Diagnostic management of acute pulmonary embolism: a prediction model based on a patient data meta-analysis.

AIMS: Risk stratification is used for decisions regarding need for imaging in patients with clinically suspected acute pulmonary embolism (PE). The aim was to develop a clinical prediction model that provides an individualized, accurate probability estimate for the presence of acute PE in patients with suspected disease based on readily available clinical items and D-dimer concentrations. METHODS AND RESULTS: An individual patient data meta-analysis was performed based on sixteen cross-sectional or prospective studies with data from 28 305 adult patients with clinically suspected PE from various clinical settings, including primary care, emergency care, hospitalized and nursing home patients. A multilevel logistic regression model was built and validated including ten a priori defined objective candidate predictors to predict objectively confirmed PE at baseline or venous thromboembolism (VTE) during follow-up of 30 to 90 days. Multiple imputation was used for missing data. Backward elimination was performed with a P-value <0.10. Discrimination (c-statistic with 95% confidence intervals [CI] and prediction intervals [PI]) and calibration (outcome:expected [O:E] ratio and calibration plot) were evaluated based on internal-external cross-validation. The accuracy of the model was subsequently compared with algorithms based on the Wells score and D-dimer testing. The final model included age (in years), sex, previous VTE, recent surgery or immobilization, haemoptysis, cancer, clinical signs of deep vein thrombosis, inpatient status, D-dimer (in µg/L), and an interaction term between age and D-dimer. The pooled c-statistic was 0.87 (95% CI, 0.85-0.89; 95% PI, 0.77-0.93) and overall calibration was very good (pooled O:E ratio, 0.99; 95% CI, 0.87-1.14; 95% PI, 0.55-1.79). The model slightly overestimated VTE probability in the lower range of estimated probabilities. Discrimination of the current model in the validation data sets was better than that of the Wells score combined with a D-dimer threshold based on age (c-statistic 0.73; 95% CI, 0.70-0.75) or structured clinical pretest probability (c-statistic 0.79; 95% CI, 0.76-0.81). CONCLUSION: The present model provides an absolute, individualized probability of PE presence in a broad population of patients with suspected PE, with very good discrimination and calibration. Its clinical utility needs to be evaluated in a prospective management or impact study. REGISTRATION: PROSPERO ID 89366.

Safety and Efficiency of Diagnostic Strategies for Ruling Out Pulmonary Embolism in Clinically Relevant Patient Subgroups : A Systematic Review and Individual-Patient Data Meta-analysis.

BACKGROUND: How diagnostic strategies for suspected pulmonary embolism (PE) perform in relevant patient subgroups defined by sex, age, cancer, and previous venous thromboembolism (VTE) is unknown. PURPOSE: To evaluate the safety and efficiency of the Wells and revised Geneva scores combined with fixed and adapted D-dimer thresholds, as well as the YEARS algorithm, for ruling out acute PE in these subgroups. DATA SOURCES: MEDLINE from 1 January 1995 until 1 January 2021. STUDY SELECTION: 16 studies assessing at least 1 diagnostic strategy. DATA EXTRACTION: Individual-patient data from 20 553 patients. DATA SYNTHESIS: Safety was defined as the diagnostic failure rate (the predicted 3-month VTE incidence after exclusion of PE without imaging at baseline). Efficiency was defined as the proportion of individuals classified by the strategy as "PE considered excluded" without imaging tests. Across all strategies, efficiency was highest in patients younger than 40 years (47% to 68%) and lowest in patients aged 80 years or older (6.0% to 23%) or patients with cancer (9.6% to 26%). However, efficiency improved considerably in these subgroups when pretest probability-dependent D-dimer thresholds were applied. Predicted failure rates were highest for strategies with adapted D-dimer thresholds, with failure rates varying between 2% and 4% in the predefined patient subgroups. LIMITATIONS: Between-study differences in scoring predictor items and D-dimer assays, as well as the presence of differential verification bias, in particular for classifying fatal events and subsegmental PE cases, all of which may have led to an overestimation of the predicted failure rates of adapted D-dimer thresholds. CONCLUSION: Overall, all strategies showed acceptable safety, with pretest probability-dependent D-dimer thresholds having not only the highest efficiency but also the highest predicted failure rate. From an efficiency perspective, this individual-patient data meta-analysis supports application of adapted D-dimer thresholds. PRIMARY FUNDING SOURCE: Dutch Research Council. (PROSPERO: CRD42018089366).

