Assessing the effect of empathy-enhancing interventions in health education and training: a systematic review of randomised controlled trials

ObjectiveTo estimate the effect of empathy interventions in health education and training from randomised controlled trials (RCTs).MethodsMEDLINE, PsycINFO, EMBASE, CINAHL and Cochrane databases were searched from inception to June 2019 for RCTs investigating the effect of empathy-enhancing interventions in medical and healthcare students and professionals. Studies measuring any aspect of ‘clinical empathy’ as a primary or secondary outcome were included. Two reviewers extracted data and assessed the risk of bias of eligible studies using the Cochrane Risk of Bias Tool. Random effects meta-analyses of the impact of empathy training on participants’ empathy levels were performed.ResultsTwenty-six trials were included, with 22 providing adequate data for meta-analysis. An overall moderate effect on participant empathy postintervention (standardised mean difference 0.52, 95% CI 0.36 to 0.67) was found. Heterogeneity across trial results was substantial (I2=63%). Data on sustainability of effect was provided by 11 trials and found a moderate effect size for improved empathy up until 12 weeks (0.69, 95% CI 0.23 to 1.15), and a small but statistically significant effect size for sustainability at 12 weeks and beyond (standardised mean difference 0.34, 95% CI 0.11 to 0.57). In total, 15 studies were considered to be either unclear or high risk of bias. The quality of evidence of included studies was low.ConclusionFindings suggest that empathy-enhancing interventions can be effective at cultivating and sustaining empathy with intervention specifics contributing to effectiveness. This review focuses on an important, growing area of medical education and provides guidance to those looking to develop effective interventions to enhance empathy in the healthcare setting. Further high-quality trials are needed that include patient-led outcome assessments and further evaluate the long-term sustainability of empathy training.Protocol registration numberPROSPERO (CRD42019126843).

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Comparative efficacy and safety of interventions for treating head lice: a protocol for systematic review and network meta-analysis

BMJ Paediatrics Open ◽

10.1136/bmjpo-2021-001129 ◽

2021 ◽

Vol 5 (1) ◽

pp. e001129

Author(s):

Bill Stevenson ◽

Wubshet Tesfaye ◽

Julia Christenson ◽

Cynthia Mathew ◽

Solomon Abrha ◽

...

Keyword(s):

Systematic Review ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Grey Literature ◽

Risk Of Bias ◽

Controlled Trials ◽

Head Lice ◽

Efficacy And Safety ◽

Randomised Controlled ◽

Meta Analyses

BackgroundHead lice infestation is a major public health problem around the globe. Its treatment is challenging due to product failures resulting from rapidly emerging resistance to existing treatments, incorrect treatment applications and misdiagnosis. Various head lice treatments with different mechanism of action have been developed and explored over the years, with limited report on systematic assessments of their efficacy and safety. This work aims to present a robust evidence summarising the interventions used in head lice.MethodThis is a systematic review and network meta-analysis which will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for network meta-analyses. Selected databases, including PubMed, Embase, MEDLINE, Web of Science, CINAHL and Cochrane Central Register of Controlled Trials will be systematically searched for randomised controlled trials exploring head lice treatments. Searches will be limited to trials published in English from database inception till 2021. Grey literature will be identified through Open Grey, AHRQ, Grey Literature Report, Grey Matters, ClinicalTrials.gov, WHO International Clinical Trials Registry and International Standard Randomised Controlled Trials Number registry. Additional studies will be sought from reference lists of included studies. Study screening, selection, data extraction and assessment of methodological quality will be undertaken by two independent reviewers, with disagreements resolved via a third reviewer. The primary outcome measure is the relative risk of cure at 7 and 14 days postinitial treatment. Secondary outcome measures may include adverse drug events, ovicidal activity, treatment compliance and acceptability, and reinfestation. Information from direct and indirect evidence will be used to generate the effect sizes (relative risk) to compare the efficacy and safety of individual head lice treatments against a common comparator (placebo and/or permethrin). Risk of bias assessment will be undertaken by two independent reviewers using the Cochrane Risk of Bias tool and the certainty of evidence assessed using the Grading of Recommendations, Assessment, Development and Evaluations guideline for network meta-analysis. All quantitative analyses will be conducted using STATA V.16.DiscussionThe evidence generated from this systematic review and meta-analysis is intended for use in evidence-driven treatment of head lice infestations and will be instrumental in informing health professionals, public health practitioners and policy-makers.PROSPERO registration numberCRD42017073375.

