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 and is it safe in elderly stroke pts?
• Are the results generalisable to an Australian population?
• Do the benefits persist after treatment has ceased?
Adverse outcomes of SSRIs in older people
BMJ 2011; 343: d4551
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Design:
Setting:
Subjects:
Follow-up:
Outcomes:
• Analysis:
Population-based cohort study
570 general practices in UK
60,746 people > 65 years with depression
364 days median (91-1029 IQR)
Death, attempted suicide/self harm, stroke, MI,
falls, fractures, upper GI bleeding, seizures,
hyponatraemia
Adjusted hazard ratios of outcomes with SSRIs vs
when antidepressants not used.
Adverse outcomes of SSRIs in older people
BMJ 2011; 343: d4551
Outcome
HR
(95% CI)
Absolute risk (%/yr)
(Fluoxetine vs no antidepressant)
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Mortality
Falls
Fractures
Stroke/TIA
MI
Attempted suicide/self-harm
Hyponatraemia
Upper GI bleed
Epilepsy/Seizures
1.54
1.66
1.58
1.17
1.15
2.16
1.52
1.27
1.83
(1.48-1.59)
(1.58-1.73)
(1.48-1.68)
(1.10-1.26)
(1.04-1.27)
(1.71-2.79)
(1.33-1.75)
(1.07-2.40)
(1.49-2.26)
4.4% (11.4% vs 7.0%)
2.1% (5.6% vs 3.5%)
1.0% (2.8% vs 1.8%)
0.4% (2.6% vs 2.2%)
0.3% (1.3% vs 1.0%)
0.3% (0.5% vs 0.2%)
0.2% (0.5% vs 0.3%)
0.1% (0.5% vs 0.4%)
0.1% (0.3% vs 0.2%)
Assessment oF Fluoxetine IN sTroke recoverY
(AFFINITY) trial
Primary aim
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.
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
Hyponatraemia (sodium < 130 mmol/l)
Hepatic impairment (ALT < 120 U/L)
Renal impairment (Creatinine > 220 micromol/L)
Trial recruitment and assessments:
from the patients’ perspective
• 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 online (www.affinitytrial.org) and randomisation
code assigned
Randomisation
• Web-based, central randomisation service
– http://affinitytrial.org
• Rx allocation ratio 1:1
• Minimisation algorithm:
– 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)
Intervention
• Fluoxetine 20 mg/day or Placebo one/day
– Oral
– Double-blind
– 6 months
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
Management of depression
• 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
Outcome measures
• Primary: simplified modified Rankin score at 6 months
– Stroke 2010; 41: 1048-50; Stroke 2011; 42: 2276-9; Stroke 2012; 43: 851-3.
• 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)
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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1
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6
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
Dr 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
Disability at end of Rx
Disability at end of Rx, by depression or not at randomisation