Search

Background: Up-to-date guidance on comprehensive study identification for systematic reviews is crucial. According to current recommendations, systematic searching should combine electronic database searching with supplementary search methods. One such supplementary search method is citation tracking. It aims at collecting directly and/or indirectly cited and citing references from "seed references". Tailored and evidence-guided recommendations concerning the use of citation tracking are strongly needed. Objective: We intend to develop recommendations for the use of citation tracking in systematic literature searching for health-related topics. Our study will be guided by the following research questions: What is the benefit of citation tracking for systematic literature searching for health-related topics? Which methods, citation indexes, and other tools are used for citation tracking? What terminology is used for citation tracking methods? Methods: Our study will have two parts: a scoping review and a Delphi study. The scoping review aims at identifying methodological studies on the benefit and use of citation tracking in systematic literature searching for health-related topics with no restrictions on study design, language, and publication date. We will perform database searching in MEDLINE (Ovid), CINAHL (EBSCOhost), Web of Science Core Collection, two information science databases, web searching, and contact experts in the field. Two reviewers will independently perform study selection. We will conduct direct backward and forward citation tracking on included articles. Data from included studies will be extracted using a prespecified extraction sheet and presented in both tabular and narrative form. The results of the scoping review will inform the subsequent Delphi study through which we aim to derive consensus recommendations for the future practice and research of citation tracking.

Background: Up-to-date guidance on comprehensive study identification for systematic reviews is crucial. According to current recommendations, systematic searching should combine electronic database searching with supplementary search methods. One such supplementary search method is citation tracking. It aims at collecting directly and/or indirectly cited and citing references from "seed references". Tailored and evidence-guided recommendations concerning the use of citation tracking are strongly needed. Objective: We intend to develop recommendations for the use of citation tracking in systematic literature searching for health-related topics. Our study will be guided by the following research questions: What is the benefit of citation tracking for systematic literature searching for health-related topics? Which methods, citation indexes, and other tools are used for citation tracking? What terminology is used for citation tracking methods? Methods: Our study will have two parts: a scoping review and a Delphi study. The scoping review aims at identifying methodological studies on the benefit and use of citation tracking in systematic literature searching for health-related topics with no restrictions on study design, language, and publication date. We will perform database searching in MEDLINE (Ovid), CINAHL (EBSCOhost), Web of Science Core Collection, two information science databases, web searching, and contact experts in the field. Two reviewers will independently perform study selection. We will conduct direct backward and forward citation tracking on included articles. Data from included studies will be extracted using a prespecified extraction sheet and presented in both tabular and narrative form. The results of the scoping review will inform the subsequent Delphi study through which we aim to derive consensus recommendations for the future practice and research of citation tracking.

Background: Up-to-date guidance on comprehensive study identification for systematic reviews is crucial. According to current recommendations, systematic searching should combine electronic database searching with supplementary search methods. One such supplementary search method is citation tracking. It aims at collecting directly and/or indirectly cited and citing references from "seed references". Tailored and evidence-guided recommendations concerning the use of citation tracking are strongly needed. Objective: We intend to develop recommendations for the use of citation tracking in systematic literature searching for health-related topics. Our study will be guided by the following research questions: What is the benefit of citation tracking for systematic literature searching for health-related topics? Which methods, citation indexes, and other tools are used for citation tracking? What terminology is used for citation tracking methods? Methods: Our study will have two parts: a scoping review and a Delphi study. The scoping review aims at identifying methodological studies on the benefit and use of citation tracking in systematic literature searching for health-related topics with no restrictions on study design, language, and publication date. We will perform database searching in MEDLINE (Ovid), CINAHL (EBSCOhost), Web of Science Core Collection, two information science databases, web searching, and contact experts in the field. Two reviewers will independently perform study selection. We will conduct direct backward and forward citation tracking on included articles. Data from included studies will be extracted using a prespecified extraction sheet and presented in both tabular and narrative form. The results of the scoping review will inform the subsequent Delphi study through which we aim to derive consensus recommendations for the future practice and research of citation tracking.

IntroductionCitation tracking (CT) collects references with citation relationships to pertinent references that are already known. This scoping review maps the benefit of and the tools and terminology used for CT in health-related systematic literature searching.MethodsWe included methodological studies on evidence retrieval by CT in health-related literature searching without restrictions on study design, language, or publication date. We searched MEDLINE/Ovid, Web of Science Core Collection, CINAHL/EBSCOhost, LLISFT/EBSCOhost, LISTA/EBSCOhost, conducted web searching via Google Scholar, backward/forward CT of included studies and pertinent reviews, and contacting of experts. Two reviewers independently assessed eligibility. Data extraction and analysis were performed by one reviewer and checked by another.ResultsWe screened 11,861 references and included 47 studies published between 1985 and 2021. Most studies (96%) assessed the benefit of CT either as supplementary or stand-alone search method. Added value of CT for evidence retrieval was found by 96% of them. Science Citation Index and Social Sciences Citation Index were the most common citation indexes used. Application of multiple citation indexes in parallel, co-citing or co-cited references, CT iterations, or software tools was rare. CT terminology was heterogeneous and frequently ambiguous.ConclusionsThe use of CT showed an added value in most of the identified studies; however, the benefit of CT in health-related systematic literature searching likely depends on multiple factors that could not be assessed with certainty. Application, terminology, and reporting are heterogeneous. Based on our results, we plan a Delphi study to develop standard recommendations for the use and reporting of CT.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed. ispartof: SEMINARS IN ARTHRITIS AND RHEUMATISM vol:55 ispartof: location:United States status: published

Background The introduction of new therapy modalities has significantly improved the outcome of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients. However, relatively little is known about the exact disease burden of AA/PNH since standardized assessments of symptoms including health-related quality of life (HRQoL) are frequently missing or inadequately designed for this rare patient group. We aimed to develop AA/PNH-specific questionnaires for self-reporting of symptoms, which could be included in electronic platforms for data collection and patient care. Methods By scoping review, we extracted any reported symptoms in AA/PNH and their prevalence from the literature (Phase I). Consensus rounds with patients and medical experts were conducted to identify core symptoms reported in the literature and to add missing items (Phase II). Ultimately, AA/PNH-specific patient-reported outcome (PRO) questionnaires including the selected measures were designed (Phase III). Results AA symptoms from 62 and PNH symptoms from 45 observational studies were extracted from the literature. Twenty-four patients and seven medical experts identified 11 core symptoms including HRQoL issues after three consensus rounds. Significant differences in the symptom ranking of patients versus medical experts could be observed. Therefore, patient- as well as expert-centered PRO questionnaires in AA and PNH were created following the concepts of validated instruments. Conclusion The development of symptom self-reporting questionnaires for AA and PNH was feasible and the disease-specific PRO questionnaires can now be validated within a web-based workflow in a subsequent feasibility study.

