Detection bias in open-label trials of anticancer drugs: a meta-epidemiological study.

OBJECTIVES: In anticancer clinical trials, particularly open-label trials, central reviewers are recommended to evaluate progression-free survival (PFS) and objective response rate (ORR) to avoid detection bias of local investigators. However, it is not clear whether the bias has been adequately identified, or to what extent it consistently distorts the results. Therefore, the objective of this study was to evaluate the detection bias in oncological open-label trials by confirming whether local investigators overestimate the PFS and ORR compared with the findings of central reviewers. DESIGN: Meta-epidemiological study. DATA SOURCES: MEDLINE via PubMed from 1 January 2010 to 30 June 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Open-label, parallel-group superiority, randomised trials of anticancer drugs that adjudicated PFS or ORR by both central reviewers and local investigators. REVIEW METHODS: We assessed the values for the same outcome (PFS and ORR) adjudicated by both central reviewers and local investigators. A random-effects model was used to estimate the ratio of HR (RHR) for PFS and the ratio of OR (ROR) for ORR between central reviewers and local investigators. An RHR lower than 1 and an ROR higher than 1 indicated an overestimation of the effect estimated by local investigators. RESULTS: We retrieved 1197 records of oncological open-label trials after full-text screening. We identified 171 records (PFS: 149 records, ORR: 136 records) in which both central reviewers and local investigators were used, and included 114 records (PFS: 92 records, ORR: 74 records) for meta-analyses. While the RHR for PFS was 0.95 (95% CI 0.91 to 0.98), the ROR of ORR was 1.00 (95% CI 0.91 to 1.09). The results remained unchanged in the prespecified sensitivity analysis. CONCLUSIONS: This meta-epidemiological study found that overestimation of local investigators has a small impact on evaluating PFS and ORR in oncological open-label trials. However, a limitation of this study is that it did not include data from all trials; hence, the results may not fully evaluate detection bias. The necessity of central reviewers in oncological open-label trials needs to be assessed by further studies that overcome this limitation. TRIAL REGISTRATION NUMBER: CTR-UMIN000044623.

Ultrasound guidance versus landmark method for peripheral venous cannulation in adults.

