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Systematic reviews that collate data about the relative effects of multiple interventions via network meta-analysis are highly informative for decision-making purposes. A network meta-analysis provides two types of findings for a specific outcome: the relative treatment effect for all pairwise comparisons, and a ranking of the treatments. It is important to consider the confidence with which these two types of results can enable clinicians, policy makers and patients to make informed decisions. We propose an approach to determining confidence in the output of a network meta-analysis. Our proposed approach is based on methodology developed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group for pairwise meta-analyses. The suggested framework for evaluating a network meta-analysis acknowledges (i) the key role of indirect comparisons (ii) the contributions of each piece of direct evidence to the network meta-analysis estimates of effect size; (iii) the importance of the transitivity assumption to the validity of network meta-analysis; and (iv) the possibility of disagreement between direct evidence and indirect evidence. We apply our proposed strategy to a systematic review comparing topical antibiotics without steroids for chronically discharging ears with underlying eardrum perforations. The proposed framework can be used to determine confidence in the results from a network meta-analysis. Judgements about evidence from a network meta-analysis can be different from those made about evidence from pairwise meta-analyses.

To develop ROBIS, a new tool for assessing the risk of bias in systematic reviews (rather than in primary studies). We used four-stage approach to develop ROBIS: define the scope, review the evidence base, hold a face-to-face meeting, and refine the tool through piloting. ROBIS is currently aimed at four broad categories of reviews mainly within health care settings: interventions, diagnosis, prognosis, and etiology. The target audience of ROBIS is primarily guideline developers, authors of overviews of systematic reviews (“reviews of reviews”), and review authors who might want to assess or avoid risk of bias in their reviews. The tool is completed in three phases: (1) assess relevance (optional), (2) identify concerns with the review process, and (3) judge risk of bias. Phase 2 covers four domains through which bias may be introduced into a systematic review: study eligibility criteria; identification and selection of studies; data collection and study appraisal; and synthesis and findings. Phase 3 assesses the overall risk of bias in the interpretation of review findings and whether this considered limitations identified in any of the phase 2 domains. Signaling questions are included to help judge concerns with the review process (phase 2) and the overall risk of bias in the review (phase 3); these questions flag aspects of review design related to the potential for bias and aim to help assessors judge risk of bias in the review process, results, and conclusions. ROBIS is the first rigorously developed tool designed specifically to assess the risk of bias in systematic reviews.

AbstractObjectiveTo compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation.DesignSystematic review, network meta-analysis, and cost effectiveness analysis.Data sourcesMedline, PreMedline, Embase, and The Cochrane Library.Eligibility criteria for selecting studiesPublished randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation.Results23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin.ConclusionsThe network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis.Systematic review registrationPROSPERO CRD 42013005324.

Cognitive-behavioural therapy (CBT) is an effective treatment for depressed adults. CBT interventions are complex, as they include multiple content components and can be delivered in different ways. We compared the effectiveness of different types of therapy, different components and combinations of components and aspects of delivery used in CBT interventions for adult depression. We conducted a systematic review of randomised controlled trials in adults with a primary diagnosis of depression, which included a CBT intervention. Outcomes were pooled using a component-level network meta-analysis. Our primary analysis classified interventions according to the type of therapy and delivery mode. We also fitted more advanced models to examine the effectiveness of each content component or combination of components. We included 91 studies and found strong evidence that CBT interventions yielded a larger short-term decrease in depression scores compared to treatment-as-usual, with a standardised difference in mean change of −1.11 (95% credible interval −1.62 to −0.60) for face-to-face CBT, −1.06 (−2.05 to −0.08) for hybrid CBT, and −0.59 (−1.20 to 0.02) for multimedia CBT, whereas wait list control showed a detrimental effect of 0.72 (0.09 to 1.35). We found no evidence of specific effects of any content components or combinations of components. Technology is increasingly used in the context of CBT interventions for depression. Multimedia and hybrid CBT might be as effective as face-to-face CBT, although results need to be interpreted cautiously. The effectiveness of specific combinations of content components and delivery formats remain unclear. Wait list controls should be avoided if possible.

