For September 2020, we have selected the following two complementary papers:
Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial by the EFFECTS Trial Collaboration. Lancet Neurol. 2020 Aug;19(8):661-669. doi: 10.1016/S1474-4422(20)30219-2.
Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial by the AFFINITY Trial Collaboration. Lancet Neurol. 2020 Aug;19(8):651-660. doi: 10.1016/S1474-4422(20)30207-6.
By Antonella Macerollo
Both research papers of the month investigated whether administration of oral fluoxetine for 6 months after acute stroke improved functional outcome, in different population settings (EFFECTS and Assessment oF FluoxetINe InsTroke recoverY (AFFINITY) trials).
The EFFECTS trial was an investigator-led, multicentre, randomised, placebo-controlled, double-blind, parallel group trial enrolling 18 years or older patients between 2 and 15 days after stroke onset in 35 stroke and rehabilitation centres in Sweden.
Selection criteria were: clinical diagnosis of ischaemic or intracerebral haemorrhage; brain imaging consistent with intracerebral haemorrhage or ischaemic stroke; at least one persisting focal neurological deficit.
The randomisation was performed between Oct 20, 2014, and June 28, 2019 through a web-based system incorporating a minimisation algorithm to randomly assign (1:1) participants to receive oral fluoxetine 20 mg once daily (750 patients) or matching placebo capsules (750 patients) for 6 months.
The primary outcome was the modified Rankin Scale (mRS) score at 6 months as measure of functional status and data were available for 737 (98%) patients in the fluoxetine group and 742 (99%) patients in the placebo group.
Of note, there was no effect of fluoxetine on the distribution across mRS score categories (primary outcome) compared with placebo (adjusted common odds ratio 0·94 [95% CI 0·78 to 1·13]; p=0·42).
As secondary outcomes, the authors showed the following data: the proportion of patients with a new diagnosis of depression was lower with fluoxetine than with placebo (54 [7%] patients vs 81 [11%] patients); fluoxetine was associated with more bone fractures (28 [4%] vs 11 [2%]) and hyponatraemia (11 [1%] vs one [<1%]) at 6 months.
In conclusion, this study found no evidence of benefit of fluoxetine on functional outcomes after acute stroke.
Our second research paper of the month reports results of the AFFINITY study, which was a randomised, parallel-group, double-blind, placebo-controlled trial performed in 43 hospital stroke units in Australia (n=29), New Zealand (4) and Vietnam (10) between Jan 11, 2013 and June 30, 2019.
1280 patients were recruited in Australia (n=532), New Zealand (n=42) and Vietnam (n=706).
Selection criteria were: age ≥18 years; clinical diagnosis of acute stroke in the previous 2–15 days; brain imaging consistent with ischaemic or haemorrhagic stroke; a persisting neurological deficit causing a modified Rankin Scale (mRS) score of 1 or more.
Similarly to the previous study, patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily oral fluoxetine 20 mg capsules (642 patients) or matching placebo (638 patients) for 6 months.
This study had the same primary outcome of the EFFECTS trial- functional status measured by the mRS, at 6 months- which was available for 97% patients in the fluoxetine group and 99% in the placebo group.
This study confirmed that patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]) as well as bone fractures (3% vs 1%) than patients in the placebo group. In addition, this trial showed that epileptic seizures occurred more frequently in the fluoxetine group compared to the placebo group at 6 months follow up.
The results of this multicentre trial were concordant with EFFECTS and showed no evidence that fluoxetine improves functional outcomes after stroke. These two well-conducted trials have clarified previously conflicting results, and inform clinical practice.