A Reporting Tool for Adapted Guidelines in Health Care: The RIGHT-Ad@pt Checklist.

BACKGROUND: Adaptation of existing guidelines can be an efficient way to develop contextualized recommendations. Transparent reporting of the adaptation approach can support the transparency and usability of the adapted guidelines. OBJECTIVE: To develop an extension of the RIGHT (Reporting Items for practice Guidelines in HealThcare) statement for the reporting of adapted guidelines (including recommendations that have been adopted, adapted, or developed de novo), the RIGHT-Ad@pt checklist. DESIGN: A multistep process was followed to develop the checklist: establishing a working group, generating an initial checklist, optimizing the checklist (through an initial assessment of adapted guidelines, semistructured interviews, a Delphi consensus survey, an external review, and a final assessment of adapted guidelines), and approval of the final checklist by the working group. SETTING: International collaboration. PARTICIPANTS: A total of 119 professionals participated in the development process. MEASUREMENTS: Participants' consensus on items in the checklist. RESULTS: The RIGHT-Ad@pt checklist contains 34 items grouped in 7 sections: basic information (7 items); scope (6 items); rigor of development (10 items); recommendations (4 items); external review and quality assurance (2 items); funding, declaration, and management of interest (2 items); and other information (3 items). A user guide with explanations and real-world examples for each item was developed to provide a better user experience. LIMITATION: The RIGHT-Ad@pt checklist requires further validation in real-life use. CONCLUSION: The RIGHT-Ad@pt checklist has been developed to improve the reporting of adapted guidelines, focusing on the standardization, rigor, and transparency of the process and the clarity and explicitness of adapted recommendations. PRIMARY FUNDING SOURCE: None.

α-Blockers for uncomplicated ureteric stones: a clinical practice guideline.

OBJECTIVE: To develop an evidence-based recommendation concerning the use of α-blockers for uncomplicated ureteric stones based on an up-to-date Cochrane review, as the role of medical expulsive therapy for uncomplicated ureteric stones remains controversial in the light of new contradictory trial evidence. METHODS: We applied the Rapid Recommendations approach to guideline development, which represents an innovative approach by an international collaborative network of clinicians, researchers, methodologists and patient representatives seeking to rapidly respond to new, potentially practice-changing evidence with recommendations developed according to standards for trustworthy guidelines. RESULTS: The panel suggests the use of α-blockers in addition to standard care over standard care alone in patients with uncomplicated ureteric stones (weak recommendation based on low-quality evidence). The panel judged that the net benefit of α-blockers was small and that there was considerable uncertainty about patients' values and preferences. This means that the panel expects that most patients would choose treatment with α-blockers but that a substantial proportion would not. This recommendation applies to both patients in whom the presence of ureteric stones is confirmed by imaging, as well as patients in whom the diagnosis is made based on clinical grounds only. CONCLUSION: The Rapid Recommendations panel suggests the use of α-blockers for patients with ureteric stones. Shared decision-making is emphasised in making the final choice between the treatment options.

Pain intensity, neck pain and longer duration of complaints predict poorer outcome in patients with shoulder pain--a systematic review.

BACKGROUND: Shoulder complaints are common and have an unfavourable prognosis in many patients. Prognostic information is helpful for both patients and clinicians in managing the complaints. The research question was which factors have prognostic value on (un)favourable outcome in patients with shoulder complaints in primary care, secondary care and occupational settings. METHODS: Update of a systematic review in primary care, secondary care and occupational settings. RESULTS: Nine articles were published since the original review in 2004. Six were of high quality covering a wide variety of prognostic factors and outcome measures. Four studies were conducted in primary care settings. A best evidence synthesis, including the results of the previous systematic review on this topic shows that there is strong evidence that higher shoulder pain intensity, concomitant neck pain and a longer duration of symptoms predict poorer outcome in primary care settings. In secondary care populations, strong evidence was found for the association between greater disability and poorer outcome and between the existence of previous shoulder pain and poorer outcome. CONCLUSION: Clinicians may take these factors into account in the management of their patients. Those with a worse prognosis may be monitored more frequently and the treatment plan modified if complaints persist.

GRADE Notes 3: two approaches to assess industry sponsorship bias used by two Dutch guidelines organizations.