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

BACKGROUND: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING: Eighteen sites between February 2011 and February 2021. PATIENTS: Patients with isolated subsegmental pulmonary embolism. INTERVENTION: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION: The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Ruling out pulmonary embolism across different healthcare settings: A systematic review and individual patient data meta-analysis.

BACKGROUND: The challenging clinical dilemma of detecting pulmonary embolism (PE) in suspected patients is encountered in a variety of healthcare settings. We hypothesized that the optimal diagnostic approach to detect these patients in terms of safety and efficiency depends on underlying PE prevalence, case mix, and physician experience, overall reflected by the type of setting where patients are initially assessed. The objective of this study was to assess the capability of ruling out PE by available diagnostic strategies across all possible settings. METHODS AND FINDINGS: We performed a literature search (MEDLINE) followed by an individual patient data (IPD) meta-analysis (MA; 23 studies), including patients from self-referral emergency care (n = 12,612), primary healthcare clinics (n = 3,174), referred secondary care (n = 17,052), and hospitalized or nursing home patients (n = 2,410). Multilevel logistic regression was performed to evaluate diagnostic performance of the Wells and revised Geneva rules, both using fixed and adapted D-dimer thresholds to age or pretest probability (PTP), for the YEARS algorithm and for the Pulmonary Embolism Rule-out Criteria (PERC). All strategies were tested separately in each healthcare setting. Following studies done in this field, the primary diagnostic metrices estimated from the models were the "failure rate" of each strategy-i.e., the proportion of missed PE among patients categorized as "PE excluded" and "efficiency"-defined as the proportion of patients categorized as "PE excluded" among all patients. In self-referral emergency care, the PERC algorithm excludes PE in 21% of suspected patients at a failure rate of 1.12% (95% confidence interval [CI] 0.74 to 1.70), whereas this increases to 6.01% (4.09 to 8.75) in referred patients to secondary care at an efficiency of 10%. In patients from primary healthcare and those referred to secondary care, strategies adjusting D-dimer to PTP are the most efficient (range: 43% to 62%) at a failure rate ranging between 0.25% and 3.06%, with higher failure rates observed in patients referred to secondary care. For this latter setting, strategies adjusting D-dimer to age are associated with a lower failure rate ranging between 0.65% and 0.81%, yet are also less efficient (range: 33% and 35%). For all strategies, failure rates are highest in hospitalized or nursing home patients, ranging between 1.68% and 5.13%, at an efficiency ranging between 15% and 30%. The main limitation of the primary analyses was that the diagnostic performance of each strategy was compared in different sets of studies since the availability of items used in each diagnostic strategy differed across included studies; however, sensitivity analyses suggested that the findings were robust. CONCLUSIONS: The capability of safely and efficiently ruling out PE of available diagnostic strategies differs for different healthcare settings. The findings of this IPD MA help in determining the optimum diagnostic strategies for ruling out PE per healthcare setting, balancing the trade-off between failure rate and efficiency of each strategy.

Association of Accuracy, Conclusions, and Reporting Completeness With Acceptance by Radiology Conferences and Journals.

