Background:Fatigue is common in many long-term medical conditions. Interventions to date have largely been in single conditions. Objective:To conduct a mixed-methods evidence synthesis of the clinical and cost-effectiveness and acceptability of non-pharmacological interventions for fatigue in adults with long-term medical conditions. Methods:Randomised controlled trials, cost-effectiveness studies, or qualitative studies of non-pharmacological interventions for fatigue in long-term medical conditions where fatigue was either a criterion for inclusion, the primary target of the intervention, or the primary or coprimary outcome. Studies of post-infectious, post-traumatic, cancer-related or idiopathic fatigue were excluded. Information sources:Searches used the MEDical Literature Analysis and Retrieval System, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature, and American Psychological Association PsycInfo® (American Psychological Association, Washington, DC, USA) databases. We used systematic CLUSTER searching for qualitative studies and Epistemonikos for systematic reviews. Involvement of patients:We held three rounds of five focus groups involving people with fatigue in long-term conditions to ensure that assumptions in, and reporting of, the research had validity with the patient population. Risk of bias:Risk-of-bias assessment of all studies included in the network meta-analysis was undertaken using an adapted version 2 of the Cochrane risk-of-bias tool for randomised controlled trials. Synthesis of results:Clinical effectiveness evaluation used random effects network meta-analyses at three time points. The cost-effectiveness analysis involved a de novo analysis of interventions identified as clinically effective. The qualitative synthesis involved a thematic synthesis of primary studies of interventions and a mega-synthesis of reviews of patient experience of fatigue across different conditions. Focus groups were analysed by thematic analysis, and findings from all work packages were integrated in a final synthesis by the research team. Results:The clinical effectiveness review included 88 randomised controlled trials, involving 27 interventions, with 6636 participants included at end of treatment, 1849 in the short term and 2322 in the long term. Synthesis of results:Compared to usual care at long-term follow-up, cognitive-behavioural therapy-based interventions and physical activity promotion showed statistically significant reductions in fatigue (standardised mean difference -0.4, 95% credible interval -0.63 to -0.21, 9 studies; and -0.52, -0.86 to -0.18, 2 studies), respectively. Effective interventions provided positive net monetary benefit versus usual care, particularly when delivered in a group format, when valuing a quality-adjusted life-year at £20,000. Individuals vary in their experience of fatigue in ways that are not simply due to their medical condition, indicating that interventions need to be adaptable to individuals' experiences and capabilities. Discussion:The evidence base is relatively small, heterogeneous and includes studies at moderate to high risk of bias. More than half of the included trials were in multiple sclerosis. Interpretation:Interventions for fatigue that support people to increase physical activity or are based on cognitive-behavioural therapy are acceptable and effective in reducing fatigue in people with different long-term medical conditions, with the potential to be cost-effective. Based on the qualitative synthesis, we propose a three-stage component model for interventions. Future work:Future trials should focus on the feasibility and effectiveness of transdiagnostic fatigue services, fatigue interventions in multimorbidity, and investigations of emerging non-invasive stimulation interventions. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR154660.
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