Objectives: We aimed to provide a systematic overview of freely available tools which may help plan or monitor costs for randomized clinical trials (RCTs). Study Design and Setting: We systematically searched MEDLINE, EMBASE, and EconLit and conducted internet searches via Google (last search, October 2018). We included all freely available tools and determined their specific purpose, which parts of clinical trial projects and which types of costs they covered, and if they were user-tested or validated in any form. Results: We identified 25 available tools. Most tools were downloadable on websites from institutions related to clinical research. Seven tools were developed to plan the budget for an entire RCT, 17 tools for calculating budgets of an individual trial center, and one tool for monitoring costs of ongoing RCTs. Eighteen tools considered fixed, variable, and indirect costs. Only two tools were clearly user-tested or validated. Conclusion: Several freely available tools aim to support investigators in planning costs of an entire trial or in planning the budget for a clinical trial site. How valid and useful they are remains to be shown for most of them. Future tools should be openly shared, user-tested, and validated.

BACKGROUND AND OBJECTIVES: Assessing changes in coverage, recall, review, conclusions and references not found when searching fewer databases. METHODS: In randomly selected 60 Cochrane reviews, we checked included study publications' coverage (indexation) and recall (findability) using different search approaches with MEDLINE, Embase, and CENTRAL and related them to authors' conclusions and certainty. We assessed characteristics of unfound references. RESULTS: Overall 1989/2080 included references, were indexed in ≥1 database (coverage = 96%). In reviews where using one of our search approaches would not change conclusions and certainty (n = 44-54), median coverage and recall were highest (range 87.9%-100.0% and 78.2%-93.3%, respectively). Here, searching ≥2 databases reached >95% coverage and ≥87.9% recall. In reviews with unchanged conclusions but less certainty (n = 2-8): 63.3%-79.3% coverage and 45.0%-75.0% recall. In reviews with opposite conclusions (n = 1-3): 63.3%-96.6% and 52.1%-78.7%. In reviews where a conclusion was no longer possible (n = 3-7): 60.6%-86.0% and 20.0%-53.8%. The 265 references that were indexed but unfound were more often abstractless (30% vs. 11%) and older (28% vs. 17% published before 1991) than found references. CONCLUSION: Searching ≥2 databases improves coverage and recall and decreases the risk of missing eligible studies. If researchers suspect that relevant articles are difficult to find, supplementary search methods should be used.

Background: To assess the current practice of developing and presenting methods guidance and explore opportunities for improvement. Study Design and Setting: We systematically surveyed methods guidance published in high-impact general and methodology-focused medical journals indexed in MEDLINE in 2020. We included articles that explicitly stated the objective to provide methods guidance for health research. We extracted characteristics related to findability, methods used for development, presentation, and transparency. Results: We included 105 methods guidance articles published in 12 different journals. Less than half had a structured abstract (42%) or was indexed with medical subject headings (38%) or author keywords (17%) related to guidance. Methods for development, reported in 42%, differed between reporting guidelines (n = 13, 100% reported methods) and other guidance articles (n = 92, 34% reported methods). Frequent methods for presentation were illustrative case studies (45%), research checklists (34%), and step-by-step guides (10%). Most articles did not describe the authors’ expertise (22%). Conflicts of interest, reported in 34%, were often unclear. Conclusion: Potential areas for improving methods guidance include better findability through more consistent labeling and indexing and standards for development and reporting.