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A Systematic Review of Cost-Effectiveness Analyses Alongside Randomised Controlled Trials of Acupuncture

Acupuncture in Medicine ◽

10.1136/acupmed-2012-010178 ◽

2012 ◽

Vol 30 (4) ◽

pp. 273-285 ◽

Cited By ~ 38

Author(s):

Song-Yi Kim ◽

Hyangsook Lee ◽

Younbyoung Chae ◽

Hi-Joon Park ◽

Hyejung Lee

Keyword(s):

Cost Effectiveness ◽

Usual Care ◽

Randomised Controlled Trials ◽

Risk Of Bias ◽

Economic Evaluations ◽

Controlled Trials ◽

German Studies ◽

Life Years ◽

Randomised Controlled ◽

The Cost

Objective To summarise the evidence on the cost-effectiveness of acupuncture. Methods We identified full economic evaluations such as cost-effectiveness analysis (CEA), cost-utility analysis (CUA) and cost-benefit analysis (CBA) alongside randomised controlled trials (RCTs) that assessed the consequences and costs of acupuncture for any medical condition. Eleven electronic databases were searched up to March 2011 without language restrictions. Eligible RCTs were assessed using the Cochrane criteria for risk of bias and a modified version of the checklist for economic evaluation. The general characteristics and the results of each economic analysis such as incremental cost-effectiveness ratios (ICERs) were extracted. Results Of 17 included studies, nine were CUAs that measured quality-adjusted life years (QALYs) and eight were CEAs that assessed effectiveness of acupuncture based on improvements in clinical symptoms. All CUAs showed that acupuncture with or without usual care was cost-effective compared with waiting list control or usual care alone, with ICERs ranging from ¢3011/QALY (dysmenorrhoea) to ¢22 298/QALY (allergic rhinitis) in German studies, and from £3855/QALY (osteoarthritis) to £9951/QALY (headache) in UK studies. In the CEAs, acupuncture was beneficial at a relatively low cost in six European and Asian studies. All CUAs were well-designed with a low risk of bias, but this was not the case for CEAs. Conclusions Overall, this review demonstrates the cost-effectiveness of acupuncture. Despite such promising results, any generalisation of these results needs to be made with caution given the diversity of diseases and the different status of acupuncture in the various countries.

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Comparative efficacy and acceptability of psychotherapies for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials

The British Journal of Psychiatry ◽

10.1192/bjp.2021.148 ◽

2021 ◽

pp. 1-13

Author(s):

Davide Papola ◽

Giovanni Ostuzzi ◽

Federico Tedeschi ◽

Chiara Gastaldon ◽

Marianna Purgato ◽

...

Keyword(s):

Systematic Review ◽

Panic Disorder ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Risk Of Bias ◽

