ARefresheroftheTreatmentofDemen0a(asweforgottheevidence)

G.MichaelAllanEvidence&CPDProgram,AlbertaCollegeofFamilyPhysicians

Professor,DeptFamilyMed,UofA.

Demen%a

1)  Understandingdemen%atreatmenttrials2)  Op%onsforTreatment

•  CholinesteraseInhibitorsBenefit•  CholinesteraseInhibitorsHarms

3)  Dose,Severity,withdrawing,preven%on.4)  Otherop%ons

1)  Meman%ne2)  Cogni%veEnhancement.

UnderstandingDemen%aResearch•  Demen%acategorybyMSE

–  Mild21-26;Moderate10-20;Severe<10

•  Scales!Needtoknow–  Mini-mentalStatusExam(MSE),0-30,higherbeVer–  Alzheimer’sDiseaseAssessmentScale(ADAS-Cog),0-70,lowerbeVer–  GlobalImpressionofChange(physicianrated),(outof7)

•  MinimalImportantClinicalDifference–  MSE=1.4andinADASCog=4

•  Toevaluate:Whatisthemeanchange&howmanygotMCID

Placebo Rivas%gimine Difference AVain1.4changeMSEAt6months -0.6 +0.2 0.74 ?

What’sNEW?

MSEchange(outof30)

ADAS-Cogchange(outof70)

GlobalImpressionofChange

2009(9RCTs) 0.82 1.99 0.66(0.55-0.79)2015(13RCTs) 0.74 1.79 0.68(0.58-0.80)

Rivas0gmineCochranereviews2009and2015

Meta-analysisofDemen0aRCTs•  Whatisthescien%ficevidenceforCholinesteraseInhibitorsinthe

treatmentofAlzheimer'sdisease.•  22Trials:12Donepezil,5Rivas%gmine,5Galantamine:27to978

pt/trial,6wks-3yrslong•  Findings:1.5-3.9(ADAS-cog&Minclinicalsign≥4)•  Limita0ons:Numerous

–  ITTflaws(ptexclusionakerrandomiza%on)=15/22(68%),–  LastObserva%onCarriedForward(decliningillness)–  UseofMeans(inscales),–  Nocorrec%onformul%plecomparison–  Funding(okenauthoredbyemployees)

BMJ2005;331:321-27

CholinesteraseInhibitors:Summary

•  CholinesterasetrialsvsPlacebo:MSE10-26*–  Poorrepor%ng(e.g.12%ofDonepezilreportmortality)–  Alzheimer’sDiseaseAssessmentScale(ADAS-cog)=4isclinicalsignificant,–  QualityofLifescoresunchanged

*HealthTechnolAssess2012;16(21).1)Cochrane.2006;(1):CD001190(10mgx6months).2)Cochrane2006;1:CD001747.3)Cochrane2015;9:CD001191.(*2009)4)Cochrane2006;Issue1:CD005593.

Donepezil1 Galantamine2 Rivastigmine3 All4

MMSE 1.44 ? 0.74 1.37 ADAS - Cog 2.81 3.38 1.79 2.73 ADAS – Cog of 4 ? NNT 6 NNT 18* ? Glob Clin State NNT 10 NNT 7 NNT 13 NNT 14 Adverse Events NNH 18 ? NNH 8 NNH 8

?Notgiven

OtherOutcomes:ExampleDonepezil

•  ADL&IADL:Moststa%s%callysignificant–  Lotsofdifferentonesused,sosumminguphard–  Basically,moveabout<4%ondifferentscales.

•  E.g.updatedrivas%gmine:change=2.15outof100.

•  QualityofLife:Pa%entrated.–  Nodifference.

•  Behavior:PrimarilyNPIused–  Nodifference12wks,10mg–  Difference(24wks,10mg):2.94(outof144)

Cochrane2006;1:CD001190.AnnInternMed.2008;148:379-97.Cochrane2015,(9):CD001191.

AdverseEvents:ExampleDonepezil

•  Sta%s%callysignificant–  Anorexia:7.3%vs2.1%,NNH20–  Diarrhea:14.5%vs5.3%,NNH11–  Nausea:14.5%vs5.4%,NNH11–  Vomi%ng:11.3%vs4.7%,NNH16– WeightLoss:8.2%vs4.5%,NNH28–  Fa%gue:9.4%vs4%,NNH19–  Asthenia(weakness):7.9%vs4.7%,NNH32–  Dizziness:8.1%vs5.4%,NNH38–  Insomnia:9.9%vs4.4%,NNH19

•  OthersBorderline(accidentalinjury,rhini%s)

AnnInternMed.2008;148:379-397.AdverseEventAppendixTable4

Isonebe[erthananother?•  3TrialscompareHeadtoHead1

– Mul%pleFlaws&poten%allybiased•  Industryfunded,EmployeewriVen,resultsfavoringsponsor.

–  InMeta-analysis:“Thereisnoevidenceofanydifferencebetweenthem”2

•  FournewRCTs:3weakandnoreliabledifference.3–  Fourth:Rivas%gminevsdonepezil,

•  Nodifferenceincogni%on/behavior•  Marginal(very)differencesinfunc%onandglobaleffect.

•  Bo[om-Line:Noreliabledifference.

1)LancetNeurol2004;3:622:26.Therapeu%csLeVer2005;56:1-4.2)CochraneDatabaseSystRev.2006Jan25;(1):CD005593.3)HealthTechnolAssess2012;16(21).

