Interventions for post-stroke fatigue

BACKGROUND: 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. OBJECTIVES: 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. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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

Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.

BACKGROUND: Stroke is the major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression. Recently, small trials have demonstrated that SSRIs might improve recovery after stroke, even in people who are not depressed. Systematic reviews and meta-analyses are the least biased way to bring together data from several trials. Given the promising effect of SSRIs on stroke recovery seen in small trials, a systematic review and meta-analysis is needed. OBJECTIVES: To determine whether SSRIs improve recovery after stroke, and whether treatment with SSRIs was associated with adverse effects. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (August 2011), Cochrane Depression Anxiety and Neurosis Group Trials Register (November 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8), MEDLINE (from 1948 to August 2011), EMBASE (from 1980 to August 2011), CINAHL (from 1982 to August 2011), AMED (Allied and Complementary Medicine) (from 1985 to August 2011), PsycINFO (from 1967 to August 2011) and PsycBITE (Pyschological Database for Brain Impairment Treatment Efficacy) (March 2012). To identify further published, unpublished and ongoing trials we searched trials registers, pharmaceutical websites, reference lists, contacted experts and performed citation tracking of included studies. SELECTION CRITERIA: We included randomised controlled trials that recruited stroke survivors (ischaemic or haemorrhagic) at any time within the first year. The intervention was any SSRI, given at any dose, for any period. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. In order to be included, trials had to collect data on at least one of our primary (dependence and disability) or secondary (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early) outcomes. DATA COLLECTION AND ANALYSIS: We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. For trials in English, two review authors independently extracted data. For Chinese papers, one review author extracted data. We used standardised mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous effects, with their 95% confidence intervals (CIs). MAIN RESULTS: We identified 56 completed trials of SSRI versus control, of which 52 trials (4059 participants) provided data for meta-analysis. There were statistically significant benefits of SSRI on both of the primary outcomes: RR for reducing dependency at the end of treatment was 0.81 (95% CI 0.68 to 0.97) based on one trial, and for disability score, the SMD was 0.91 (95% CI 0.60 to 1.22) (22 trials involving 1343 participants) with high heterogeneity between trials (I(2) = 87%; P < 0.0001). For neurological deficit, depression and anxiety, there were statistically significant benefits of SSRIs. For neurological deficit score, the SMD was -1.00 (95% CI -1.26 to -0.75) (29 trials involving 2011 participants) with high heterogeneity between trials (I(2) = 86%; P < 0.00001). For dichotomous depression scores, the RR was 0.43 (95% CI 0.24 to 0.77) (eight trials involving 771 participants) with high heterogeneity between trials (I(2) = 77%; P < 0.0001). For continuous depression scores, the SMD was -1.91 (95% CI -2.34 to -1.48) (39 trials involving 2728 participants) with high heterogeneity between trials (I(2) = 95%; P < 0.00001). For anxiety, the SMD was -0.77 (95% CI -1.52 to -0.02) (eight trials involving 413 participants) with high heterogeneity between trials (I(2) = 92%; P < 0.00001). There was no statistically significant benefit of SSRI on cognition, death, motor deficits and leaving the trial early. For cognition, the SMD was 0.32 (95% CI -0.23 to 0.86), (seven trials involving 425 participants) with high heterogeneity between trials (I(2) = 86%; P < 0.00001). The RR for death was 0.76 (95% CI 0.34 to 1.70) (46 trials involving 3344 participants) with no heterogeneity between trials (I(2) = 0%; P = 0.85). For motor deficits, the SMD was -0.33 (95% CI -1.22 to 0.56) (two trials involving 145 participants). The RR for leaving the trial early was 1.02 (95% CI 0.86 to 1.21) in favour of control, with no heterogeneity between trials. There was a non-significant excess of seizures (RR 2.67; 95% CI 0.61 to 11.63) (seven trials involving 444 participants), a non-significant excess of gastrointestinal side effects (RR 1.90; 95% CI 0.94 to 3.85) (14 trials involving 902 participants) and a non-significant excess of bleeding (RR 1.63; 95% CI 0.20 to 13.05) (two trials involving 249 participants) in those allocated SSRIs. Data were not available on quality of life, fatigue or healthcare costs.There was no clear evidence from subgroup analyses that one SSRI was consistently superior to another, or that time since stroke or depression at baseline had a major influence on effect sizes. Sensitivity analyses suggested that effect sizes were smaller when we excluded trials at high or unclear risk of bias.Only eight trials provided data on outcomes after treatment had been completed; the effect sizes were generally in favour of SSRIs but CIs were wide. AUTHORS' CONCLUSIONS: SSRIs appeared to improve dependence, disability, neurological impairment, anxiety and depression after stroke, but there was heterogeneity between trials and methodological limitations in a substantial proportion of the trials. Large, well-designed trials are now needed to determine whether SSRIs should be given routinely to patients with stroke