OBJECTIVE: Our objective is to develop a step-by-step approach for our institutes to evaluate the influence of the funding body 1. on risk of bias of an individual study and 2. on publication bias in reviews and meta-analyses for guidelines. STUDY DESIGN AND SETTING: Methodologists from guideline organizations in the Netherlands discussed the influence of the funding body in clinical trials researching interventions. Results were discussed in our organizations and presented at the Dutch GRADE Network. RESULTS: Two step-by-step approaches were developed to guide methodologists from our institutes in assessing the influence of the funding body 1. on risk of bias of an individual study and 2. on publication bias in reviews and meta-analyses for guidelines. For risk of bias, the involvement of the funding body in the study is checked as well as the direction of the effect. For publication bias, the exploration by the authors is evaluated, and any difference between industry-funded and non-funded studies in effect is checked. Guiding questions were proposed. CONCLUSION: The step-by-step approaches make the evaluation of the influence of the funding body more objective and transparent in our institutes. The developed approaches will also be brought forward to the Grading of Recommendations Assessment, Development and Evaluation working group.

A Delphi consensus checklist helped assess the need to develop rapid guideline recommendations.

BACKGROUND AND OBJECTIVES: We aimed to develop a checklist to aid guideline developers in determining which scientific or societal cause ("triggers") are relevant when considering to initiate a rapid recommendation procedure. METHODS: We conducted a two-round modified Delphi procedure with a panel of Dutch guideline experts, clinicians, and patient representatives. A previously conducted systematic literature review and semistructured interviews with four science journalists were used to generate a list of potential items. This item list was submitted to the panel for discussion, reduction and refinement into a checklist. RESULTS: Thirteen experts took part. Two questionnaires were completed in which participants scored an initial list of 64 items based on relevance. During two online meetings, the scores were discussed, irrelevant items were removed, and relevant items were reformulated into seven questions. The final "quickscan assessment of the need for a rapid recommendation" covers user perspective, scientific evidence, clinical relevance, clinical practice variation, applicability, quality of care and public health outcomes, and ethical/legal considerations. CONCLUSION: The quickscan aids guideline developers in systematically assessing whether a trigger expresses a valid need for developing a rapid recommendation. Future research could focus on the applicability and validity of the checklist within guideline development programs.

Trends over time in the size and quality of randomised controlled trials of interventions for chronic low-back pain.

PURPOSE: Previous reviews of randomised controlled trials (RCTs) for low-back pain (LBP) have failed to identify any positive trend in study quality with more recent years of publication. This study aimed to identify and describe trends over time in the study design characteristics and risk of bias in chronic LBP trials performed over the past 30 years. METHODS: One fifty-seven randomised trials of interventions for chronic LBP were extracted from recently published systematic reviews. The reviews included RCTs on physical and rehabilitation interventions, injection therapy and denervation procedures, complementary and alternative therapies and pharmacological interventions for chronic LBP. Study level data were extracted and analysed for trends associated with year of publication. RESULTS: Overall, the mean sample size in the RCTs was 141 (median 70; range 17-3093). There was a slight increase in the median number of risk of bias criteria fulfilled from trials published prior to 1995 to those published after 1996. The analysis showed that in more recent years RCTs of medical interventions were more likely to be successfully blinded than RCTs of non-medical interventions. CONCLUSIONS: The continuing uncertainty regarding the efficacy of many interventions for chronic LBP again stresses the need for large RCTs with low risk of bias. Further research is needed into specific risks of bias within the RCTs for chronic LBP and the effect they have on the plausibility of the results.

[Low back pain in daily clinical practice; article for education and training purposes]. / Lagerugpijn.

Low back pain is a very common reason for patient visits to a general practitioner or medical specialist. It is associated with a negative effect on daily living and high costs of care. The differential diagnosis of low back pain is extensive, and usually no specific cause can be identified. In such a case, we speak of non-specific low back pain. In this article, we present practical pointers to recognising specific causes of low back pain and answer some frequently-asked questions regarding the diagnosis and treatment of low back pain.

[Transparency in the body of evidence in medicine: developments of the GRADE method in the past ten years]. / Transparante wetenschappelijke onderbouwing van zorg.

