affinity trial a ssessment o f f luoxet in e i n s t roke recover y
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/1.jpg)
AFFINITY trialAssessment 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
![Page 2: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/2.jpg)
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?
![Page 3: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/3.jpg)
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
![Page 4: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/4.jpg)
FLAME trial: Modified Rankin score at 90 daysmRS 0-2: 26.3% fluoxetine vs 8.9% placebo
OR = 3.8, 95% CI 1.2 to 10.7
![Page 5: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/5.jpg)
FLAME trial: Fugl Meyer Motor scoresAdjusted mean Fugl-Meyer motor scale (FMMS) total scores at days 0, 30, and 90
Error bars represent 95% CI
![Page 6: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/6.jpg)
![Page 7: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/7.jpg)
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?
![Page 8: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/8.jpg)
Adverse outcomes of SSRIs in older peopleBMJ 2011; 343: d4551
• Design: Population-based cohort study• Setting: 570 general practices in UK• Subjects: 60,746 people > 65 years with depression• Follow-up: 364 days median (91-1029 IQR)• Outcomes: Death, attempted suicide/self harm, stroke,
MI, falls, fractures, upper GI bleeding, seizures, hyponatraemia
• Analysis: Adjusted hazard ratios of outcomes with SSRIs vs when antidepressants not used.
![Page 9: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/9.jpg)
Adverse outcomes of SSRIs in older peopleBMJ 2011; 343: d4551
Outcome HR (95% CI) Absolute risk (%/yr) (Fluoxetine vs no antidepressant)
• Mortality 1.54 (1.48-1.59) 4.4% (11.4% vs 7.0%)• Falls 1.66 (1.58-1.73) 2.1% (5.6% vs 3.5%)• Fractures 1.58 (1.48-1.68) 1.0% (2.8% vs 1.8%)• Stroke/TIA 1.17 (1.10-1.26) 0.4% (2.6% vs 2.2%)• MI 1.15 (1.04-1.27) 0.3% (1.3% vs 1.0%)• Attempted suicide/self-harm 2.16 (1.71-2.79) 0.3% (0.5% vs 0.2%)• Hyponatraemia 1.52 (1.33-1.75) 0.2% (0.5% vs 0.3%)• Upper GI bleed 1.27 (1.07-2.40) 0.1% (0.5% vs 0.4%)• Epilepsy/Seizures 1.83 (1.49-2.26) 0.1% (0.3% vs 0.2%)
![Page 10: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/10.jpg)
Assessment oF Fluoxetine IN sTroke recoverY (AFFINITY) trial
![Page 11: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/11.jpg)
Primary aim
1 ◦ To determine if :fluoxetine, 20 mg, once daily, started 2-15 days after acute stroke, andcontinued for 6 months, improves recovery & functional ability.
![Page 12: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/12.jpg)
Secondary aims
2◦ To determine if fluoxetine…– Improves at 6 months
• 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
![Page 13: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/13.jpg)
Inclusion criteria
• 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)
![Page 14: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/14.jpg)
Exclusion criteria
• History of:• 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)
![Page 15: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/15.jpg)
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 on-
line (www.affinitytrial.org) and randomisation code assigned
![Page 16: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/16.jpg)
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)
![Page 17: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/17.jpg)
Intervention
• Fluoxetine 20 mg/day or Placebo one/day– Oral– Double-blind– 6 months
![Page 18: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/18.jpg)
Adverse effects of newer antidepressants and suggested management.
BMJ 2012; 344: d8300.
Adverse effect Comment Management
• Dizziness < 10% 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 benzodiazepinesNeuromuscular hyperactivity Consider cyproheptadine or chlorpromazine in severe cases
• Discontinuation syndrome Decrease dose over four weeks. Warn the patient
![Page 19: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/19.jpg)
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
![Page 20: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/20.jpg)
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– 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)
![Page 21: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/21.jpg)
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 0 1 2 3 4 5 6Control 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
![Page 22: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/22.jpg)
Trial design:Flow of participants and assessments
3 month on-intervention assessment and dispensing
1,580 patients
Central randomisation 2 to 15 days post-stroke
Intervention group (n=790) Control group (n=790)
Informed consent and trial specific screen and baseline assessment
End of 6-month intervention assessment
1 month on-intervention assessment
6-month off-intervention (12 month) assessment
![Page 23: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/23.jpg)
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
![Page 24: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/24.jpg)
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.
![Page 25: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/25.jpg)
We welcome interested collaborators
![Page 26: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/26.jpg)
Disability at end of Rx
![Page 27: AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y](https://reader035.vdocuments.us/reader035/viewer/2022062322/56814909550346895db641f3/html5/thumbnails/27.jpg)
Disability at end of Rx, by depression or not at randomisation