Transcript Slide 1

AFFINITY trial
Assessment oF FluoxetINe In sTroke recoverY
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
• 4th leading cause of global disease burden
• 16 million 1st-ever events
• 51 million disability-adjusted life years
• 5.7 million deaths
• 50% of stroke survivors have long-term residual disability.
– How can we improve recovery & reduce disability after stroke?
Fluoxetine
Animal studies suggest fluoxetine is effective
?directly improves motor function
? indirectly improves motivation and attention
FLAME trial (Lancet Neurology, 2011;10:123-130)
• Fluoxetine on Motor Rehabilitation after ischaemic stroke
• RCT: 118 with acute ischaemic stroke & unilateral motor
weakness
• Intervention: 20 mg fluoxetine daily, 3 months vs. placebo
FLAME trial: Modified Rankin score at 90 days
mRS 0-2:
26.3% fluoxetine vs 8.9% placebo
OR = 3.8, 95% CI 1.2 to 10.7
FLAME trial: Fugl Meyer Motor scores
Adjusted mean Fugl-Meyer motor scale (FMMS) total scores at days 0, 30, and 90
Error bars represent 95% CI
Rationale for a new trial
FLAME results promising, however:
• ? Internal validity (Random error)
– only 57 pts assigned fluoexetine vs 56 placebo
– Wide 95% CI of estimates (Independency OR = 3.8, 95% CI 1.2 to 10.7)
• ? External validity (generalisability)
We need to know:
• Does fluoxetine really work?
• Are the results generalisable to an Australian population?
• Do the benefits persist after treatment has ceased?
Assessment oF Fluoxetine IN sTroke recoverY
(AFFINITY) trial
Primary aim
1 ◦ To determine if taking fluoxetine, 20 mg, once
daily, for 6 months, started 2-15 days post
acute stroke improves participants’
neurological outcome (functional ability).
Secondary aims
2◦ To determine if fluoxetine…
– Improves at 6 months
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survival,
mood (PHQ-9),
cognitive function (TICSm),
HRQoL (SF-12),
– Reduces at 6 months
• fatigue (SF-36 vitality domain)
– Is safe
– Reduces the cost of health and social care
– Has persisting effects at 12 months on:
• functional ability, survival, mood, cognitive function, HRQoL, and
fatigue
Inclusion criteria
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Male or female
≥ 18 years of age
Clinical diagnosis of stroke; onset 2-15 days ago
Imaging consistent with ICH or ischaemic stroke
Neurological deficits at randomisation which
are severe enough to warrant Rx (pt or carer
perspective)
Exclusion criteria
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History of:
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Epileptic seizures
Bipolar disorders
Drug overdose
Attempted suicide
Allergy to fluoxetine
Current or recent (<5/52) Rx with MAOI or pimozide
Current or recent (<1/12) depression requiring Rx with SSRI
Current Rx with other antidepressants unless agree to discontinue on randomisation
Unlikely to be contactable or available for follow-up over 12 months
Unlikely to survive 12 months (e.g. life-threatening illness)
SAH (except if 2◦ to ICH)
Pregnant or breast feeding, female of child bearing age not on adequate contraception
Hepatic impairment (ALT < 120 U/L)
Renal impairment (Creatinine > 220 micromol/l)
Hyponatraemia (Sodium < 130mmol/L)
Trial recruitment and assessments:
from the patients’ perspective
• Approached by member of clinical
team
• Receive patient information leaflet
and verbal explanation
• They have time to consider whether
they wish to take part
• They, or their next of kin give consent
if wish to join the trial
• They provide information which is
entered into the trial database
Randomisation
• Web-based, central randomisation service
• Rx allocation ratio 1:1
• Stratified randomisation:
– Presence of a motor deficit
– Presence of aphasia
• (i.e. allocates each patients to the Rx that leads to the least
