Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Abstract

SummaryBackgroundResults of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.MethodsFOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.FindingsBetween Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.InterpretationFluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.FundingUK Stroke Association and NIHR Health Technology Assessment Programme.

Update on the EFFECTS study of fluoxetine for stroke recovery: a randomised controlled trial in Sweden

“…In fact, EFFECTS is now the largest ever stroke RCT conducted in Sweden. Further, EFFECTS is the second largest RCT of fluoxetine for stroke recovery after the FOCUS trial [8].…”

“…Data from EFFECTS will test the external validity of the FOCUS trial results and increase the precision of the estimates of the efficacy and safety of fluoxetine in ischaemic and haemorrhagic stroke. The planned individual patient data meta-analysis of EFFECTS, AFFINITY and FOCUS [8], as well as a subsequent update of the Cochrane systematic review [6] will likely give us a definitive answer as to whether fluoxetine has any role to play in stroke recovery.…”

“…This led us to develop a family of three large trials of fluoxetine for stroke recovery [7]: EFFECTS (Efficacy oF Fluoxetinea randomisEd Controlled Trial in Stroke), AFFINITY (The Assessment oF FluoxetINe In sTroke recovery) and FOCUS (Fluoxetine Or Control Under Supervision) [8]. Each trial was funded and run separately with oversight from its own Steering Committee.…”

“…The FOCUS trial (N = 3127) is the only trial to date to have finished and published its results [8]. For the primary outcome measure, the distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0.95 [95% CI 0.84-1.08]; p = 0.44).…”

Antidepressant Use for Improving Functional Ischemic Stroke Outcomes

“…Subsequent meta-analyses of additional placebo-controlled trials post-stroke found similar results to the FLAME trial, correlating fluoxetine treatment with greater independent living functions (mRS of 0-2). These collective results were called into question with the recent "Effects of fluoxetine on functional outcomes after acute stroke" (FOCUS) trial, which did not find significant improvements in functional outcomes among patients given 20 mg fluoxetine daily over six months of follow-up [3]. The trial did, however, find a decreased incidence of depression among patients receiving fluoxetine and increased incidence of bone fractures [3].…”