Interventions for post‐stroke fatigue

Simiao Wu, Mansur A Kutlubaev, Ho‐Yan Y Chun, Eileen Cowey, Alex Pollock, Malcolm R Macleod, Martin Dennis, Elizabeth Keane, Michael Sharpe, Gillian E Mead

Post-stroke fatigue (PSF) is a common and distressing problem after stroke. The best ways to prevent or treat PSF are uncertain. Several different interventions can be argued to have a rational basis. To determine whether, among people with stroke, any intervention reduces the proportion of people with fatigue, fatigue severity, or both; and to determine the effect of intervention on health-related quality of life, disability, dependency and death, and whether such intervention is cost effective. We searched the Cochrane Stroke Group Trials Register (last searched May 2014), Cochrane Central Register of Controlled Trials (The Cochrane Library, 2014, Issue 4), MEDLINE (1950 to May 2014), EMBASE (1980 to May 2014), CINAHL (1982 to May 2014), AMED (1985 to May 2014), PsycINFO (1967 to May 2014), Digital Dissertations (1861 to May 2014), British Nursing Index (1985 to May 2014), PEDro (searched May 2014) and PsycBITE (searched May 2014). We also searched four ongoing trials registries, scanned reference lists, performed citation tracking of included trials and contacted experts. Two review authors independently scrutinised all titles and abstracts and excluded obviously irrelevant studies. We obtained the full texts for potentially relevant studies and three review authors independently applied the inclusion criteria. We included randomised controlled trials (RCTs) that compared an intervention with a control, or compared different interventions for PSF. Two review authors independently extracted data and assessed risk of bias for each included trial. The primary outcomes were severity of fatigue, or proportion of people with fatigue after treatment. We performed separate analyses for trials investigating efficacy in treating PSF, trials investigating efficacy in preventing PSF and trials not primarily investigating efficacy in PSF but which reported fatigue as an outcome. We pooled results from trials that had a control arm. For trials that compared different potentially active interventions without a control arm, we performed analyses for individual trials without pooling.We calculated standardised mean difference (SMD) as the effect size for continuous outcomes and risk ratio (RR) for dichotomous outcomes. We pooled the results using a random-effects model and assessed heterogeneity using the I(2) statistic. We performed separate subgroup analyses for pharmacological and non-pharmacological interventions. We also performed sensitivity analyses to assess the influence of methodological quality. We retrieved 12,490 citations, obtained full texts for 58 studies and included 12 trials (three from the 2008 search and nine from the 2014 search) with 703 participants. Eight trials primarily investigated the efficacy in treating PSF, of which six trials with seven comparisons provided data suitable for meta-analysis (five pharmacological interventions: fluoxetine, enerion, (-)-OSU6162, citicoline and a combination of Chinese herbs; and two non-pharmacological interventions: a fatigue education programme and a mindfulness-based stress reduction programme). The fatigue severity was lower in the intervention groups than in the control groups (244 participants, pooled SMD -1.07, 95% confidence interval (CI) -1.93 to -0.21), with significant heterogeneity between trials (I(2) = 87%, degrees of freedom (df) = 6, P value < 0.00001). The beneficial effect was not seen in trials that had used adequate allocation concealment (two trials, 89 participants, SMD -0.38, 95% CI -0.80 to 0.04) or trials that had used adequate blinding of outcome assessors (four trials, 198 participants, SMD -1.10, 95% CI -2.31 to 0.11).No trial primarily investigated the efficacy in preventing PSF.Four trials (248 participants) did not primarily investigate the efficacy on fatigue but other symptoms after stroke. None of these interventions showed any benefit on reducing PSF, which included tirilazad mesylate, continuous positive airway pressure for sleep apnoea, antidepressants and a self management programme for recovery from chronic diseases. There was insufficient evidence on the efficacy of any intervention to treat or prevent fatigue after stroke. Trials to date have been small and heterogeneous, and some have had a high risk of bias. Some of the interventions described were feasible in people with stroke, but their efficacy should be investigated in RCTs with a more robust study design and adequate sample sizes.