difference between the two groups with respect to these features)
Intervention
• Fluoxetine 20 mg/day or Placebo one/day
– Oral
– Double-blind
– 6 months
Outcome measures
• Primary: modified Rankin score at 6 months
• Secondary
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Adherence to medication
New clinical diagnosis of depression
Survival
Depression (PHQ 9; 9 questions)
Cognition (TICSm; 13 questions)
Fatigue (Vitality score of SF-36; 4 questions)
Resource use (3 questions)
Optional
– Overall health status: Stroke impact score (59 items, 8 domains)
– Health-related quality of life (SF 12; 12 questions)
Adverse effects
BMJ 2011; 343: d4551; d4660
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Stroke or TIA (HR 1.15; 95% CI: 1.05 to 1.26)
Myocardial infarction
Epileptic seizures (HR 1.80; 1.32 to 2.43)
Falls (HR 1.27; 1.20 to 1.35)
Fractures (HR 1.26; 1.15 to 1.37)
Hyponatraemia (HR 1.44; 1.19 to 1.75
Attempted suicide/self harm (HR 1.27; 0.97 to 1.66)
Upper GI bleeding (HR 1.22; 1.07 to 1.40)
Adverse effects of newer antidepressants and
suggested management.
BMJ 2012; 344: d8300.
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Adverse effect
Comment
Dizziness
< 10%
Management
Check BP standing and lying; symptoms may improve over time;
Decrease dose or change treatment. Ensure adequate fluid intake
Sedation
Not common
May be desirable; May improve over time.
Change time of dosing and treatment
Dry mouth
Probably dose related
Tolerance may develop; change treatment;
Sugarless gum or saliva substitutes
Sexual dysfunction
Common
Reduce dose, wait for improvement, switch to a different antidepressant, or
consider sildenafil
Insomnia
Common
Try to distinguish from insomnia caused by depression
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
Suicidal thoughts
Age < 30
Review often (within a week of starting Rx and until no longer needed).
No evidence that asking about suicide increases likelihood of self- harm.
Prescribe small amounts of medication.
Anxiety
Often when starting Rx
Consider using a benzodiazepine for no longer than two weeks
Hyponatraemia
A problem in the elderly
Check sodium before and after starting treatment
Consider changing to mirtazapine if it becomes problematic
Serotonin syndrome
Confusion/agitation,
Stop the antidepressant
Autonomic instability,and
Hydration, Rx of hyperthermia, and benzodiazepines
Neuromuscular hyperactivity Consider cyproheptadine or chlorpromazine in severe cases
Discontinuation syndrome
Decrease dose over four weeks. Warn the patient
Sample size calculations
• Expect % of independent participants (mRS 0-2) in
intervention group to:
– increase by 7.5% absolute percentage points (from 50% to 57.5%)
– increase by 15 relative percentage points,
– odds ratio of 1.35
• (cf. FLAME: OR = 3.8, 95%: CI 1.2 to 10.7)
Expected distributions of mRS scores at 6 months (end of fluoxetine)
mRS score
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Control group
0.10
0.20
0.20
0.15
0.10
0.10
0.15
Intervention group
0.13
0.24
0.21
0.14
0.09
0.08
0.12
Trial design:
Flow of participants and assessments
1,580 patients
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) assessment
Collaborators (UK FOCUS)
Prof Martin Dennis
Prof Gillian Mead
• Larger, similar trial
• FOCUS pilot phase
– Funded by The Stroke Association
– Protocol funded by NIHR Stroke Research Network
• FOCUS main phase
– Funding application to NIHR HTA
• Planned prospective meta-analysis
AFFINITY/FOCUS joint analyses
• 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.
We welcome interested collaborators
Back up
Management of depression
• Options
– Give fluoxetine 20mg od (but potentially ‘dilute’
treatment effect)
– Tricyclic antidepressant
– Mirtazipine: favoured by Allan House, literature
suggests interactions are uncommon and not
serious