Twelve-Month Outcomes of the AFFINITY Trial of Fluoxetine for Functional Recovery After Acute Stroke: AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration

Abstract

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. REGISTRATION: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.

Cost-effective pharmacological approaches to poststroke recovery and enhanced neuroplasticity: highlighting discoveries both old and new!

“…It did show a decreased occurrence of depression in the fluoxetine group but an increased risk of bone fractures 6 . The AFFINITY (Assessment of fluoxetine in stroke recovery) trial showed similar results, as did another randomized controlled trial by the name of EFFECTS (Efficacy oF Fluoxetine – a randomisEed Controlled Trial in Stroke) 7 , 8 . Another phase 2 trial by the name of FLOW (fluoxetine opens window to improve motor recovery after stroke) is currently ongoing.…”

Cognitive Impairment After Ischemic and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association/American Stroke Association

“…The few studies that evaluated cognitive outcomes after acute stroke treatments suggest that intravenous thrombolysis and mechanical thrombectomy improve cognitive outcomes (compared with no treatment) but that these benefits are strongly associated with functional outcome. [140][141][142] Systematic reviews of dopamine agonists 143 and selective serotonin reuptake inhibitors [144][145][146] show no consistent beneficial effects on cognition after stroke. Individual small clinical trials have reported various pharmaceutical agents that may have a potential benefit on global cognition: neurotrophics (Cortexin), 147 peptides such as Cerebrolysin 148 and relaxin, 149 citicoline (cytidine-5ʹ-diphosphocholine), 150 and nitrates (glyceryl trinitrate).…”

Advances in Stroke Neurorehabilitation

“…However, a subsequent Cochrane systematic review, including 52 randomized trials, challenged these results, given the methodological limitations and heterogeneity of studies [102]. Therefore, three additional large randomized controlled clinical trials (AFFINITY: Assessment of Fluoxetine in Stroke Recovery, FOCUS: Fluoxetine or Control Under Supervision trials, and EFFECTS: Efficacy of Fluoxetine-a Randomised Controlled Trial in Stroke) were conducted and they did not show functional improvement at 6 months, measured by a modified Rankin Scale (mRS) [103][104][105]. The main issues with these trials include the heterogeneous study population with mainly mild stroke patients, which might decrease the sensitivity to detect group differences.…”