How can policy makers decide which of five treatments is the best? Standard meta-analysis provides little help but evidence based decisions are possible

Public health and health service interventions are typically complex: they are multifaceted, with impacts at multiple levels and on multiple stakeholders. Systematic reviews evaluating the effects of complex health interventions can be challenging to conduct. This paper is part of a special series of papers considering these challenges particularly in the context of WHO guideline development. We outline established and innovative methods for synthesising quantitative evidence within a systematic review of a complex intervention, including considerations of the complexity of the system into which the intervention is introduced. We describe methods in three broad areas: non-quantitative approaches, including tabulation, narrative and graphical approaches; standard meta-analysis methods, including meta-regression to investigate study-level moderators of effect; and advanced synthesis methods, in which models allow exploration of intervention components, investigation of both moderators and mediators, examination of mechanisms, and exploration of complexities of the system. We offer guidance on the choice of approach that might be taken by people collating evidence in support of guideline development, and emphasise that the appropriate methods will depend on the purpose of the synthesis, the similarity of the studies included in the review, the level of detail available from the studies, the nature of the results reported in the studies, the expertise of the synthesis team and the resources available.

Some have suggested the quality of reporting of network meta-analyses (a technique used to synthesize information to compare multiple interventions) is sub-optimal. We sought to review information addressing this claim. To conduct an overview of existing evaluations of quality of reporting in network meta-analyses and indirect treatment comparisons, and to compile a list of topics which may require detailed reporting guidance to enhance future reporting quality. An electronic search of Medline and the Cochrane Registry of methodologic studies (January 2004-August 2013) was performed by an information specialist. Studies describing findings from quality of reporting assessments were sought. Screening of abstracts and full texts was performed by two team members. Descriptors related to all aspects of reporting a network meta-analysis were summarized. We included eight reports exploring the quality of reporting of network meta-analyses. From past reviews, authors found several aspects of network meta-analyses were inadequately reported, including primary information about literature searching, study selection, and risk of bias evaluations; statement of the underlying assumptions for network meta-analysis, as well as efforts to verify their validity; details of statistical models used for analyses (including information for both Bayesian and Frequentist approaches); completeness of reporting of findings; and approaches for summarizing probability measures as additional important considerations. While few studies were identified, several deficiencies in the current reporting of network meta-analyses were observed. These findings reinforce the need to develop reporting guidance for network meta-analyses. Findings from this review will be used to guide next steps in the development of reporting guidance for network meta-analysis in the format of an extension of the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) Statement.

Because NMA pools the relative treatment effects estimated across RCTs, within-trial randomisation is preserved. [...]Bayesian NMAs are more commonly used as they naturally produce ranking and probability outputs useful for decision-making and allow for greater flexibility in the models fitted.10 For example, a ‘class model’ can be used where interventions that have a similar mode of action (ie, belong to the same ‘class’) are assumed to have similar, but not identical, effects compared with the reference treatment as used in the tocolytics example13 14 (figure 2 shows the networks at class level). Conversely, prostaglandin inhibitors were ranked first out of all seven treatment classes and had a 74% probability of being the most effective treatment and a 97% probability of being in the top three treatment classes to increase EGA.Table 3 Posterior rank statistics and probabilities for the outcome EGA at delivery Interventions Rank statistics Probabilities Mean Median 95% CrI Best Top 3 Placebo/control 6.74 7 (6 to 7) 0.00 0.00 Prostaglandin inhibitors 1.38 1 (1 to 4) 0.74 0.97 Magnesium sulfate 4.26 4 (2 to 6) 0.01 0.28 Betamimetics 4.48 5 (2 to 6) 0.00 0.16 Calcium channel blockers 2.84 3 (1 to 5) 0.07 0.76 Nitrates 3.04 3 (1 to 6) 0.13 0.65 Oxytocin receptor blockers 5.27 6 (1 to 7) 0.05 0.19 An alternative way of reporting ranks is to consider the cumulative probabilities using the surface under the cumulative ranking curve (SUCRA),25 which transforms the cumulative probabilities into a single value between 0 and 1, where a larger value indicates the more effective treatment. Joint funding (MR/KO232331/1) from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the Welsh Government and the Wellcome Trust, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged.