BACKGROUND: Peripheral intravenous cannulation is one of the most fundamental and common procedures in medicine. Securing a peripheral line is occasionally difficult with the landmark method. Ultrasound guidance has become a standard procedure for central venous cannulation, but its efficacy in achieving peripheral venous cannulation is unclear. OBJECTIVES: To evaluate the effectiveness and safety of ultrasound guidance compared to the landmark method for peripheral intravenous cannulation in adults.  SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 29 November 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which participants are systematically allocated based on data such as date of birth or recruitment) comparing the effects of ultrasound guidance to the landmark method for peripheral intravenous cannulation in adults. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were first-pass success of cannulation, overall success of cannulation, and pain. Our secondary outcomes were procedure time for first-pass cannulation, procedure time for overall cannulation, number of attempts, patient satisfaction, and overall complications. We used GRADE to assess the certainty of the evidence.  Placing a peripheral intravenous line in individuals can be classed as 'difficult', 'moderate', or 'easy'. We use the terms 'difficult participants', 'moderate/moderately difficult participants' and 'easy participants' as shorthand to characterise the difficulty level in placing a peripheral line using the landmark method. We used the original studies' definitions of difficulty levels of peripheral intravenous cannulation with the landmark method. We analysed the results in these subgroups: 'difficult participants', 'moderate participants', and 'easy participants'. We did this because we expected the effect of ultrasound-guided peripheral venous cannulation to be largest in participants classed as 'difficult' and smaller in participants classed as 'moderate' and 'easy'.  MAIN RESULTS: We included 14 RCTs and two quasi-RCTs involving 2267 participants undergoing peripheral intravenous cannulation. Participants were classed as 'difficult' in 12 studies (880 participants), 'moderate' in one study (401 participants), and 'easy' in one study (596 participants). Two studies (390 participants) did not restrict by landmark method difficulty level. The overall risk of bias assessments ranged from low to high. We judged studies to be at high risk of bias mainly because of concerns about blinding for subjective outcomes. In difficult participants, ultrasound guidance increased the first-pass success of cannulation (risk ratio (RR) 1.50, 95% confidence interval (95% CI) 1.15 to 1.95; 10 studies, 815 participants; low-certainty evidence), and the overall success of cannulation (RR 1.40, 95% CI 1.10 to 1.77; 10 studies, 670 participants; very low-certainty evidence). There was no clear difference in pain (mean difference (MD) -0.20, 95% CI -1.13 to 0.72; 4 studies, 323 participants; very low-certainty evidence; numerical rating scale (NRS) 0 to 10 where 10 is maximum pain). Ultrasound guidance increased the procedure time for first-pass cannulation (MD 119.9 seconds, 95% CI 88.6 to 151.1; 2 studies, 219 participants; low-certainty evidence), and patient satisfaction (standardised mean difference (SMD) 0.49, 95% CI 0.07 to 0.92; 5 studies, 333 participants; very low-certainty evidence; NRS 0 to 10 where 10 is maximum satisfaction). Ultrasound guidance decreased the number of cannulation attempts (MD -0.33, 95% CI -0.64 to -0.02; 9 studies, 568 participants; very low-certainty evidence). Ultrasound guidance showed no clear difference in the procedure time for overall cannulation (MD -24.9 seconds, 95% CI -323.1 to 273.3; 8 studies, 413 participants; very low-certainty evidence) and overall complications (RR 0.64, 95% CI 0.37 to 1.10; 5 studies, 431 participants; low-certainty evidence).  In moderate participants, ultrasound guidance increased the first-pass success of cannulation (RR 1.14, 95% CI 1.02 to 1.27; 1 study, 401 participants; moderate-certainty evidence). No studies assessed the overall success of cannulation. There was no clear difference in pain (MD 0.10, 95% CI -0.47 to 0.67; 1 study, 401 participants; low-certainty evidence; NRS 0 to 10 where 10 is maximum pain). Ultrasound guidance increased the procedure time for first-pass cannulation (MD 95.2 seconds, 95% CI 72.8 to 117.6; 1 study, 401 participants; high-certainty evidence). Ultrasound guidance showed no clear difference in overall complications (RR 0.83, 95% CI 0.38 to 1.82; 1 study, 401 participants; moderate-certainty evidence). No studies assessed the procedure time for overall cannulation, number of cannulation attempts, or patient satisfaction.  In easy participants, ultrasound guidance decreased the first-pass success of cannulation (RR 0.89, 95% CI 0.85 to 0.94; 1 study, 596 participants; high-certainty evidence). No studies assessed the overall success of cannulation. Ultrasound guidance increased pain (MD 0.60, 95% CI 0.17 to 1.03; 1 study, 596 participants; moderate-certainty evidence; NRS 0 to 10 where 10 is maximum pain). Ultrasound guidance increased the procedure time for first-pass cannulation (MD 94.8 seconds, 95% CI 81.2 to 108.5; 1 study, 596 participants; high-certainty evidence). Ultrasound guidance showed no clear difference in overall complications (RR 2.48, 95% CI 0.90 to 6.87; 1 study, 596 participants; moderate-certainty evidence). No studies assessed the procedure time for overall cannulation, number of cannulation attempts, or patient satisfaction.  AUTHORS' CONCLUSIONS: There is very low- and low-certainty evidence that, compared to the landmark method, ultrasound guidance may benefit difficult participants for increased first-pass and overall success of cannulation, with no difference detected in pain. There is moderate- and low-certainty evidence that, compared to the landmark method, ultrasound guidance may benefit moderately difficult participants due to a small increased first-pass success of cannulation with no difference detected in pain. There is moderate- and high-certainty evidence that, compared to the landmark method, ultrasound guidance does not benefit easy participants: ultrasound guidance decreased the first-pass success of cannulation with no difference detected in overall success of cannulation and increased pain.

Inadequate reporting of adjudicators in open-label trials of anticancer drugs between 2017 and 2021: a methodological review.

