【高血压英文课件】Clinical-Trials-of-Anti-Hypertensive

ClinicalTrialsofAnti-HypertensiveMedicationforMCIanddementiaIngmarSkoog,M.D.,Ph.D.InstituteofNeuroscienceandPhysiologyUnitofNeuropsychiatric

EpidemiologySahlgrenskaAcademyatGöteborgUniversityGöteborg,SwedenDISCLOSURESConsultant:AstraZenecafortheSCOPEtrialSpeakersBureau:Esai,JansenCilag,AstraZeneca,Shire,Pfizer,NovartisBackgroundPrevalenceofhypertensionincreaseswithageMore

than50%ofelderlypopulationshavehypertensionwithcurrent

criteria(140/90)AnemergingprobleminthedevelopingworldEnd-organ

damageThearterial

treeHeartKidneyBrainEyesSystolicBloodPressure140CardiovascularRiskHYPERTENSIONINRELATIONTOCOGNITION Hypertension Stroke WhiteMatterLesions

CognitiveimpairmentABörjessonHanson2001HypertensionandthebrainCerebralautoregulationBlood

brain

barrier

dysfunctionDecreasedcerebralblood

floowStroke(hemorrhagic,ischemic)WhitematterlesionsDementiaandAlzheimer’s

diseaseRISKOFDEMENTIAINRELATIONTOSTROKE

70+GöteborgAgeStrokepatientsAge-matched

controls%%OR95%-CI70-801836.7(2.6-17.6)80+34104.8(2.8-8.3)All2874.7(3.0-7.4)Lindén,SkoogetalNeuroepidemiology2004Cognitive

impairmentin

non-dementedstrokepatients

70+GöteborgStrokeControlsCognitive

Disturbance%%ORMemory622.6*Language16113.8*Praxis36212.1*Gnosia2054.8*Abstraction1792.0*Any61313.5*Lindén,SkoogetalNeuroepidemiology2004SILENTINFARCTSThefrequencyofsilent

infarctsonMRIincreaseswithage

(Vermeeretal,Stroke2003)Increasestheincidenceofdementia(HR2.3(95-%CI1.1-4.7)during3.6years

follow-upRelatedtoworseperformanceonpsychometrictestingatbaselineIncreasesriskofclinicalstrokeonfollow-up

(Vermeeretal.NEnglJMed2003)RISKOFDEMENTIAINRELATIONTOINFARCTSONCTANDHISTORYOFSTROKEATAGE85H-70STUDY,GÖTEBORG,SWEDENORNoinfarcts/Nohistory1.0Infarcts/Nohistory(”silent

infarcts”)2.5*Noinfarcts/History

4.4*Infarcts+History5.2*Liebetrau&Skoog.Stroke2004HypertensionandthebrainCerebralautoregulationBlood

brain

barrier

dysfunctionDecreasedcerebralblood

floowStroke(hemorrhagic,ischemic)WhitematterlesionsDementiaandAlzheimer’s

diseaseWHITEMATTERLESIONSINRELATIONTODEMENTIAIN85-YEAR-OLDS

% Nodementia 34 Alzheimer´sdisease 64**Vasculardementia 70***Otherdementias 80*SkoogetalJGeriatrPsychiatryNeurol1994Cognitive

functioninnon-demented85-year-oldsinrelationtowhite

matterlesionsNoWMLsWMLs(N)Mean(N)meanVerbalability(76)19(36)17Visuospatial

ability(81)13(42)9**Perceptualspeed(78)14(38)12*Skoogetal.Acta

Neurol

Scand1996HypertensionandthebrainCerebralautoregulationBlood

brain

barrier

dysfunctionDecreasedcerebralblood

floowStroke(hemorrhagic,ischemic)WhitematterlesionsAlzheimer’s

diseaseLONGITUDINALSTUDIESONBLOODPRESSUREANDALZHEIMER’SDISEASEPrevioushighbloodpressure