BACKGROUND: Trial monitoring is an important component of good clinical practice to ensure the safety and rights of study participants, confidentiality of personal information, and quality of data. However, the effectiveness of various existing monitoring approaches is unclear. Information to guide the choice of monitoring methods in clinical intervention studies may help trialists, support units, and monitors to effectively adjust their approaches to current knowledge and evidence. OBJECTIVES: To evaluate the advantages and disadvantages of different monitoring strategies (including risk‐based strategies and others) for clinical intervention studies examined in prospective comparative studies of monitoring interventions. SEARCH METHODS: We systematically searched CENTRAL, PubMed, and Embase via Elsevier for relevant published literature up to March 2021. We searched the online 'Studies within A Trial' (SWAT) repository, grey literature, and trial registries for ongoing or unpublished studies. SELECTION CRITERIA: We included randomized or non‐randomized prospective, empirical evaluation studies of different monitoring strategies in one or more clinical intervention studies. We applied no restrictions for language or date of publication. DATA COLLECTION AND ANALYSIS: We extracted data on the evaluated monitoring methods, countries involved, study population, study setting, randomization method, and numbers and proportions in each intervention group. Our primary outcome was critical and major monitoring findings in prospective intervention studies. Monitoring findings were classified according to different error domains (e.g. major eligibility violations) and the primary outcome measure was a composite of these domains. Secondary outcomes were individual error domains, participant recruitment and follow‐up, and resource use. If we identified more than one study for a comparison and outcome definitions were similar across identified studies, we quantitatively summarized effects in a meta‐analysis using a random‐effects model. Otherwise, we qualitatively summarized the results of eligible studies stratified by different comparisons of monitoring strategies. We used the GRADE approach to assess the certainty of the evidence for different groups of comparisons. MAIN RESULTS: We identified eight eligible studies, which we grouped into five comparisons. 1. Risk‐based versus extensive on‐site monitoring: based on two large studies, we found moderate certainty of evidence for the combined primary outcome of major or critical findings that risk‐based monitoring is not inferior to extensive on‐site monitoring. Although the risk ratio was close to 'no difference' (1.03 with a 95% confidence interval [CI] of 0.81 to 1.33, below 1.0 in favor of the risk‐based strategy), the high imprecision in one study and the small number of eligible studies resulted in a wide CI of the summary estimate. Low certainty of evidence suggested that monitoring strategies with extensive on‐site monitoring were associated with considerably higher resource use and costs (up to a factor of 3.4). Data on recruitment or retention of trial participants were not available. 2. Central monitoring with triggered on‐site visits versus regular on‐site visits: combining the results of two eligible studies yielded low certainty of evidence with a risk ratio of 1.83 (95% CI 0.51 to 6.55) in favor of triggered monitoring intervention. Data on recruitment, retention, and resource use were not available. 3. Central statistical monitoring and local monitoring performed by site staff with annual on‐site visits versus central statistical monitoring and local monitoring only: based on one study, there was moderate certainty of evidence that a small number of major and critical findings were missed with the central monitoring approach without on‐site visits: 3.8% of participants in the group without on‐site visits and 6.4% in the group with on‐site visits had a major or critical monitoring finding (odds ratio 1.7, 95% CI 1.1 to 2.7; P = 0.03). The absolute number of monitoring findings was very low, probably because defined major and critical findings were very study specific and central monitoring was present in both intervention groups. Very low certainty of evidence did not suggest a relevant effect on participant retention, and very low‐quality evidence indicated an extra cost for on‐site visits of USD 2,035,392. There were no data on recruitment. 4. Traditional 100% source data verification (SDV) versus targeted or remote SDV: the two studies assessing targeted and remote SDV reported findings only related to source documents. Compared to the final database obtained using the full SDV monitoring process, only a small proportion of remaining errors on overall data were identified using the targeted SDV process in the MONITORING study (absolute difference 1.47%, 95% CI 1.41% to 1.53%). Targeted SDV was effective in the verification of source documents but increased the workload on data management. The other included study was a pilot study which compared traditional on‐site SDV versus remote SDV and found little difference in monitoring findings and the ability to locate data values despite marked differences in remote access in two clinical trial networks. There were no data on recruitment or retention. 5. Systematic on‐site initiation visit versus on‐site initiation visit upon request: very low certainty of evidence suggested no difference in retention and recruitment between the two approaches. There were no data on critical and major findings or on resource use. AUTHORS' CONCLUSIONS: The evidence base is limited in terms of quantity and quality. Ideally, for each of the five identified comparisons, more prospective, comparative monitoring studies nested in clinical trials and measuring effects on all outcomes specified in this review are necessary to draw more reliable conclusions. However, the results suggesting risk‐based, targeted, and mainly central monitoring as an efficient strategy are promising. The development of reliable triggers for on‐site visits is ongoing; different triggers might be used in different settings. More evidence on risk indicators that identify sites with problems or the prognostic value of triggers is needed to further optimize central monitoring strategies. In particular, approaches with an initial assessment of trial‐specific risks that need to be closely monitored centrally during trial conduct with triggered on‐site visits should be evaluated in future research.

Background: Electronic health records (EHRs) may support randomized controlled trials (RCTs). We aimed to describe the current use and costs of EHRs in RCTs, with a focus on recruitment and outcome assessment. Methods: This descriptive study was based on a PubMed search of RCTs published since 2000 that evaluated any medical intervention with the use of EHRs. Cost information was obtained from RCT investigators who used EHR infrastructures for recruitment or outcome measurement but did not explore EHR technology itself. Results: We identified 189 RCTs, most of which (153 [81.0%]) were carried out in North America and were published recently (median year 2012 [interquartile range 2009–2014]). Seventeen RCTs (9.0%) involving a median of 732 (interquartile range 73–2513) patients explored interventions not related to EHRs, including quality improvement, screening programs, and collaborative care and disease management interventions. In these trials, EHRs were used for recruitment (14 [82%]) and outcome measurement (15 [88%]). Overall, in most of the trials (158 [83.6%]), the outcome (including many of the most patient-relevant clinical outcomes, from unscheduled hospital admission to death) was measured with the use of EHRs. The per-patient cost in the 17 EHR-supported trials varied from US$44 to US$2000, and total RCT costs from US$67 750 to US$5 026 000. In the remaining 172 RCTs (91.0%), EHRs were used as a modality of intervention. Interpretation: Randomized controlled trials are frequently and increasingly conducted with the use of EHRs, but mainly as part of the intervention. In some trials, EHRs were used successfully to support recruitment and outcome assessment. Costs may be reduced once the data infrastructure is established.