Preven0onofDemen0a:

•  VitaminE:Nohelp•  Exercise:Nohelp.•  Meta-analysisDonepezil:

–  In1of2trials,1of5scoreshada3%lessdecline– Stoppingduetoadverseevents:NNH7.

•  Meta-analysisGalantamine:– MarginaltonoclinicalBenefit– ++Harms:NNH(fordeath)=94.

•  Bo[om-Line:None.1)NEJM2005;352:2379-88.2)Cochrane2015;(4):CD0053813)CochraneDatabaseSystRev.2006;3:CD006104.4)Cochrane2006;(1):CD001747.Therapeu%csLeVer2005;56:1-4.

Whataboutwithdrawing?

•  295CommunitydwellingPa%entsonDonepezil(most>2yrs)– meanage77,meanMSE9,followed1yr.

– StoppingofmedworsenedMSEby1.9pts•  Lesseffectifseveredemen%a(<9MSE)•  Don’tgivenumberaVainingMCID(1.4)

– Withdrawalfromstudymoreifstopped!– Death:nodifference

N Engl J Med 2012;366:893-903.

DoesDoseMaVer?•  ModeratedosemaymaVer

– Donepezil:ADAS-Cog2.15(5mg)vs2.45(10mg)•  MSEresultsequalat5or10mg.

– Rivas%gmine:ADAS-Cog0.84(1-4mg)vs1.99(6-12mg)

– Galantamine:Globalra%ngOR1.17(8mg)vs1.63-1.84(16-32mg)

•  Bo[om-Line:Usemostlyindirectcomparison.Maybethatsomelowdoseshaveasomewhatweakereffect.ProbablyavoidGalantamine8mgandrivas0gmine1-4mg.

1)  Cochrane.2006;(1):CD001190(10mgx6months).2)Cochrane2006;1:CD001747.3)Cochrane2015;9:CD001191.(*2009)

DoesSeverityMaVer

•  BoVom-Line:Maybemoreeffec%veinmoderateseverity,butnoformalpa%entlevelanalysis,datasparseandsomewhatinconsistent?

Donepezil@24wksChangeinMSE

Donepezil@24wksVaryingCogOutcomes

Donepezil@24wksChangeinFunc0on

Donepezil@24wksGlobalChange

HealthTechnolAssess2012;16(21).

Cogni0veEnhancement•  15RCTswith718par%cipants

–  Example:namingobjects&people,wordassocia%on,rememberingthepast,discussionofhobbies,ac%vi%es&currentaffairs,usingmoney,knowingthewayaroundandorienta%ontopics

•  Outcomes:changeinscale– ADAS-Cogat1-12months:2.27(0.99,3.55)– MSEat1-12months:1.74(1.13,2.36)beVer

•  LongerseemsbeVerbutbasedononlyonestudy.

•  Bo[om-Line:Seemstohavesomeposi0veeffects(similartodrugs).

Cochrane2012;2:CD005562.

Drugs with Potential: Memantine

•  Mostly Moderate - Severe Dementia – ADCS -ADL score, Severe impairment battery,

Functional assessment Staging, Clinician Impression of Change (CIBIC): All 0-4% change

– Possibly <agitation (NNT= 63) - if already on – Well Tolerated (no diff in drop-out due to AE) – Other studies use SMD statistic & can’t interpret.3

•  Bottom-Line: Effects are small & inconsistent.

Cochrane 2006;(2):CD003154. Health Technol Assess 2012;16(21). 3) PLoS ONE 10(4): e0123289.

CombiningMedicines

•  AddingMeman%netoCholinesteraseinhibitors– 4RCTswith1439pts,~10(meanrange7-16)

•  6months– ADAScog:1.6beVer– MSE:0.5beVer– Neuro-Psychiatricinventory:1.6beVer(outof144)

•  Bo[om-Line:Thebestthiscombina0oncanofferis1-2%change.

HealthTechnolAssess2012;16(21).

ANewHope:Aducanumab•  RCT165pts,age73,50%female,doseq-monthIV1,3,6,10mg/kgorplacebo

•  Outcome:atoneyear

•  Bo[om-Line:Preliminaryevidencesuggestspoten0albenefitbutveryearlyandwillneedevidenceinmoderatetoseveredemen0a.

Measure Scale Worse Baseline Placebovs10 MainTypesofAE

MSE 0-30 low 24 2.7vs0.5worse Edema(NNH3),Headache(NNH5),superficialirondeposi%oninCNS(8)

CDR-SoB 0-18 high 3.2 1.8vs0.7worse

FCSRT 0-48 lower 14 Nodiff

Discon%nueduetoAE 10%vs31%(ss)

ClinicalDemen%aRa%ng—SumofBoxes.FreeandCuedSelec%veRemindingTest;

Nature.2016Aug31;537(7618):50-6.

Summing-Up

•  Cholinesteraseinhibitorsbasically –  Improvedemen%afor1in10(overplacebo)–  CauseAdverseeventssevereenoughtostoptakingfor1in10(overplacebo)

–  Ifreallyworking(orwasworking),stayon.•  Allmedsthesame,Don’tgiveforpreven%on,don’tcombinemeds

•  Cogni%veenhancementmeasureswhereverpossible

•  HopeforAducanumab(buts%lljusthope)