The GUIDES checklist: development of a tool to improve the successful use of guideline-based computerised clinical decision support

Background: Computerised decision support (CDS) based on trustworthy clinical guidelines is a key component of a learning healthcare system. Research shows that the effectiveness of CDS is mixed. Multifaceted context, system, recommendation and implementation factors may potentially affect the success of CDS interventions. This paper describes the development of a checklist that is intended to support professionals to implement CDS successfully. Methods: We developed the checklist through an iterative process that involved a systematic review of evidence and frameworks, a synthesis of the success factors identified in the review, feedback from an international expert panel that evaluated the checklist in relation to a list of desirable framework attributes, consultations with patients and healthcare consumers and pilot testing of the checklist. Results: We screened 5347 papers and selected 71 papers with relevant information on success factors for guideline-based CDS. From the selected papers, we developed a 16-factor checklist that is divided in four domains, i.e. the CDS context, content, system and implementation domains. The panel of experts evaluated the checklist positively as an instrument that could support people implementing guideline-based CDS across a wide range of settings globally. Patients and healthcare consumers identified guideline-based CDS as an important quality improvement intervention and perceived the GUIDES checklist as a suitable and useful strategy. Conclusions: The GUIDES checklist can support professionals in considering the factors that affect the success of CDS interventions. It may facilitate a deeper and more accurate understanding of the factors shaping CDS effectiveness. Relying on a structured approach may prevent that important factors are missed

Strategies for monitoring and updating clinical practice guidelines: a systematic review

Background: Scientific knowledge is in constant change. The flow of new information requires a frequent re-evaluation of the available research results. Clinical practice guidelines (CPGs) are not exempted from this phenomenon and need to be kept updated to maintain the validity of their recommendations. The objective of our review is to systematically identify, describe and assess strategies for monitoring and updating CPGs. Study design and setting: We conducted a systematic review of studies evaluating one or more methods of updating (with or without monitoring) CPGs or recommendations. We searched MEDLINE (PubMed) and The Cochrane Methodology Register (The Cochrane Library) from 1966 to June 2012. Additionally, we hand-searched reference lists of the included studies and the Guidelines International Network book of abstracts. If necessary, we contacted study authors to obtain additional information. Results: We included a total of eight studies. Four evaluated if CPGs were out of date, three updated CPGs, and one continuously monitored and updated CPGs. The most detailed reported phase of the process was the identification of new evidence. As opposed to studies updating guidelines, studies evaluating if CPGs were out of date applied restricted searches. Only one study compared a restricted versus an exhaustive search suggesting that a restricted search is sufficient to assess recommendations’ Validity. One study analyzed the survival time of CPGs and suggested that these should be reassessed every three years. Conclusions: There is limited evidence about the optimal strategies for monitoring and updating clinical practice guidelines. A restricted search is likely to be sufficient to monitor new evidence and assess the need to update, however, more information is needed about the timing and type of search. Only the exhaustive search strategy has been assessed for the update of CPGs. The development and evaluation of more efficient strategies is needed to improve the timeliness and reduce the burden of maintaining the validity of CPGs. Keywords: Clinical practice guidelines, Diffusion of innovation, Evidence-based medicine, Information storage and retrieval, Methodology, Updating, Implementation science, Dissemination and implementation, Knowledge translation

Decision aids linked to evidence summaries and clinical practice guidelines : results from user-testing in clinical encounters

Acknowledgements We thank Frankie Achille (interaction designer/developer), Rob Fracisco (designer/developer), and Deno Vichas and Chris Degiere (developers) for their contributions in development of the online authoring and publication platform (www.magicevidence.org). Funding AFH was fnancially supported by a PhD fellowship from Innlandet Hospital Trust and have received innovation grants from South-Eastern Norway Regional Health Authority. TA was fnancially supported by a fellowship for prospective researchers Grant No P3SMP3-155290/1 from the Swiss National Science Foundation. The funding body had no role in design of the study, collection, analysis, and interpretation of data or in writing the manuscript.Peer reviewedPublisher PD

Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus : systematic review and meta-analysis of randomised and non-randomised studies

Objective To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus. Design Systematic review and meta-analysis. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. Eligibility criteria Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs. Data collection and analysis Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis. Results 60 studies (n=353 639), consisting of 55 randomised controlled trials (n=33 350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320 289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13). Conclusions The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk

PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis.