Psychodynamic Therapy ◽

Controlled Trials ◽

First Line ◽

Short Term ◽

Randomised Controlled

Background Psychotherapies are the treatment of choice for panic disorder, but which should be considered as first-line treatment is yet to be substantiated by evidence. Aims To examine the most effective and accepted psychotherapy for the acute phase of panic disorder with or without agoraphobia via a network meta-analysis. Method We conducted a systematic review and network meta-analysis of randomised controlled trials (RCTs) to examine the most effective and accepted psychotherapy for the acute phase of panic disorder. We searched MEDLINE, Embase, PsycInfo and CENTRAL, from inception to 1 Jan 2021 for RCTs. Cochrane and PRISMA guidelines were used. Pairwise and network meta-analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO (CRD42020206258). Results We included 136 RCTs in the systematic review. Taking into consideration efficacy (7352 participants), acceptability (6862 participants) and the CINeMA confidence in evidence appraisal, the best interventions in comparison with treatment as usual (TAU) were cognitive–behavioural therapy (CBT) (for efficacy: standardised mean differences s.m.d. = −0.67, 95% CI −0.95 to −0.39; CINeMA: moderate; for acceptability: relative risk RR = 1.21, 95% CI −0.94 to 1.56; CINeMA: moderate) and short-term psychodynamic therapy (for efficacy: s.m.d. = −0.61, 95% CI −1.15 to −0.07; CINeMA: low; for acceptability: RR = 0.92, 95% CI 0.54–1.54; CINeMA: moderate). After removing RCTs at high risk of bias only CBT remained more efficacious than TAU. Conclusions CBT and short-term psychodynamic therapy are reasonable first-line choices. Studies with high risk of bias tend to inflate the overall efficacy of treatments. Results from this systematic review and network meta-analysis should inform clinicians and guidelines.

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The Effect of Vitamin D Supplementation on Glycaemic Control in Women with Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16101716 ◽

2019 ◽

Vol 16 (10) ◽

pp. 1716 ◽

Cited By ~ 10

Author(s):

Omorogieva Ojo ◽

Sharon M. Weldon ◽

Trevor Thompson ◽

Elisabeth J. Vargo

Keyword(s):

Diabetes Mellitus ◽

Vitamin D ◽

Glycaemic Control ◽

Gestational Diabetes ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Vitamin D Supplementation ◽

Risk Of Bias ◽

Controlled Trials ◽

Randomised Controlled

Vitamin D deficiency is highly prevalent amongst pregnant women and is linked to a range of adverse complications, including gestational diabetes. However, there is no consensus among researchers regarding the impact of vitamin D supplementation in alleviating adverse effects in gestational diabetes. The objective of this systematic review and meta-analysis was to determine whether supplementation of vitamin D given to women with gestational diabetes can promote glycaemic control. EMBASE and PubMed were searched up to November, 2018. The selection criteria included randomised controlled trials of the effect of vitamin D supplementation (1000–4762 IU/day) on pregnant women with gestational diabetes mellitus. Study data and outcome measures (fasting blood glucose, glycated haemoglobin and serum insulin) were extracted from included studies. Random-effects models were used for meta-analyses. Heterogeneity tests, and analysis of the risk of bias were conducted. Most of the studies were graded as having either low risk or moderate risk of bias although two studies had a high risk of bias in the areas of blinding of participants and personnel, and incomplete outcome data. On the other hand, the heterogeneity statistic (I2) ranged from 0–41% in the studies included. Five randomised controlled trials were selected for this review and meta-analysis (involving a total of 173 participants supplemented with vitamin D and 153 participants as control drawn from the studies). Vitamin D supplementation was associated with a decrease in fasting blood glucose by a mean of 0.46 mmol/L (−0.68, −0.25) (p < 0.001), glycated haemoglobin by a mean of 0.37% (−0.65, −0.08) (p < 0.01) and serum insulin concentration by mean of 4.10 µIU/mL (−5.50, −2.71) (p < 0.001) compared to controls. This review shows evidence that vitamin D supplementation has the potential to promote glycaemic control in women with Gestational Diabetes Mellitus (GDM). However, due to the limited number of studies in the meta-analysis, the conclusion should be interpreted with caution. Further studies are needed to fully understand the exact mechanism by which vitamin D influences glucose metabolism.

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Surgical interventions for women with stress urinary incontinence: systematic review and network meta-analysis of randomised controlled trials

BMJ ◽

10.1136/bmj.l1842 ◽

2019 ◽

pp. l1842 ◽

Cited By ~ 6

Author(s):

Mari Imamura ◽

Jemma Hudson ◽

Sheila A Wallace ◽

Graeme MacLennan ◽

Michal Shimonovich ◽

...