GRADE ("Grading of Recommendations Assessment, Development and Evaluation") provides a transparent framework to evaluate scientific evidence and to develop healthcare recommendations. The GRADE method has been further developed, its application has been significantly broadened and over 100 organizations have endorsed GRADE. In this article, we give an overview of the most important methodological developments and discuss the basic principles. The transparent approach to make it easier for users of evidence to assess the judgments behind recommendations is not only applicable to the EBM domains but also to other disciplines. The methods developments show that GRADE is still evolving, and is constantly being further developed based on the latest methodological insights and users perspective. GRADE is not an instrument to determine the "true" certainty of the evidence. The value of applying GRADE is that judgments about the quality of evidence and the considerations behind recommendations are structured, transparent and explicit.

Interventions for Menière's disease: an umbrella systematic review.

OBJECTIVES: To systematically review the efficacy of interventions for Menière's disease (MD) to report clinical implications of the results and to identify areas for future valuable research. METHODS: In line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Abstracts (PRISMA-A) guideline, a systematic online database search was conducted in which MEDLINE (PubMed), Embase (Ovid) and CENTRAL (Cochrane Library) were searched until May 2021 in order to search for the efficacy of treatment was analysed in a systematic review. Systematic reviews (SRs) on treatments for MD were screened for eligible interventions. From these SRs, we included placebo randomised controlled trials (RCTs). A separate search was conducted to identify RCTs on treatment modalities that were systematically reviewed yet published after the conduction of these SRs. The primary outcome was control of vertigo as defined by the American guideline as published in 1995. The PRISMA-A and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to appraise and evaluate the certainty of evidence. RESULTS: We found five SRs from which 19 RCTs were extracted. Five RCTs were added by the separate search resulting in a total of 25 RCTs (n=1248) which evaluated the efficacy of betahistine dihydrochloride, intratympanic injections with gentamicin or steroids, endolymphatic sac surgery and pressure pulse therapy. Evidence on the efficacy of interventions for patients with MD is generally of low certainty. Betahistine (48 mg per day and 144 mg per day) and positive pressure therapy probably do not reduce MD symptoms when compared with placebo. Intratympanic injection with gentamicin or steroids, or treatment with endolymphatic surgery may reduce symptoms in MD when compared with placebo. CONCLUSIONS: A definite effective and well-tolerated therapy for MD has yet to be discovered and information on the natural course of disease is one of the biggest flaws in current research. PROSPERO REGISTRATION NUMBER: CRD4201502424.

A systematic review on the effectiveness of physical and rehabilitation interventions for chronic non-specific low back pain.

Low back pain (LBP) is a common and disabling disorder in western society. The management of LBP comprises a range of different intervention strategies including surgery, drug therapy, and non-medical interventions. The objective of the present study is to determine the effectiveness of physical and rehabilitation interventions (i.e. exercise therapy, back school, transcutaneous electrical nerve stimulation (TENS), low level laser therapy, education, massage, behavioural treatment, traction, multidisciplinary treatment, lumbar supports, and heat/cold therapy) for chronic LBP. The primary search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL, and PEDro up to 22 December 2008. Existing Cochrane reviews for the individual interventions were screened for studies fulfilling the inclusion criteria. The search strategy outlined by the Cochrane Back Review Groups (CBRG) was followed. The following were included for selection criteria: (1) randomized controlled trials, (2) adult (≥ 18 years) population with chronic (≥ 12 weeks) non-specific LBP, and (3) evaluation of at least one of the main clinically relevant outcome measures (pain, functional status, perceived recovery, or return to work). Two reviewers independently selected studies and extracted data on study characteristics, risk of bias, and outcomes at short, intermediate, and long-term follow-up. The GRADE approach was used to determine the quality of evidence. In total 83 randomized controlled trials met the inclusion criteria: exercise therapy (n = 37), back school (n = 5), TENS (n = 6), low level laser therapy (n = 3), behavioural treatment (n = 21), patient education (n = 1), traction (n = 1), and multidisciplinary treatment (n = 6). Compared to usual care, exercise therapy improved post-treatment pain intensity and disability, and long-term function. Behavioural treatment was found to be effective in reducing pain intensity at short-term follow-up compared to no treatment/waiting list controls. Finally, multidisciplinary treatment was found to reduce pain intensity and disability at short-term follow-up compared to no treatment/waiting list controls. Overall, the level of evidence was low. Evidence from randomized controlled trials demonstrates that there is low quality evidence for the effectiveness of exercise therapy compared to usual care, there is low evidence for the effectiveness of behavioural therapy compared to no treatment and there is moderate evidence for the effectiveness of a multidisciplinary treatment compared to no treatment and other active treatments at reducing pain at short-term in the treatment of chronic low back pain. Based on the heterogeneity of the populations, interventions, and comparison groups, we conclude that there are insufficient data to draw firm conclusion on the clinical effect of back schools, low-level laser therapy, patient education, massage, traction, superficial heat/cold, and lumbar supports for chronic LBP.

