Search

Background: Any surgical procedure carries a risk for venous thromboembolism (VTE), albeit variable. Improvements in medical and surgical practices and the shortening of care pathways due to the development of day surgery and enhanced recovery after surgery, have reduced the perioperative risk for VTE., Objective: A collaborative working group of experts in perioperative haemostasis updated in 2024 the recommendations for the Prevention of perioperative venous thromboembolism published in 2011., Methods: The addressed questions were defined by 40 experts (GIHP, SFAR, SFTH and SFMV) and formulated in a PICO format. They performed the literature review and formulated recommendations according to the Grading of GRADE system. Recommendations were then validated by a vote determining the strength of each recommendation. Of note, these recommendations do not cover all surgical specialties. Especially, thromboprophylaxis in cardiac surgery, neurosurgery and obstetrics is not addressed., Results: 78 recommendations were formalized into 17 sections, including patient-related VTE risk factors, types of surgery, extreme body weight, renal impairment, mechanical prophylaxis, distal deep vein thrombosis; 27 were found to have a high level of evidence (GRADE 1) and 41 a low level of evidence (GRADE 2) and 10 were expert opinion. All had strong agreement among the experts., Conclusions: These guidelines help to weigh the perioperative risk for VTE (which includes the risk associated to surgery and the patient-related risk) against the adverse effects of thromboprophylaxis, either pharmacological or mechanical. This includes particularly the bleeding risk induced by antithrombotic drugs as well as costs., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Limited language proficiency is an established barrier to research participation among racialized populations. While prior studies have highlighted the under-representation of racialized populations in venous thromboembolism (VTE) research, the impact of limited language proficiency as a reason for non-consent among eligible patients is unknown., Methods: We reviewed all prospective VTE studies conducted at a research-intensive academic thrombosis research program in Canada between 2014 and 2024. Studies with screening logs that systematically and consecutively captured eligibility assessment and reasons for non-consent were included. Primary outcome was non-consent of a screen-eligible patient due to limited language proficiency as the reported reason. We derived pooled estimates of non-consents due to limited language proficiency as a proportion of consented participants, and determined subgroup rates by phase of VTE management, associated medical conditions, and recruitment settings., Results: Screening logs of 28 studies with 22,057 screening events, 8,317 screen-eligible patients and 3,320 consented participants were included. For every 100 consented participants, 3.2 (95% CI 2.0 - 5.3) screen-eligible individuals were unable to be consented due to limited language proficiency. Rates of non-consent were highest in studies involving cancer (5.6 per 100 participants, 95% CI 2.9 - 10.4) and in studies recruiting patients from ambulatory settings outside of the thrombosis clinic (10.8 per 100 participants, 95% CI 4.8 - 22.6)., Conclusions: Language proficiency is a key barrier to VTE research participation. Urgent implementation of targeted interventions aimed at mitigating linguistic barriers is essential to ensure equitable opportunities for VTE research participation for racialized patients disproportionately affected by language proficiency., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) remains a malignancy with high rates of locoregional recurrence and poor prognosis for recurrent cases. Early detection of subclinical lesions is challenging but critical for effective patient management. Imaging surveillance after treatment, particularly 18 F-FDG PET/CT, has shown promise in the diagnosis of HNSCC recurrence. The aim was to evaluate the diagnostic performance of 18 F-FDG PET/CT according to delay after treatment in detecting subclinical recurrence (SCR) in HNSCC patients. Methods: In this retrospective study, all 18 F-FDG PET/CT scans were performed at a single center. All adults with histologically proven HNSCC who were treated with curative intent between January 1, 2006, and December 31, 2021, were included. They had a normal clinical examination before each scan. Patients who underwent an intensive follow-up strategy after treatment had 18 F-FDG PET/CT with an intravenous contrast agent at 3-6 mo and annually thereafter for 5 y. The primary endpoint was diagnostic performance (positive and negative predictive values, sensitivity, specificity, and accuracy). Results: In total, 2,566 18 F-FDG PET/CT scans were performed among 852 patients, with an average of 3 scans per patient. The overall diagnostic performance measures were as follows: positive predictive value (88%), negative predictive value (98%), sensitivity (98%), specificity (89%), and accuracy (93%). There were no significant differences in diagnostic performance over time. The scans detected 126 cases of SCR (14.8%) and 118 cases of metachronous cancer (13.8%). The incidence of SCR decreased over time, with the highest detection rate in the first 2 y after treatment. Positive predictive value improved over time, reaching 90% for the digital Vision 600 system (third period) compared with 76% for the analog Gemini GXLi system (first period, P < 0.001). Multivariate analysis identified advanced stage, high body mass index, and initial PET/CT upstaging as predictive factors for detection of SCR. Conclusion: Our study demonstrates that 18 F-FDG PET/CT has high diagnostic performance in detecting SCR during follow-up after treatment of HNSCC, especially in the first 2 y. Advanced tumor stage, initial PET/CT upstaging, and high body mass index were associated with a higher likelihood of SCR detection. The routine use of 18 F-FDG PET/CT during follow-up seems justified for patients with HNSCC., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Although ventilation/perfusion (V/Q) scintigraphy is a widely used imaging test, different options are possible for the acquisition and interpretation of the scan. The aim of this study was to assess current practices regarding the use and interpretation of lung scintigraphy in various clinical indications., Patients and Methods: An online survey comprising 25 questions was sent to nuclear medicine departments in Australia, Canada, France, Germany, and United States between 2022 and 2023. A single response per department was consolidated., Results: Four hundred nineteen responses were collected (Australia: 32, Canada: 58, France: 149, Germany: 92, and United States: 88). For acute pulmonary embolism (PE) diagnosis, 82.8% of centers reported using SPECT acquisitions (Australia: 93.3%, Canada: 91.8%, France: 99.2%, Germany: 96.2%, and United States: 32.1%). Among them, SPECT images were combined with a CT scan in 70.5% of centers. A total of 10.6% of centers reported not using ventilation for acute PE diagnosis. SPECT acquisition was used in 97.8% of centers using 99m Tc carbon particles, 97.1% 81m Kr gas, 58.7% 99m Tc-DTPA, and 19.4% 133 Xe gas, respectively. For V/Q SPECT interpretation, the EANM criteria were used in 65.0% of departments. A very wide variety of practices were observed in pregnant women and in COVID-19 patients. SPECT acquisition was widely used in the follow-up of PE and for the screening of chronic thromboembolic pulmonary hypertension (>90% of centers), with inconsistency regarding the interpretation of matched perfusion defects in this setting., Conclusions: This survey shows the strong adoption of SPECT in the various clinical indications of lung scintigraphy, except in the United States, where planar imaging is still mostly used. The survey also shows variability in interpretation criteria both for PE diagnosis and screening for chronic thromboembolic pulmonary hypertension, highlighting the need for further standardizations of practices., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Approximately 10 % of all diagnosed pulmonary embolism are isolated to the subsegmental vessels. The risk of recurrent venous thromboembolism (VTE) in patients with an acute subsegmental pulmonary embolism (SSPE) managed with or without anticoagulant therapy remains poorly understood., Methods: This is an observational cohort study including consecutive adult patients diagnosed with acute isolated SSPE between June 01, 2019, and August 31, 2022. We excluded patients with a concomitant diagnosis of deep vein thrombosis and those who had an indication for long-term anticoagulation. The primary outcome was objectively confirmed recurrent VTE., Results: Overall, 118 patients with acute SSPE were included in the analysis. The mean (± standard deviation [SD]) age of the participants was 59 ± 17 years and 44 % of them had active cancer. Mean (±SD) duration of follow-up was 438 ± 426 days. Seventy-seven patients (65 %) were initially treated with anticoagulation, whereas 41 patients (35 %) were not. Of the 77 patients receiving anticoagulant therapy, 23 (30 %) received extended-duration anticoagulation (beyond 3 months) for secondary prevention. Overall, recurrent VTE events occurred in 6/118 (5 %, 95 % CI 2.4 to 10.7) patients. Four events (4/77 = 5.2 %, 95 % CI 2.0 to 12.6) occurred in initially treated patients. Two recurrent VTE occurred in patients initially left untreated (2/41 = 4.9 %, 95 % CI 1.4 to 16.1). Half of the recurrent VTE occurred in patients with active cancer., Conclusions: Most patients diagnosed with an acute SSPE received anticoagulation. The incidence of recurrent VTE detected over time was relatively high, especially in patients with cancer., Competing Interests: Declaration of competing interest L. Girardi, L. A. Ciuffini, V. Mai, D. Santagata and TF. Wang report no conflicts of interests. W. Ageno reports advisory board honoraria from Bayer, Boehringer Inghelheim, Daiichi Sankyo, BMS/Pfizer, Sanofi, and Portola, and reports research funding and personal fees from Bayer, and personal fees from BMS/Pfizer, Daiichi Sankyo, Sanofi, Aspen, Janssen, and Portola, outside the submitted work. M. Carrier has received research funding from BMS, Pfizer, and Leo Pharma, and honoraria from Bayer, Pfizer, BMS, Servier, and Leo Pharma. G. Le Gal reports advisory board honoraria from Inari, Pfizer, Sanofi. G. Le Gal holds a Chair on Diagnosis of Venous Thromboembolism at the Faculty of Medicine, University of Ottawa., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) increases the risk of pulmonary embolism (PE). AECOPD and PE have similar symptoms which results in a high proportion of patients with AECOPD undergoing imaging to rule out PE. Finding predictors and explanatory factors of PE in AECOPD, such as purulence status, could help reduce the need for imaging. This systematic review with meta-analysis aims to evaluate if there is an association between purulence status in AECOPD and PE diagnosis., Methods and Analysis: MEDLINE, EMBASE and CENTRAL will be searched from database inception to April 2024. Randomised trials, cohort studies and cross-sectional studies on the prevalence of PE in patients with AECOPD will be included if the prevalence of PE based on the AECOPD purulence status is available. There will be no restriction on language. The primary outcome will be PE at the initial assessment and secondary outcomes will be all venous thromboembolism (deep venous thrombosis (DVT) and PE) and DVT, respectively, diagnosed at the initial assessment. Relative risks with their 95% CI will be calculated by using a Mantel-Haenszel random-effect model to compare the association between the risk of PE and the AECOPD purulence status (purulent vs non-purulent/unknown). Subgroup analyses will be performed based on the type of study, systematic search of PE versus no systematic search of PE and localisation of PE. Risk of bias will be evaluated by the ROBINS-E tool, publication bias will be evaluated with the funnel plot. The manuscript will be drafted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement., Ethics and Dissemination: This study does not require ethics approval. This work will be submitted for presentation at an international conference and for publication in a peer-reviewed journal., Prospero Registration Number: CRD42023459429., Competing Interests: Competing interests: VM, LG, KdW, SA, FC and DAF do not have conflicts of interest. LC’s research institution has received honoraria from Bayer, BMS-Pfizer Alliance, The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, LEO Pharma, Sanofi, Valeo Pharma and Servier. GLG is a coinvestigator for a clinical trial from Pfizer and one from Bristol-Myers Squibb and GLG received honoraria from Pfizer, Sanofi and Aspen Pharma., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diagnosis of pulmonary embolism remains a challenge for clinicians as its differential diagnosis is wide. The use of sequential diagnostic strategies based on the assessment of clinical probability, D-dimer measurement, and computed tomography pulmonary angiography have been validated in large prospective outcome studies. D-dimer measurement at a standard cutoff of 500 μg/L has gained wide acceptance to rule out pulmonary embolism in around 20 to 30% of patients with a clinically suspected pulmonary embolism. To improve the efficiency of D-dimer measurement, different ways of selecting a higher, albeit safe cutoff were explored: the age-adjusted D-dimer cutoff and the clinical adapted D-dimer cutoff. While both have been prospectively validated in large studies, some differences do exist. In particular, the prevalence of pulmonary embolism in these different validation studies was very different. Overall, the age-adjusted cutoff seems to be safer and less efficient, while the clinical probability adapted cutoff seems more efficient and less safe. Here, we report the available data regarding these two different ways to increase the diagnostic yield of D-dimer. Also, well beyond the accuracy of these adjusted/adapted cutoffs, some external factors, such as the prevalence of pulmonary embolism in the tested population and the clinical setting, have an important impact of the negative predictive value and on the overall efficiency of these cutoffs. Therefore, we also discuss which cutoff should be used according to the expected prevalence of the disease and according to the clinical setting.