•Psychological factors have been show to alter the human immune response to vaccines.•We explore if psychological interventions can enhance the immune response to vaccines.•Trial results suggest such interventions may improve antibody responses to vaccines.•However, intervention effects varied between outcome measures and over time. The effectiveness of vaccines is known to be altered by a range of psychological factors. We conducted a systematic review to evaluate the effects of psychological interventions on the ability of vaccines to protect against disease, as measured by antibody responses. Electronic databases (EMBASE, Medline, PsychINFO, CINAHL) were searched from their inception to 6th February 2018. The search yielded 9 eligible trials conducted with 1603 participants and four broad categories of intervention: meditation/mindfulness (n = 3), massage (n = 3), expressive writing (n = 2) and cognitive behavioural stress management (n = 1). Some evidence of benefit on the antibody response to vaccination was observed in 6/9 of all trials and in 4/7 of randomised controlled trials. However, effects on antibody levels were often mixed, with only 3 of 6 trials showing benefit demonstrating an improvement in all antibody outcomes and at all time points assessed. Trials demonstrating benefit also provided direct or indirect evidence of adequate adherence with the intervention; and in 50% of these trials, there was also evidence that the intervention was effective in changing the mediating psychological constructs targeted by the intervention. This literature is characterised by considerable heterogeneity in terms of intervention type, vaccine type, age of participants and the temporal relationship between vaccination and intervention. We conclude that there is early evidence to suggest that psychological interventions may enhance the antibody response to vaccination. However, the effects are inconsistent, with the greatest likelihood of benefit seen in trials evidencing adequate adherence with the intervention. Future work would benefit from rigorous intervention development that focuses on achieving adequate adherence and large well-controlled randomised trials with a focus on an agreed set of outcomes.

Background Engagement in multiple substance use risk behaviours such as tobacco smoking, alcohol and drug use during adolescence can result in adverse health and social outcomes. The impact of interventions that address multiple substance use risk behaviours, and the differential impact of universal versus targeted approaches, is unclear given findings from systematic reviews have been mixed. Our objective was to assess effects of interventions targeting multiple substance use behaviours in adolescents. Methods Eight databases were searched to October 2019. Individual and cluster randomised controlled trials were included if they addressed two or more substance use behaviours in individuals aged 8-25 years. Data were pooled in random-effects meta-analyses, reported by intervention and setting. Quality of evidence was assessed using GRADE. Heterogeneity was assessed using between-study variance, τ2 and Ι 2 , and the p -value of between-study heterogeneity statistic Q. Sensitivity analyses were undertaken using the highest and lowest intra-cluster correlation coefficient (ICC). Results Of 66 included studies, most were universal ( n =52) and school-based ( n =41). We found moderate quality evidence that universal school-based interventions are likely to have little or no short-term benefit (up to 12 months) in relation to alcohol use (OR 0.94, 95% CI: 0.84, 1.04), tobacco use (OR 0.98, 95% CI: 0.83, 1.15), cannabis use (OR 1.06, 95% CI: 0.86, 1.31) and other illicit drug use (OR 1.09, 95% CI: 0.85, 1.39). For targeted school-level interventions, there was low quality evidence of no or a small short-term benefit: alcohol use (OR 0.90, 95% CI: 0.74-1.09), tobacco use (OR 0.86, 95% CI: 0.66, 1.11), cannabis use (OR 0.84, 95% CI: 0.66-1.07) and other illicit drug use (OR 0.79, 95% CI 0.62-1.02). There were too few family-level ( n =4), individual-level ( n =2) and combination level ( n =5) studies to draw confident conclusions. Sensitivity analyses of ICC did not change results. Conclusions There is low to moderate quality evidence that universal and targeted school-level interventions have no or a small beneficial effect for preventing substance use multiple risk behaviours in adolescents. Higher quality trials and study reporting would allow better evidence syntheses, which is needed given small benefit of universal interventions can have high public health benefit. Trial registration Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD011374. DOI: 10.1002/14651858.CD011374.