The search for stable prognostic models in multiple imputed data sets.

BACKGROUND: In prognostic studies model instability and missing data can be troubling factors. Proposed methods for handling these situations are bootstrapping (B) and Multiple imputation (MI). The authors examined the influence of these methods on model composition. METHODS: Models were constructed using a cohort of 587 patients consulting between January 2001 and January 2003 with a shoulder problem in general practice in the Netherlands (the Dutch Shoulder Study). Outcome measures were persistent shoulder disability and persistent shoulder pain. Potential predictors included socio-demographic variables, characteristics of the pain problem, physical activity and psychosocial factors. Model composition and performance (calibration and discrimination) were assessed for models using a complete case analysis, MI, bootstrapping or both MI and bootstrapping. RESULTS: Results showed that model composition varied between models as a result of how missing data was handled and that bootstrapping provided additional information on the stability of the selected prognostic model. CONCLUSION: In prognostic modeling missing data needs to be handled by MI and bootstrap model selection is advised in order to provide information on model stability.

Injection therapy and denervation procedures for chronic low-back pain: a systematic review.

Injection therapy and denervation procedures are commonly used in the management of chronic low-back pain (LBP) despite uncertainty regarding their effectiveness and safety. To provide an evaluation of the current evidence associated with the use of these procedures, a systematic review was performed. Existing systematic reviews were screened, and the Cochrane Back Review Group trial register was searched for randomized controlled trials (RCTs) fulfilling the inclusion criteria. Studies were included if they recruited adults with chronic LBP, evaluated the use of injection therapy or denervation procedures and measured at least one clinically relevant outcome (such as pain or functional status). Two review authors independently assessed studies for eligibility and risk of bias (RoB). A meta-analysis was performed with clinically homogeneous studies, and the GRADE approach was used to determine the quality of evidence. In total, 27 RCTs were included, 14 on injection therapy and 13 on denervation procedures. 18 (66%) of the studies were determined to have a low RoB. Because of clinical heterogeneity, only two comparisons could be pooled. Overall, there is only low to very low quality evidence to support the use of injection therapy and denervation procedures over placebo or other treatments for patients with chronic LBP. However, it cannot be ruled out that in carefully selected patients, some injection therapy or denervation procedures may be of benefit.

A systematic review on the effectiveness of complementary and alternative medicine for chronic non-specific low-back pain.

The purpose of this systematic review was to assess the effects of spinal manipulative therapy (SMT), acupuncture and herbal medicine for chronic non-specific LBP. A comprehensive search was conducted by an experienced librarian from the Cochrane Back Review Group (CBRG) in multiple databases up to December 22, 2008. Randomised controlled trials (RCTs) of adults with chronic non-specific LBP, which evaluated at least one clinically relevant, patient-centred outcome measure were included. Two authors working independently from one another assessed the risk of bias using the criteria recommended by the CBRG and extracted the data. The data were pooled when clinically homogeneous and statistically possible or were otherwise qualitatively described. GRADE was used to determine the quality of the evidence. In total, 35 RCTs (8 SMT, 20 acupuncture, 7 herbal medicine), which examined 8,298 patients, fulfilled the inclusion criteria. Approximately half of these (2 SMT, 8 acupuncture, 7 herbal medicine) were thought to have a low risk of bias. In general, the pooled effects for the studied interventions demonstrated short-term relief or improvement only. The lack of studies with a low-risk of bias, especially in regard to SMT precludes any strong conclusions; however, the principal findings, which are based upon low- to very-low-quality evidence, suggest that SMT does not provide a more clinically beneficial effect compared with sham, passive modalities or any other intervention for treatment of chronic low-back pain. There is evidence, however, that acupuncture provides a short-term clinically relevant effect when compared with a waiting list control or when acupuncture is added to another intervention. Although there are some good results for individual herbal medicines in short-term individual trials, the lack of homogeneity across studies did not allow for a pooled estimate of the effect. In general, these results are in agreement with other recent systematic reviews on SMT, but in contrast with others. These results are also in agreement with recent reviews on acupuncture and herbal medicine. Randomized trials with a low risk of bias and adequate sample sizes are directly needed.