Key Points Question Is evidence from randomized clinical trials associated with the reimbursement decisions that determine access to off-label use of cancer drugs in Switzerland? Findings In this cross-sectional study including 3046 patients with cancer, there were a total of 695 off-label use requests for 598 patients (20%). A total of 67% of requests were reimbursed when supporting trials showed overall survival benefit, but 65% of requests were reimbursed without evidence for overall survival or progression-free survival benefit. Meaning These findings suggest that reimbursement for off-label cancer treatment in Switzerland was not evidence-based and that a transparent process considering clinical evidence is urgently needed for reimbursement decisions to guarantee fair access to off-label cancer drugs., This cross-sectional study examines the association of evidence for benefit from randomized clinical trials with off-label cancer drug reimbursement decisions in Switzerland., Importance In many health systems, access to off-label drug use is controlled through reimbursement restrictions by health insurers, especially for expensive cancer drugs. Objective To determine whether evidence from randomized clinical trials is associated with reimbursement decisions for requested off-label use of anticancer drugs in the Swiss health system. Design, Setting, and Participants This cross-sectional study used reimbursement requests from routinely collected health records of 5809 patients with drug treatment for cancer between January 2015 and July 2018 in 3 major cancer centers, covering cancer care of approximately 5% of the Swiss population, to identify off-label drug use. For each off-label use indication with 3 or more requests, randomized clinical trial evidence on treatment benefits was systematically identified for overall survival (OS) or progression-free survival (PFS). Data were analyzed from August 2018 to December 2020. Exposures Available randomized clinical trial evidence on benefits for OS or PFS for requested off-label use indications. Main Outcomes and Measures The main outcome was the association between evidence for treatment benefit (expressed as improved OS or PFS) and reimbursement in multivariable regression models. Results Among 3046 patients with cancer, 695 off-label use reimbursement requests in 303 different indications were made for 598 patients (median [interquartile range] age, 64 [53-73] years; 420 [60%] men). Off-label use was intended as first-line treatment in 311 requests (45%). Reimbursement was accepted in 446 requests (64%). For 71 indications, including 431 requests for 376 patients, there were 3 or more requests. Of these, 246 requests (57%) had no supporting evidence for OS or PFS benefit. Reimbursement was granted in 162 of 246 requests without supporting evidence (66%). Of 117 requests supported by OS benefit, 79 (67%) were reimbursed, and of 68 requests supported by PFS benefit alone, 54 (79%) were reimbursed. Evidence of OS benefit from randomized clinical trials was not associated with a higher chance of reimbursement (odds ratio, 0.76, 95% CI, 0.45-1.27). Conclusions and Relevance These findings suggest that in a health care system enabling access to off-label use, it was frequently intended as a first-line treatment in cancer care. Availability of randomized clinical trial evidence showing survival benefit was not associated with reimbursement decisions for off-label anticancer drug treatment in Switzerland. A transparent process with criteria considering clinical evidence is needed for evidence-based reimbursement decisions to ensure fair access to cancer treatments.

The administration of antimicrobial prophylaxis for postoperative urinary tract infections following transurethral resection of bladder tumors is controversial. We aimed to systematically review evidence on the potential effect of antimicrobial prophylaxis on postoperative urinary tract infections and asymptomatic bacteriuria.We conducted a systematic search in Embase®, Medline® and the Cochrane Central Register of Controlled Trials. Randomized controlled trials and nonrandomized controlled trials assessing the effect of any form of antimicrobial prophylaxis in patients with transurethral resection of bladder tumors on postoperative urinary tract infections or asymptomatic bacteriuria were included. Risk of bias was assessed using RoB 2.0 or the Newcastle-Ottawa Scale. Fixed and random effects meta-analyses were conducted. As a potential basis for a scoping review, we exploratorily searched Medline for risk factors for urinary tract infections after transurethral resection of bladder tumors. The protocol was registered on PROSPERO (CRD42019131733).Of 986 screened publications, 7 studies with 1,725 participants were included; the reported effect sizes varied considerably. We found no significant effect of antimicrobial prophylaxis on urinary tract infections: the pooled odds ratio of the random effects model was 1.55 (95% CI 0.73-3.31). The random effects meta-analysis examining the effect of antimicrobial prophylaxis on asymptomatic bacteriuria showed an OR of 0.43 (0.18-1.04). Risk of bias was moderate. Our exploratory search identified 3 studies reporting age, preoperative pelvic radiation, preoperative hospital stay, duration of operation, tumor size, preoperative asymptomatic bacteriuria and pyuria as risk factors for urinary tract infections following transurethral resection of bladder tumors.We observed insufficient evidence supporting routine antimicrobial prophylaxis in patients undergoing transurethral resection of bladder tumors for the prevention of postoperative urinary tract infections; our findings may inform harmonization of international guidelines.

Background Target-specific anticancer drugs are under rapid development. Little is known, however, about the risk of administering target-specific drugs to patients who have tumours with molecular alterations or other characteristics that can make the drug ineffective or even harmful. An increasing number of randomised clinical trials (RCTs) investigating target-specific anticancer drugs include subgroup analyses based on tumour characteristics. Such subgroup analyses have the potential to be more credible and influential than subgroup analyses based on traditional factors such as sex or tumour stage. In addition, they may more frequently lead to qualitative subgroup effects, that is, show benefit in one but harm in another subgroup of patients (eg, if the tumour characteristic makes the drug ineffective or even enhance tumour growth). If so, subgroup analyses based on tumour characteristics would be highly relevant for patient safety. The aim of this study is to systematically assess the frequency and characteristics of subgroup analyses based on tumour characteristics, the frequency of qualitative subgroup effects, their credibility, and the interpretations that investigators and guidelines developers report. Methods and analysis We will perform a systematic survey of 433 RCTs testing the effect of target-specific anticancer drugs. Teams of methodologically trained investigators and oncologists will identify eligible studies, extract relevant data and assess the credibility of putative subgroup effects using a recently developed formal instrument. We will systematically assess how trial investigators interpret apparent subgroup effects based on tumour characteristics and the extent to which they influence subsequent practice guidelines. Our results will provide empirical data characterising an increasingly used type of subgroup analysis in cancer trials and its potential impact on precision medicine to predict benefit or harm. Ethics and dissemination Formal ethical approval is not required for this study. We will disseminate the findings in a peer-reviewed and open-access journal publication.

Background The necessity of antibiotic prophylaxis for postoperative urinary tract infections (UTIs) after transurethral resection of bladder tumours is controversial. This potentially leads to the overuse of antibiotic prophylaxis and rising antimicrobial resistance rates. The objective of this systematic review and meta-analysis is to compare the impact of different antimicrobial prophylaxis schemes versus placebo on the prevention of postoperative UTI and asymptomatic bacteriuria. Methods We designed and registered a study protocol for a systematic review and meta-analysis of randomized controlled trials and non-randomized (e.g. cohort, case-control) studies examining any form of antibiotic prophylaxis in patients with transurethral resection of bladder tumours. Literature searches will be conducted in several electronic databases (from inception onwards), including MEDLINE (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials (CENTRAL). Grey literature will be identified through searching conference abstracts. The primary outcome will be postoperative urinary tract infections. The secondary outcome will be asymptomatic bacteriuria. Two reviewers will independently screen all citations, full-text articles, and abstract data. Potential conflicts will be resolved through discussion. The study methodological quality (or bias) will be appraised using appropriate tools (e.g. Risk of Bias 2.0 tool and Newcastle-Ottawa Scale). If feasible, we will conduct random-effects meta-analysis of outcome data. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g. study design, publication year, the setting of the study, and antibiotics regimen). We will also search, identify, and discuss potential risk factors for urinary tract infections following transurethral resection of bladder tumours. This may serve as basis for a scoping review. Discussion In times of rising antimicrobial resistance rates, sound evidence on the necessity of antibiotic prophylaxis is essential for implementation into guideline recommendations and for decision-making in clinical practice. Systematic review registration PROSPERO, CRD42019131733

