CitalopramInPatientsWithAcuteIschaemicStroke(TALOS)- ADanishRandomisedControlledTrialonFunctionalRecoveryandCardiovascularProtection

KLKraglund,JKMortensen1,AGLauritsen1,BModrau2,SASimonsen3,HKIversen3,MMadsen4,ELGrove5,SPJohnsen4,GAndersen1

1 Dept.ofNeurology,AarhusUniversityHospital,Denmark2 Dept.ofNeurology,AalborgUniversityHospital,Denmark3 Dept.ofNeurology,CopenhagenUniversityHospital,Denmark4 Dept.ofClinicalEpidemiology,AarhusUniversityHospital,Denmark5 Dept.ofCardiology,AarhusUniversityHospital,Denmark

Aninvestigatorinitiatedtrial• Investigatordriven• 3Danishinclusionsites

• Strokeunits• Aarhus,Aalborg&Glostrup

• Nocommercialfunding

Funding• TheTRYGFoundation• TheDanishCouncilforIndependentResearch• TheRegionalMedicineFund• TheAarhusUniversityResearchFoundation

Background- PotentialNeuroprotectionImprovedrecoveryClinicaldatafromtheFLAME1 gaverisetooptimism• Fluoxetine/placebo• 118moderatetoseverischaemicstrokes• Increasedmotorrecovery(Fugl-Meyermotorscale)

Vascularprotection• Noclinicaltrials• Observationalstudiesareinconsistentandconfoundedbydepression• Signaltowardsvascularprevention2

1 Chollet et al.: FLAME, Lancet Neurol 2011; 10: 123–302 Mortensen et al.: Stroke 2013; 44(82):420-6

Aim

Thereweretwoco-primaryoutcomes:1. Changesinfunctionaldisabilityfromonetosixmonthsmeasured

bythemodifiedRankinScale,and2. Compositevascularendpointoftransientischaemicattack/stroke,

myocardialinfarctionorvascularmortalityduringthefirstsixmonths

949 patients assessed for eligibility

307 excluded92 not meeting inclusion criteria 126 declined to participate89 other reasons

642 randomly assigned

284 included in per-protocol analysis (6 months or LOCF)

36 discontinued intervention <31 days13 consent withdrew4 adverse event12 indication for open-label7 other reasons

323 allocated to placebo 323 included in intention-to-treat analysis

0 patients lost to follow-up primary, vascular endpoint320 received placebo3 did not receive placebo

50 discontinued intervention <31 days29 consent withdrew6 adverse event6 indication for open-label9 other reasons

319 allocated to citalopram 319 included in intention-to-treat analysis

0 patients lost to follow-up for primary, vascular endpoint318 received citalopram1 did not receive allocated intervention

268 included in per-protocol analysis (6 months or LOCF)

ParticipantFlow

Methods1

• First-everischaemicstrokenon-depressedpatients• Noupperlimitinageorstrokeseverity

• Onset<7days• Double-blind,placebocontrolled,randomised• 1:1allocation• Standarddosage

1 Kraglund et al., International Journal of Stroke, 2015; 10(6), 985-87

TrialCharacteristics

• Sept2013toJune2016• Totalof642patients• Early6monthsfollow-up

• Mean146days• Allpatientshadfollow-uporregistryinformationonvitalstatus

CHARACTERISTICS Citalopram(n=319) Placebo(n=323) P-value

Meanage,years(range;SD) 68·3(24 to97;12·5) 68·4(19to99;12·8) 0·91

Malesex 199(62%) 222(69%) 0·09

NIHSSatadmission(range;SD) 5·3(0 to27;5·6) 4·8(0to28;4·8) 0·28

Onsettotreatment,days (range;SD) 1·73(0 to6;1·6) 1·55(0to10;1·5) 0·17

PREMORBIDMODIFIEDRANKINSCALE

Mean(range;SD) 0·27(0to3;0·7) 0·27(0to3;0·6) 0·90

REPERFUSIONTHERAPY

Any 109(34%) 123(41%) 0·056

rt-PA 105(33%) 129(40%) 0·06

EVT 24(8%) 22(7%) 0·73

rt-PA:intravenousrecombinanttissueplasminogenactivator;EVT:Endovasculartreatment

Results–ImprovementonthemodifiedRankinScale1

Odds Ratio for mRS improvement: 1·27 (95% CI: 0·92 to 1·74, p=0·14)

Placebo

0 20 40 60 80 100percent

Aktiv (Citalopram)

0

Angiv mRS

0. Ingen symptomer overhovedet 1. Lette symptomer2. Mindre handicap 3. Moderat handicap4. Beh¯ver megen hjÊlp 5. Beh¯ver konstant opsyn6

0 20 40 60 80 100percent

Aktiv (Citalopram)

0

Angiv mRS

0. Ingen symptomer overhovedet 1. Lette symptomer2. Mindre handicap 3. Moderat handicap4. Beh¯ver megen hjÊlp 5. Beh¯ver konstant opsyn6

0 20 40 60 80 100percent

Aktiv (Citalopram)

0

Angiv mRS

0. Ingen symptomer overhovedet 1. Lette symptomer2. Mindre handicap 3. Moderat handicap4. Beh¯ver megen hjÊlp 5. Beh¯ver konstant opsyn6

0 20 40 60 80 100percent

Aktiv (Citalopram)

0

Angiv mRS

0. Ingen symptomer overhovedet 1. Lette symptomer2. Mindre handicap 3. Moderat handicap4. Beh¯ver megen hjÊlp 5. Beh¯ver konstant opsyn6

Citalopram

1month

1month

6month

6month

0 654321

1 Taking the whole mRS range into account (ordinal, logistic regression)

0.00

0.08

319 306 301 300 299 299 298Citalopram323 313 309 306 302 301 300Placebo

Number at risk

0 1 2 3 4 5 6Months since randomization

PlaceboCitalopram

Vascular Death, TIA/Stroke or Myocardial Infarction,HR 0·89, p=0·69

Results– CardiovascularProtectionCombined Vascular Outcome1

• HR: 0·89 (95%CI: 0·5 to 1·6)

TIA/Stroke • HR: 1·07 (95%CI: 0·6 to 2·1)

Myocardial Infarction• HR: 2·03 (95%CI: 0·2 to 22)

Vascular Mortality • HR: 0·67 (95%CI: 0·2 to 1·9)

1 TIA/stroke, myocardial infarction or vascular mortality

Conclusions• Citalopramtreatmentafterischaemicstrokesignalspositiveeffect-thoughnotstatisticalsignificant

• improvedfunctionalrecovery• vascularprotection

• Moreplacebodrop-outsduetodepressionmayleadtoconfoundingbydepression

• TimeisnotyettorecommendSSRIasstandardtreatmentinnon-depressedafterstroke

• TALOSconfirmsthatSSRIissafeinischaemicstrokepatients