Keyword(s):

Urinary Incontinence ◽

Stress Urinary Incontinence ◽

Adverse Events ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Risk Of Bias ◽

Controlled Trials ◽

Surgical Interventions ◽

Randomised Controlled ◽

Meta Analyses

Abstract Objectives To compare the effectiveness and safety of surgical interventions for women with stress urinary incontinence. Design Systematic review and network meta-analysis. Eligibility criteria for selecting studies Randomised controlled trials evaluating surgical interventions for the treatment of stress urinary incontinence in women. Methods Identification of relevant randomised controlled trials from Cochrane reviews and the Cochrane Incontinence Specialised Register (searched May 2017), which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Medline In-Process, Medline Epub Ahead of Print, CINAHL, ClinicalTrials.gov, and WHO ICTRP. The reference lists of relevant articles were also searched. Primary outcomes were “cure” and “improvement” at 12 months, analysed by means of network meta-analyses, with results presented as the surface under the cumulative ranking curve (SUCRA). Adverse events were analysed using pairwise meta-analyses. Risk of bias was assessed using the Cochrane risk of bias tool. The quality of evidence for network meta-analysis was assessed using the GRADE approach. Results 175 randomised controlled trials assessing a total of 21 598 women were included. Most studies had high or unclear risk across all risk of bias domains. Network meta-analyses were based on data from 105 trials that reported cure and 120 trials that reported improvement of incontinence symptoms. Results showed that the interventions with highest cure rates were traditional sling, retropubic midurethral sling (MUS), open colposuspension, and transobturator MUS, with rankings of 89.4%, 89.1%, 76.7%, and 64.1%, respectively. Compared with retropubic MUS, the odds ratio of cure for traditional sling was 1.06 (95% credible interval 0.62 to 1.85), for open colposuspension was 0.85 (0.54 to 1.33), and for transobtrurator MUS was 0.74 (0.59 to 0.92). Women were also more likely to experience an improvement in their incontinence symptoms after receiving retropubic MUS or transobturator MUS compared with other surgical procedures. In particular, compared with retropubic MUS, the odds ratio of improvement for transobturator MUS was 0.76 (95% credible interval 0.59 to 0.98), for traditional sling was 0.69 (0.39 to 1.26), and for open colposuspension was 0.65 (0.41 to 1.02). Quality of evidence was moderate for retropubic MUS versus transobturator MUS and low or very low for retropubic MUS versus the other two interventions. Data on adverse events were available mainly for mesh procedures, indicating a higher rate of repeat surgery and groin pain but a lower rate of suprapubic pain, vascular complications, bladder or urethral perforation, and voiding difficulties after transobturator MUS compared with retropubic MUS. Data on adverse events for non-MUS procedures were sparse and showed wide confidence intervals. Long term data were limited. Conclusions Retropubic MUS, transobturator MUS, traditional sling, and open colposuspension are more effective than other procedures for stress urinary incontinence in the short to medium term. Data on long term effectiveness and adverse events are, however, limited, especially around the comparative adverse events profiles of MUS and non-MUS procedures. A better understanding of complications after surgery for stress urinary incontinence is imperative. Systematic review registration PROSPERO CRD42016049339.

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What to do with female drug-using offenders?

BJPsych Advances ◽

10.1192/apt.bp.116.016246 ◽

2016 ◽

Vol 22 (6) ◽

pp. 359-362

Author(s):

Keith J. B. Rix

Keyword(s):

Randomised Controlled Trials ◽

Criminal Activity ◽

Risk Of Bias ◽

Controlled Trials ◽

Policy Makers ◽

Arrest Rates ◽

Quality Research ◽

Randomised Controlled ◽

Unclear Risk ◽

Shed Light

SummaryFemale drug-using offenders are a large but under-researched and vulnerable population with specific needs. Only a handful of randomised controlled trials of interventions for this population are of sufficient quality to shed light on what might work to reduce their criminal activity and drug use, and interpretation of the results of most of these trials is limited by an ‘unclear’ risk of bias due to a lack of descriptive information. Better-quality research is needed to inform practitioners and policy makers. In the meantime, this month's Cochrane Corner review provides cautious support for the use of some psychosocial treatments, particularly if delivered in a gender-responsive way addressing issues of abuse and victimisation, in the expectation that re-imprisonment can be prevented, even if there is no proven effect on re-arrest rates and only uncertain effects on substance use.