Interventions for improving upper limb function after stroke

Background: Improving upper limb function is a core element of stroke rehabilitation needed to maximise patient outcomes and reduce disability. Evidence about effects of individual treatment techniques and modalities is synthesised within many reviews. For selection of effective rehabilitation treatment, the relative effectiveness of interventions must be known. However, a comprehensive overview of systematic reviews in this area is currently lacking. Objectives: To carry out a Cochrane overview by synthesising systematic reviews of interventions provided to improve upper limb function after stroke. Methods: Search methods: We comprehensively searched the Cochrane Database of Systematic Reviews; the Database of Reviews of Effects; and PROSPERO (an international prospective register of systematic reviews) (June 2013). We also contacted review authors in an effort to identify further relevant reviews. Selection criteria: We included Cochrane and non‐Cochrane reviews of randomised controlled trials (RCTs) of patients with stroke comparing upper limb interventions with no treatment, usual care or alternative treatments. Our primary outcome of interest was upper limb function; secondary outcomes included motor impairment and performance of activities of daily living. When we identified overlapping reviews, we systematically identified the most up‐to‐date and comprehensive review and excluded reviews that overlapped with this. Data collection and analysis: Two overview authors independently applied the selection criteria, excluding reviews that were superseded by more up‐to‐date reviews including the same (or similar) studies. Two overview authors independently assessed the methodological quality of reviews (using a modified version of the AMSTAR tool) and extracted data. Quality of evidence within each comparison in each review was determined using objective criteria (based on numbers of participants, risk of bias, heterogeneity and review quality) to apply GRADE (Grades of Recommendation, Assessment, Development and Evaluation) levels of evidence. We resolved disagreements through discussion. We systematically tabulated the effects of interventions and used quality of evidence to determine implications for clinical practice and to make recommendations for future research. Main results: Our searches identified 1840 records, from which we included 40 completed reviews (19 Cochrane; 21 non‐Cochrane), covering 18 individual interventions and dose and setting of interventions. The 40 reviews contain 503 studies (18,078 participants). We extracted pooled data from 31 reviews related to 127 comparisons. We judged the quality of evidence to be high for 1/127 comparisons (transcranial direct current stimulation (tDCS) demonstrating no benefit for outcomes of activities of daily living (ADLs)); moderate for 49/127 comparisons (covering seven individual interventions) and low or very low for 77/127 comparisons. Moderate‐quality evidence showed a beneficial effect of constraint‐induced movement therapy (CIMT), mental practice, mirror therapy, interventions for sensory impairment, virtual reality and a relatively high dose of repetitive task practice, suggesting that these may be effective interventions; moderate‐quality evidence also indicated that unilateral arm training may be more effective than bilateral arm training. Information was insufficient to reveal the relative effectiveness of different interventions. Moderate‐quality evidence from subgroup analyses comparing greater and lesser doses of mental practice, repetitive task training and virtual reality demonstrates a beneficial effect for the group given the greater dose, although not for the group given the smaller dose; however tests for subgroup differences do not suggest a statistically significant difference between these groups. Future research related to dose is essential. Specific recommendations for future research are derived from current evidence. These recommendations include but are not limited to adequately powered, high‐quality RCTs to confirm the benefit of CIMT, mental practice, mirror therapy, virtual reality and a relatively high dose of repetitive task practice; high‐quality RCTs to explore the effects of repetitive transcranial magnetic stimulation (rTMS), tDCS, hands‐on therapy, music therapy, pharmacological interventions and interventions for sensory impairment; and up‐to‐date reviews related to biofeedback, Bobath therapy, electrical stimulation, reach‐to‐grasp exercise, repetitive task training, strength training and stretching and positioning. Authors' conclusions: Large numbers of overlapping reviews related to interventions to improve upper limb function following stroke have been identified, and this overview serves to signpost clinicians and policy makers toward relevant systematic reviews to support clinical decisions, providing one accessible, comprehensive document, which should support clinicians and policy makers in clinical decision making for stroke rehabilitation. Currently, no high‐quality evidence can be found for any interventions that are currently used as part of routine practice, and evidence is insufficient to enable comparison of the relative effectiveness of interventions. Effective collaboration is urgently needed to support large, robust RCTs of interventions currently used routinely within clinical practice. Evidence related to dose of interventions is particularly needed, as this information has widespread clinical and research implications

The purpose of rating quality of evidence differs in an overview, as compared to guidelines or recommendations

No abstract available

An algorithm was developed to assign GRADE levels of evidence to comparisons within systematic reviews

Objectives: One recommended use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach is supporting quality assessment of evidence of comparisons included within a Cochrane overview of reviews. Within our overview, reviewers found that current GRADE guidance was insufficient to make reliable and consistent judgments. To support our ratings, we developed an algorithm to grade quality of evidence using concrete rules. Methods: Using a pragmatic, exploratory approach, we explored the challenges of applying GRADE levels of evidence and developed an algorithm to applying GRADE levels of evidence in a consistent and transparent approach. Our methods involved application of algorithms and formulas to samples of reviews, expert panel discussion, and iterative refinement and revision. Results: The developed algorithm incorporated four key criteria: number of participants, risk of bias of trials, heterogeneity, and methodological quality of the review. A formula for applying GRADE level of evidence from the number of downgrades assigned by the algorithm was agreed. Conclusion: Our algorithm which assigns GRADE levels of evidence using a set of concrete rules was successfully applied within our Cochrane overview. We propose that this methodological approach has implications for assessment of quality of evidence within future evidence syntheses