Introduction: Pulmonary embolism (PE) is a challenge to diagnose and when missed, exposes patients to potentially fatal recurrent events. Beyond CT pulmonary angiography (CTPA) and planar ventilation/perfusion (V/Q) scan, single photon emission CT (SPECT) V/Q emerged a new diagnostic modality of scintigraphic acquisition that has been reported to improve diagnostic performances. To date, no management outcome study or randomised trial evaluated an algorithm based on SPECT V/Q for PE diagnosis. We present the design of a randomised multicentre, international management study comparing SPECT V/Q with validated strategies., Material and Methods: We will include a total of 3672 patients with suspected PE requiring chest imaging, randomised into three different groups, each using a different diagnostic strategy based on SPECT V/Q, CTPA and planar V/Q scan. Randomisation will be unbalanced (2:1:1), with twice as many patients in SPECT V/Q arm (n=1836) as in CTPA and planar V/Q arms (n=918 in each). Our primary objective will be to determine whether a diagnostic strategy based on SPECT V/Q is non-inferior to previously validated strategies in terms of diagnostic exclusion safety as assessed by the 3-month risk of thromboembolism in patients with a negative diagnostic workup. Secondary outcomes will be the proportion of patients diagnosed with PE in each arm, patients requiring additional tests, the incidence of major and clinically relevant non-major bleeding and the incidence and cause of death in each arm., Ethics and Dissemination: This trial is funded by a grant from Brest University Hospital and by INVENT. The study protocol was approved by Biomedical Research Ethics Committee. The investigator or delegate will obtain signed informed consent from all patients prior to inclusion in the trial. Our results will inform future clinical practice guidelines and solve the current discrepancy between nuclear medicine guidelines and clinical scientific society guidelines., Trial Registration Number: NCT02983760., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The risk of venous thromboembolism (VTE) is increased postpartum and contributes to important morbidity and mortality. While there have been advances in evaluating diagnostic algorithms for suspected VTE during pregnancy, there is limited data for postpartum individuals., Objective: We conducted a scoping review to describe and evaluate diagnostic strategies used to investigate suspected VTE in postpartum individuals., Methods: A comprehensive search strategy was conducted in Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (January 1, 2000-September 30, 2022) to identify original articles that reported on diagnostic strategies in postpartum individuals with suspected VTE. We extracted demographics, clinical decision rules used, D-dimer and imaging completed, including test performance and VTE outcomes., Results: A total of 13 studies conducted across 11 countries with separate postpartum data were included for 759 individuals with suspected PE (n = 634) or DVT (n = 125), including unpublished data (n = 251). Among those with suspected PE, computed tomography pulmonary angiography was conducted more commonly (n = 522) than ventilation-perfusion scans (n = 69), with PE positivity rates that ranged from 4 %-27.6 % and 0-50 % across studies, respectively. Among 131 postpartum individuals with suspected PE who had a D-dimer measured, only 4.6 % (6/131) had a negative D-dimer test. For postpartum individuals with suspected DVT, the most common diagnostic test was compression ultrasonography (positivity rate 12.2 %-18.6 %). There were limited retrospective data evaluating the clinical decision rules., Conclusions: There are heterogeneous approaches globally in the diagnosis of suspected postpartum VTE. Limited high-quality data available underscores the need for more robust evidence to inform clinical practice., Competing Interests: Declaration of competing interest Dr. Skeith holds unrelated research funding from CSL Behring and honoraria from Leo Pharma and Sanofi. The remaining authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this work was to compare anatomic and functional dose-volume parameters as predictors of acute radiation-induced lung toxicity (RILT) in patients with lung tumors treated with stereotactic body radiation therapy., Methods and Materials: Fifty-nine patients treated with stereotactic body radiation therapy were prospectively included. All patients underwent gallium 68 lung perfusion positron emission tomography (PET)/computed tomography (CT) imaging before treatment. Mean lung dose (MLD) and volumes receiving x Gy (VxGy, 5-30 Gy) were calculated in 5 lung volumes: the conventional anatomic volume (AV) delineated on CT images, 3 lung functional volumes (FVs) defined on lung perfusion PET imaging (FV50%, FV70%, and FV90%; ie, the minimal volume containing 50%, 70%, and 90% of the total activity within the AV), and a low FV (LFV; LFV = AV - FV90%). The primary endpoint of this analysis was grade ≥2 acute RILT at 3 months as assessed with National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Dose-volume parameters in patients with and without acute RILT were compared. Receiver operating characteristic curves assessing the ability of dose-volume parameters to discriminate between patients with and without acute RILT were generated, and area under the curve (AUC) values were calculated., Results: Of the 59 patients, 10 (17%) had grade ≥2 acute RILT. The MLD and the VxGy in the AV and LFV were not statistically different between patients with and without acute RILT (P > .05). All functional parameters were significantly higher in acute RILT patients (P < .05). AUC values (95% CI) for MLD AV, LFV, FV50%, FV70%, and FV90% were 0.66 (0.46-0.85), 0.60 (0.39-0.80), 0.77 (0.63-0.91), 0.77 (0.64-0.91), and 0.75 (0.58-0.91), respectively. AUC values for V20Gy AV, LFV, FV50%, FV70%, and FV90% were 0.65 (0.44-0.87), 0.64 (0.46-0.83), 0.82 (0.69-0.95), 0.81 (0.67-0.96), and 0.75 (0.57-0.94), respectively., Conclusions: The predictive value of PET perfusion-based functional parameters outperforms the standard CT-based dose-volume parameters for the risk of grade ≥2 acute RILT. Functional parameters could be useful for guiding radiation therapy planning and reducing the risk of acute RILT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The 4-level clinical pretest probability score (4PEPS) was recently introduced as a clinical decision rule for the diagnosis of pulmonary embolism (PE). Based on the score, patients are classified into clinical pretest probability categories (c-PTP). The "very low" category aims at excluding PE without further testing; "low" and "moderate" categories require D-dimer testing with specific thresholds, while patients with a "high" pretest directly proceed to imaging., Objectives: To provide further external validation of the 4PEPS model., Methods: The 4PEPS was applied to a previously collected prospective database of 756 patients with clinically suspected PE enrolled from European emergency departments in 2002 to 2003. The safety threshold for the failure rate in our study was calculated at 1.95% based on a 26% prevalence of PE in our study, as per the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee guidance., Results: Patients were classified as follows: 90 (12%) in the very low c-PTP group, of whom 5 (5.6%; 95% CI, 2.4%-12.4%) had PE; 363 (49%) in the low c-PTP group, of whom 34 had PE (9.4%); 246 (34%) in the moderate c-PTP group, of whom 124 (50%) had PE; and 35 (5%) in the high c-PTP group of whom 30 (86%) had PE. Overall, the failure rate of the 4PEPS was 9/734 (1.2%; 95% CI, 0.59%-2.23%) Overall, 9 out of 734 patients (1.2%; 95% CI, 0.59%-2.23%) were diagnosed with PE despite a negative 4PEPS rule; 5 (5.6%) from the very low c-PTP group, 3 (1.4%) in the low c-PTP group, and 1 (3.2%) in the moderate c-PTP group., Conclusion: We provide external validation data of the 4PEPS. In this high-prevalence cohort (26% prevalence), PE prevalence in the very low-risk group was higher than expected. A prospective validation study is needed before implementing the 4PEPS model in routine clinical practice., (© 2024 The Author(s).)

