanbenefitfromanattainedsystolicpressurebelow120mmHgwas
notedinananalysisfromthePreventionRegimenforEffectivelyAvoidingSecondStrokes(PRoFESS)trialcitedabove
(byfar,thelargesttrial),inwhichtheaveragereductioninbloodpressurewithtelmisartantherapywasonly3.8/2.0
mmHgmorethanwithplacebo[22].(See'PRoFESStrial'above.)
Atameanfollowupof2.5years,patientswithapostbaselinemeansystolicpressureof130to139mmHghadthe
lowestrateofrecurrentstrokeandthelowestrateofacompositeoutcomeofstroke,myocardialinfarction,orvascular
death.Patientswithameansystolicpressureof120to129mmHghadslightlybutnonsignificantlyhigherratesof
recurrentstroke,whiletheriskofrecurrentstrokewassignificantlyincreasedinpatientswithmeansystolicblood
pressuresoflessthan120mmHgsystolic(adjustedHR1.29,95%CI1.071.56),140to149mmHgsystolic(adjusted
HR1.23),and150mmHgsystolic(adjustedHR2.08).Thesamegroupshadasimilarincreaseinriskforthe
compositeendpointofstroke,myocardialinfarction,orvasculardeath.
Asdiscussedinthefollowingsections,thegoalbloodpressuredependsuponwhetherornotthepatienthas
hemodynamicallysignificantlargearterystenosis,whichsomehavedefinedonimagingstudiesas80percentstenosis
and/orpoorcollateralflow(ifitcanbedetected).(See"Evaluationofcarotidarterystenosis".)
PatientswithhemodynamicallysignificantlargearterystenosisIdentifyinghemodynamicallyorclinically
significantstenosisinalargecervicocephalicartery(ie,internalcarotid,middlecerebral,vertebral,orbasilarartery)is
clinicallyimportantsincethesepatientshaveanincreasedlongtermriskofrecurrentstrokeandmaydevelopischemic
symptomsafterbloodpressurelowering.Thiswasillustratedinastudyof102patientswhohadahistoryofischemic
strokeorTIAandalargearterystenosisof50percentormore[23]."Hemodynamicallysignificant"wasdefinedclinically
astheoccurrenceofsymptomsrelatedtothestenosisduringachangeofpositionfromsupinetoprone,followingeffort,
oraftertheintroductionorincreaseindoseofanantihypertensivedrug.TherateofrecurrentstrokeorTIAinthe
territoryofthestenoticarteryattwoyearswas61percentinpatientswithahemodynamicallysignificantstenosis
comparedwith32percentinpatientswithoutasignificantstenosis.
Thereisnoconsensusregardingthecriteriafordefininghemodynamicallysignificantstenosis.Inadditiontotheclinical
criteriausedintheprecedingstudy,somehaveusedcriteriabaseduponimagingstudies.Asanexample,wehave
usedthefollowingcriteria:80percentstenosisand/orpoorcollateralflow(ifcollateralflowcanbedetected).Others
haveusedparameterssuchascerebralbloodvolumeandoxygenextraction[24].
Anotherproblemisthat,eveninpatientsatincreasedrisk,thereisnoreliablemethodofdeterminingwhichpatientscan
safelytolerateintensivebloodpressurelowering.
Insummary,inpatientsthoughttohaveahemodynamicallysignificantstenosisofalargecervicocerebralarterybased
upononeormoreoftheabovecriteria,wesuggestcautiousbloodpressureloweringastoleratedbutwithoutaspecific
bloodpressuregoalotherthanaminimumreductionof10/5mmHgbelowthepreviousbaseline.
Thepatientshouldbecarefullymonitoredforhypotensiveorneurologicsymptomscausedbyeitherfailureof
autoregulationofcerebralbloodfloworbyhemodynamiccompromiseduetolargevesselstenosis.Ifthepatient
developsrecurrentneurologicsymptomsreferabletoastenoticarterywhenthebloodpressureisloweredbelowa

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particularthreshold,werecommendmanagementtomaintainbloodpressureabovethatthreshold.(See'Gradualblood
pressurereduction'below.)