5-15yearsAlzheimer’sdiseaseinlatelifeTheH70-studyinGothenburg

Skoogetal.Lancet1996

TheHonolulu-AsiaAgingStudy

Launeretal.NeurobiolAging2000

TheRotterdamStudy

Ruitenbergetal.Dissertation2000KaiserPermanente,USA

Whitmeretal.Neurology2005

Kuopio,FinlandKivipeltoetal.BMJ2001KungsholmenStudy

QiuetalArch

Neurol2003Chinese

StudyWuetalLifeScience2003RelationtoADpathologyHONOLULU-ASIAAGINGSTUDYHighmidlife

systolic

blood

pressure

NeuriticplaqueinoldagePetrovitchetal.NeurobiologyofAging2000Possible

pathogenetic

mechanismsIschemia

increases

productionofbeta-amyloidBlood-brain

barrier

dysfunctionRenin-angiotensinsystemA15-yearfollow-upof

blood

pressureanddementiaSkoogetal.Lancet1996BLOODPRESSUREIN

ALZHEIMER´SDISEASEIncreasedbeforeonsetLowerjustbeforeorafteronsetHypertensionandriskofMCIHR(95%-CI)AllMCI1.40

(1.06-1.77)

AmnesticMCI1.10

(0.79-1.63)

Non-amnesticMCI1.70

(1.13-2.42)

Reitzetal.ArchNeurol.2007;64:1734-40

Blood

pressureandcognitive

functionMidlife:High

blood

pressure

relatedtolower

cognitive

functionOldage:Low

blood

pressure

relatedtolower

cognitive

functionTreatmentofhypertensionandMCI/dementia/AlzheimerdiseaseANTIHYPERTENSIVEDRUGSAngiotensin

Converting

EnzymeInhibitorsorAngiotensinIItype1(AT1)receptorblockerBeta-blockers

Calcium-channel

blockersDiureticsTreatment

targetsinrelationtodementia/MCIDementiaADLSocialabiliyMildCognitive

ImpairmentNormalObservationalstudiesBLOODPRESSUREANDDEMENTIA

ISITDANGEROUSTOTREATHYPERTENSIONINTHEELDERLY?A15-yearfollow-upof

blood

pressureandAlzheimer’s

diseaseSkoogetal.Lancet1996BLOODPRESSUREINRELATIONTODEMENTIAIN85-YEAR-OLDS

Blood pressure mmHgmmHg mmHgSystolic 162 148*** 151***Diastolic 79 78 76*NoAlzheimer’sVascularDementiadiseasedementiaSkoogetal.Hypertension1998LOWBLOODPRESSUREANDALZHEIMER’SDISEASEAriskfactorforAlzheimer’s

disease???AconsequenceofAlzheimer’s

diseaseBlood

pressure

decreases

during

thecourseofAlzheimer’s

diseaseLower

blood

pressureisrelatedtobrain

atrophyand

numberofneuronsincertainareasofthebrainHONOLULU-ASIAAGINGSTUDYHighmidlife

blood

pressure

inmennottreatedforhypertension

Alzheimer’sdiseaseinoldageVasculardementiainoldageLauneretal.NeurobiologyofAging2000ProspectivePopulationStudyofWomeninGothenburgHighmidlife

blood

pressure

inwomen

nottreatedforhypertension

DementiainoldageSkoogetal2008ANTIHYPERTENSIVEDRUGSANDRISKOFDEMENTIAIndianapolis(prevalence) ORDementia 0.67Alzheimer’s

Disease 0.59(Richardsetal.JAmGeriatr

Soc2000;48:1035-41Kungsholmen(incidence) RR(95%-CI)Dementia 0.7(0.6-1.0) (Guoetal.Arch

Neurol1999;56:991-996Rotterdam(incidence) RR(95%-CI)

Dementia 0.76(0.52-1.12)Vascular

dementia 0.30(0.11-0.99)(In`t

Veldetal.Neurobiol

Aging,2001;22:407-412

CasheCountyStudy(incidence) RR(95%-CI)

Alzheimer’s

disease0.64(0.41-0.98)(Khachaturian

etal.