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Risk of bias and reporting completeness of randomised controlled trials in burn care: protocol for a systematic review

BMJ Open ◽

10.1136/bmjopen-2019-033472 ◽

2019 ◽

Vol 9 (12) ◽

pp. e033472

Author(s):

Amber Young ◽

Barnaby C Reeves ◽

Hung-Yuan Cheng ◽

Jason Wasiak ◽

Duncan Muir ◽

...

Keyword(s):

Randomised Controlled Trials ◽

Treatment Strategies ◽

Risk Of Bias ◽

Therapeutic Interventions ◽

Cochrane Library ◽

Controlled Trials ◽

Free Text ◽

Burn Care ◽

Care Protocol ◽

Randomised Controlled

IntroductionBurn care represents a healthcare and economic burden to patients internationally. Choice of the most clinically effective treatment strategies requires evidence which is best obtained through high-quality randomised controlled trials (RCT). The number of published RCTs of burn care is increasing. However, trial quality and reporting standards are unclear. This study will assess the risk of bias and adequacy of reporting in recent burn care RCTs using tools endorsed by the Cochrane Collaboration.Methods and analysisA systematic literature review will be undertaken, assessing parallel group RCTs evaluating therapeutic interventions for patients with cutaneous burns. Literature searches will use Ovid Medline, Ovid Embase, Web of Science and the Cochrane Library. Separate searches for each database will include medical subject heading and free text terms including ‘burn’, ‘scald’, ‘thermal injury’ and ‘RCT’. Two reviewers will independently assess each study for inclusion. Risk of bias (RoB) will be assessed with the revised tool (RoB 2) and reporting completeness with the CONsolidated Standards of Reporting Trials (CONSORT) 2010 guidelines. We will report a narrative synthesis of all studies, including domain specific, and overall risk of bias for the primary outcome of each trial. Inter-rater agreement for RoB 2 will be reported using Fleiss’s Kappa. For adherence to the CONSORT guidelines, we will generate a completeness of reporting index for the ﬁve domains.Ethics and disseminationNo ethics approval is required because published documents will be used. Findings of the study will be disseminated in a peer-reviewed journal and presented at conferences.PROSPERO registration numberCRD42018111020.

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Efficacy and safety profile of statins in patients with cancer: a systematic review of randomised controlled trials

European Journal of Clinical Pharmacology ◽

10.1007/s00228-020-02967-0 ◽

2020 ◽

Vol 76 (12) ◽

pp. 1639-1651

Author(s):

John P. Thomas ◽

Yoon K. Loke ◽

Leo Alexandre

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Review ◽

Statin Therapy ◽

Safety Profile ◽

Randomised Controlled Trials ◽

Risk Of Bias ◽

Controlled Trials ◽

Efficacy And Safety ◽

Patients With Cancer ◽

Randomised Controlled

Abstract Purpose A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. Methods Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). Results Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30–1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. Conclusion The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research.

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Inequity in rehabilitation interventions after hip fracture: a systematic review

Age and Ageing ◽

10.1093/ageing/afz031 ◽

2019 ◽

Vol 48 (4) ◽

pp. 489-497 ◽

Cited By ~ 14

Author(s):

K J Sheehan ◽

L Fitzgerald ◽

S Hatherley ◽

C Potter ◽

S Ayis ◽

...