Ifahemodynamicallysignificantstenosisofanextracranialcarotidarteryiscorrectedbyendarterectomyorstenting,we
attempttograduallyachievethebloodpressuregoalsdescribedinthefollowingsectiononpatientswithout
hemodynamicallysignificantlargearterystenosisinordertoreducetherisksofrecurrentstrokeandother
cardiovascularevents.
PatientswithouthemodynamicallysignificantlargearterystenosisInpatientswhohavehadastrokeorTIA
thatdidnotresultfromahemodynamicallysignificantlargecervicocephalicarterystenosisasdefinedinthepreceding
section,ourrecommendationsforgoalbloodpressurearesimilartothoseinotherpatientswithatherosclerotic
cardiovasculardisease:
Werecommendloweringthebloodpressureaminimumof10/5mmHginallpatients.However,insuchpatients
whoseinitialbloodpressureislessthan120/70mmHg,wedonotgiveantihypertensivetherapy.
Inpatientswithunderlyinghypertension,werecommendagoalbloodpressureoflessthan140/90mmHg
comparedwithhigherpressures,andwesuggest(aweakerrecommendation)loweringthesystolicpressurebelow
130to135mmHgifitcanbeachievedwithoutproducingsignificantsideeffects.Theevidencesupportingthis
approachinpatientswithatheroscleroticcardiovasculardiseaseingeneralisdiscussedindetailelsewhere.(See
"Goalbloodpressureinpatientswithcardiovasculardiseaseorathighrisk",sectionon'Goalbloodpressure'.)
Forpatientswithrecentsmallvessel(ie,lacunar)ischemicstroke,wesuggest(aweakrecommendation)lowering
thesystolicbloodpressurebelow130mmHg.(See'Datafromrandomizedtrials'above.)
GradualbloodpressurereductionThenormalresponsetoanacutereductioninbloodpressureistomaintain
tissueperfusionbyautoregulatoryprecapillaryvasodilation.Sinceflowisequaltopressuredividedbyresistance,
parallelreductionsinbothparametersallowflowtobemaintained.Thisresponsemaybeimpairedinpatientswith
chronichypertension,includingthosewhohavenothadastroke.
Persistenthypertensionleadstoarteriolarthickening.Inthecerebralandothercirculations,thisisinpartan
appropriateadaptationinthatitpreventstheincreaseinpressurefrombeingtransmittedtothecapillarycirculation
[25].
However,arteriolarthickeningcanalsolimittheabilitytomaintainperfusionwhenthebloodpressureisloweredwith
antihypertensivetherapysincethevasodilatorresponseisoftenimpaired.Asaresult,thelowerbloodpressurelimitat
whichcerebralperfusionismaintainedishigherinhypertensivethaninnormotensivesubjects(figure1)[26].Ingeneral,
ischemicsymptomsarenotlikelytooccurunlessthebloodpressureisacutelyreducedbymorethan25percentbelow
thebaselinelevel.
Basedupontheseconcerns,gradualbloodpressurereduction(ie,nomorethana5mmHgreductioninsystolic
pressureatatime)isrecommendedinpatientswithknowncerebrovasculardiseaseorlongstandinguncontrolled
hypertensionunlessthereisahypertensiveemergency.Gradualbloodpressurereductioncanbeaidedbyhomeblood
pressuremonitoring.(See"Evaluationandtreatmentofhypertensiveemergenciesinadults"and"Ambulatoryandhome
bloodpressuremonitoringandwhitecoathypertensioninadults",sectionon'Homebloodpressuremeasurements'.)
AHA/ASAGUIDELINESFORTHEPREVENTIONOFRECURRENTSTROKEGuidelinesforthepreventionof
recurrentstrokeandtransientischemicattack(TIA)issuedin2014bytheAmericanHeartAssociationandAmerican
StrokeAssociation(AHA/ASA)recommendinitiationofbloodpressuretherapyforpreviouslyuntreatedpatientswith
ischemicstrokeorTIAwho,afterthefirstseveraldays,haveanestablishedbloodpressureof140mmHgsystolicor
90mmHgdiastolic[10].Theguidelinesalsorecommendresumptionofbloodpressuretherapyforpreviouslytreated
patientswithknownhypertensionforbothpreventionofrecurrentstrokeandpreventionofothervasculareventsin
thosewhohavehadanischemicstrokeorTIAandarebeyondthefirstseveraldaysafterstrokeonset.
Wegenerallyagreewiththeserecommendations.