Background: Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation., Objectives: The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin., Methods: Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21., Results: Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low., Conclusions: Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis., Competing Interests: The ACTIV-4a platform was sponsored by the 10.13039/100000050National Heart, Lung, and Blood Institute, 10.13039/100000002National Institutes of Health, Bethesda and administered through OTA-20 to 011. The research was, in part, funded by the 10.13039/100000002National Institutes of Health (NIH) Agreement 1OT2HL156812 through the 10.13039/100000050National Heart, Lung, and Blood Institute (NHLBI) CONNECTS program. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the NIH. The ATTACC platform was supported by grants from the 10.13039/501100000024Canadian Institutes of Health Research, 10.13039/100012357LifeArc, Thistledown Foundation, Peter Munk Cardiac Centre, 10.13039/100008794Research Manitoba, 10.13039/100009395CancerCare Manitoba Foundation, 10.13039/501100023238Victoria General Hospital Foundation, and the 10.13039/501100000226Ontario Ministry of Health. The REMAP-CAP platform was supported by the European Union—through FP7-HEALTH-2013-INNOVATION: the Platform for European Preparedness Against (Re)emerging Epidemics (PREPARE) consortium (602525), and 10.13039/100010661Horizon 2020 research and innovation program: the Rapid European Covid-19 Emergency Research response (RECOVER) consortium (101003589)—and by the Australian 10.13039/501100000925National Health and Medical Research Council (APP1101719), the 10.13039/501100001505Health Research Council of New Zealand (16/631), the 10.13039/501100000024Canadian Institutes of Health Research (Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant - 158584, and COVID-19 Rapid Research Operating Grant - 447335), the U.K. NIHR and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Minderoo Foundation, Amgen, Eisai, the Global Coalition for Adaptive Research, and the Wellcome Trust Innovations Project (215522). Dr Godoy is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the 10.13039/501100000024Canadian Institutes of Health Research. Dr Neal has received grants from the 10.13039/100000002National Institutes of Health and 10.13039/100000005United States Department of Defense; has received research support from Haemonetics, Janssen and Instrumentation Laboratories; has received honoraria from Haemonetics, 10.13039/100005565Janssen, and 10.13039/501100014255CSL Behring; and serves on the Scientific Advisory Board of Haima Therapeutics. Dr Goligher has received personal fees and nonfinancial support from Getinge, nonfinancial support from Timpel, outside the submitted work. Dr Cushman has received personal fees from the 10.13039/100000002National Institutes of Health, during the conduct of the study. Dr Bradbury has received personal fees from BMS Pfizer; nonfinancial support from 10.13039/100002429Amgen; personal fees and nonfinancial support from Bayer; personal fees and nonfinancial support from 10.13039/100004336Novartis; personal fees from Janssen; personal fees from Portola; and personal fees from Ablynx, outside the submitted work. Dr Tritschler is a member of the Canadian Venous Thromboembolism Research Network (CanVECTOR); the network receives grant funding from the 10.13039/501100000024Canadian Institutes of Health Research (CDT-142654). Dr Kahn is supported by a Tier 1 10.13039/501100001804Canada Research Chair. Dr L. Berry has received grants from PREPARE Network, 10.13039/501100000780European Commission through University Antwerp, grants from OPTIMISE CAP. She reports Australia funding through Monash University; grants from REMAP-CAP; New Zealand funding through Medical Research Institute of New Zealand; grants from Global Coalition for Adaptive Research (GCAR); United States funding through grants from ATTACC; Canada funding through 10.13039/100009663University Health Network, grants from ACTIV-4; and reports IP funding, 10.13039/100007921University of Pittsburgh, during the conduct of the study. Dr Lorenzi has received grants from PREPARE in EU (University Antwerp), grants from OPTIMISE-CAP in Australia (Monash University), grants from REMAP-CAP in New Zealand (Medical Research Institute of New Zealand (MRINZ)), grants from REMAP-COVID in the US (GCAR), grants from ATTACC in Canada (10.13039/100009663University Health Network), grants from ACTIV-4 IP in the U.S. (10.13039/100007125University of Pittsburgh), during the conduct of the study. Dr Higgins has received grants from 10.13039/501100000925National Health and Medical Research Council, grants from 10.13039/501100016056Minderoo Foundation, during the conduct of the study. Dr Berger has received grants from 10.13039/100000002National Institutes of Health - 10.13039/100000050NHLBI, during the conduct of the study; personal fees from Astra Zeneca, personal fees from Janssen, personal fees from Amgen, outside the submitted work. Dr Gong has received grants from 10.13039/100000050NHLBI, during the conduct of the study. Dr Castellucci has received unrelated honoraria received from Bayer, BMS-Pfizer Alliance, The Academy, LEO Pharma, Sanofi, Servier, and Valeo; and holds a Heart and Stroke Foundation of Canada National New Investigator Award, and a Tier 2 research Chair in Thrombosis and Anticoagulation Safety from the University of Ottawa. Dr Le Gal holds a Heart and Stroke Foundation of Canada National Clinician-Scientist Award, and the Chair on Diagnosis of Venous Thromboembolism from the University of Ottawa. Dr Rosenson has a patent EFSID 40934007 pending. Dr Derde has received grants from EU FP7-HEALTH-2013-INNOVATION-1, grant number 602525, grants from H2020 RECOVER grant agreement No 101003589, during the conduct of the study; COVID-19 guideline committee SCCM/ESICM/ SSC, ESICM COVID-19 taskforce, Dutch intensivists (NVIC) taskforce infectious threats, outside the submitted work. Dr Kumar has received grants from Merck, outside the submitted work. Dr McVerry has received grants from 10.13039/100000002NIH - National Heart, Lung and Blood Institute, during the conduct of the study; grants from Bayer Pharmaceuticals, Inc, outside the submitted work. Dr Nicolau has received personal fees from AMGEN, grants from 10.13039/100004325AstraZeneca, grants and personal fees from Bayer, grants from 10.13039/501100022336Esperion, grants from CLS Behring, personal fees from Daiichi-Sankyo, grants from Dalcor, grants from Janssen, grants and personal fees from Novartis, grants from NovoNordisk, grants and personal fees from Sanofi, personal fees from Servier, grants from Vifor, outside the submitted work. Dr Huang has received grants from the 10.13039/100000002NIH, during the conduct of the study. Dr Reynolds has received grants from 10.13039/100000050National Heart, Lung and Blood Institute, during the conduct of the study; nonfinancial support from 10.13039/100011949Abbott Vascular, nonfinancial support from BioTelemetry Inc, nonfinancial support from 10.13039/100004340Siemens, outside the submitted work. Dr Carrier has received grants from 10.13039/100004319Pfizer, grants from 10.13039/501100000024Canadian Institutes of Health Research, grants from 10.13039/100002491BMS, during the conduct of the study; grants and personal fees from Leo Pharma, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Bayer, personal fees from Sanofi Aventis, personal fees from Pfizer, outside the submitted work. Dr S. Berry reports grants from PREPARE Network, grants from Optimise-CAP, grants from REMAP-CAP, grants from GCAR, grants from 10.13039/100009663University Health Network, grants from 10.13039/100007125University of Pittsburgh, during the conduct of the study. Dr Webb reports grants from 10.13039/501100000925National Health and Medical Research Council, grants from 10.13039/501100016056Minderoo Foundation, during the conduct of the study. Dr Turgeon reports grants from 10.13039/100022992Canadian Institutes of Health Research, during the conduct of the study. Dr McArthur has received grants from 10.13039/501100001505Health Research Council of New Zealand, during the conduct of the study. Dr Farkouh has received grants from 10.13039/100002429Amgen, grants from Novo Nordisk, grants from 10.13039/100004336Novartis, outside the submitted work. Dr Hochman is a principal investigator for the ISCHEMIA trial which, in addition to funding by 10.13039/100000002NIH, received support in the form of devices and medications provided by: Medtronic, Inc; Abbott Vascular, Inc (formerly St. Jude Medical, Inc); Royal Philips NV (formerly Volcano Corporation); Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corp; Omron Healthcare, Inc; Sunovion Pharmaceuticals, Inc; Espero BioPharma; and Amgen Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr Zarychanski has received unrelated grant funding from the 10.13039/501100000024Canadian Institutes of Health Research, 10.13039/100009395CancerCare Manitoba Foundation, and 10.13039/100008794Research Manitoba and receives operating support as the Lyonel G. Israels Research Chair in Hematology at the 10.13039/100010318University of Manitoba. Dr Lawler has received unrelated consulting fees from Novartis, CorEvitas, and Brigham and Women’s Hospital, and unrelated royalties from McGraw-Hill Publishing; and is supported by a Heart and Stroke Foundation of Canada National New Investigator career award. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Introduction:  Obesity is a risk factor for venous thromboembolism, but studies evaluating its association with pulmonary embolism (PE) in patients with suspected PE are lacking., Objectives:  To evaluate whether body mass index (BMI) and obesity (i.e., BMI ≥30 kg/m 2 ) are associated with confirmed PE in patients with suspected PE and to assess the efficiency and safety of the age-adjusted D-dimer strategy in obese patients., Methods:  We conducted a secondary analysis of a multinational, prospective study, in which patients with suspected PE were managed according to the age-adjusted D-dimer strategy and followed for 3 months. Outcomes were objectively confirmed PE at initial presentation, and efficiency and failure rate of the diagnostic strategy. Associations between BMI and obesity, and PE were examined using a log-binomial model that was adjusted for clinical probability and hypoxia., Results:  We included 1,593 patients (median age: 59 years; 56% women; 22% obese). BMI and obesity were not associated with confirmed PE. The use of the age-adjusted instead of the conventional D-dimer cut-off increased the proportion of obese patients in whom PE was considered ruled out without imaging from 28 to 38%. The 3-month failure rate in obese patients who were left untreated based on a negative age-adjusted D-dimer cut-off test was 0.0% (95% confidence interval: 0.0-2.9%)., Conclusion:  BMI on a continuous linear scale and obesity were not predictors of confirmed PE among patients presenting with a clinical suspicion of PE. The age-adjusted D-dimer strategy appeared safe in ruling out PE in obese patients with suspected PE., Competing Interests: None declared., (Thieme. All rights reserved.)