Background: Up-to-date guidance on comprehensive study identification for systematic reviews is crucial. According to current recommendations, systematic searching should combine electronic database searching with supplementary search methods. One such supplementary search method is citation tracking. It aims at collecting directly and/or indirectly cited and citing references from "seed references". Tailored and evidence-guided recommendations concerning the use of citation tracking are strongly needed. Objective: We intend to develop recommendations for the use of citation tracking in systematic literature searching for health-related topics. Our study will be guided by the following research questions: What is the benefit of citation tracking for systematic literature searching for health-related topics? Which methods, citation indexes, and other tools are used for citation tracking? What terminology is used for citation tracking methods? Methods: Our study will have two parts: a scoping review and a Delphi study. The scoping review aims at identifying methodological studies on the benefit and use of citation tracking in systematic literature searching for health-related topics with no restrictions on study design, language, and publication date. We will perform database searching in MEDLINE (Ovid), CINAHL (EBSCOhost), Web of Science Core Collection, two information science databases, web searching, and contact experts in the field. Two reviewers will independently perform study selection. We will conduct direct backward and forward citation tracking on included articles. Data from included studies will be extracted using a prespecified extraction sheet and presented in both tabular and narrative form. The results of the scoping review will inform the subsequent Delphi study through which we aim to derive consensus recommendations for the future practice and research of citation tracking.

Objectives The objective of this study was to assess the agreement of treatment effect estimates from meta-analyses based on abbreviated or comprehensive literature searches. Study Design and Setting This was a meta-epidemiological study. We abbreviated 47 comprehensive Cochrane review searches and searched MEDLINE/Embase/CENTRAL alone, in combination, with/without checking references (658 new searches). We compared one meta-analysis from each review with recalculated ones based on abbreviated searches. Results The 47 original meta-analyses included 444 trials (median 6 per review [interquartile range (IQR) 3–11]) with 360045 participants (median 1,371 per review [IQR 685–8,041]). Depending on the search approach, abbreviated searches led to identical effect estimates in 34–79% of meta-analyses, to different effect estimates with the same direction and level of statistical significance in 15–51%, and to opposite effects (or effects could not be estimated anymore) in 6–13%. The deviation of effect sizes was zero in 50% of the meta-analyses and in 75% not larger than 1.07-fold. Effect estimates of abbreviated searches were not consistently smaller or larger (median ratio of odds ratio 1 [IQR 1–1.01]) but more imprecise (1.02–1.06-fold larger standard errors). Conclusion Abbreviated literature searches often led to identical or very similar effect estimates as comprehensive searches with slightly increased confidence intervals. Relevant deviations may occur.

Objectives Off-label drug use is highly prevalent but controversial and often discouraged assuming generally inferior medical effects associated with off-label use. Study Design and Setting We searched PubMed, MEDLINE, PubMed Health, and the Cochrane Library up to May 2015 for systematic reviews including meta-analyses of randomized clinical trials (RCTs) comparing off-label and approved drugs head-to-head in any population and on any medical outcome. We combined the comparative effects in meta-analyses providing summary odds ratios (sOR) for each treatment comparison and outcome, and then calculated an overall summary of the sOR across all comparisons (ssOR). Results We included 25 treatment comparisons with 153 RCTs and 24,592 patients. In six of 25 comparisons (24%), off-label drugs were significantly superior (five of 25) or inferior (one of 25) to approved treatments. There was substantial statistical heterogeneity across comparisons (I2 = 43%). Overall, off-label drugs were more favorable than approved treatments (ssOR 0.72; 95% CI = 0.54–0.95). Analyses of patient-relevant outcomes were similar (statistical significant differences in 24% (six of 25); ssOR 0.74; 95% CI = 0.56–0.98; I2 = 60%). Analyses of primary outcomes of the systematic reviews (n = 22 comparisons) indicated less heterogeneity and no statistically significant difference overall (ssOR 0.85; 95% CI = 0.67–1.06; I2 = 0%). Conclusion Approval status does not reliably indicate which drugs are more favorable in situations with clinical trial evidence comparing off-label with approved use. Drug effectiveness assessments without considering off-label use may provide incomplete information. To ensure that patients receive the best available care, funding, policy, reimbursement, and treatment decisions should be evidence based considering the entire spectrum of available therapeutic choices.

The Medical Faculty and the University Medical Library of the University of Basel jointly developed a new learning unit called Searchaton. This learning unit aimed at providing knowledge for the point-of-care literature search in everyday clinical practice. To make this as practical and customer-oriented as possible, the faculty and library interacted closely with medical experts. During the Searchaton, the task was to translate a patient case into a clinical question and to find an answer to that question. The format combined collaborative working and gamification with an aspect of time pressure to better reflect everyday clinical situations. The participants benefited greatly from the intensive support and were able to assess their searching skills in the context of evidence-based clinical decision-making.

Background & aims Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD. Methods We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses. Results The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. Conclusions There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings.