TheAHA/ASAmadethefollowingadditionalcommentsaboutlongtermantihypertensivetherapytopreventrecurrent
stroke[10]:

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Thetargetbloodpressurelevelanddegreeofreductionareuncertain,andtreatmentshouldbeindividualized,but
itisreasonabletoachieveasystolicpressureof<140mmHgandadiastolicpressureof<90mmHg.Forpatients
witharecentlacunarstroke,itmightbereasonabletotargetasystolicbloodpressureof<130mmHg.(See'What
isthegoalbloodpressure?'above.)
Lifestylemodificationshavebeenassociatedwithbloodpressurereductionsandareareasonablepartofthe
antihypertensiveregimen.Importantmodificationsincludeweightlosssaltrestrictionadietrichinfruits,
vegetables,andlowfatdairyproductsregularaerobicphysicalactivityandlimitedalcoholconsumption.(See
"Overviewofhypertensioninadults",sectionon'Nonpharmacologictherapy'.)
Theoptimalantihypertensivedrugregimenisuncertain,buttheavailabledataindicatethatdiureticsorthe
combinationofdiureticsandanangiotensinconvertingenzyme(ACE)inhibitorareuseful.Thechoiceofspecific
drugsshouldbeindividualizedwithrespecttopatientcharacteristicssuchasextracranialcerebrovascular
occlusivedisease,renalimpairment,cardiacdisease,anddiabetes.
Wedisagreewiththerecommendationforcombinedtherapywithdiureticsandanangiotensininhibitor.Ourreasonsfor
disagreeingwiththeAHS/ASAguidelinesandourpreferenceforcombinationantihypertensivetherapyarediscussedin
detailabove.(See'Combinationtherapy'above.)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereading
level,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesare
bestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatient
educationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgrade
readinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicsto
yourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"and
thekeyword(s)ofinterest.)
Basicstopics(see"Patienteducation:Stroke(TheBasics)"and"Patienteducation:Medicinesafteranischemic
stroke(TheBasics)")
BeyondtheBasicstopics(see"Patienteducation:Strokesymptomsanddiagnosis(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Treatmentofhypertensionmaybeanimmediateconcerninpatientswithanacuteischemicstrokeandthosewith
asubarachnoidorintracerebralhemorrhage.Bloodpressuremanagementintheacutephaseofstrokeisdifferent
fromchronictherapyandisdiscussedindetailelsewhere.(See"Initialassessmentandmanagementofacute
stroke",sectionon'Bloodpressuremanagement'and"Spontaneousintracerebralhemorrhage:Treatmentand
prognosis",sectionon'Bloodpressure'and"Treatmentofaneurysmalsubarachnoidhemorrhage",sectionon
'Intracranialpressure'.)
Oncethestrokehasstabilized,antihypertensivetherapycanreducetherateofrecurrentstroke,independentof
thebaselinebloodpressure.(See'Trialsoflongtermantihypertensivetherapy'above.)
Thetargetbloodpressurelevelanddegreeofreductionareuncertain,andtreatmentshouldbeindividualized.
Benefithasbeenassociatedwithanaveragebloodpressurereductionofapproximately10mmHgsystolicand5
mmHgdiastolic.(See'PROGRESStrial'above.)
Lifestylemodificationsthathavebeenassociatedwithbloodpressurereductionsshouldbeincludedaspartofthe
antihypertensiveregimen.Importantmodificationsincludeweightlosssaltrestrictionadietrichinfruits,
vegetables,andlowfatdairyproductsregularaerobicphysicalactivityandlimitedalcoholconsumption.(See
'AHA/ASAguidelinesforthepreventionofrecurrentstroke'above.)
Forpreviouslytreatedpatientswithknownhypertensionwhoarebeyondthefirstfewdaysafterstrokeonset,we
recommendresumptionofantihypertensivetherapyforbothpreventionofrecurrentstrokeandpreventionofother
vascularevents.Forpatientspreviouslyuntreatedwithantihypertensivetherapywhoarebeyondthefirstfewdays
afterstrokeonset,wemakethefollowingrecommendations(see'Whichpatientsshouldbetreated?'above):
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Forpatientswithischemicstrokeortransientischemicattack(TIA)ofanytypewhohaveanestablished
bloodpressureof140mmHgsystolicor90mmHgdiastolic,werecommendinitiationofantihypertensive
therapy(Grade1A).