Importance: Intensive interventions are provided to young children with unilateral cerebral palsy (UCP), classically focused on the upper extremity despite the frequent impairment of gross motor function. Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) effectively improves manual dexterity and gross motor function in school-aged children., Objective: To verify if HABIT-ILE would improve manual abilities in young children with UCP more than usual motor activity., Design, Setting, and Participants: This prospective randomized clinical trial (November 2018 to December 2021), including 2 parallel groups and a 1:1 allocation, recruitment took place at European university hospitals, cerebral palsy specialized centers, and spontaneous applications at 3 sites: Brussels, Belgium; Brest, France; and Pisa, Italy. Matched (age at inclusion, lesion type, cause of cerebral palsy, and affected side) pairs randomization was performed. Young children were assessed at baseline (T0), 2 weeks after baseline (T1), and 3 months after baseline (T2). Health care professionals and assessors of main outcomes were blinded to group allocation. At least 23 young children (in each group) aged 12 to 59 months with spastic/dyskinetic UCP and able to follow instructions were needed. Exclusion criteria included uncontrolled seizures, scheduled botulinum toxin injections, orthopedic surgery scheduled during the 6 months before or during the study period, severe visual/cognitive impairments, or contraindications to magnetic resonance imaging., Interventions: Two weeks of usual motor activity including usual rehabilitation (control group) vs 2 weeks (50 hours) of HABIT-ILE (HABIT-ILE group)., Main Outcomes and Measures: Primary outcome: Assisting Hand Assessment (AHA); secondary outcomes: Gross Motor Function Measure-66 (GMFM-66), Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), and Canadian Occupational Performance Measure (COPM)., Results: Of 50 recruited young children (26 girls [52%], median age; 35.3 months for HABIT-ILE group; median age, 32.8 months for control group), 49 were included in the final analyses. Change in AHA score from T0 to T2 was significantly greater in the HABIT-ILE group (adjusted mean score difference [MD], 5.19; 95% CI, 2.84-7.55; P < .001). Changes in GMFM-66 (MD, 4.72; 95% CI, 2.66-6.78), PEDI-CAT daily activities (MD, 1.40; 95% CI, 0.29-2.51), COPM performance (MD, 3.62; 95% CI, 2.91-4.32), and satisfaction (MD, 3.53; 95% CI, 2.70-4.36) scores were greater in the HABIT ILE group., Conclusions and Relevance: In this clinical trial, early HABIT-ILE was shown to be an effective treatment to improve motor performance in young children with UCP. Moreover, the improvements had an impact on daily life activities of these children., Trial Registration: ClinicalTrials.gov Identifier: NCT04020354.

Background: Guidelines suggest but cannot recommend the optimal management of superficial vein thrombosis (SVT)., Objectives: To identify the prevalence of asymptomatic deep vein thrombosis (DVT) at the time of SVT diagnosis, and to report the treatment and 3-month complications of patients with only SVT more than 3 cm from deep vein junction (or unknown distance)., Methods: We performed a single-center retrospective review of patients referred to the Ottawa Hospital thrombosis unit with ultrasound (US)-diagnosed SVT, and followed patients with only SVT for 3 months., Results: Three hundred sixteen patients with SVT were included. Of the 218 patients without DVT symptoms at presentation, 19 (8.7%; 95% CI, 5.7%-13.2%) were found to have asymptomatic concomitant DVT (11 proximal and 8 distal), and 45 (20.6%) had SVT within 3 cm of the saphenofemoral or saphenopopliteal junctions. Among the 192 patients diagnosed with SVT only, we observed 3-month thrombotic complications in 56 (29.2%; 95% CI, 23.2%-36.0%) patients, with a total of 69 events: 11 (5.7%) DVTs, 2 (1.0%) pulmonary embolisms, 37 (19.2%) SVT extensions, and 19 (9.8%) SVT recurrences. Eighty-two percent (9/11) of the 3-month DVT and pulmonary embolism events occurred in patients who initially received conservative management. Therapeutic treatment doses were most effective., Conclusion: At the time of SVT diagnosis, many patients had asymptomatic DVT and SVT near the deep venous system, supporting the systematic use of initial US in patients clinically diagnosed with SVT. The observed differences in 3-month complication rates, according to the treatment provided, highlight the need for large-scale randomized controlled trials to establish optimal management., (© 2023 The Authors.)

Ventilation-perfusion (V/Q) lung scans constitute one of the oldest nuclear medicine procedures, remain one of the few studies performed in the acute setting, and are amongst the few performed in the emergency setting. V/Q studies have witnessed a long fluctuation in adoption rates in parallel to continuous advances in image processing and computer vision techniques. This review provides an overview on the status of artificial intelligence (AI) in V/Q scintigraphy. To clearly assess the past, current, and future role of AI in V/Q scans, we conducted a systematic Ovid MEDLINE(R) literature search from 1946 to August 5, 2022 in addition to a manual search. The literature was reviewed and summarized in terms of methodologies and results for the various applications of AI to V/Q scans. The PRISMA guidelines were followed. Thirty-one publications fulfilled our search criteria and were grouped into two distinct categories: (1) disease diagnosis/detection (N = 22, 71.0%) and (2) cross-modality image translation into V/Q images (N = 9, 29.0%). Studies on disease diagnosis and detection relied heavily on shallow artificial neural networks for acute pulmonary embolism (PE) diagnosis and were primarily published between the mid-1990s and early 2000s. Recent applications almost exclusively regard image translation tasks from CT to ventilation or perfusion images with modern algorithms, such as convolutional neural networks, and were published between 2019 and 2022. AI research in V/Q scintigraphy for acute PE diagnosis in the mid-90s to early 2000s yielded promising results but has since been largely neglected and thus have yet to benefit from today's state-of-the art machine-learning techniques, such as deep neural networks. Recently, the main application of AI for V/Q has shifted towards generating synthetic ventilation and perfusion images from CT. There is therefore considerable potential to expand and modernize the use of real V/Q studies with state-of-the-art deep learning approaches, especially for workflow optimization and PE detection at both acute and chronic stages. We discuss future challenges and potential directions to compensate for the lag in this domain and enhance the value of this traditional nuclear medicine scan., Competing Interests: Declaration of Competing Interest Eric Moulton reports a relationship with Jubilant DraxImage Inc that includes: employment. Ran Klein reports a relationship with Jubilant DraxImage Inc that includes: consulting or advisory. Ran Klein received revenue shares from Jubilant DraxImage, Inc and Invia Medical Solutions for myocardial blood flow quantification., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: While several risk stratification tools have been developed to predict the risk of recurrence in patients with an unprovoked venous thromboembolism (VTE), only 1 in 4 patients are categorized as low-risk. Rather than a one-time measure, serial D-dimer assessment holds promise to enhance the prediction of VTE recurrence after oral anticoagulant (OAC) cessation., Methods: Using the REVERSE cohort, we compared VTE recurrence among patients with normal D-dimer levels (<490 ng/mL among males under age 70, <500 ng/mL in others) at OAC cessation and 1-month follow-up, to those with an elevated D-dimer level at either timepoint. We also evaluated VTE recurrence based on absolute increase in D-dimer levels between the two timepoints (e.g., ∆D-dimer) according to quartiles., Results: Among 214 patients with serial D-dimer levels measured at OAC cessation and 1-month follow-up, an elevated D-dimer level at either timepoint was associated with a numerically higher risk of recurrent VTE than patients with normal D-dimer levels at both timepoints (6.9 % vs. 4.2 % per year, hazard ratio 1.6; 95 % CI 0.9-2.7). Among women with <2 HERDOO2 criteria, a normal D-dimer level at both timepoints predicted a very low risk of recurrent VTE during follow-up (0.8 % per year, 95 % CI 0.1-2.8). Irrespective of baseline value, recurrent VTE risk was only 3 % per year (95 % CI 1.4-5.6) among patients in the lowest ∆D-dimer quartile., Conclusion: Serial normal D-dimer levels have the potential to identify patients at a low risk of recurrent VTE. In addition, ∆D-dimer, irrespective of its elevation above cutoff threshold, may predict recurrent VTE., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Drs. Xu, Khan, Kovacs, Sabri, Righini, Kahn, Anderson, Chagnon, White, Rodger and Le Gal have no conflicts of interest to report. Dr. Carrier reports research funding from BMS, Leo Pharma, and Pfizer; and honoraria from Bayer, Pfizer, BMS, Leo Pharma, Servier, and Sanofi. Dr. Wells reports speaker honoraria from BMS and Bayer Healthcare and prior grant funding from BMS/Pfizer. Dr. Crowther reports honoraria from Pfizer, CSL Behring, and Diagnostica Stago; consultation services to/served on advisory boards for Servier Canada, Asahi Kasei, and Precision Biologics; serving on the data safety monitoring board for Bayer; stock ownership in Alnylam; and holds the Leo Pharma Chair in Thromboembolism research, the funding for which is held in perpetuity at McMaster University (the interest is used to support M.A.C.'s research activities)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The prevalence of pulmonary embolism (PE) is approximately 11-17 % in patients with an acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). The optimal diagnostic strategy for PE in these patients remains undetermined., Aims: To evaluate the safety and efficacy of standard (revised Geneva and Wells PE scores combined with fixed D-dimer cut-off) and computed tomography pulmonary angiogram (CTPA)-sparing diagnostic strategies (ADJUST-PE, YEARS, PEGeD, 4PEPS) in patients with AE-COPD., Method: Post-hoc analyses of data from the multicenter prospective PEP study were performed. The primary outcome was the diagnostic failure rate of venous thromboembolism (VTE) during the entire study period. Secondary outcomes included diagnostic failure rate of PE and deep venous thrombosis (DVT), respectively, during the entire study period and the number of CTPA needed per diagnostic strategy., Results: 740 patients were included. The revised Geneva and Wells PE scores combined with fixed D-dimer cut-off had a diagnostic failure rate of VTE of 0.7 % (95%CI 0.3 %-1.7 %), but >70.0 % of the patients needed imaging. All CTPA-sparing diagnostic algorithms reduced the need for CTPAs (-10.1 % to -32.4 %, depending on the algorithm), at the cost of an increased VTE diagnosis failure rate of up to 2.1 % (95%CI 1.2 %-3.4 %)., Conclusion: Revised Geneva and Wells PE scores combined with fixed D-dimer cut-off were safe, but a high number of CTPA remained needed. CTPA-sparing algorithms would reduce imaging, at the cost of an increased VTE diagnosis failure rate that exceeds the safety threshold. Further studies are needed to improve diagnostic management in this population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Couturaud reports having received research grant support from Bristol-Myers Squibb/Pfizer and Bayer and fees for board memberships or symposia from Bayer, Bristol-Myers Squibb/Pfizer, Merck Sharp and Dohme, Merck Sharp and Dohme, Sanofi, Leo Pharma, Janssen and Astra Zeneca and having received travel support from Bayer, Bristol-Myers Squibb/Pfizer, Leo Pharma, Pfizer. Dr. Bertoletti reports having received research grant support from Bayer and fees for board memberships or symposia from Actelion, Aspen, Bayer, Bristol-Myers Squibb/Pfizer and MSD, and having received travel support from Aspen, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Leo Pharma, MSD and Actelion. Dr. Pastre declares he has no conflict of interest related to this research. Dr. Roy declares he has no conflict of interest related to this research. Dr. Rambaud declares he has no conflict of interest related to this research. Dr. Mai declares she has no conflict of interest related to this research. Dr. Motreff declares she has no conflict of interest related to this research. Dr. Auffret declares he has no conflict of interest related to this research. Dr. Le Mao declares he has no conflict of interest related to this research. Dr. Gagnadoux declares he has no conflict of interest related to this research. Dr. Paleiron declares he has no conflict of interest related to this research. Dr. Schmidt declares he has no conflict of interest related to this research. Dr. Schmidt declares he has no conflict of interest related to this research. Dr. Sanchez reports having received research grant support from Bayer, Daiichi-Sankyo and Portola Pharmaceuticals, and fees or non-financial support for consultancy activities from Actelion, GlaxoSmithKline, Boehringer Ingelheim and Chiesi. Dr. Bressollette declares he has no conflict of interest related to this research. Dr. Nonent declares he has no conflict of interest related to this research. Dr. Tromeur declares she has no conflict of interest related to this research. Dr. Salaun declares he has no conflict of interest related to this research. Dr. Mismetti reports having received research grants from Bayer, fees for board memberships from Bayer, Bristol-Myers Squibb/Pfizer and Daiichi Sankyo, for lectures from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo and Sanofi, and for development of educational presentations from Bayer and Bristol-Myers Squibb/Pfizer. Dr. Girard reports having received personal fees and non-financial support from Bayer and Leo Pharma. Dr. Lacut reports having received personal fees from Bayer-Health Care, Bristol-Myers Squibb and Boehringer Ingelheim. Dr. Lemarie declares she has no conflict of interest related to this research. Dr. Meyer reports having received research grant support from Bayer, Boehringer Ingelheim, LEO Pharma Research Foundation and Sanofi, having been an uncompensated board member and a consultant for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Leo Pharma and Pfizer, and having received travel support from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Leo Pharma and Sanofi. Dr. Leroyer reports having received research grant support from Pfizer and fees for board memberships or symposia from Bayer and Astra Zeneca and having received travel support from Bayer, Leo Pharma. No other potential conflict of interest relevant to this article was reported., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interests There are no competing interests to disclose. Funding information S.R. Kahn, A. Delluc, N. Langlois, G. Le Gal, and T. Tritschler are members of the Canadian Venous Thromboembolism Research Network (CanVECTOR); the Network received grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654). S.R. Kahn holds a Tier 1 Canada Research Chair in venous thromboembolism. A. Delluc is recipient of a University of Ottawa Department of Medicine Research Salary Award. G. Le Gal holds a mid-career clinician scientist award from the Heart and Stroke Foundation of Ontario, and the Chair on the Diagnosis of Venous Thromboembolism, Department of Medicine, University of Ottawa., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