BackgroundOff-label drug use (OLU) reflects a perceived unmet medical need, which is common in oncology. Cancer drugs are often highly expensive and their reimbursement is a challenge for many health care systems. OLU is frequently regulated by reimbursement restrictions. For evidence-based health care, treatment ought to be reimbursed if there is sufficient clinical evidence for treatment benefit independently of patient factors not related to the treatment indication. However, little is known about the reality of OLU reimbursement and its association with the underlying clinical evidence. Here we aim to investigate the relationship of reimbursement decisions with the underlying clinical evidence.Methods/DesignWe extract patient characteristics and details on treatment and reimbursement of cancer drugs from over 3000 patients treated in three Swiss hospitals. We systematically search for clinical trial evidence on benefits associated with OLU in the most common indications. We will describe the prevalence of OLU in Switzerland and its reimbursement in cancer care, and use multivariable logistic regression techniques to investigate the association of approval/rejection of a reimbursement requests to the evidence on treatment effects and to further factors, including type of drug, molecular predictive markers and the health insurer.DiscussionOur study will provide a systematic overview and assessment of OLU and its reimbursement reality in Switzerland. We may provide a better understanding of the access to cancer care that is regulated by health insurers and we hope to identify factors that determine the level of evidence-based cancer care in a highly diverse Western health care system.

Objectives To evaluate how estimated treatment effects agree between nonrandomized studies using causal modeling with marginal structural models (MSM-studies) and randomized trials (RCTs). Study Design Meta-epidemiological study. Setting MSM-studies providing effect estimates on any healthcare outcome of any treatment were eligible. We systematically sought RCTs on the same clinical question and compared the direction of treatment effects, effect sizes, and confidence intervals. Results The main analysis included 19 MSM-studies (1,039,570 patients) and 141 RCTs (120,669 patients). MSM-studies indicated effect estimates in the opposite direction from RCTs for eight clinical questions (42%), and their 95% CI (confidence interval) did not include the RCT estimate in nine clinical questions (47%). The effect estimates deviated 1.58-fold between the study designs (median absolute deviation OR [odds ratio] 1.58; IQR [interquartile range] 1.37 to 2.16). Overall, we found no systematic disagreement regarding benefit or harm but confidence intervals were wide (summary ratio of odds ratios [sROR] 1.04; 95% CI 0.88 to 1.23). The subset of MSM-studies focusing on healthcare decision-making tended to overestimate experimental treatment benefits (sROR 1.44; 95% CI 0.99 to 2.09). Conclusion Nonrandomized studies using causal modeling with MSM may give different answers than RCTs. Caution is still required when nonrandomized “real world” evidence is used for healthcare decisions.

Whether specific communication interventions to discuss code status alter patient decisions regarding do-not-resuscitate code status and knowledge about cardiopulmonary resuscitation (CPR) remains unclear.; To conduct a systematic review and meta-analysis regarding the association of communication interventions with patient decisions and knowledge about CPR.; PubMed, Embase, PsycINFO, and CINAHL were systematically searched from the inception of each database to November 19, 2018.; Randomized clinical trials focusing on interventions to facilitate code status discussions. Two independent reviewers performed the data extraction and assessed risk of bias using the Cochrane Risk of Bias Tool. Data were pooled using a fixed-effects model, and risk ratios (RRs) with corresponding 95% CIs are reported.; The study was performed according to the PRISMA guidelines.; The primary outcome was patient preference for CPR, and the key secondary outcome was patient knowledge regarding life-sustaining treatment.; Fifteen randomized clinical trials (2405 patients) were included in the qualitative synthesis, 11 trials (1463 patients) were included for the quantitative synthesis of the primary end point, and 5 trials (652 patients) were included for the secondary end point. Communication interventions were significantly associated with a lower preference for CPR (390 of 727 [53.6%] vs 284 of 736 [38.6%]; RR, 0.70; 95% CI, 0.63-0.78). In a preplanned subgroup analysis, studies using resuscitation videos as decision aids compared with other interventions showed a stronger decrease in preference for life-sustaining treatment (RR, 0.56; 95% CI, 0.48-0.64 vs 1.03; 95% CI, 0.87-1.22; between-group heterogeneity P

Objective The objective of the study was to systematically survey the methodological literature and collect suggested criteria for assessing the credibility of effect modification and associated rationales. Study Design and Setting We searched MEDLINE, Embase, and WorldCat up to March 2018 for publications providing guidance for assessing the credibility of effect modification identified in randomized trials or meta-analyses. Teams of two investigators independently identified eligible publications and extracted credibility criteria and authors’ rationale, reaching consensus through discussion. We created a taxonomy of criteria that we iteratively refined during data abstraction. Results We identified 150 eligible publications that provided 36 criteria and associated rationales. Frequent criteria included significant test for interaction (n = 54), a priori hypothesis (n = 49), providing a causal explanation (n = 47), accounting for multiplicity (n = 45), testing a small number of effect modifiers (n = 38), and prespecification of analytic details (n = 39). For some criteria, we found more than one rationale; some criteria were connected through a common rationale. For some criteria, experts disagreed regarding their suitability (e.g., added value of stratified randomization; trustworthiness of biologic rationales). Conclusion Methodologists have expended substantial intellectual energy providing criteria for critical appraisal of apparent effect modification. Our survey highlights popular criteria, expert agreement and disagreement, and where more work is needed, including testing criteria in practice.