Are systematic review and guideline development tools useful? A Guidelines International Network survey of user preferences.

BACKGROUND: There are now over 140 tools/programs that can assist in developing systematic reviews or clinical practice guidelines (CPGs). It is currently unclear which tools are used by systematic reviewers and CPG developers, which development processes they are used for, and what facilitators or barriers to their use exist. METHODS: To determine which tools are currently being used by systematic reviewers and CPG developers, an online survey was administered during July-August 2017. Guidelines International Network individual and organizational members were invited to participate. Survey questions focused on the nature and frequency of members' use of tools to support systematic review and CPG development. RESULTS: The overall response rate was 34%. The largest number of respondents developed one to five guidelines a year (48%). GRADEpro GDT was the most popular tool (26% of respondents) followed by Dropbox (16%) and RevMan (14%). From the options provided, the reason most respondents (85%) used particular tools was 'to be more efficient'. Most users stated they would use the tool again (95%), and 95% would recommend it to other organizations. However, respondents reported that tool efficiency and facilitators such as data sharing functionality were offset by their availability and cost, issues with structured data fields (that did not allow customization), and other technical and usability factors (e.g., features, workflows). CONCLUSION: The results of this survey provide a focus for discussing improvements in tools to meet the needs of systematic reviewers and CPG developers, and a basis from which to test the efficacy and appropriateness of various tools and platforms across a number of purposes and contexts.

GRADE Guidelines 28: Use of GRADE for the assessment of evidence about prognostic factors: rating certainty in identification of groups of patients with different absolute risks.

OBJECTIVE: The objective of this study was to provide guidance on the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to determine certainty in estimates of association between prognostic factors and future outcomes. STUDY DESIGN AND SETTING: We developed our guidance through an iterative process that involved review of published systematic reviews and meta-analyses of prognostic factors, consultation with members, feedback, presentation, and discussion at the GRADE Working Group meetings. RESULTS: For questions of prognosis, a body of observational evidence (potentially including patients enrolled in randomized controlled trials) begins as high certainty in the evidence. The five domains of GRADE for rating down certainty in the evidence, that is, risk of bias, imprecision, inconsistency, indirectness, and publication bias, as well as the domains for rating up, also apply to estimates of associations between prognostic factors and outcomes. One should determine if their ratings do not consider (noncontextualized) or consider (contextualized) the clinical context as this will may result in variable judgments on certainty of the evidence. CONCLUSIONS: The same principles GRADE proposed for bodies of evidence addressing treatment and overall prognosis work well in assessing individual prognostic factors, both in noncontextualized and contextualized settings.

GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions.

OBJECTIVES: Clear communication of systematic review findings will help readers and decision makers. We built on previous work to develop an approach that improves the clarity of statements to convey findings and that draws on Grading of Recommendations Assessment, Development and Evaluation (GRADE). STUDY DESIGN AND SETTING: We conducted workshops including 80 attendants and a survey of 110 producers and users of systematic reviews. We calculated acceptability of statements and revised the wording of those that were unacceptable to ≥40% of participants. RESULTS: Most participants agreed statements should be based on size of effect and certainty of evidence. Statements for low, moderate and high certainty evidence were acceptable to >60%. Key guidance, for example, includes statements for high, moderate and low certainty for a large effect on intervention x as: x results in a large reduction…; x likely results in a large reduction…; x may result in a large reduction…, respectively. CONCLUSIONS: Producers and users of systematic reviews found statements to communicate findings combining size and certainty of an effect acceptable. This article provides GRADE guidance and a wording template to formulate statements in systematic reviews and other decision tools.

Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.