ForpatientswithischemicstrokeorTIAofatherothrombotic,lacunar(smallvesselocclusive),orcryptogenic
type,andanestablishedbloodpressureof>120mmHgsystolicor>70mmHgdiastolic,wesuggestinitiation
ofantihypertensivetherapy(Grade2C).
Wedonotsuggestantihypertensivetherapyinthefollowingsettings:
Nonhypertensivepatients(ie,bloodpressureof<140/90mmHg)whohavehadastrokeorTIAduetoa
cardioembolicphenomenon(eg,atrialfibrillation).
Patientswhosebaselinebloodpressureis<120/<70mmHg.Thesepatientshaveanincreasedriskof
recurrentstrokeiftheirbloodpressureisfurtherreducedcomparedwithpatientswhohavehigherblood
pressures.(See'Datafromrandomizedtrials'above.)
Thetimingofinhospitalinitiationorreinitiationofantihypertensivetherapyduringtheacutephaseofstrokeis
discussedindetailelsewhere.Forpatientswhohavenotbeentreatedinthehospital,antihypertensivetherapy
shouldbeinitiatedorreinitiatedasanoutpatientinallappropriatepatients.(See"Initialassessmentand
managementofacutestroke",sectionon'Bloodpressuremanagement'and'Whenshouldtherapybeinitiated?'
above.)
OurpreferencesforantihypertensivetherapyinpatientswhohavehadastrokeorTIAdifferaccordingtowhether
monotherapyorcombinationantihypertensivetherapyisrequiredtoachieveanadequatereductioninblood
pressure(see'Whichantihypertensivedrugsshouldbeused?'above):
Thereisnocompellingevidencefavoringoneclassofantihypertensivedrugsoveranotherasmonotherapy
forsecondarypreventioninpatientswhohavehadastroke.Angiotensininhibitors(mosttrialshaveused
angiotensinconvertingenzyme[ACE]inhibitors),calciumchannelblockers,anddiureticsarereasonable
optionsforinitialantihypertensivemonotherapyinsuchpatients.Unlessthereisacompellingindicationfor
theiruse,betablockersshouldnotbeusedforpreventionofrecurrentstroke.(See'Monotherapy'above.)
Wedisagreewiththe2014AmericanHeartAssociationandAmericanStrokeAssociation(AHA/ASA)
guidelinesthatrecommendanACEinhibitorplusadiureticforpatientswhohavehadastrokeorTIAand
requirecombinationantihypertensivetherapy.BaseduponobservationsfromtheACCOMPLISHtrial,we
recommendthecombinationofanangiotensininhibitorplusalongactingdihydropyridinecalciumchannel
blockerratherthanadiureticasthecombinationantihypertensiveregimenofchoiceinthetreatmentof
patientswhohavehadastroke.Thisrecommendationassumesthatthepatientcantolerateanddoesnot
haveacontraindicationtotheuseofeitherdrugclassanddoesnothaveaspecificindicationfortheuseof
anotherclassofantihypertensivedrugs.(See'Combinationtherapy'above.)
OurrecommendationsforgoalbloodpressureinpatientswhohavehadastrokeorTIAdependuponwhetheror
nottheeventwasduetoahemodynamicallysignificantstenosisinalargecervicocephalicartery(ie,internal
carotid,middlecerebral,vertebral,orbasilarartery)(see'Whatisthegoalbloodpressure?'above):
Inpatientswithhemodynamicallysignificantlargearterydisease,wesuggestcautiousbloodpressure
loweringastolerated,butwithoutaspecificbloodpressuregoalotherthanaminimumreductionof10/5
mmHg.However,insuchpatientswhoseinitialbloodpressureislessthan120/70mmHg,wedonotgive
antihypertensivetherapy.(See'Patientswithhemodynamicallysignificantlargearterystenosis'above.)
Inpatientswithouthemodynamicallysignificantlargearterystenosis,wetakethefollowingapproach(see
'Patientswithouthemodynamicallysignificantlargearterystenosis'above):
Werecommendloweringthebloodpressureaminimumof10/5mmHginnearlyallpatients.However,
insuchpatientswhoseinitialbloodpressureislessthan120/70mmHg,wedonotgiveantihypertensive
therapy.