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 (I 2 , 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., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Challenges and Lessons from Our VTE Prophylaxis TrialIn this Clinical Trials Case Study, the authors describe the challenges faced and lessons learned conducting a trial of venous thromboembolism prophylaxis among hospitalized older adults.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sequential diagnostic algorithms are used in the case of suspected pulmonary embolism (PE). The PEGeD study proposed a new diagnostic strategy to reduce the use of computed tomography pulmonary angiography (CTPA). We aimed to externally validate this diagnostic strategy in an independent cohort. We analyzed data from 3 prospective studies of outpatients with suspected PE. As per the PEGeD algorithm, patients were classified as having a low, moderate, or high clinical pretest probability (C-PTP). PE was excluded with a D-dimer <1000 ng/mL in case of low C-PTP and <500 ng/mL in case of moderate C-PTP. We assessed the yield and safety of this approach and compared them with those of previously validated algorithms. Among the 3308 evaluated patients, 1615 (49%) patients could have had PE excluded according to the PEGeD algorithm, without the need for imaging. Of these patients, 38 (2.3%; 95% confidence interval [CI], 1.7-3.2) were diagnosed with a symptomatic PE at initial testing or during the 3-month follow-up. On further analysis, 36 patients out of these 38 patients had a positive age-adjusted D-dimer. The risk of venous thromboembolic events among the 414 patients with a D-dimer <1000 ng/mL but above the age-adjusted D-dimer cut-off was 36 of 414 (8.7%; 95% CI, 6.4-11.8). We provide external validation of the PEGeD algorithm in an independent cohort. Compared with standard algorithms, the PEGeD decreased the number of CTPA examinations. However, caution is required in patients with a low C-PTP and a D-dimer <1000 ng/mL but above their age-adjusted D-dimer cut-off., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Importance: Patients with head and neck squamous cell carcinoma (HNSCC) have a significant risk of locoregional recurrence within the first 2 years, with approximately two-thirds of patients experiencing such recurrence. While early recurrence detection may be associated with improved patient outcomes, the association of such detection with survival remains uncertain., Objective: To investigate the association of an intensive posttreatment follow-up strategy using 18F-fludeoxyglucose-positron emission tomography with computed tomography (18FDG-PET/CT) with survival among patients with HNSCC., Design, Setting, and Participants: This case-control study was conducted among patients treated at 1 of 3 locations in Brest, France (University Hospital, Military Hospital, or Pasteur Clinic). The statistical analysis was conducted from January to June 2023. All adults with histologically proven HNSCC who were treated with curative intent between January 1, 2006, and December 31, 2019, and achieved a complete response on imaging at 3 to 6 months were included. They had a minimum of 3 years of follow-up., Exposures: Patients undergoing an intensive posttreatment follow-up strategy had 18FDG-PET/CT (PET/CT group) at months 12, 24, and 36, chosen at the discretion of ear, nose, and throat surgeons., Main Outcomes and Measures: Overall survival (OS) at 3 years., Results: Among 782 patients with HNSCC (642 males [82.1%]; median [IQR] age, 61 [56-68] years), 497 patients had 18FDG-PET/CT during follow-up and 285 patients had conventional follow-up (CFU group). Cox regression analysis showed an association between undergoing 18FDG-PET/CT and lower risk of death (odds ratio, 0.71; 95% CI, 0.57-0.88; P = .002) after adjustment for covariates (age, sex, comorbidities, primary location, stage, surgeon, year of treatment, and treatment). The mean (SD) 3-year OS was significantly better in the PET/CT vs CFU group (72.5% [2.0%] vs 64.3% [2.9%]; P = .002). Analysis based on American Joint Committee on Cancer stage showed significantly better mean (SD) 3-year OS for advanced stages III and IV in the PET/CT group (373 patients) vs CFU group (180 patients; 68.5% [2.4%] vs 55.4% [3.8%]; P < .001), while no significant difference was observed between patients with stage I or II HNSCC. Analysis based on primary tumor site revealed significantly longer mean (SD) 3-year OS for oropharyngeal tumor in the PET/CT group (176 patients) than the CFU group (100 patients; 69.9% [3.5%] vs 60.5% [5.0%]; P = .04)., Conclusions and Relevance: This case-control study found that use of 18FDG-PET/CT in the standard annual CFU of HNSCC was associated with a 3-year survival benefit, with a larger benefit for patients with advanced initial tumor stage (III-IV) and oropharyngeal disease.