Background:GCA is characterized by cranial symptoms but imaging techniques show that patients with non-specific symptoms such as systemic inflammation or PMR may have undiagnosed large vessel (LV) GCA1. Although silent GCA in patients with clinically isolated PMR may have consequences for patients’ outcome, little is known about its prevalence and characteristics of affected patients.Objectives:To review data on the prevalence of silent GCA in newly diagnosed PMR patients without cranial GCA symptoms and to analyze which characteristics are associated with vascular involvement among PMR patients.Methods:We systematically screened PubMed, Embase and Web of Science databases and included studies screening for GCA in steroid naïve PMR patients without cranial symptoms consistent with GCA. Authors of the publications that used PET for vasculitis screening were invited to share their individual patient data (IPD) for a meta-analysis. We sought to define patient characteristics that were associated with vasculitis using univariable mixed effects logistic regression models with vascular involvement as the outcome, missing values were imputed using multilevel joint modeling multiple imputation. To fit a multivariable model with the candidate predictors we excluded variables that were hypothesized to have less medical relevance for the outcome and highly correlated inflammation markers (ESR, Lc).Results:Out of the 3047 studies screened independently by 2 authors (DG and TD), 13 fulfilled the inclusion criteria. These studies (published 1963-2019) reported on 543 PMR patients examined by temporal artery biopsy (n=175), ultrasound (n=110), PET or PET-CT (n=258). 115 PMR patients were diagnosed with GCA (21.2%), with prevalence ranging from 0-92%.We collected IPD for 243 patients from 4 cohorts using PET and 3 using PET/CT for GCA diagnosis. The overall median age of patients was 72.3 years (IQR 66.4-78.0) and vasculitis was found in 65 patients (26.7%) (table 1).Table 1.OverallPMRPMR+GCAn (%)243178 (73.3)65 (26.7)Female sex (%)146 (60.1)98 (55.1)48 (73.8)Shoulder girdle pain (%)236 (97.1)174 (97.8)62 (95.4)Pelvic girdle pain (%)174 (71.6)127 (71.3)47 (72.3)Inflammatory back pain (%)No107 (44.0)83 (46.6)24 (36.9)Yes106 (43.6)70 (39.3)36 (55.4)Lower limb pain (%)No87 (35.8)61 (34.3)26 (40.0)Yes81 (33.3)68 (38.2)13 (20.0)Weight loss (%)112 (46.1)78 (43.8)34 (52.3)CRP (mg/l) (median [IQR])46.0 [19.0, 77.7]44.0 [16.9, 74.2]52.0 [27.9, 85.0]ESR (mm/h) (mean (SD))65.2 (30.3)62.7 (30.2)72.3 (29.7)Hemoglobin (g/dl) (mean (SD))12.1 (1.5)12.2 (1.5)11.7 (1.6)Thrombocytes (1e+09/ml) (mean (SD))341.9 (106.3)323.9 (103.2)375.8 (104.6)In the univariable analyses the following factors were most strongly associated with vasculitic PET findings: female sex (OR 2.31, CI 1.17-4.58), inflammatory back pain (OR 2.73, CI 1.32-5.64), temperature >37° (OR 1.83, CI 0.90-3.7), weight loss (OR 1.83, CI 0.96-3.51), thrombocytosis (i.e., patients with a thrombocyte count 1 SD above mean have an OR of 1.51, CI 1.05-2.18), anemia (i.e., 1 g/dl decrease in Hb below mean corresponds to an OR of 1.25, CI 1.00-1.56). Patients with lower limb pain were less likely to have vasculitis (OR 0.43, CI 0.19–0.95). The estimated ORs were very similar in the multivariable model although the 95%CIs became wider.Conclusion:Although the prevalence across published studies showed substantial variation, 6 out of 13 studies reported a prevalence of silent GCA in 18-40% of all PMR patients. The exploratory analysis of the collected IPD identified female sex, inflammatory back pain, fever, weight loss, absence of lower leg pain, thrombocytosis and anemia as factors associated with LV-GCA. These findings should be validated in future prospective cohort studies. The presence or absence of these factors may further aid in diagnosing LV-GCA in PMR patients.References:[1]Buttgereit F, Dejaco C, Matteson EL, Dasgupta B. Polymyalgia Rheumatica and Giant Cell Arteritis: A Systematic Review. JAMA. 2016 Jun 14;315(22):2442–58.Acknowledgements:The study is funded by the “Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (SSEM)”.Disclosure of Interests:Daniele Silvio Gozzoli: None declared, Andrea Hemmig: None declared, Lars Hemkens: None declared, Laura Werlen: None declared, Hannah Ewald: None declared, Christoph Berger: None declared, Diego Kyburz Grant/research support from: DK reports personal fees from Abbvie, Gilead, Lilly, Novartis and Pfizer, outside of the submitted work, Stephan Imfeld: None declared, Markus Aschwanden: None declared, Mihaela Stegert: None declared, Dario Camellino: None declared, Marco Amedeo Cimmino: None declared, Corrado Campochiaro Grant/research support from: personal fees from Roche, Alessandro Tomelleri: None declared, Liesbet Henckaerts: None declared, Daniel Blockmans Speakers bureau: Paid speaker for Roche, Consultant of: Paid consultant for Roche, Patricia Moya: None declared, Hector Corominas: None declared, Russell Buchanan: None declared, Claire Owen Speakers bureau: CO has received speaking honoraria from Roche, Janssen, Novartis and Pfizer, and meeting sponsorship from Roche, UCB and Janssen, Yannick van Sleen: None declared, Elisabeth Brouwer Speakers bureau: E. Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017, 2018 which were paid to the UMCG, Consultant of: E. Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017, 2018 which were paid to the UMCG, Hiroyuki Ymashita: None declared, Thomas Daikeler: None declared

Objective To compare effect estimates of randomised clinical trials that use routinely collected data (RCD-RCT) for outcome ascertainment with traditional trials not using routinely collected data. Design Meta-research study. Data source Studies included in the same meta-analysis in a Cochrane review. Eligibility criteria for study selection Randomised clinical trials using any type of routinely collected data for outcome ascertainment, including from registries, electronic health records, and administrative databases, that were included in a meta-analysis of a Cochrane review on any clinical question and any health outcome together with traditional trials not using routinely collected data for outcome measurement. Review methods Effect estimates from trials using or not using routinely collected data were summarised in random effects meta-analyses. Agreement of (summary) treatment effect estimates from trials using routinely collected data and those not using such data was expressed as the ratio of odds ratios. Subgroup analyses explored effects in trials based on different types of routinely collected data. Two investigators independently assessed the quality of each data source. Results 84 RCD-RCTs and 463 traditional trials on 22 clinical questions were included. Trials using routinely collected data for outcome ascertainment showed 20% less favourable treatment effect estimates than traditional trials (ratio of odds ratios 0.80, 95% confidence interval 0.70 to 0.91, I 2 =14%). Results were similar across various types of outcomes (mortality outcomes: 0.92, 0.74 to 1.15, I 2 =12%; non-mortality outcomes: 0.71, 0.60 to 0.84, I 2 =8%), data sources (electronic health records: 0.81, 0.59 to 1.11, I 2 =28%; registries: 0.86, 0.75 to 0.99, I 2 =20%; administrative data: 0.84, 0.72 to 0.99, I 2 =0%), and data quality (high data quality: 0.82, 0.72 to 0.93, I 2 =0%). Conclusions Randomised clinical trials using routinely collected data for outcome ascertainment show smaller treatment benefits than traditional trials not using routinely collected data. These differences could have implications for healthcare decision making and the application of real world evidence.

