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AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y. Co- principal investigators: Hackett M, Hankey GJ. Steering committee: Almeida O, Anderson CS, Beer C, Billot L, Dennis MS, Flicker L, Ford A, Jan S, Mead G. The burden of disability due to stroke.
Co- principal investigators: Hackett M, Hankey GJ.
Steering committee: Almeida O, Anderson CS, Beer C, Billot L, Dennis MS, Flicker L, Ford A, Jan S, Mead G
Animal studies suggest fluoxetine is effective
? directly improves motor function
? indirectly improves motivation and attention
FLAME trial (Lancet Neurology, 2011;10:123-130)
Adjusted mean Fugl-Meyer motor scale (FMMS) total scores at days 0, 30, and 90
Error bars represent 95% CI
FLAME results promising, however:
We need to know:
Outcome HR (95% CI) Absolute risk (%/yr)
(Fluoxetine vs no antidepressant)
1 ◦ To determine if :
fluoxetine, 20 mg, once daily,
started 2-15 days after acute stroke, and
continued for 6 months,
improves recovery & functional ability.
2◦ To determine if fluoxetine…
Approached by clinician who checks inclusion and exclusion criteria and discusses rationale for fluoxetine vs placebo trial
Receives patient information leaflet and verbal explanation
Time to consider whether to take part
Signs informed consent form (or next of kin)
Information entered into trial database on-line (www.affinitytrial.org) and randomisation code assigned
Web-based, central randomisation service
Rx allocation ratio 1:1
Time since stroke onset (2-8 vs 9-15 days)
Presence of a motor deficit
Presence of aphasia
Probability of survival free of dependency at 6 months (0-15% vs 16-100%)
(i.e. allocates each patient to the treatment group that leads to the least difference between the two groups with respect to these features)
Adverse effect Comment Management
Change time of dosing and treatment
Sugarless gum or saliva substitutes
Change time of dosing (earlier or later may help), improve sleep hygiene,
try a different antidepressant, or short course of benzodiazepine, zopiclone, or low dose trazadone
No evidence that asking about suicide increases likelihood of self- harm. Prescribe small amounts of medication.
Consider changing to mirtazapine if it becomes problematic
Autonomic instability,and Hydration, Rx of hyperthermia, and benzodiazepines
Neuromuscular hyperactivity Consider cyproheptadine or chlorpromazine in severe cases
Consider non-pharmacological treatments
Advise an increase in social outlets and regular exercise
Consider referral to a clinical psychologist.
Clinical psychology can be accessed through the Medicare Better Access initiative free of charge to Australian residents & citizens for up to 12 sessions/year (http://www.health.gov.au/internet/main/publishing.nsf/Content/mental-ba-over
Consider adding 10 mg of fluoxetine to the participant’s trial medications and increasing this further to 20 mg after 4-6 weeks if ineffective.
This would mean that some participants would potentially be on 40 mg of fluoxetine a day. This dose has been shown to be effective and safe.
Combination therapy (using >2 antidepressants simultaneously) should best be avoided in view of the risk of serotonergic syndrome, especially if using another SSRI.
If choose to initiate possible combination therapy, use a non-serotonergic antidepressant such as reboxetine or one with less serotonergic activity such as mirtazapine
Consider referral to a specialist psychiatrist
Informed consent and trial specific screen and baseline assessment
Central randomisation 2 to 15 days post-stroke
Intervention group (n=790)
Control group (n=790)
1 month on-intervention assessment
3 month on-intervention assessment and dispensing
End of 6-month intervention assessment
6-month off-intervention (12 month) assessmentTrial design:Flow of participants and assessments
FOCUS aims to recruit 3000
If we complete both FOCUS and AFFINITY and enrol 4500 patients we could reliably detect a 4.4% absolute increase in mRS 0-2.