Keyword(s):

Nursing Home ◽

Cognitive Impairment ◽

Hip Fracture ◽

Randomised Controlled Trials ◽

Care Pathway ◽

Data Extraction ◽

Risk Of Bias ◽

Controlled Trials ◽

Eligibility Criteria ◽

Randomised Controlled

Abstract Objective to determine the extent to which equity factors contributed to eligibility criteria of trials of rehabilitation interventions after hip fracture. We define equity factors as those that stratify healthcare opportunities and outcomes. Design systematic search of MEDLINE, Embase, CINHAL, PEDro, Open Grey, BASE and ClinicalTrials.gov for randomised controlled trials of rehabilitation interventions after hip fracture published between 1 January 2008 and 30 May 2018. Trials not published in English, secondary prevention or new models of service delivery (e.g. orthogeriatric care pathway) were excluded. Duplicate screening for eligibility, risk of bias (Cochrane Risk of Bias Tool) and data extraction (Cochrane’s PROGRESS-Plus framework). Results twenty-three published, eight protocol, four registered ongoing randomised controlled trials (4,449 participants) were identified. A total of 69 equity factors contributed to eligibility criteria of the 35 trials. For more than 50% of trials, potential participants were excluded based on residency in a nursing home, cognitive impairment, mobility/functional impairment, minimum age and/or non-surgical candidacy. Where reported, this equated to the exclusion of 2,383 out of 8,736 (27.3%) potential participants based on equity factors. Residency in a nursing home and cognitive impairment were the main drivers of these exclusions. Conclusion the generalisability of trial results to the underlying population of frail older adults is limited. Yet, this is the evidence base underpinning current service design. Future trials should include participants with cognitive impairment and those admitted from nursing homes. For those excluded, an evidence-informed reasoning for the exclusion should be explicitly stated. PROSPERO CRD42018085930.

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Psychological interventions for positive symptoms in schizophrenia: protocol for a network meta-analysis of randomised controlled trials

BMJ Open ◽

10.1136/bmjopen-2017-019280 ◽

2018 ◽

Vol 8 (3) ◽

pp. e019280 ◽

Cited By ~ 5

Author(s):

Irene Bighelli ◽

Georgia Salanti ◽

Cornelia Reitmeir ◽

Sofia Wallis ◽

Corrado Barbui ◽

...

Keyword(s):

Randomised Controlled Trials ◽

Psychological Intervention ◽

Meta Analysis ◽

Risk Of Bias ◽

Evaluation Framework ◽

Sensitivity Analyses ◽

Controlled Trials ◽

Positive Symptoms ◽

Psychological Treatments ◽

Randomised Controlled

IntroductionThere is rising awareness that we need multidisciplinary approaches integrating psychological treatments for schizophrenia, but a comprehensive evidence based on their relative efficacy is lacking. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs) to rank psychological treatments for schizophrenia according to their efficacy, acceptability and tolerability.Methods and analysisWe will include all RCTs comparing a psychological treatment aimed at positive symptoms of schizophrenia with another psychological intervention or with a no treatment condition (waiting-list and treatment as usual). We will include studies on adult patients with schizophrenia, excluding specific subpopulations (eg, first-episode patients or patients with psychiatric comorbidities). Primary outcome will be the change in positive symptoms on a published rating scale. Secondary outcomes will be acceptability (dropout), change in overall and negative symptoms of schizophrenia, response, relapse, adherence, depression, quality of life, functioning and adverse events. Published and unpublished studies will be sought through database searches, trial registries and websites. Study selection and data extraction will be conducted by at least two independent reviewers. We will conduct random-effects NMA to synthesise all evidences for each outcome and obtain a comprehensive ranking of all treatments. NMA will be conducted in Stata and R within a frequentist framework. The risk of bias in studies will be evaluated using the Cochrane Risk of Bias tool and the credibility of the evidence will be evaluated using an adaptation of the Grading of Recommendations Assessment, Development and Evaluation framework to NMA, recommended by the Cochrane guidance. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings.Ethics and disseminationNo ethical issues are foreseen. Results from this study will be published in peer-reviewed journals and presented at relevant conferences.PROSPERO registration numberCRD42017067795.

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