ArchNeurol2006;63:686-92)

HonoluluAsia

StudyForeachadditionalyearofantihypertensivetreatmenttherewasareductionintheriskofincidentdementia(hazardratio[HR]=0.94,95%CI,0.89to0.99)SameresultforincidentAlzheimer’sdisease

Thus,thelongertimeontreatment,thelowerriskofdementiaPeilaetal.Stroke2006RISKFACTORSDEMENTIA(SBU)Strong/moderateevidenceAge**ApoEe4FamilyaggregationMidlife

blood

pressureDiabetesmellitusAntihypertensive

drugs(protective)**Low

educationLeisureactivity(protective)FratiglionietalPREVIOUSDATAAREBASEDONOBSERVATIONALSTUDIES

RANDOMISEDCONTROLLEDTRIALSMORERELIABLETHANOBSERVATIONALSTUDIESWHATHAVEWELEARNEDFROMRANDOMISEDCONTROLLEDPREVENTIONTRIALS?LARGEHYPERTENSIONTRIALSSystolicHypertensionintheElderlyProgram(SHEP)(N=4736):Chlorthalidon

(D)MedicalResearchCouncil’s(MRC)TreatmentTrialofhypertension(N=4396):Atenolol

(B),

Hydrochlorthiazide

(D)TheSystolicHypertensioninEuropeStudy(Syst-Eur)(N=2418):Nitrendipine

(C)TheStudyonCognitionandPrognosisintheElderly(SCOPE)(N=4937):Candersatan

(A)Perindopril

Protection

against

RecurrentStrokeStudy(PROGRESS)(N=6105):Perindopril

(A)TheHypertensionintheVeryElderlyTrial(HYVET)(N=3336):Indapamide

(D)+perindopril

(A)LARGEHYPERTENSIONTRIALSSystolicHypertensionintheElderlyProgram(SHEP)(N=4736):ChlorthalidonMedicalResearchCouncil’s(MRC)TreatmentTrialofhypertension(N=4396):Atenolol,HydrochlorthiazideTheSystolicHypertensioninEuropeStudy(Syst-Eur)(N=2418):NitrendipineTheStudyonCognitionandPrognosisintheElderly(SCOPE)(N=4937):CandersatanPerindopril

Protection

against

RecurrentStrokeStudy(PROGRESS)(N=6105):PerindoprilTheHypertensionintheVeryElderlyTrial(HYVET)(N=3336):Indapamide+perindopril

(NEnglJMed2008,Lancet

Neurol2008)SAMPLESSHEP160-219/<90MRC160-209/<115Syst-Eur160-219/<95NodementiaPROGRESSPriorstrokeorTIAMean

age64SCOPE160-179/90-99MMSE24-30NodementiaHYVETSBPabove160Ageabove80COGNITIVEEND-POINTSDementia(SHEP,Syst-Eur,SCOPE,PROGRESS,HYVET)Significant

Cognitive

Decline(PROGRESS,SCOPE)COGNITIVEEND-POINTSMean

changeincognitive

function

Syst-Eur,Progress,SCOPEMiniMentalStateExamination(MMSE)MRC:

Paired

associate

learning,Trail

MakingTest

MAINRESULTS

CardiovascularendpointsAntihypertensive

treatment

reducedriskofmost

cardiovascularendpoints

inclstrokeAlsoinHYVET,which

only

includedpersonsabove

age80(NEnglJMed2008)MAINRESULTS

DEMENTIADecreased

incidenceofdementia(Syst-Eur)Nodifference(SHEP,SCOPE,Progress,HYVET)Nohypertensiontrialshowincreasedriskfordementiaorcognitive

declineMAINRESULTS

MEANCOGNITIVECHANGENodifference:MRC,SHEP,SCOPE,Syst-Eur,Lessdeclineinactive

treatmentgroup:PROGRESSWHYSONEGATIVERESULTS?Methodological

issuesAgeHealthy

volunteer

effectSelectiveattrition/missingdataTimeoffollow-upTimeinrelationtodementiaDiagnosisanddetectionofdementiaTesting

