Post on 10-Jun-2018
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