Key Points Question What are the available data on cancer treatment outcomes for new cancer therapies approved by the US Food and Drug Administration? Findings In this comparative effectiveness study of 92 novel cancer therapies approved for 100 indications over 17 years, 44% of drug approvals were based on data from nonrandomized clinical trials. Randomized clinical trials typically reported that these drugs were associated with substantial tumor responses and delays in the time to progression or death, but the median absolute increase in overall survival was only 2 months. Meaning This study’s findings indicate that, at the time of drug approval, limited supporting data are available to decision-makers, and the increase in overall survival associated with new cancer drugs is typically small., Importance Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted. Objective To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016. Design, Setting, and Participants This comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study. Main Outcomes and Measures Regulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately. Results Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months). Conclusions and Relevance In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry., This comparative effectiveness research examines clinical trial data on treatment outcomes used to support US Food and Drug Administration approval of novel cancer therapies that were approved for the first time between 2000 and 2016.

Background The available evidence on the benefits and harms of novel drugs and therapeutic biologics at the time of approval is reported in publicly available documents provided by the US Food and Drug Administration (FDA). We aimed to create a comprehensive database providing the relevant information required to systematically analyze and assess this early evidence in meta-epidemiological research. Methods We designed a modular and flexible database of systematically collected data. We identified all novel cancer drugs and therapeutic biologics approved by the FDA between 2000 and 2016, recorded regulatory characteristics, acquired the corresponding FDA approval documents, identified all clinical trials reported therein, and extracted trial design characteristics and treatment effects. Herein, we describe the rationale and design of the data collection process, particularly the organization of the data capture, the identification and eligibility assessment of clinical trials, and the data extraction activities. Discussion We established a comprehensive database on the comparative effects of drugs and therapeutic biologics approved by the FDA over a time period of 17 years for the treatment of cancer (solid tumors and hematological malignancies). The database provides information on the clinical trial evidence available at the time of approval of novel cancer treatments. The modular nature and structure of the database and the data collection processes allow updates, expansions, and adaption for a continuous meta-epidemiological analysis of novel drugs. The database allows us to systematically evaluate benefits and harms of novel drugs and therapeutic biologics. It provides a useful basis for meta-epidemiological research on the comparative effects of innovative cancer treatments and continuous evaluations of regulatory developments.

BackgroundSubacute cough following a non-specific viral infection lasting 3–8 weeks is common. However, despite many treatment options there are no systematic reviews evaluating these.AimTo provide a systematic overview of treatment options and outcomes evaluated in randomised clinical trials (RCTs).Design and settingSystematic review and meta-analyses assessing the overall effects of any treatment for subacute cough.MethodThe authors systematically searched PubMed/MEDLINE and the Cochrane Central Register of Controlled Trials (last search March 2017) for RCTs in adult patients with subacute cough. The authors considered trials evaluating any outcome of any drug or non-drug treatments, apart from traditional Chinese and Asian medicines. They combined treatment effects on cough-related outcomes in random effects meta-analyses.ResultsSix eligible RCTs including 724 patients were identified. These assessed montelukast, salbutamol plus ipratropium bromide, gelatine, fluticasone propionate, budesonide, and nociception opioid 1 receptor agonist and codeine. Five studies reported effects on various cough severity scores at various timepoints. No treatment option was associated with a clear benefit on cough recovery or other patient-relevant outcomes in any of the studies or in meta-analyses for cough outcomes at 14 days and 28 days. Reported adverse events were rather mild and reported for 14% of patients across all treatments.ConclusionEvidence on treatment options for subacute cough is weak. There is no treatment showing clear patient-relevant benefits in clinical trials.

Objectives To determine how marginal structural models (MSMs), which are increasingly used to estimate causal effects, are used in randomized clinical trials (RCTs) and compare their results with those from intention-to-treat (ITT) or other analyses. Study Design and Setting We searched PubMed, Scopus, citations of key references, and Clinicaltrials.gov. Eligible RCTs reported clinical effects based on MSMs and at least one other analysis. Results We included 12 RCTs reporting 138 analyses for 24 clinical questions. In 19/24 (79%), MSM-based and other effect estimates were all in the same direction, 22/22 had overlapping 95% confidence intervals (CIs), and in 19/22 (86%), the MSM effect estimate lay within all 95% CIs of all other effects (in two cases no CIs were reported). For the same clinical question, the largest effect estimate from any analysis was 1.19-fold (median; interquartile range 1.13-1.34) larger than the smallest. All MSM and ITT effect estimates were in the same direction and had overlapping 95% CIs. In 71% (12/17), they also agreed on the presence of statistical significance. MSM-based effect estimates deviated more from the null than those based on ITT (P = 0.18). The effect estimates of both approaches differed 1.12-fold (median; interquartile range 1.02-1.22). Conclusions MSMs provided largely similar effect estimates as other available analyses. Nevertheless, some of the differences in effect estimates or statistical significance may become important in clinical decision-making, and the multiple estimates require utmost attention of possible selective reporting bias.

There is compelling evidence that published trial information is selectively reported and that results not showing favourable effects of the tested treatments often remain unpublished. Clinical trial information published by regulatory authorities such as the US Food and Drug Administration (FDA) may help to reduce such reporting biases. FDA approval documents are long and do not follow the typical structure of medical journal articles, which may discourage reviewers from using them for evidence syntheses. Our practical guidance on how to efficiently identify and use approval documents to find the relevant information may help promoting the use of this valuable data source for evidence syntheses.