Ceiling

effect

Learning

effect

SensitivitytochangeSubgroups?Riskgroups?TypeofdrugEffect

other

than

blood

pressureSAMPLESSHEPAbove

age60MRCAge65-74Syst-EurAbove

age60(mean70)NodementiaHYVETAgeabove80PROGRESSPriorstrokeorTIAMean

age64SCOPEAge70-89(mean76)MMSE24-30NodementiaMethodological

issuesAgeHealthy

volunteer

effectSelectiveattrition/missingdataTimeoffollow-upTimeinrelationtodementiaDiagnosisanddetectionofdementiaTesting

Ceiling

effect

Learning

effect

SensitivitytochangeSubgroups?Riskgroups?TypeofdrugEffect

other

than

blood

pressureMeantestscoreatbaselineSYST-EUR:28.5(max30)inMMSESCOPE:28.5inMMSEMethodological

issuesAgeHealthy

volunteer

effectSelectiveattrition/missingdataTimeoffollow-upTimeinrelationtodementiaDiagnosisanddetectionofdementiaTesting

Ceiling

effect

Learning

effect

SensitivitytochangeSubgroups?Riskgroups?TypeofdrugEffect

other

than

blood

pressureEffectofdifferentialdrop-outinSHEPPlacebogrouphad

more

missed

assessmentsCaVaeventspredicted

missed

assessments20-30%ofmissed

assessments

were

assumedtobecognitively

impairedThen

active

treatment

reducedtheriskofcognitive

impairmentDiBarietal.AmJEpidemiol2001Methodological

issuesAgeHealthy

volunteer

effectSelectiveattrition/missingdataTimeoffollow-upTimeinrelationtodementiaDiagnosisanddetectionofdementiaTesting

Ceiling

effect

Learning

effect

SensitivitytochangeSubgroups?Riskgroups?TypeofdrugEffect

other

than

blood

pressureTimeoffollow-upSHEP5yearsMRC4.5yearsSyst-EurMedian2.0yearsPROGRESSMean3.9yearsSCOPEMean3.7yearsHYVETMean2.2yearsLONGITUDINALSTUDIESONBLOODPRESSUREANDALZHEIMER’SDISEASEPrevioushighbloodpressure

5-15yearsAlzheimer’sdiseaseinlatelifeTheH70-studyinGothenburg

Skoogetal.Lancet1996

TheHonolulu-AsiaAgingStudy

Launeretal.NeurobiolAging2000

TheRotterdamStudy

Ruitenbergetal.Dissertation2000

Kuopio,FinlandKivipeltoetal.BMJ2001KungsholmenStudyQiuetalArch

Neurol2003Chinese

StudyWuetalLifeScience2003USAWhittmeretal.Neurology2005Too

short

follow-uptoevaluateaneffectondementia

Declining

blood

pressure

before

dementia

onsetA15-yearfollow-upof

blood

pressureanddementiaSkoogetal.Lancet1996SAMPLESSHEP160-219/<90MRC160-209/<115Syst-Eur160-219/<95NodementiaPROGRESSPriorstrokeorTIAMean

age64SCOPE160-179/90-99MMSE24-30NodementiaHYVETSBP>160

If

lowered

blood

pressureisamarkerofpreclinical

dementia,

those

includedinhypertensiontrials

maybeatlow

short-termriskfordementiaMethodological

issuesHealthy

volunteer

effectSelectiveattrition/missingdataTimeoffollow-upDiagnosisanddetectionofdementiaTesting

Ceiling

effect

Learning

effect

SensitivitytochangeSubgroups?Riskgroups?TypeofdrugEffect

other

than

blood

pressureCHANGEINMMSESCORECeiling

effectinthosewith29-30Learning

effect(testevery6months)Lesspossibilityforincreaseinthosewith29-30

MMSE30MMSE30CHANGEINCOGNITIVEFUNCTIONMMSE24CHANGEINMMSESCORECeiling

effectinthosewith29-30Learning

effect(testevery6months)Lesspossibilityforincreaseinthosewith29-30

IncreaseintestscoresMRCtrialinhypertensionSyst-EurSCOPECHANGEINMMSESCORECeiling

effectinthosewith29-30Learning

effect(testevery6months)Lesspossibilityforincreaseinthosewith29-30

CHANGEINMMSESCOREFROMBASELINE(SCOPE)MMSEscoreatbaselineIncrease%Decrease%30(N=1653)04429(N=1214)363728(N=929)433427(N=528)493726(N=354)493725(N=177)543324(N=81)3645Methodological