BACKGROUND: Preferential publication of studies with positive findings can lead to overestimation of diagnostic test accuracy (i.e. publication bias). Understanding the contribution of the editorial process to publication bias could inform interventions to optimize the evidence guiding clinical decisions. PURPOSE/HYPOTHESIS: To evaluate whether accuracy estimates, abstract conclusion positivity, and completeness of abstract reporting are associated with acceptance to radiology conferences and journals. STUDY TYPE: Meta-research. POPULATION: Abstracts submitted to radiology conferences (European Society of Gastrointestinal and Abdominal Radiology (ESGAR) and International Society for Magnetic Resonance in Medicine (ISMRM)) from 2008 to 2018 and manuscripts submitted to radiology journals (Radiology, Journal of Magnetic Resonance Imaging [JMRI]) from 2017 to 2018. Primary clinical studies evaluating sensitivity and specificity of a diagnostic imaging test in humans with available editorial decisions were included. ASSESSMENT: Primary variables (Youden's index [YI > 0.8 vs. <0.8], abstract conclusion positivity [positive vs. neutral/negative], number of reported items on the Standards for Reporting of Diagnostic Accuracy Studies [STARD] for Abstract guideline) and confounding variables (prospective vs. retrospective/unreported, sample size, study duration, interobserver agreement assessment, subspecialty, modality) were extracted. STATISTICAL TESTS: Multivariable logistic regression to obtain adjusted odds ratio (OR) as a measure of the association between the primary variables and acceptance by radiology conferences and journals; 95% confidence intervals (CIs) and P-values were obtained; the threshold for statistical significance was P < 0.05. RESULTS: A total of 1000 conference abstracts (500 ESGAR and 500 ISMRM) and 1000 journal manuscripts (505 Radiology and 495 JMRI) were included. Conference abstract acceptance was not significantly associated with YI (adjusted OR = 0.97 for YI > 0.8; CI = 0.70-1.35), conclusion positivity (OR = 1.21 for positive conclusions; CI = 0.75-1.90) or STARD for Abstracts adherence (OR = 0.96 per unit increase in reported items; CI = 0.82-1.18). Manuscripts with positive abstract conclusions were less likely to be accepted by radiology journals (OR = 0.45; CI = 0.24-0.86), while YI (OR = 0.85; CI = 0.56-1.29) and STARD for Abstracts adherence (OR = 1.06; CI = 0.87-1.30) showed no significant association. Positive conclusions were present in 86.7% of submitted conference abstracts and 90.2% of journal manuscripts. DATA CONCLUSION: Diagnostic test accuracy studies with positive findings were not preferentially accepted by the evaluated radiology conferences or journals. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Risk Assessment Models for Thrombosis and Anticoagulant-Related Bleeding in Ambulatory Cancer Patients.

Cancer patients have a high risk of developing venous thromboembolism and arterial thrombosis, along with an increased risk of anticoagulant-related bleeding with primary and secondary prophylaxis of cancer-associated thrombosis. Decisions on initiation, dosing, and duration of anticoagulant therapy for prevention and treatment of cancer-associated thrombosis are challenging, as clinicians have to balance patients' individual risk of (recurrent) thrombosis against the risk of bleeding complications. For this purpose, several dedicated risk assessment models for venous thromboembolism in cancer patients have been suggested. However, most of these scores perform poorly and have received limited to no validation. For bleeding and arterial thrombosis, no risk scores have been developed specifically for cancer patients, and treatment decisions remain based on clinical gestalt and rough and unstructured estimation of the risks. The aims of this review are to summarize the characteristics and performance of risk assessment scores for (recurrent) venous thromboembolism and discuss available data on risk assessment for bleeding and arterial thrombosis in the cancer population. This summary can help clinicians in daily practice to make a balanced decision when considering the use of risk assessment models for cancer-associated venous thromboembolism. Future research attempts should aim at improving risk assessment for arterial thrombosis and anticoagulant-related bleeding in cancer patients.

How I treat cancer-associated venous thromboembolism.

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a common complication of cancer and is associated with significant morbidity and mortality. Several cancer-related risk factors contribute to the development of VTE including cancer type and stage, chemotherapy, surgery, and patient-related factors such as advanced age and immobilization. Patients with cancer frequently undergo diagnostic imaging scans for cancer staging and treatment response evaluation, which is increasing the underlying risk of VTE detection. The management of cancer-associated VTE is challenging. Over the years, important advances have been made and, recently, randomized controlled trials have been published helping clinicians' management of this patient population. In this review, we will discuss common cancer-associated VTE scenarios and critically review available evidence to guide treatment decisions.

Clinical implications of incidental venous thromboembolism in cancer patients.