Background: It remains uncertain which diet is best for people with type 2 diabetes (T2D). Objective: We compared the effects of dietary carbohydrate restriction with fat restriction on markers of metabolic syndrome and quality of life in people with T2D. Design: This systematic review of randomized controlled trials (RCTs) and controlled clinical trials (CCTs) compares the effects of a low-carbohydrate [≤40% of energy (%)] diet with those of a low-fat (≤30%) diet over a period of ≥4 wk in patients with T2D. Two investigators independently selected studies, extracted data, and assessed risk of bias. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was used to assess the certainty of evidence. Pooled mean differences (MDs) and 95% CIs were calculated with the use of a random-effects model. Results: Thirty-three RCTs and 3 CCTs (n = 2161) were included. Glycated hemoglobin declined more in people who consumed low-carbohydrate food than in those who consumed low-fat food in the short term (MD: -1.38%; 95% CI: -2.64%, -0.11%; very-low-certainty evidence). At 1 y, the MD was reduced to -0.36% (95% CI: -0.58%, -0.14%; low-certainty evidence); at 2 y, the difference had disappeared. There is low to high (majority moderate) certainty for small improvements of unclear clinical importance in plasma glucose, triglycerides, and HDL concentrations favoring low-carbohydrate food at half of the prespecified time points. There was little to no difference in LDL concentration or any of the secondary outcomes (body weight, waist circumference, blood pressure, quality of life) in response to either of the diets (very-low- to high-certainty evidence). Conclusions: Currently available data provide low- to moderate-certainty evidence that dietary carbohydrate restriction to a maximum of 40% yields slightly better metabolic control of uncertain clinical importance than reduction in fat to a maximum of 30% in people with T2D. This systematic review is registered at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017052467 as CRD42017052467.

Patent foramen ovale closure, antiplatelet therapy or anticoagulation in patients with patent foramen ovale and cryptogenic stroke: a systematic review and network meta-analysis incorporating complementary external evidence.

OBJECTIVE: To examine the relative impact of three management options in patients aged <60 years with cryptogenic stroke and a patent foramen ovale (PFO): PFO closure plus antiplatelet therapy, antiplatelet therapy alone and anticoagulation alone. DESIGN: Systematic review and network meta-analysis (NMA) supported by complementary external evidence. DATA SOURCES: Medline, EMBASE and Cochrane CENTRAL. STUDY SELECTION: Randomised controlled trials (RCTs) addressing PFO closure and/or medical therapies in patients with PFO and cryptogenic stroke. REVIEW METHODS: We conducted an NMA complemented with external evidence and rated certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Ten RCTs in eight studies proved eligible (n=4416). Seven RCTs (n=3913) addressed PFO closure versus medical therapy. Of these, three (n=1257) addressed PFO closure versus antiplatelet therapy, three (n=2303) addressed PFO closure versus mixed antiplatelet and anticoagulation therapies and one (n=353) addressed PFO closure versus anticoagulation. The remaining three RCTs (n=503) addressed anticoagulant versus antiplatelet therapy. PFO closure versus antiplatelet therapy probably results in substantial reduction in ischaemic stroke recurrence (risk difference per 1000 patients over 5 years (RD): -87, 95% credible interval (CrI) -100 to -33; moderate certainty). Compared with anticoagulation, PFO closure may confer little or no difference in ischaemic stroke recurrence (low certainty) but probably has a lower risk of major bleeding (RD -20, 95% CrI -27 to -2, moderate certainty). Relative to either medical therapy, PFO closure probably increases the risk of persistent atrial fibrillation (RD 18, 95% CI +5 to +56, moderate certainty) and device-related adverse events (RD +36, 95% CI +23 to +50, high certainty). Anticoagulation, compared with antiplatelet therapy, may reduce the risk of ischaemic stroke recurrence (RD -71, 95% CrI -100 to +17, low certainty), but probably increases the risk of major bleeding (RD +12, 95% CrI -5 to +65, moderate certainty). CONCLUSIONS: In patients aged <60 years, PFO closure probably confers an important reduction in ischaemic stroke recurrence compared with antiplatelet therapy alone but may make no difference compared with anticoagulation. PFO closure incurs a risk of persistent atrial fibrillation and device-related adverse events. Compared with alternatives, anticoagulation probably increases major bleeding. PROSPERO REGISTRATION NUMBER: CRD42017081567.