OBJECTIVES: In open-label trials, the details of the adjudicators are essential to evaluate the risk of detection bias. We aimed to describe how the adjudicators of progression-free survival (PFS) and objective response rate (ORR) have been reported in open-label trials of anticancer drugs. STUDY DESIGN AND SETTING: A literature search was conducted using MEDLINE via PubMed. We included open-label, parallel-group superiority randomized trials that investigated the PFS and ORR of anticancer drugs for solid tumors. After screening based on the titles and abstracts, 200 articles were randomly selected from 2017 to 2021. The researchers independently checked the eligibility and collected the adjudicators' information in the protocol, registry, and original article. RESULTS: One hundred fifty five studies reported the PFS and ORR. Approximately half of the studies did not report adjudicators (47.7% in PFS and 47.6% in ORR) in the published articles. The inconsistency between the protocol/registry and the published article was 31.0% for PFS and 33.5% for ORR. The prespecified outcomes were not reported in 5.2% of the studies evaluating PFS and 4.5% evaluating ORR. CONCLUSION: This methodological review found that adjudicators were poorly and inconsistently reported between the protocol/registry and the final publication in open-label trials of anticancer drugs.

Prediction models for severe manifestations and mortality due to COVID-19: A systematic review.

BACKGROUND: Throughout 2020, the coronavirus disease 2019 (COVID-19) has become a threat to public health on national and global level. There has been an immediate need for research to understand the clinical signs and symptoms of COVID-19 that can help predict deterioration including mechanical ventilation, organ support, and death. Studies thus far have addressed the epidemiology of the disease, common presentations, and susceptibility to acquisition and transmission of the virus; however, an accurate prognostic model for severe manifestations of COVID-19 is still needed because of the limited healthcare resources available. OBJECTIVE: This systematic review aims to evaluate published reports of prediction models for severe illnesses caused COVID-19. METHODS: Searches were developed by the primary author and a medical librarian using an iterative process of gathering and evaluating terms. Comprehensive strategies, including both index and keyword methods, were devised for PubMed and EMBASE. The data of confirmed COVID-19 patients from randomized control studies, cohort studies, and case-control studies published between January 2020 and May 2021 were retrieved. Studies were independently assessed for risk of bias and applicability using the Prediction Model Risk Of Bias Assessment Tool (PROBAST). We collected study type, setting, sample size, type of validation, and outcome including intubation, ventilation, any other type of organ support, or death. The combination of the prediction model, scoring system, performance of predictive models, and geographic locations were summarized. RESULTS: A primary review found 445 articles relevant based on title and abstract. After further review, 366 were excluded based on the defined inclusion and exclusion criteria. Seventy-nine articles were included in the qualitative analysis. Inter observer agreement on inclusion 0.84 (95%CI 0.78-0.89). When the PROBAST tool was applied, 70 of the 79 articles were identified to have high or unclear risk of bias, or high or unclear concern for applicability. Nine studies reported prediction models that were rated as low risk of bias and low concerns for applicability. CONCLUSION: Several prognostic models for COVID-19 were identified, with varying clinical score performance. Nine studies that had a low risk of bias and low concern for applicability, one from a general public population and hospital setting. The most promising and well-validated scores include Clift et al.,15 and Knight et al.,18 which seem to have accurate prediction models that clinicians can use in the public health and emergency department setting.

High variability in results and methodological quality among overlapping systematic reviews on the same topics in surgery: a meta-epidemiological study.