Inpatientswithunderlyinghypertension,werecommendagoalbloodpressureoflessthan140/90
mmHgcomparedwithhigherpressuresandwesuggest(aweakerrecommendation)loweringthe
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systolicpressurebelow130to135mmHgifitcanbeachievedwithoutproducingsignificantside
effects.Theevidencesupportingthisapproachinpatientswithatheroscleroticcardiovasculardiseasein
generalisdiscussedindetailelsewhere.
Forpatientswithrecentsmallvessel(ie,lacunar)ischemicstroke,wesuggest(aweak
recommendation)loweringthesystolicbloodpressurebelow130mmHg.
Patientswithhemodynamicallysignificantlargearterydiseasewhoaregivenantihypertensivetherapyshouldbe
carefullymonitoredforhypotensiveorneurologicsymptomscausedbyeitherfailureofautoregulationofcerebral
bloodfloworbyhemodynamiccompromiseduetolargevesselstenosis.Ifsuchapatientdevelopsrecurrent
neurologicsymptomsreferabletoastenoticarterywhenthebloodpressureisloweredbelowaparticular
threshold,werecommendmanagementtomaintainbloodpressureabovethatthreshold.(See'Patientswith
hemodynamicallysignificantlargearterystenosis'above.)
Ifahemodynamicallysignificantstenosisofanextracranialcarotidarteryiscorrectedbyendarterectomyor
stenting,weattempttograduallyachievethebloodpressuregoalsdescribedintheprecedingsectiononpatients
withouthemodynamicallysignificantlargearterystenosisinordertoreducetherisksofrecurrentstrokeandother
cardiovascularevents.(See'Patientswithouthemodynamicallysignificantlargearterystenosis'above.)
Regardlessoftheregimen,bloodpressurereductionshouldbegradual.(See'Gradualbloodpressurereduction'
above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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2.MesserliFH,BangaloreS.Bloodpressureandstroke:findingsfromrecenttrials.JAmCollCardiol201157:114.
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4.PROGRESSCollaborativeGroup.Randomisedtrialofaperindoprilbasedbloodpressureloweringregimen
among6,105individualswithpreviousstrokeortransientischaemicattack.Lancet2001358:1033.
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8.ArimaH,ChalmersJ,WoodwardM,etal.Lowertargetbloodpressuresaresafeandeffectiveforthepreventionof
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9.LeeM,SaverJL,HongKS,etal.ReninAngiotensinsystemmodulatorsmodestlyreducevascularriskinpersons
withpriorstroke.Stroke201243:113.
10.KernanWN,OvbiageleB,BlackHR,etal.Guidelinesforthepreventionofstrokeinpatientswithstrokeand
transientischemicattack:aguidelineforhealthcareprofessionalsfromtheAmericanHeartAssociation/American
StrokeAssociation.Stroke201445:2160.
11.BoanAD,LacklandDT,OvbiageleB.Loweringofbloodpressureforrecurrentstrokeprevention.Stroke2014
45:2506.
12.ChenN,ZhouM,YangM,etal.Calciumchannelblockersversusotherclassesofdrugsforhypertension.
CochraneDatabaseSystRev2010:CD003654.
13.WiysongeCS,BradleyH,MayosiBM,etal.Betablockersforhypertension.CochraneDatabaseSystRev2007
:CD002003.
14.BangaloreS,ParkarS,GrossmanE,MesserliFH.Ametaanalysisof94,492patientswithhypertensiontreated
withbetablockerstodeterminetheriskofnewonsetdiabetesmellitus.AmJCardiol2007100:1254.
15.BangaloreS,WildD,ParkarS,etal.Betablockersforprimarypreventionofheartfailureinpatientswith
hypertensioninsightsfromametaanalysis.JAmCollCardiol200852:1062.
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16.JamersonK,WeberMA,BakrisGL,etal.Benazeprilplusamlodipineorhydrochlorothiazideforhypertensionin
highriskpatients.NEnglJMed2008359:2417.
17.SPS3StudyGroup,BenaventeOR,CoffeyCS,etal.Bloodpressuretargetsinpatientswithrecentlacunarstroke:
theSPS3randomisedtrial.Lancet2013382:507.