INTRODUCTION: In cancer patients, current guidance suggests similar treatment for incidental and symptomatic venous thromboembolism (VTE), mainly based on retrospective data. We aimed to evaluate anticoagulant therapy in cancer patients with incidental and symptomatic VTE. METHODS: The Hokusai VTE Cancer Study was a randomised controlled trial comparing edoxaban with dalteparin for cancer-associated VTE. The primary outcome was the composite of first recurrent VTE or major bleeding. Secondary outcomes included major bleeding, recurrent VTE and mortality. Outcomes in patients with incidental and symptomatic VTE were evaluated during the 12-month study period. RESULTS: 331 patients with incidental VTE and 679 patients with symptomatic VTE were enrolled, of whom the index event was confirmed by an independent radiologist. Median durations of anticoagulant treatment were 195 and 189 days, respectively. In patients with incidental VTE, the primary outcome occurred in 12.7% of patients, major bleeding in 6.6% of patients and recurrent VTE in 7.9% of patients. Out of the 26 VTE recurrences in patients with incidental VTE, five (31%) were incidental, seven (44%) were symptomatic and four (25%) were deaths for which pulmonary embolism could not be ruled out. In patients with symptomatic VTE, the primary outcome occurred in 13.8% of patients, major bleeding in 4.9% of patients and recurrent VTE in 10.9% of patients. All-cause mortality was similar in both groups. CONCLUSION: Clinical adverse outcomes are substantial in both cancer patients with incidental and symptomatic VTE, supporting current guideline recommendations that suggest treating incidental VTE in the same manner as symptomatic VTE.

Publication bias in diagnostic imaging: conference abstracts with positive conclusions are more likely to be published.

OBJECTIVE: To evaluate whether imaging diagnostic test accuracy conference abstracts with positive conclusions or titles are more likely to reach full-text publication than those with negative (or neutral) conclusions or titles. METHODS: Diagnostic accuracy research abstracts were included if they were presented at the 2011 or 2012 Radiological Society of North America conference. Full-text publication status at 5 years post conference abstract submission was determined. Conclusion and title positivity of conference abstracts were extracted, as well as potential confounding factors. The associations of conclusion and title positivity with publication status at 5 years post conference abstract submission were assessed using a multivariable logistic regression model. Conditional odds ratios were calculated to express the strength of associations, adjusting for the confounders. RESULTS: In total, 282/400 (71%) of included conference abstracts reached full-text publication. A total of 246 out of 337 (74%) conference abstracts with positive conclusions resulted in full-text publications, compared with 26/48 (54%) with neutral conclusions and 5/15 (33%) with negative conclusions. In multivariable logistic regression, conclusion positivity was significantly associated with full-text publication (odds ratio 3.6; 95% CI 1.9-6.7 for conference abstracts with positive conclusions, compared with those with non-positive conclusions); this did not apply to title positivity (odds ratio 1.2; 95% CI 0.47-3.0). CONCLUSION: Imaging conference abstracts with positive conclusions were more likely to be published as full-text articles. Title positivity was not associated with publication. This preferential publication pattern may lead to an overrepresentation of positive studies in the literature. An overrepresentation of positive studies may contribute to inflated estimates of test accuracy and has the potential to adversely influence patient care. KEY POINTS: • Imaging diagnostic test accuracy conference abstracts with positive conclusions were more likely to be reported as full-text articles than those with non-positive conclusions. • The majority (75%) of imaging diagnostic test accuracy conference abstracts with positive conclusions were published, compared with only 53% and 33% with neutral and negative conclusions, respectively. • Conclusion positivity remained associated with the full-text publication of conference abstracts when controlling for multiple potential confounding variables.

Completeness of Reporting of Systematic Reviews of Diagnostic Test Accuracy Based on the PRISMA-DTA Reporting Guideline.