BACKGROUND: Redundant publication of systematic reviews and meta-analyses (SRs/MAs) on the same topic presents an increasing burden for clinicians. The aim of this study was to describe variabilities in effect size and methodological quality of overlapping surgery-related SRs/MAs and to investigate factors associated with their postpublication citations. METHODS: PubMed/MEDLINE was searched to identify SRs/MAs of RCTs on thoracoabdominal surgeries published in 2015. Previous SRs/MAs on the same topics published within the preceding 5 years (2011-2015) were identified and 5-year citation counts (through to 2020) were evaluated. Discrepancies in pooled effect sizes and their methodological quality using A Measurement Tool to Assess Systematic Reviews (AMSTAR) among overlapping SRs/MAs were assessed. The SR/MA-level factors associated with 5-year citation counts were explored, using a mixed-effects regression model with a random intercept for surgical topics. RESULTS: A total of 57 surgery-related SRs/MAs (48 topics) published in 2015 were identified, and 146 SRs/MAs had overlapping publications on 29 topics (60.4 per cent of all topics) in the preceding 5 years. There was considerable variability in methodological quality of SRs/MAs and coverage probability for relevant RCTs, resulting in discrepant effect size estimates for the same topic. High quality (AMSTAR score 8-11) was independently associated with higher 5-year citation counts (coefficient = 32.82; 95 per cent c.i. 15.63 to 50.02; P < 0.001). CONCLUSION: Overlapping SRs/MAs with high variability in results and methodological quality were common in surgery. A high-quality SR/MA score was an independent predictor of more frequent citations. Researchers and journal editors should concentrate their efforts on limiting publications to higher-quality reviews.

Five Key Papers About Emergency Department Fall Evaluation: A Curated Collection for Emergency Physicians.

The evaluation of patients who have experienced a fall has been an integral part of geriatric emergency care. All physicians who engage in the care of the geriatric population in acute settings need to familiarize themselves with the current literature on this topic. However, it can be challenging to navigate the large body of literature on this topic. The purpose of this article is to identify and summarize the key studies that can be helpful for faculty interested in an evidence-based fall evaluation. The authors compiled a list of key papers on emergency department (ED) based upon a structured literature search supplemented with suggestions by key informants and an open call on social media; 32 studies on ED evaluation were identified. Our authorship group then engaged in a modified Delphi technique to develop consensus on the most important studies about fall evaluation for emergency physicians. This process eventually resulted in the selection of the top five articles on fall evaluation. Additionally, we summarize these studies with regard to their relevance to emergency medicine (EM) trainees and junior faculty. Evaluation of older patients with a history of falls is a challenging but crucial component of EM training. We believe our review will be educational for junior and senior EM faculty to better understand these patients' care and to design an evidence-based practice.

A comprehensive validation of very early rule-out strategies for non-ST-segment elevation myocardial infarction in emergency departments: protocol for a multicentre prospective cohort study.

INTRODUCTION: Recent advances in troponin sensitivity enabled early and accurate judgement of ruling-out myocardial infarction, especially non-ST elevation myocardial infarction (NSTEMI) in emergency departments (EDs) with development of various prediction-rules and high-sensitive-troponin-based strategies (hs-troponin). Reliance on clinical impression, however, is still common, and it remains unknown which of these strategies is superior. Therefore, our objective in this prospective cohort study is to comprehensively validate the diagnostic accuracy of clinical impression-based strategies, prediction-rules and hs-troponin-based strategies for ruling-out NSTEMIs. METHODS AND ANALYSIS: In total, 1500 consecutive adult patients with symptoms suggestive of acute coronary syndrome will be prospectively recruited from five EDs in two tertiary-level, two secondary-level community hospitals and one university hospital in Japan. The study has begun in July 2018, and recruitment period will be about 1 year. A board-certified emergency physician will complete standardised case report forms, and independently perform a clinical impression-based risk estimation of NSTEMI. Index strategies to be compared will include the clinical impression-based strategy; prediction rules and hs-troponin-based strategies for the following types of troponin (Roche Elecsys hs-troponin T; Abbott ARCHITECT hs-troponin I; Siemens ADVIA Centaur hs-troponin I; Siemens ADVIA Centaur sensitive-troponin I). The reference standard will be the composite of type 1 MI and cardiac death within 30 days after admission to the ED. Outcome measures will be negative predictive value, sensitivity and effectiveness, defined as the proportion of patients categorised as low risk for NSTEMI. We will also evaluate inter-rater reliability of the clinical impression-based risk estimation. ETHICS AND DISSEMINATION: The study is approved by the Ethics Committees of the Kyoto University Graduate School and Faculty of Medicine and of the five hospitals where we will recruit patients. We will disseminate the study results through conference presentations and peer-reviewed journals.

Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology: A Systematic Review and Quantitative Analysis.

Importance: Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs. However, it is not clear if delay in progression leads to improved quality of life with or without overall survival benefit. Objective: To evaluate the association between PFS and health-related quality of life (HRQoL) in oncology through a systematic review and quantitative analysis of published randomized clinical trials. Eligible trials addressed oral, intravenous, intraperitoneal, or intrapleural chemotherapy or biological treatments, and reported PFS or health-related quality of life. Data Sources: For this systematic review and quantitative analysis of randomized clinical trials of patients with cancer, we searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 2000, through May 4, 2016. Study Selection: Paired reviewers independently screened citations, extracted data, and assessed risk of bias of included studies. Data Extraction and Synthesis: We examined the association of difference in median PFS duration (in months) between treatment groups with difference in global, physical, and emotional HRQoL scores between groups (standardized to a range of 0-100, with higher scores representing better HRQoL) using weighted simple regressions. Main Outcome and Measure: The association between PFS duration and HRQoL. Results: Of 35 960 records screened, 52 articles reporting on 38 randomized clinical trials involving 13 979 patients across 12 cancer types using 6 different HRQoL instruments were included. The mean (SD) difference in median PFS between the intervention and the control arms was 1.91 (3.35) months. The mean (SD) differences in change of HRQoL adjusted to per-month values were -0.39 (3.59) for the global domain, 0.26 (5.56) for the physical domain, and 1.08 (3.49) for the emotional domain. The slope of the association between the difference in median PFS and the difference in change for global HRQoL (n = 30 trials) was 0.12 (95% CI, -0.27 to 0.52); for physical HRQoL (n = 20 trials) it was -0.20 (95% CI, -0.62 to 0.23); and for emotional HRQoL (n = 13 trials) it was 0.78 (95% CI, -0.05 to 1.60). Conclusions and Relevance: We failed to find a significant association between PFS and HRQoL in cancer clinical trials. These findings raise questions regarding the assumption that interventions prolonging PFS also improve HRQoL in patients with cancer. Therefore, to ensure that patients are truly obtaining important benefit from cancer therapies, clinical trial investigators should measure HRQoL directly and accurately, ensuring adequate duration and follow-up.

Redundant systematic reviews on the same topic in surgery: a study protocol for a meta-epidemiological investigation.

INTRODUCTION: We are witnessing an explosive increase in redundant and overlapping publications of systematic reviews and meta-analyses (SRs/MAs) on the same topic, which often present conflicting results and interpretations, in the current medical literature. They represent wasted efforts on the part of investigators and peer reviewers and may confuse and possibly mislead clinicians and policymakers. Here, we present a protocol for a meta-epidemiological investigation to describe how often there are overlapping SRs/MAs on the same topic, to assess the quality of these multiple publications, and to investigate the causes of discrepant results between multiple SRs/MAs in the field of major surgery. METHODS AND ANALYSIS: We will use MEDLINE/PubMed to identify all SRs/MAs of randomised controlled trials (RCTs) published in 2015 regarding major surgical interventions. After identifying the 'benchmark' SRs/MAs published in 2015, a process of screening in MEDLINE will be carried out to identify the previous SRs/MAs of RCTs on the same topic that were published within 5 years of the 'benchmark' SRs/MAs. We will tabulate the number of previous SRs/MAs on the same topic of RCTs, and then describe their variations in numbers of RCTs included, sample sizes, effect size estimates and other characteristics. We will also assess the differences in quality of each SR/MA using A Measurement Tool to Assess Systematic Reviews (AMSTAR) score. Finally, we will investigate the potential reasons to explain the discrepant results between multiple SRs/MAs. ETHICS AND DISSEMINATION: No formal ethical approval and informed consent are required because this study will not collect primary individual data. The intended audiences of the findings include clinicians, healthcare researchers and policymakers. We will publish our findings as a scientific report in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: In PROSPERO CRD42017059077, March 2017.