18.MantJ,McManusRJ,RoalfeA,etal.Differentsystolicbloodpressuretargetsforpeoplewithhistoryofstrokeor
transientischaemicattack:PASTBP(PreventionAfterStrokeBloodPressure)randomisedcontrolledtrial.BMJ
2016352:i708.
19.RodgersA,MacMahonS,GambleG,etal.Bloodpressureandriskofstrokeinpatientswithcerebrovascular
disease.TheUnitedKingdomTransientIschaemicAttackCollaborativeGroup.BMJ1996313:147.
20.ThompsonAM,HuT,EshelbrennerCL,etal.Antihypertensivetreatmentandsecondarypreventionof
cardiovasculardiseaseeventsamongpersonswithouthypertension:ametaanalysis.JAMA2011305:913.
21.ACCORDStudyGroup,CushmanWC,EvansGW,etal.Effectsofintensivebloodpressurecontrolintype2
diabetesmellitus.NEnglJMed2010362:1575.
22.OvbiageleB,DienerHC,YusufS,etal.Levelofsystolicbloodpressurewithinthenormalrangeandriskof
recurrentstroke.JAMA2011306:2137.
23.MazighiM,TanasescuR,DucrocqX,etal.Prospectivestudyofsymptomaticatherothromboticintracranial
stenoses:theGESICAstudy.Neurology200666:1187.
24.DerdeynCP,VideenTO,YundtKD,etal.Variabilityofcerebralbloodvolumeandoxygenextraction:stagesof
cerebralhaemodynamicimpairmentrevisited.Brain2002125:595.
25.RashidP,LeonardiBeeJ,BathP.Bloodpressurereductionandsecondarypreventionofstrokeandother
vascularevents:asystematicreview.Stroke200334:2741.
26.StrandgaardS,OlesenJ,SkinhojE,LassenNA.Autoregulationofbraincirculationinseverearterialhypertension.
BrMedJ19731:507.
Topic3823Version27.0

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GRAPHICS
Cerebralautoregulationinhypertension

Schematicrepresentationofautoregulationofcerebralbloodflowin
normotensiveandhypertensivesubjects.Inbothgroups,initial
increasesordecreasesinmeanarterialpressureareassociatedwith
maintenanceofcerebralbloodflowduetoappropriatechangesin
arteriolarresistance.Moremarkedchangesinpressureareeventually
associatedwithlossofautoregulation,leadingtoareduction(with
hypotension)oranelevation(withmarkedhypertension)incerebral
bloodflow.Thesechangesoccurathigherpressuresinpatientswith
hypertension,presumablyduetoarteriolarthickening.Thus,aggressive
antihypertensivetherapywillproducecerebralischemiaatahigher
meanarterialpressureinpatientswithunderlyinghypertension.
Redrawnfrom:Kaplan,NM.Managementofhypertensiveemergencies.
Lancet1994344:1335.
Graphic57676Version3.0

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ContributorDisclosures
NormanMKaplan,MDNothingtodisclose.RaymondRTownsend,MDConsultant/AdvisoryBoards:Medtronic
[Hypertension(Renaldenervationcatheter)].GeorgeLBakris,MDGrant/Research/ClinicalTrialSupport:Bayer,
BoehringerIngelheim,Relypsa,VascularDynamics,Medtronic[Diabeticneuropathy,diabetes,hypertension
(Empagliflozin,patiromer)].Consultant/AdvisoryBoards:AstraZeneca,ArborPharmaceuticals,Bayer,Boehringer
Ingelheim,Relypsa,VascularDynamics,Medtronic[Diabeticneuropathy,diabetes,hypertension(Empagliflozin,
patiromer)].ScottEKasner,MDGrant/Research/ClinicalTrialSupport:WLGoreandAssociates[Stroke(PFO
closure)]Acorda[Stroke(dalfampridine)]AstraZeneca[Stroke(ticagrelor)]Bayer[Stroke(rivaroxaban)].
Consultant/AdvisoryBoards:Bayer[Stroke]BMS[Stroke]Novartis[Stroke]Merck[Stroke]DaiichiSankyo[Stroke]
BoehringerIngelheim[Stroke].JohnPForman,MD,MScNothingtodisclose.JohnFDashe,MD,PhDNothingto
disclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthe
content.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsof
evidence.
Conflictofinterestpolicy

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