BACKGROUND: Admission to the hospital is a major risk factor for the development of venous thromboembolism (VTE). Whether thromboprophylaxis with low-molecular-weight heparin prevents symptomatic VTE in medically ill, hospitalized older adults remains debated. METHODS: In a prospective, randomized, placebo-controlled, double-blind, multicenter trial, older adults (>70 years of age) hospitalized for acute medical conditions were randomly assigned to receive 40 mg a day of low-molecular-weight heparin (enoxaparin) or placebo for 6 to 14 days. The primary efficacy outcome was the cumulative incidence of symptomatic VTE (distal or proximal deep vein thrombosis, fatal or nonfatal pulmonary embolism) at 30 days. The primary safety outcome was major bleeding. Secondary outcomes included efficacy and safety outcomes at 90 days. RESULTS: The trial was prematurely discontinued in September 2020, 5 years after enrollment began, because of drug supply issues. By the time of trial discontinuation, 2559 patients had been randomly assigned at 47 centers. Median age was 82 years and 60% of patients were female. In the intention-to-treat population, the primary efficacy outcome occurred in 22 out of 1278 (cumulative incidence, 1.8%) patients in the enoxaparin group and in 27 out of 1263 (cumulative incidence, 2.2%) patients in the placebo group (cumulative incidence difference, −0.4 percentage points; 95% confidence interval, −1.5 to 0.7), with no significant difference in time to VTE (P=0.46). The incidence of major bleeding was 0.9% in the enoxaparin group and 1.0% in the placebo group. At 90 days there were 14 symptomatic pulmonary emboli in the enoxaparin group and 25 in the placebo group; all 39 pulmonary embolism events resulted in hospital readmission and/or death, with 5 deaths from pulmonary embolism in the enoxaparin group and 11 deaths in the placebo group. CONCLUSIONS: This trial of thromboprophylaxis in medically ill, hospitalized older adults did not demonstrate that enoxaparin reduced the risk of symptomatic VTE after 1 month. Because the trial was prematurely discontinued, larger trials are needed to definitively address this question. (Funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique, grant number PHRC-N-13-0283; ClinicalTrials.gov number, NCT02379806.)

Background: Clinical practice guidelines recommend indefinite anticoagulation for a first unprovoked venous thromboembolism (VTE)., Objective: To estimate the benefit-harm tradeoffs of indefinite anticoagulation in patients with a first unprovoked VTE., Design: Markov modeling study., Data Sources: Systematic reviews and meta-analyses for the long-term risks and case-fatality rates of recurrent VTE and major bleeding. Published literature for costs, quality of life, and other clinical events., Target Population: Patients with a first unprovoked VTE who have completed 3 to 6 months of initial anticoagulant treatment., Time Horizon: Lifetime., Perspective: Canadian health care public payer., Intervention: Indefinite anticoagulation with direct oral anticoagulants., Outcome Measures: Recurrent VTE events, major bleeding events, costs in 2022 Canadian dollars (CAD), and quality-adjusted life-years (QALYs)., Results of Base-Case Analysis: When compared with discontinuing anticoagulation after initial treatment in a hypothetical cohort of 1000 patients aged 55 years, indefinite anticoagulation prevented 368 recurrent VTE events, which included 14 fatal pulmonary emboli, but induced an additional 114 major bleeding events, which included 30 intracranial hemorrhages and 11 deaths from bleeding. Indefinite anticoagulation cost CAD $16 014 more per person and did not increase QALYs (-0.075 per person)., Results of Sensitivity Analysis: Model results were most sensitive to the case-fatality rate of major bleeding and the annual risk for major bleeding during extended anticoagulation., Limitation: The model assumed that risks for recurrent VTE and major bleeding measured in clinical trials at 1 year remained constant during extended anticoagulation., Conclusion: Clinicians should use shared decision making to incorporate individual patient preferences and values when considering treatment duration for unprovoked VTE., Primary Funding Source: Canadian Institutes of Health Research., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3559.

We aimed to assess the relationship between residual pulmonary vascular obstruction (RPVO) on planar lung scan after completion of at least 3 months of anticoagulant therapy for acute pulmonary embolism (PE) and the risk of recurrent venous thromboembolism (VTE) or death due to PE one year after treatment discontinuation. The systematic review was registered with the International Prospective Registry of Systematic Reviews (PROSPERO: CRD42017081080). The primary outcome measure was to generate a pooled estimate of the rate of recurrent VTE at one year in patient with RPVO diagnosed on planar lung scan after discontinuation of at least 3 months of anticoagulant treatment for an acute PE. Individual data were obtained for 809 patients. RPVO (ie, obstruction >0%) was found in 407 patients (50.3%) after a median of 6.6 months of anticoagulant therapy for a first acute PE. Recurrent VTE or death due to PE occurred in 114 patients (14.1%), for an annual risk of 6.4% (95% confidence interval, 4.7%-8.6%). Out of the 114 recurrent events, 63 occurred within one year after discontinuation of anticoagulant therapy corresponding to a risk of 8.1% (6.4%-9.8%) at 1 year. The risk of recurrent VTE at one year was 5.8% (4.4-7.2) in participants with RPVO <5%, vs 11.7% (9.5-13.8) in participants with RPVO ≥5%. RPVO is a significant predictor of the risk of recurrent venous thromboembolism. However, the risk of recurrent events remains too high in patients without residual perfusion defect for it to be used as a stand-alone test to decide on anticoagulation discontinuation., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interests G.L.G. received honoraria for lectures from Aspen Pharma, BMS, Leo Pharma, Pfizer, and Sanofi, all outside this work and paid to his institution. F.A.K. has received research grants from Bayer, BMS, BSCI, MSD, LEO Pharma, Actelion, The Netherlands Organization for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation, and the Horizon Europe Program, all outside this work and paid to his institution. The remaining authors state that they have no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Gallium-68 lung perfusion PET/CT is an emerging imaging modality for the assessment of regional lung function, especially to optimise radiotherapy (RT) planning. A key step of lung functional avoidance RT is the delineation of lung functional volumes (LFVs) to be integrated into radiation plans. However, there is currently no consistent and reproducible delineation method for LFVs. The aim of this study was to develop and evaluate an automated delineation threshold method based on total lung function for LFVs delineation with Gallium-68 MAA lung PET/CT imaging., Material and Method: Patients prospectively enrolled in the PEGASUS trial-a pilot study assessing the feasibility of lung functional avoidance using perfusion PET/CT imaging for lung stereotactic body radiotherapy (SBRT) of primary or secondary lesion-were analysed. Patients underwent lung perfusion MAA-68Ga PET/CT imaging and pulmonary function tests (PFTs) as part of pre-treatment evaluation. LFVs were delineated using two methods: the commonly used relative to the maximal pixel value threshold method (pmax threshold method, X%pmax volumes) and a new approach based on a relative to whole lung function threshold method (WLF threshold method, FVX% volumes) using a dedicated iterative algorithm. For both methods, LFVs were expressed in terms of % of the anatomical lung volume (AV) and of % of the total lung activity. Functional volumes were compared for patients with normal PFTs and pre-existing airway disease., Results: 60 patients were analysed. Among the 48 patients who had PFTs, 31 (65%) had pre-existing lung disease. The pmax and WLF threshold methods clearly provided different functional volumes with a wide range of relative lung function for a given pmax volume, and conversely, a wide range of corresponding pmax values for a given WLF volume. The WLF threshold method provided more reliable and consistent volumes with much lower dispersion of LFVs as compared to the pmax method, especially in patients with normal PFTs., Conclusions: We developed a relative to whole lung function threshold segmentation method to delineate lung functional volumes on perfusion PET/CT imaging. The automated algorithm allows for reproducible contouring. This new approach, relatively unaffected by the presence of hot spots, provides reliable and consistent functional volumes, and is clinically meaningful for clinicians.