BACKGROUND: We evaluated the completeness of reporting of diagnostic test accuracy (DTA) systematic reviews using the recently developed Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA)-DTA guidelines. METHODS: MEDLINE® was searched for DTA systematic reviews published October 2017 to January 2018. The search time span was modulated to reach the desired sample size of 100 systematic reviews. Reporting on a per-item basis using PRISMA-DTA was evaluated. RESULTS: One hundred reviews were included. Mean reported items were 18.6 of 26 (71%; SD = 1.9) for PRISMA-DTA and 5.5 of 11 (50%; SD = 1.2) for PRISMA-DTA for abstracts. Items in the results were frequently reported. Items related to protocol registration, characteristics of included studies, results synthesis, and definitions used in data extraction were infrequently reported. Infrequently reported items from PRISMA-DTA for abstracts included funding information, strengths and limitations, characteristics of included studies, and assessment of applicability. Reporting completeness was higher in higher impact factor journals (18.9 vs 18.1 items; P = 0.04), studies that cited PRISMA (18.9 vs 17.7 items; P = 0.003), or used supplementary material (19.1 vs 18.0 items; P = 0.004). Variability in reporting was associated with author country (P = 0.04) but not journal (P = 0.6), abstract word count limitations (P = 0.9), PRISMA adoption (P = 0.2), structured abstracts (P = 0.2), study design (P = 0.8), subspecialty area (P = 0.09), or index test (P = 0.5). Abstracts with a higher word count were more informative (R = 0.4; P < 0.001). No association with word counts was observed for full-text reports (R = -0.03; P = 0.06). CONCLUSIONS: Recently published reports of DTA systematic reviews are not fully informative when evaluated against the PRISMA-DTA guidelines. These results should guide knowledge translation strategies, including journal level (e.g., PRISMA-DTA adoption, increased abstract word count, and use of supplementary material) and author level (PRISMA-DTA citation awareness) strategies.

Best practices for MRI systematic reviews and meta-analyses.

As defined by the Cochrane Collaboration, a systematic review is a review of evidence with a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant primary research, and to extract and analyze data from the studies that are included in the review. Meta-analysis is a statistical method to combine the results from primary studies that accounts for sample size and variability to provide a summary measure of the studied outcome. Systematic reviews of diagnostic test accuracy present unique methodological and reporting challenges not present in systematic reviews of interventions. This review provides guidance and further resources highlighting current best practices in methodology and reporting of systematic reviews of diagnostic test accuracy, with a specific focus on challenges and opportunities for MRI imaging. Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Comparative reviews of diagnostic test accuracy in imaging research: evaluation of current practices.

PURPOSE: The purpose of this methodological review was to determine the extent to which comparative imaging systematic reviews of diagnostic test accuracy (DTA) use primary studies with comparative or non-comparative designs. METHODS: MEDLINE was used to identify DTA systematic reviews published in imaging journals between January 2000 and May 2018. INCLUSION CRITERIA: systematic reviews comparing at least two index tests (one of which was imaging-based); review characteristics were extracted. Study design and other characteristics of primary studies included in the systematic reviews were evaluated. RESULTS: One hundred three comparative imaging reviews were included; 11 (11%) included only comparative studies, 12 (11%) included only non-comparative primary studies, and 80 (78%) included both comparative and non-comparative primary studies. For reviews containing both comparative and non-comparative primary studies, the median proportion of non-comparative primary studies was 81% (IQR 57-90%). Of 92 reviews that included non-comparative primary studies, 86% did not recognize this as a limitation. Furthermore, among 4182 primary studies, 3438 (82%) were non-comparative and 744 (18%) were comparative in design. CONCLUSION: Most primary studies included in comparative imaging reviews are non-comparative in design and awareness of the risk of bias associated with this is low. This may lead to incorrect conclusions about the relative accuracy of diagnostic tests and be counter-productive for informing guidelines and funding decisions about imaging tests. KEY POINTS: • Few comparative accuracy imaging reviews include only primary studies with optimal comparative study designs. Among the rest, few recognize the risk of bias conferred from inclusion of primary studies with non-comparative designs. • The demand for accurate comparative accuracy data combined with minimal awareness of valid comparative study designs may lead to counter-productive research and inadequately supported clinical decisions for diagnostic tests. • Using comparative accuracy imaging reviews with a high risk of bias to inform guidelines and funding decisions may have detrimental impacts on patient care.

Citation bias in imaging research: are studies with higher diagnostic accuracy estimates cited more often?