OBJECTIVE To compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or who are statin intolerant. DESIGN Network meta-analysis. DATA SOURCES Medline, EMBASE, and Cochrane Library up to 31 December 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Randomised controlled trials of ezetimibe and PCSK9 inhibitors with ≥500 patients and follow-up of ≥6 months. MAIN OUTCOME MEASURES We performed frequentist fixed-effects network meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) to assess certainty of evidence. Results included relative risks (RR) and absolute risks per 1000 patients treated for five years for non-fatal myocardial infarction (MI), non-fatal stroke, all-cause mortality, and cardiovascular mortality. We estimated absolute risk differences assuming constant RR (estimated from network meta-analysis) across different baseline therapies and cardiovascular risk thresholds; the PREDICT risk calculator estimated cardiovascular risk in primary and secondary prevention. Patients were categorised at low to very high cardiovascular risk. A guideline panel and systematic review authors established the minimal important differences (MID) of 12 per 1000 for MI and 10 per 1000 for stroke. RESULTS We identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. Adding ezetimibe to statins reduced MI (RR 0.87 (95% confidence interval 0.80 to 0.94)) and stroke (RR 0.82 (0.71 to 0.96)) but not all-cause mortality (RR 0.99 (0.92 to 1.06)) or cardiovascular mortality (RR 0.97 (0.87 to 1.09)). Similarly, adding PCSK9 inhibitor to statins reduced MI (0.81 (0.76 to 0.87)) and stroke (0.74 (0.64 to 0.85)) but not all-cause (0.95 (0.87 to 1.03)) or cardiovascular mortality (0.95 (0.87 to 1.03)). Among adults with very high cardiovascular risk, adding PCSK9 inhibitor was likely to reduce MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); whereas adding ezetimibe was likely to reduce stroke (14 per 1000), but the reduction of MI (11 per 1000) (moderate certainty) did not reach MID. Adding ezetimibe to PCSK9 inhibitor and statin may reduce stroke (11 per 1000), but the reduction of MI (9 per 1000) (low certainty) did not reach MID. Adding PCSK9 inhibitors to statins and ezetimibe may reduce MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with high cardiovascular risk, adding PCSK9 inhibitor probably reduced MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); adding ezetimibe probably reduced stroke (11 per 1000), but the reduction in MI did not achieve MID (8 per 1000) (moderate certainty). Adding ezetimibe to PCSK9 inhibitor and statins did not reduce outcomes beyond MID, while adding PCSK9 inhibitor to ezetimibe and statins may reduce stroke (13 per 1000). These effects were consistent in statin-intolerant patients. Among moderate and low cardiovascular risk groups, adding PCSK9 inhibitor or ezetimibe to statins yielded little or no benefit for MI and stroke. CONCLUSIONS Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk

Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis

Objective: To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19. Design: Systematic review and network meta-analysis. Data sources: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021). Review methods: Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis. Results: Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88; 35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000; moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92; 43 fewer per 1000, 73 fewer to 12 fewer; low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34; eight more per 1000, 20 fewer to 35 more; low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38; 20 more per 1000, 16 fewer to 59 more; low certainty) and sarilumab (1.07, 0.81 to 1.40; 11 more per 1000, 38 fewer to 55 more; low certainty), when used alone, suggested an increase in the risk of death. Conclusion: These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.This project is supported by two Canadian Institutes of Health Research grants (VR4-172738; MM1-174897). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.publishedVersio

Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes : systematic review and meta-analysis of randomised and observational studies

Objectives To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes. Design Systematic review and meta-analysis of randomised and observational studies. Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts. Eligibility criteria Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure. Data collection and analysis Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach. Results Eligible studies included 43 trials (n=68 775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1 777 358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15 701 v 33/12 591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18 554 v 552/18 474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use. Conclusions The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use

Effects of dietary and physical activity interventions on the risk of type 2 diabetes in South Asians: meta-analysis of individual participant data from randomised controlled trials

Aims/hypothesis: Individuals of South Asian origin have a high risk of type 2 diabetes and of dying from a diabetes-attributable cause. Lifestyle modification intervention trials to prevent type 2 diabetes in high-risk South Asian adults have suggested more modest effects than in European-origin populations. The strength of the evidence of individual studies is limited, however. We performed an individual participant data meta-analysis of available RCTs to assess the effectiveness of lifestyle modification in South Asian populations worldwide. Methods: We searched PubMed, EMBASE, Cochrane Library and Web of Science (to 24 September 2018) for RCTs on lifestyle modification interventions incorporating diet and/or physical activity in South Asian adults. Reviewers identified eligible studies and assessed the quality of the evidence. We obtained individual participant data on 1816 participants from all six eligible trials (four from Europe and two from India). We generated HR estimates for incident diabetes (primary outcome) and mean differences for fasting glucose, 2 h glucose, weight and waist circumference (secondary outcomes) using mixed-effect meta-analysis overall and by pre-specified subgroups. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence of the estimates. The study is registered with the International Prospective Register of Systematic Reviews ([PROSPERO] CRD42017078003). Results: Incident diabetes was observed in 12.6% of participants in the intervention groups and in 20.0% of participants in the control groups. The pooled HR for diabetes incidence was 0.65 (95% CI 0.51, 0.81; I2 = 0%) in intervention compared with control groups. The absolute risk reduction was 7.4% (95% CI 4.0, 10.2), with no interactions for the pre-specified subgroups (sex, BMI, age, study duration and region where studies were performed). The quality of evidence was rated as moderate. Mean difference for lifestyle modification vs control groups for 2 h glucose was −0.34 mmol/l (95% CI −0.62, −0.07; I2 = 50%); for weight −0.75 kg (95% CI −1.34, −0.17; I2 = 71%) and for waist −1.16 cm (95% CI −2.16, −0.16; I2 = 75%). No effect was found for fasting glucose. Findings were similar across subgroups, except for weight for European vs Indian studies (−1.10 kg vs −0.08 kg, p = 0.02 for interaction). Conclusions/interpretation: Despite modest changes for adiposity, lifestyle modification interventions in high-risk South Asian populations resulted in a clinically important 35% relative reduction in diabetes incidence, consistent across subgroups. If implemented on a large scale, lifestyle modification interventions in high-risk South Asian populations in Europe would reduce the incidence of diabetes in these populations