Background: Patients with cancer are at an increased risk of developing atrial fibrillation (AF) and often need to undergo procedures or surgery that requires periprocedural interruption of anticoagulation. Anticoagulated patients with cancer might be at increased risk of postprocedural thromboembolic and bleeding complications. Data on postprocedural outcomes among patients with concurrent active cancer and AF are sparse., Objective: To assess the 30-day risk of postoperative thromboembolic and major bleeding complications after the periprocedural interruption of anticoagulation among patients with AF and active cancer., Methods: We conducted a single-center retrospective cohort study in patients with active cancer and AF who required periprocedural interruption of anticoagulation for invasive procedures between August 2015 and May 2019. The primary endpoints were the 30-day postoperative risks of arterial thromboembolism (ATE) and major bleeding. The secondary endpoints included the 30-day risks of venous thromboembolism, clinically relevant nonmajor bleeding, and overall mortality., Results: Two hundred sixty-four patients undergoing 302 periprocedural interruptions were included in our study. The 30-day risk of ATE was 0.7% (95% CI, 0.1%-2.4%), and the 30-day risk of major bleeding was 1.7% (95% CI, 0.6%-3.9%). The 30-day risks of venous thromboembolism and clinically relevant nonmajor bleeding were 0.7% (95% CI, 0.1%-2.4%) and 4.3% (95% CI, 2.5%-7.3%), respectively. The overall risk of mortality at 30 days was 1.3% (95% CI, 0.4%-3.4%). There was one fatal postoperative stroke., Conclusions: Patients with AF and active cancer in this study were at relatively low risk for ATE and postoperative bleeding complications when patients were managed according to commonly applied perioperative management recommendations., Competing Interests: Declaration of competing interest T-F. Wang reports research funding from Leo Pharma; advisory board/honoraria: Servier and Valeo. D. Siegal has received honoraria indirectly to her research institute from Astra Zeneca, BMS-Pfizer, Leo Pharma, Roche, Servier. J. Douketis has received research support from Boehringer-Ingelheim, royalties from UptoDate and the Merck Manual, as well as consultant/advisory board fees from Actelion, AGEN, Astra Zeneca, Bayer, Biotie, BMS, Daiichi-Sankyo, Portola, Boehringer-Ingelheim, Cytori, Janssen, Leo Pharma, Pfizer, Medicine CO., Sanofi, Servier, Bristol Meyers Squibb and PhaseBio, in addition to speaker’s fees from Bayer, Boehringer-Ingelheim, Pfizer, Leo Pharma, Sanofi, with all funds deposited into a university-based research account of through the St. Joseph’s Healthcare Foundation. Dr. Le Gal reports grants from Pfizer and Bristol-Myers Squibb and honoraria (not taken as salary) from Pfizer, Leo Pharma and Sanofi and Aspen Pharma. M Carrier reports research funding from Leo Pharma, BMS and Pfizer; advisory board/honoraria: Bayer, Sanofi, Leo Pharma, Pfizer, Servier and Valeo. J.R. Shaw has received fellowship funding through the Thrombosis Canada BMS-Pfizer Fellowship Award and has received research support from Diagnostica Stago., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Few studies evaluated the performance of noninvasive diagnostic strategies for suspected acute pulmonary embolism (PE) in pregnant women., Objectives: The aim of this study was to establish the safety and efficiency of the Wells rule with fixed and adapted D-dimer threshold, and the YEARS algorithm, combined with compression ultrasonography (CUS), in pregnant women with suspected PE in an individual patient data meta-analysis., Methods: We performed a systematic review to identify prospective diagnostic management studies in pregnant women with suspected PE. Primary outcomes were safety, defined as the failure rate, ie, the 3-month venous thromboembolism (VTE) incidence after excluding PE without chest imaging, and efficiency, defined as the proportion of patients in whom chest imaging could be avoided., Results: We identified 2 relevant studies, of which individual patient-level data were analyzed in a fixed-effect meta-analysis, totaling 893 pregnant women. The Wells rule with fixed and adapted D-dimer threshold as well as the YEARS algorithm could safely rule out acute PE (failure rate, 0·37%-1·4%), but efficiency improved considerably when applying pretest probability-adapted D-dimer thresholds. The efficiency of bilateral CUS was limited (2·3% overall; number needed to test 43), especially in patients without symptoms of deep-vein thrombosis (efficiency 0·79%; number needed to test 127)., Conclusion: This study supports the latest guideline recommendations (European Society of Cardiology 2019) to apply pretest probability assessment and D-dimer tests to rule out PE in pregnant women. From an efficiency perspective, the use of a strategy with pretest probability-adapted D-dimer threshold is preferred. The yield of CUS was very limited in patients without concomitant symptoms of deep-vein thrombosis., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Introduction: Deciding whether to stop or extend anticoagulant therapy indefinitely after completing at least 3 months of initial treatment for a first unprovoked venous thromboembolism (VTE) remains a challenge for clinicians, patients and policy makers. Guidelines suggest an indefinite duration of anticoagulant therapy in these patients, yet its benefits, harms and costs have not been formally assessed. The aim of this proposed modelling study is to assess the differences in clinical benefits, harms and costs of stopping versus continuing anticoagulant therapy indefinitely for a first unprovoked VTE., Methods and Analysis: We will develop a probabilistic Markov model, adopting a 1-month cycle length and a lifetime horizon, to estimate life-years, quality-adjusted life-years, costs and the incremental cost-effectiveness ratios for a simulated population of patients with a first unprovoked VTE who will receive indefinite duration of anticoagulant therapy versus a population who will not receive extended treatment after completing 3 months of initial anticoagulant therapy. The economic evaluation will adopt a third-party payer perspective relating to a Canadian publicly funded healthcare system. Estimates for the probability of relevant clinical events will be informed by systematic reviews and meta-analyses, while costs and utility values will be obtained from published Canadian sources. Stratified analyses based on sex, age and site of initial VTE will also be performed to identify subgroups of patients with a first unprovoked VTE in whom continuing anticoagulant therapy indefinitely might prove to be clinically beneficial and cost-effective over stopping treatment. We will also conduct sensitivity and scenario analyses to assess robustness of study findings to changes in individual or groups of key parameters., Ethics and Dissemination: Ethical approval is not applicable for this study. The results will be disseminated through presentations at relevant conferences and in a manuscript that will be submitted to a peer-reviewed journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

D-dimer containing species are soluble fibrin degradation products derived from plasmin-mediated degradation of cross-linked fibrin, i.e., 'D-dimer'. D-dimer can hence be considered a biomarker of in vivo activation of both coagulation and fibrinolysis, the leading clinical application in daily practice of which is ruling out venous thromboembolism (VTE). D-dimer has been further evaluated for assessing the risk of VTE recurrence and helping define optimal duration of anticoagulation treatment in VTE, for diagnosing disseminated intravascular coagulation (DIC), and for screening those at enhanced risk of VTE. D-dimer assays should however be performed as intended by regulatory agencies, as their use outside these indications might make them a laboratory-developed test (LDT). This narrative review is aimed at: (1) reviewing the definition of D-dimer, (2) discussing preanalytical variables affecting D-dimer measurement, (3) reviewing and comparing the assays performance and some postanalytical variables (e.g., different units and age-adjusted cutoffs), and (4) discussing the interest of D-dimer measurement across different clinical settings, including pregnancy, cancer, and coronavirus disease 2019 (COVID-19)., (Copyright © 2023. Published by Elsevier Inc.)

D-dimer is a multifaceted biomarker of concomitant activation of coagulation and fibrinolysis, which is routinely used for ruling out pulmonary embolism (PE) and/or deep vein thrombosis (DVT) combined with a clinical pretest probability assessment. The intended use of the tests depends largely on the assay used, and local guidance should be applied. D-dimer testing may suffer from diagnostic errors occurring throughout the pre-analytical, analytical, and post-analytical phases of the testing process. This review aims to provide an overview of D-dimer testing and its value in diagnosing PE and discusses the variables that may impact the quality of its laboratory assessment.

Background: Assessment of the case-fatality rate (CFR) of major bleeding on dual antiplatelet therapy (DAPT) may improve balancing risks and benefits of different durations of DAPT following percutaneous coronary intervention (PCI)., Objectives: To determine the CFR of major bleeding in patients on DAPT after PCI and to compare rates among different durations of DAPT., Methods: Medline, Embase, and CENTRAL were searched from inception to August 2021 for randomized trials that reported fatal bleeding among patients who were randomized to ≥1 month of DAPT following PCI. Summary estimates for CFRs of major bleeding were calculated using the random-effects inverse-variance method. Statistical heterogeneity was evaluated using the I 2 statistic., Results: Of 2777 citations obtained by the search, 15 (48%) of 31 potentially eligible studies were excluded because fatal bleeding was not reported, leaving 16 studies that were included in the analysis. Overall, there were 823 major bleeding events including 91 fatal events in 48,884 patients who were assigned to receive DAPT during study follow-up. The CFR of major bleeding was 10.8% (95% confidence interval [CI], 7.1-16.2; I 2  = 50%) in the entire study population, and 13.8% (95% CI, 6.5-27.1; I 2  = 28%), 11.2% (95% CI, 6.7-18.0; I 2  = 0%), and 5.8% (95% CI, 3.0-11.1; I 2  = 0%) in those on short-term (≤6 months; n  = 16,553), standard-term (12 months; n  = 19,453), and long-term DAPT (>12 months; n  = 10,238), respectively., Conclusion: Fatal bleeding is not reported in many studies evaluating DAPT after PCI. The CFR of major bleeding on DAPT is substantial and may be higher in the first 12 months of DAPT than during long-term DAPT., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Neonatal hypothyroidism is often raised as a potential concern for the use of computed tomography pulmonary angiography (CTPA) in pregnant women with suspected pulmonary embolism (PE)., Objectives: To assess the incidence of neonatal hypothyroidism among newborns from mothers exposed to CTPA., Patients/methods: Pregnant women with clinically suspected PE were included in a multicenter, multinational prospective diagnostic management outcome study, based on pretest clinical probability assessment, high-sensitivity D-dimer testing, bilateral lower limb venous compression ultrasonography, and CTPA. Results of Guthrie tests were systematically collected for newborns of all women who required CTPA as part of the diagnostic strategy. A thyroid-stimulating hormone (TSH) level above 15 U/ml was used to define hypothyroidism., Results: Out of the 166 women included in the Swiss participating centers, 149 underwent a CTPA including 14 with twin pregnancies. Eight women suffered a pregnancy loss and results of the Guthrie test could not be retrieved for four newborns. All TSH levels were reported as being below 15 U/ml. The incidence of neonatal hypothyroidism was 0/151 (0.0%, 95% confidence interval: 0.0%-2.5%)., Conclusions: We did not identify any cases of neonatal hypothyroidism in our cohort of 149 pregnant women investigated for suspected PE using a CTPA. Along with previous literature data, this provides further reassuring data regarding the use of CTPA in this indication., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Introduction: Quantifying the pulmonary vascular obstruction index (PVOI) is essential for the management of patients with pulmonary embolism or chronic thromboembolic pulmonary hypertension (CTEPH). The reference method for quantifying the PVOI with planar lung ventilation/perfusion (V/Q) scintigraphy is the Meyer score, which was validated using pulmonary angiography as a reference standard. However, it is complex to use in daily practice. In contrast, a rapid and fast quantification method consists in estimating the PVOI based on the number of segmental perfusion defects. However, the accuracy of this method has never been evaluated. In this study, we aimed to compare PVOI quantification on planar V/Q scintigraphy assessed by a segmental visual scoring (SVS) to the Meyer score., Materials and Methods: The eligible study population consisted of consecutive patients who underwent planar V/Q scan for CTEPH screening. A central review was performed by three nuclear medicine physicians. PVOI was assessed by summing the number of segmental perfusion defects or equivalent (2 sub-segments = 1 segment = 5%) and by Meyer's method. The two interpretations were performed 6 months apart. A Spearman rank correlation coefficient was calculated to evaluate correlation between the two measurement methods. An intra-class correlation (ICC) was calculated to assess agreement. A Bland et Altman plot analysis was used to evaluate agreement between the two measurements., Results: A total of 226 V/Q scans were interpreted. Spearman rank correlation coefficient between SVS and Meyer was 0.963 (95%CI 0.952-0.971) for mismatched perfusion defects and 0.963 (95%CI 0.953-0.972) for perfusion defects regardless of ventilation. Intra-class correlation (ICC) for agreement was 0.978 (95%CI 0.972-0.983) for mismatched perfusion defects and 0.968 (95%CI 0.959-0.976) for perfusion defects regardless of ventilation. In Bland & Altmann analysis, the mean difference between the SVS method and the Meyer score was 0.42 and 0.61 for the mismatched or matched evaluation, respectively., Conclusion: Our study shows a high correlation, and low differences in PVOI quantification when using a segmental visual scoring (SVS) as compared to the Meyer score. The SVS has the great advantage to be easy and rapid to apply in daily practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Le Pennec, Tromeur, Orione, Robin, Le Mao, Gut-Gobert, Le Gal, Salaün and Le Roux.)