OBJECTIVES: To assess the risk of citation bias in imaging diagnostic accuracy research by evaluating whether studies with higher accuracy estimates are cited more frequently than those with lower accuracy estimates. METHODS: We searched Medline for diagnostic accuracy meta-analyses published in imaging journals from January 2005 to April 2016. Primary studies from the meta-analyses were screened; those assessing the diagnostic accuracy of an imaging test and reporting sensitivity and specificity were eligible for inclusion. Studies not indexed in Web of Science, duplicates, and inaccessible articles were excluded. Topic (modality/subspecialty), study design, sample size, journal impact factor, publication date, times cited, sensitivity, and specificity were extracted for each study. Negative binomial regression was performed to evaluate the association of citation rate (times cited per month since publication) with Youden's index (sensitivity + specificity -1), highest sensitivity, and highest specificity, controlling for the potential confounding effects of modality, subspecialty, impact factor, study design, sample size, and source meta-analysis. RESULTS: There were 1016 primary studies included. A positive association between Youden's index and citation rate was present, with a regression coefficient of 0.33 (p = 0.016). The regression coefficient for sensitivity was 0.41 (p = 0.034), and for specificity, 0.32 (p = 0.15). CONCLUSION: A positive association exists between diagnostic accuracy estimates and citation rates, indicating that there is evidence of citation bias in imaging diagnostic accuracy literature. Overestimation of imaging test accuracy may contribute to patient harm from incorrect interpretation of test results. KEY POINTS: • Studies with higher accuracy estimates may be cited more frequently than those with lower accuracy estimates. • This citation bias could lead clinicians, reviews, and clinical practice guidelines to overestimate the accuracy of imaging tests, contributing to patient harm from incorrect interpretation of test results.

Selective Citation Practices in Imaging Research: Are Diagnostic Accuracy Studies With Positive Titles and Conclusions Cited More Often?

OBJECTIVE. The purpose of this study was to examine the existence of selective citation practices in the imaging literature by assessing whether diagnostic accuracy studies with positive titles or conclusions are cited more frequently than those with negative (or neutral) titles or conclusions. MATERIALS AND METHODS. MEDLINE was searched for meta-analyses of diagnostic accuracy studies published in imaging journals from January 2005 to April 2016. Primary studies from the meta-analyses were screened for eligibility. Titles and conclusions were classified independently in duplicate. A negative binomial regression analysis controlling for several confounding variables was performed to obtain regression coefficients; p values were obtained via likelihood ratio testing. RESULTS. A total of 995 primary studies were included. Fifty-one titles (5.1%) and 782 conclusions (78.6%) were positive or positive with qualifiers; 942 titles (94.7%) and 127 conclusions (12.8%) were neutral; and two titles (0.02%) and 86 conclusions (8.6%) were negative. Studies with positive, neutral, and negative titles were cited a mean of 0.66, 0.50, and 0.06 times per month. Studies with positive, neutral, and negative conclusions were cited a mean of 0.54, 0.42, and 0.34 times per month. Regression coefficients were 1.10 (95% CI, -0.08 to 2.20) and 0.91 (95% CI, -0.27 to 2.00) for positive and neutral titles, relative to negative titles. Regression coefficients were 0.19 (95% CI, 0.03-0.35) and 0.08 (95% CI, -0.12 to 0.27) for positive and neutral conclusions, relative to negative conclusions. Title and conclusion positivity demonstrated positive association with citation rate (p = 0.031 for both). CONCLUSION. Studies with positive titles or conclusions are cited more frequently in imaging diagnostic accuracy literature. This difference may contribute to overestimation of the accuracy of a test and, consequently, suboptimal patient outcomes.

Venous Thromboembolism: Advances in Diagnosis and Treatment.