issuesHealthy

volunteer

effectSelectiveattrition/missingdataTimeoffollow-upDiagnosisanddetectionofdementiaTestingCeiling

effectLearning

effectSensitivitytochangeSubgroups?Riskgroups?TypeofdrugEffect

other

than

blood

pressureSCOPE.Newcastlesubstudy

ChangeintestscoresCandesartanPlacebopAttention

0.004-0.036

0.04

Episodicmemory0.14-0.22

0.04

Speedofcognition-2.3-17.4

0.15

Workingmemory0.00140.0010

0.90

Executivefunction

-0.0031-0.0023

0.95

Saxbyetal.Neurology2008;70:1858-66

Treatmentofhypertension

in

mildcognitive

impairment(MCI)Treatment

targetsinrelationtodementiaDementiaADLSocialabiliyMildCognitive

ImpairmentNormalMMSE24-28ATBASELINE(SCOPE)More

previousstroke(5.2%vs3.0%)Morediabetesmellitus(14%vs10%)Lessmyocardial

infarction(4.3vs4.7%)Older(77.3vs75.8)SkoogetalAmJHypertension2005MajorCardiovasculareventsinSCOPE

(per1000person-years)MMSE24-2833.629-3024.7***Cardiovascular

mortality,stroke,myocardial

infarctionSkoogetalAmJHypertension2005Non-fatalstroke

(per1000person-years)inSCOPEMMSE24-2810.629-307.6*SkoogetalAmJHypertension2005Dementia(cumulative

incidence)inSCOPEMMSE%24-284.429-301.0***SkoogetalAmJHypertension2005ChangeinMMSEScore,ITT-0.8-0.7-0.6-0.5-0.4-0.3-0.2-0.10ChangeinMMSEScore

(adjusted)Candn=1419Contn=1399BaselineMMSE29-30Candn=998Contn=1010BaselineMMSE24-28p>0.20p=0.04Candn=2417Contn=2409Allpatientsp=0.20SkoogetalAmJHypertension2005TreatmentofhypertensionindementedTreatment

targetsinrelationtodementiaDementiaADLSocialabiliyMildCognitive

ImpairmentNormalNotmanystudiesonantihypertensive

treatmentindemented

individuals

and

noRCTPrevalenceofhypertension

(=blood

pressure

above160/90)

in85-year-olds%Non-demented(N=346)63.9Demented(N=147)46.3***Alzheimerdisease(N=64)42.2

Vascular

dementia(N=69)53.6Hypertensionaccelerates

cognitive

declineinAlzheimer’s

diseaseHypertensionatbaseline

was

associatedwithsteeper

cognitive

declineinAlzheimerpatientsbelowtheageof65.Noeffectofantihypertensive

treatment(Bellewetal2004)Systolichypertensionatbaseline

was

relatedtosteeper

cognitive

declineinAlzheimerpatientsfromtheCasheCountyStudy.Mainly

amongtheelderly.Antihypertensive

treatment

was

relatedtoaslower

decline(Mielkeetal2007)AcetylcholinesteraseinhibitorsinAlzheimerpatientswithhypertensionBetter

long-term

effectofRivastigmineinAlzheimerpatientswithhypertension(Erkinjunttietal2003)Better

effectofDonepezilinAlzheimerpatientswithhypertension(Fukuietal2005)Antihypertensive

treatment

slowsprogressionofAlzheimerdisease?Treated

hypertensiveswithAlzheimerdisease,vascular

dementia,mildcognitive

impairment

had

better

cognitive

function(Hajjaretal2005,Hanonetal2006)InAlzheimerpatientsonacetylcholinesteraseinhibitors,thoseonantihypertensive

treatment

performed

betteronMMSEafter40weeksoftreatment(Rozzinietal2005)Treatmentofhypertensionmay

haveaneffectoncerebrovascular

diseaseinindividuals