Background: The development of a core outcome set (COS), defined as an agreed minimum set of outcome domains that should be measured and reported in all trials of a specific disease, aims to increase the relevance of study findings to stakeholder groups and improve standardization., Objectives: As the first step in developing a COS for venous thromboembolism (VTE) treatment studies, we aimed to generate an inclusive list of unique outcomes reported in previous VTE treatment studies and classify them into domains and core areas., Methods: MEDLINE, Embase and CENTRAL were searched for prospective studies reporting on interventions for VTE in non-pregnant adults. Study selection and data extraction were performed in blocks based on publication date, starting with 2015-2020 and subsequent 1-year periods, until no new outcome was identified. Outcomes were classified into domains, which are groups of closely related outcomes, and domains into four core areas including death, pathophysiological manifestations/abnormalities, life impact, and resource use., Results: Of 7100 records identified, 240 publications were included, representing 165 distinct studies. A total of 205 unique outcomes were identified that were grouped into 48 domains; 30 (13%) studies covered at least three core areas; death was included in 102 (43%), pathophysiological manifestations/abnormalities in 218 (91%), life impact in 41 (17%), and resource use in 25 (10%) studies., Conclusion: Most VTE treatment studies evaluated pathophysiological features of VTE, but few studies reported outcomes that measured life impact or resource use. The findings will inform next steps in the development of a COS for VTE treatment studies., (© 2022 International Society on Thrombosis and Haemostasis.)

Background: Venous thromboembolism (VTE) is a prevalent disease with high morbidity and mortality. VTE has well-documented physical sequelae; however, the psychological and emotional impacts are seldom evaluated in randomized controlled trials., Objective: We conducted a scoping review of published qualitative studies aiming to understand the physical, psychological, and emotional impact of VTE as reflected from patients' perspectives. This scoping review is part of a larger initiative to develop a core outcome set for VTE treatment studies., Methods: A systematic literature search was conducted to identify qualitative studies assessing patient experience of VTE. Two authors independently screened titles and abstracts using Covidence systematic review software. Full-text reviews were conducted independently by 2 study team members. A modified method of "thematic synthesis" was used to collate themes upon reading and rereading of the publications., Results: Our search strategy returned a total of 4944 citations; 28 were ultimately included in the analysis. The studies were conducted across 13 countries and representative of 436 participants including a spectrum of VTE subpopulations. There were seven major themes identified: Acute impacts: an unforeseen blow, Sustained psychological distress, Loss of self: life is changed, Challenges of thrombosis management, Balancing coping and control, Negative experience with the medical system, and VTE in the context of other conditions., Conclusions: The physical, psychological, and emotional impacts of VTE extend beyond objective outcomes typically evaluated in clinical trials. An improved understanding of the outcomes most important to patients will improve patient-centered care in VTE., (© 2022 International Society on Thrombosis and Haemostasis.)

Pulmonary CTA is a commonly performed study and the radiologist's role is not limited to simply producing a report. The process from identifying the appropriate patients who will benefit from the study to improving performance in the radiology department requires the radiologist's involvement, expertise, and leadership. The focus of this narrative review is to highlight the different steps and the ways to improve the quality in the assessment of thromboembolic disease where the radiologists can have an impact. This article provides an update on the commonly used and more recently published clinical decision tools, specific parameter adjustments of pulmonary CTA for more challenging patients and potential improvement for the radiology department., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I 2  = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I 2  = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I 2  = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer., Design: Multicentre, open label, randomised controlled trial., Settings: 12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020., Participants: 614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection., Interventions: Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only., Main Outcome Measures: Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population., Results: The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1)., Conclusions: Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups., Trial Registration: ClinicalTrials.gov NCT01455831., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Canadian Institute of Health Research, Ottawa Hospital Academic Medical Organisation, and Leo Pharma, as well as through generous patient donations through the Ottawa Hospital Foundation for the submitted work. MC has received research funding from BMS, Pfizer, and Leo Pharma, and honorariums from Bayer, Pfizer, BMS, Servier, and Leo Pharma. VT received consulting honorariums from Pfizer-BMS and Daiichi-Sankyo and has received research funding from Sanofi. MB received consulting honorariums from Johnson and Johnson. ACM received consulting honorariums from Johnson and Johnson. MO received consulting honorariums from Johnson and Johnson Ethicon. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

No clinical prediction model has been specifically developed or validated to identify patients with unprovoked venous thromboembolism (VTE) who are at high risk of major bleeding during extended anticoagulation. In a prospective multinational cohort study of patients with unprovoked VTE receiving extended anticoagulation after completing ≥3 months of initial treatment, we derived a new clinical prediction model using a multivariable Cox regression model based on 22 prespecified candidate predictors for the primary outcome of major bleeding. This model was then compared with modified versions of 5 existing clinical scores. A total of 118 major bleeding events occurred in 2516 patients (annual risk, 1.7%; 95% confidence interval [CI], 1.4-2.1). The incidences of major bleeding events per 100 person-years in high-risk and non-high-risk patients, respectively, were 3.9 (95% CI, 3.0-5.1) and 1.1 (0.8-1.4) using the newly derived creatinine, hemoglobin, age, and use of antiplatelet agent (CHAP) model; 3.3 (2.6-4.1) and 1.0 (0.7-1.3) using modified ACCP score, 5.3 (0.6-19.2) and 1.7 (1.4-2.0) using modified RIETE score, 3.1 (2.3-3.9) and 1.1 (0.9-1.5) using modified VTE-BLEED score, 5.2 (3.3-7.8) and 1.5 (1.2-1.8) using modified HAS-BLED score, and 4.8 (1.3-12.4) and 1.7 (1.4-2.0) using modified outpatient bleeding index score. Modified versions of the ACCP, VTE-BLEED, and HAS-BLED scores help identify patients with unprovoked VTE who are at high risk of major bleeding and should be considered for discontinuation of anticoagulation after 3 to 6 months of initial treatment. The CHAP model may further improve estimation of bleeding risk by using continuous predictor variables, but external validation is required before its implementation in clinical practice., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Although rare, pulmonary embolism (PE) remains one of the most common causes of severe maternal morbidity and mortality during pregnancy. Among pregnant women with suspected PE, the prevalence of confirmed disease is far lower than in the general population, reflecting the fear of missing the diagnosis and a low threshold to suspect PE in this setting. Two prospective management outcome trials have recently assessed two different diagnostic algorithms based on the assessment of clinical probability, D-dimer, venous compression ultrasonography of the lower limbs (CUS), and computed tomography pulmonary angiography (CTPA). Both demonstrated the safety of such strategies to exclude PE, with a very low failure rate defined as the rate of subsequent 3-month venous thromboembolism in women left untreated after a negative work-up. These studies were also the first to prospectively demonstrate the safety of negative D-dimer associated with a clinical prediction rule to exclude PE without any chest imaging. Pregnant women are known to be a subgroup at particularly high risk of inappropriate diagnostic management, so the implementation of such validated diagnostic strategies in clinical practice should represent a high priority goal.

Background:  The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain., Objectives:  To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE., Methods:  We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE&#95;)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies., Results:  Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding ( n  = 41) and fatal bleeding ( n  = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20-0.54) and 0.09 (95% CI: 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6-31.1%)., Conclusion:  The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE., Competing Interests: M.C. reports receiving research support form Leo Pharma and BMS, and honoraria from Pfizer, Bayer, BMS, and Sanofi, outside the submitted work. S.S. reports receiving honoraria from Boehringer Ingelheim, Bayer HealthCare, Daiichi Sankyo, and Sanofi, and research support from Boehringer Ingelheim, Baxter, and Octapharma, outside the submitted work. J.I.W. reports receiving honoraria from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Servier, Bristol-Myers Squibb, Janssen, Novartis, and Ionis Pharmaceuticals, and research support from Boehringer Ingelheim outside the scope of the submitted work. F.C. reports having received research grant support from Pfizer, honoraria for board memberships or symposia from Bayer and AstraZeneca, and travel support from Bayer, Daiichi Sankyo, Leo Pharma, Intermune, and Actelion, outside the submitted work. C.B. reports receiving lecture fees from Bayer HealthCare, Bristol Meyer Squibb, and Boehringer Ingelheim, outside the submitted work. G.A. reports personal fees from Bristol-Myers-Squibb, Pfizer, Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo, outside the submitted work. T.A.B. reports receiving personal fees from Bayer, Bayer Australia, Novo Nordisk, and GlaxoSmithKline, outside the submitted work. W.A.L. reports being an employee of Bayer HealthCare. G.P. reports advisory Board for Alfa-Wassermann, Daiichi-Sankyo, Pfizer, and Roche, and speaker fees from Werfen, outside the submitted work. B.H. reports receiving honoraria from Cornerstone Research Group for provision of methodologic advice related to systematic reviews and meta-analysis. P.P. reports receiving consultancy and lectures fees from Bayer Pharma, Sanofi, Daiichi-Sankyo, and Pfizer, outside the submitted work. H.R.B. reports receiving research support and consultancy fees from Sanofi-Aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics, and Boehringer Ingelheim, outside the submitted work. G.L.-G. holds the Chair on Diagnosis of Venous Thromboembolism at the Department of Medicine, University of Ottawa, and a Clinician-Scientist Award from the Heart and Stroke Foundation of Canada. M.R. is the McGill University Harry Webster Thorp Professor of Medicine. G.L.-G reports other support from Portola Pharmaceuticals, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, LEO Pharma, Daiichi Sankyo, Bayer, Sanofi, and bioMerieux, outside the submitted work. No other authors disclosed any competing interests., (Thieme. All rights reserved.)