IMPORTANCE: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common and potentially fatal disease. OBJECTIVE: To summarize the advances in diagnosis and treatment of VTE of the past 5 years. EVIDENCE REVIEW: A systematic search was conducted in EMBASE Classic, EMBASE, Ovid MEDLINE, and other nonindexed citations using broad terms for diagnosis and treatment of VTE to find systematic reviews and meta-analyses, randomized trials, and prospective cohort studies published between January 1, 2013, and July 31, 2018. The 10th edition of the American College of Chest Physicians Antithrombotic Therapy Guidelines was screened to identify additional studies. Screening of titles, abstracts, and, subsequently, full-text articles was performed in duplicate, as well as data extraction and risk-of-bias assessment of the included articles. FINDINGS: Thirty-two articles were included in this review. The application of an age-adjusted D-dimer threshold in patients with suspected PE has increased the number of patients in whom imaging can be withheld. The Pulmonary Embolism Rule-Out Criteria safely exclude PE when the pretest probability is low. The introduction of direct oral anticoagulants has allowed for a simplified treatment of VTE with a lower risk of bleeding regardless of etiology or extent of the VTE (except for massive PE) and has made extended secondary prevention more acceptable. Thrombolysis is best reserved for patients with massive PE or those with DVT and threatened limb loss. Insertion of inferior vena cava filters should be avoided unless anticoagulation is absolutely contraindicated in patients with recent acute VTE. Graduated compression stockings are no longer recommended to treat DVT but may be used when acute or chronic symptoms are present. Anticoagulation may no longer be indicated for patients with isolated distal DVT at low risk of recurrence. CONCLUSIONS AND RELEVANCE: Over the past 5 years, substantial progress has been made in VTE management, allowing for diagnostic and therapeutic strategies tailored to individual patient characteristics, preferences, and values.

Risk assessment tools for bleeding in patients with unprovoked venous thromboembolism: an analysis of the PLATO-VTE study.

BACKGROUND: Guidelines suggest indefinite anticoagulation after unprovoked venous thromboembolism (VTE) unless the bleeding risk is high, yet there is no consistent guidance on assessing bleeding risk. OBJECTIVES: This study aimed to evaluate the performance of 5 bleeding risk tools (RIETE, VTE-BLEED, CHAP, VTE-PREDICT, and ABC-Bleeding). METHODS: PLATO-VTE, a prospective cohort study, included patients aged ≥40 years with a first unprovoked VTE. Risk estimates were calculated at VTE diagnosis and after 3 months of treatment. Primary outcome was clinically relevant bleeding, as per International Society on Thrombosis and Haemostasis criteria, during 24-month follow-up. Discrimination was assessed by the area under the receiver operating characteristic curve (AUROC). Patients were classified as having a "high risk" and "non-high risk" of bleeding according to predefined thresholds; bleeding risk in both groups was compared by hazard ratios (HRs). RESULTS: Of 514 patients, 38 (7.4%) had an on-treatment bleeding. AUROCs were 0.58 (95% CI, 0.48-0.68) for ABC-Bleeding, 0.56 (95% CI, 0.46-0.66) for RIETE, 0.53 (95% CI, 0.43-0.64) for CHAP, 0.50 (95% CI, 0.41-0.59) for VTE-BLEED, and 0.50 (95% CI, 0.40-0.60) for VTE-PREDICT. The proportion of high-risk patients ranged from 1.4% with RIETE to 36.9% with VTE-BLEED. The bleeding incidence in the high-risk groups ranged from 0% with RIETE to 13.0% with ABC-Bleeding, and in the non-high-risk groups, it varied from 7.7% with ABC-Bleeding to 9.6% with RIETE. HRs ranged from 0.93 (95% CI, 0.46-1.9) for VTE-BLEED to 1.67 (95% CI, 0.86-3.2) for ABC-Bleeding. Recalibration at 3-month follow-up did not alter the results. CONCLUSION: In this cohort, discrimination of currently available bleeding risk tools was poor. These data do not support their use in patients with unprovoked VTE.

Definitions of fatal bleeding in clinical studies evaluating anticoagulant treatment for venous thromboembolism: A scoping review.

BACKGROUND: Fatal bleeding is a component of the primary safety outcome in most studies evaluating anticoagulation for venous thromboembolism (VTE), but a standardized definition for fatal bleeding is lacking. OBJECTIVES: To summarize definitions of fatal bleeding and describe the range of case-fatality rates of major bleeding in VTE studies. METHODS: MEDLINE, Embase, and CENTRAL databases were searched from January 2008 to July 2021 for prospective studies that enrolled patients with VTE and evaluated the efficacy/safety of anticoagulation for VTE treatment or included fatal or major bleeding as primary outcome. Two authors independently performed study selection and data extraction. The primary outcome was the definition of fatal bleeding. The secondary outcome was the case-fatality rate of major bleeding. Data were analyzed using descriptive statistics. RESULTS: Of 4911 records identified, we included 132 articles representing 89 distinct studies. Twenty-seven (20%) articles and 7 of 89 (8%) studies reported a definition of fatal bleeding. Overall, we identified 3 different types of definitions that were either on the basis of a specific time interval between bleeding and death, bleeding location (intracranial) or clinical presentation (hemodynamic deterioration), or mainly relied on the judgment of the adjudication committee to determine the cause of death. The case-fatality rate of major bleeding ranged from 0 to 60% (median, 9.1%; interquartile range, 2.8%-18%). CONCLUSION: Less than 10% of studies assessing anticoagulant treatment for VTE reported a definition for fatal bleeding. The lack of a (standardized) definition for fatal bleeding may lead to inaccurate estimates of the risk of fatal bleeding, particularly when compared across studies.

