Kate Hayward, PhD, PT

ESO-WSO 2020 Large Clinical Trials Webinar
Presentation: Assessment of fluoxetine in stroke recovery (AFFINITY): A randomised double-blind, placebo-controlled trial
Presenter: Prof. Graeme Hankey

There is much interest in identifying a drug to boost post-stroke recovery. Fluoxetine has received considerable attention since the FLAME trial,1 which demonstrated an improvement in motor recovery (Fugl Meyer Assessment) and functional independence (modified Rankin Scale) in acute stroke patients with moderate to severe hemiparesis.

To address uncertainty that existed concerning the use of fluoxetine,2 a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials were established: EFFECTS (also presented on the ESO-WSO large clinical trials webinar, Sweden), FOCUS (published in 2019,3 United Kingdom), and AFFINITY, which is the focus of this blog post. These international trials collectively aimed to determine whether the routine administration of fluoxetine (20mg daily) for six months after an acute stroke improves patients’ functional outcome.4

In AFFINITY, an international trial across 43 sites in Vietnam, Australia and New Zealand, the aim was to evaluate whether a 6-month course of fluoxetine was safe and effective, compared to placebo, for improving functional outcome (modified Rankin Scale) after recent stroke in an ethnically diverse population. Patients with a clinical diagnosis of recent stroke (2-15 days) and persistent neurological deficits (mRS ≥1) were randomized to 20mg fluoxetine per day (n=642) or matching placebo control capsule (n=638). Median NIHSS score of included patients was 6 (3-9).

The primary outcome (mRS) at 6 months was similar between groups: common odds ratio 0.94 (95% CI: 0.76 to 1.15), p=.53. The outcome was consistent across pre-specified subgroups and minimization variables. There was no difference in secondary outcomes including new depression, cognition or quality of life. There was a significant between group difference in mood (per the self-reported Stroke Impact Scale domain of Mood/Emotion), favouring the fluoxetine group. With regards to adverse events, there was an increase in epileptic seizures (1.56% vs 0.31%), fall with injury (3.12% vs 1.10%) and new bone fracture (2.96% vs 0.94%) in the fluoxetine group compared to the control group, respectively. There was no difference in death between groups.

Reflecting on the outcomes across the family of fluoxetine trials, it was consistently demonstrated that fluoxetine does not improve functional outcome (mRS) at 6 months (common odds ratio: FOCUS 0.95, EFFECTS 0.94, AFFINITY 0.94), but does increase rates of epileptic seizure, fall and fracture (e.g., fractures absolute increase: FOCUS 1.41%, EFFECTS 2.20%, AFFINITY 2.02%). In these studies, fluoxetine was not paired with a standardized program of physical, cognitive or social rehabilitation. This highlights that a drug alone does not improve recovery. The ability for fluoxetine to boost stroke recovery when paired with intensive rehabilitation such as exercise remains unknown. This is the question of the FLOW trial in progress in Canada (CTRN xxx). Pairing a drug with sufficient (i.e., high dose) rehabilitation such as exercise might be key to realizing greater functional benefit, whilst minimising adverse events such as falls and fracture.  


1.           Chollet F, Tardy J, Albucher JF, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011;10:123-130.

2.           Legg LA, Tilney R, Hsieh CF, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. The Cochrane database of systematic reviews. 2019;2019.

3.           FOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. Lancet. 2019;393:265-274.

4.           Graham C, Lewis S, Forbes J, et al. The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis. Trials. 2017;18:627.