Accuracy and interrater agreement of death event adjudications by physician trainees: validation of the ISTH definition of pulmonary embolism-related death in an autopsy cohort.

BACKGROUND: We previously determined good agreement and high specificity of the International Society on Thrombosis and Haemostasis (ISTH) definition of pulmonary embolism (PE)-related death among an expert central adjudication committee (CAC). CACs are often composed of experts in the corresponding research field. Involving physician trainees in CACs would allow investigators to divide the workload and foster trainees' research experience. OBJECTIVE: To evaluate the accuracy of the ISTH definition of PE-related death for PE- versus non-PE-related deaths as confirmed by autopsy and its interrater agreement among physician trainees. METHODS: This retrospective autopsy cohort included all patients with PE-related deaths between January 2010 and July 2019 as well as patients who died in 2018 from a cause other than PE at the New York-Presbyterian Hospital. Based on premortem clinical summaries, two physician trainees independently determined the cause of death using the ISTH definition of PE-related death. We calculated the sensitivity and specificity of the ISTH definition to identify autopsy-confirmed PE-related death and its interrater agreement. RESULTS: Overall, 126 death events were adjudicated (median age, 68 years; 60 [48%] women), of which 29 (23%) were due to PE, as confirmed by autopsy. Sensitivity and specificity of the ISTH definition for autopsy-confirmed PE-related death was 48% (95% CI, 29-67) and 100% (95% CI, 96-100), respectively. Interrater reliability for PE-related death was good (percentage agreement, 93%; 95% CI, 87-96, Cohen's Kappa, 0.67; 95% CI, 44-85). CONCLUSION: Our findings are consistent with our previous validation study. They further support the use of the ISTH definition of PE-related death and revealed high agreement between adjudicators with varied experience.

Accuracy of physicians' intuitive risk estimation in the diagnostic management of pulmonary embolism: an individual patient data meta-analysis.

BACKGROUND: In patients clinically suspected of having pulmonary embolism (PE), physicians often rely on intuitive estimation ("gestalt") of PE presence. Although shown to be predictive, gestalt is criticized for its assumed variation across physicians and lack of standardization. OBJECTIVES: To assess the diagnostic accuracy of gestalt in the diagnosis of PE and gain insight into its possible variation. METHODS: We performed an individual patient data meta-analysis including patients suspected of having PE. The primary outcome was diagnostic accuracy of gestalt for the diagnosis of PE, quantified as risk ratio (RR) between gestalt and PE based on 2-stage random-effect log-binomial meta-analysis regression as well as gestalts' sensitivity and specificity. The variability of these measures was explored across different health care settings, publication period, PE prevalence, patient subgroups (sex, heart failure, chronic lung disease, and items of the Wells score other than gestalt), and age. RESULTS: We analyzed 20 770 patients suspected of having PE from 16 original studies. The prevalence of PE in patients with and without a positive gestalt was 28.8% vs 9.1%, respectively. The overall RR was 3.02 (95% CI, 2.35-3.87), and the overall sensitivity and specificity were 74% (95% CI, 68%-79%) and 61% (95% CI, 53%-68%), respectively. Although variation was observed across individual studies (I2, 90.63%), the diagnostic accuracy was consistent across all subgroups and health care settings. CONCLUSION: A positive gestalt was associated with a 3-fold increased risk of PE in suspected patients. Although variation was observed across studies, the RR of gestalt was similar across prespecified subgroups and health care settings, exemplifying its diagnostic value for all patients suspected of having PE.