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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.)

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: 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.)

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.)

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: 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.)

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.)

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.)

Background: The diagnosis of pulmonary embolism (PE) in pregnant women represents an ongoing challenge. As in the general population, the first step in pregnant women with suspected PE consists of assessing clinical pre-test probability (PTP). However, no dedicated clinical decision rule has been developed in this population., Objective: To propose a new version of the Geneva score adapted to pregnant women with suspected PE., Methods: Data from a multicenter, prospective management outcome study including 395 women with suspected PE, in whom PTP was assessed using the Geneva score, were used. We first removed items which were present in none of the patients (cancer, age >65 years). Receiver operating characteristic (ROC) curve analysis was then performed for quantitative variables and the optimal threshold defined. The obtained Pregnancy-Adapted Geneva Score (PAG Score) comprised seven items, including an age 40 years or older and a heart rate >110 beats per minute., Results: The PAG Score showed a high discriminative power to identify patients with a low, intermediate, or high PTP, associated with increasing prevalence of PE, 2.3%, 11.6%, and 61.5%, respectively. The ROC curves showed an area under the curve of 0.795 for the PAG Score compared to 0.684 for the Geneva score., Conclusion: In pregnant women with suspected PE, the PAG Score shows a high discriminative power to identify patients at low, intermediate, or high PTP. It has the strength of being a fully objective decision rule, is clinically relevant, easy to compute, and should now be tested in a prospective outcome study., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain., Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE., Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results., Results: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%)., Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: The usefulness of D-dimer measurement to rule out venous thromboembolism (VTE) during pregnancy is debated., Objectives: We performed a systematic review and meta-analysis to investigate the safety of D-dimer to rule out acute VTE in pregnant women with suspected pulmonary embolism and/or deep vein thrombosis., Methods: Two reviewers independently identified studies through PubMed and Embase until June 2021, week 1. We supplemented our search by manually reviewing reference lists of all retrieved articles, clinicalTrials.gov, and reference literature. Prospective or retrospective studies in which a formal diagnostic algorithm was used to evaluate the ability of D-dimer to rule out VTE during pregnancy were eligible., Results: We identified 665 references through systematic database and additional search strategies; 45 studies were retrieved in full, of which four were included, after applying exclusion criteria. Three studies were prospective, and one had a retrospective design. The 3-month thromboembolic rate in pregnant women left untreated after a negative D-dimer was 1/312 (0.32%; 95% CI, 0.06-1.83). The pooled estimate values were 99.5% for sensitivity (95% CI, 95.0-100.0; I², 0%) and 100% for negative predictive value (95% CI, 99.19-100.0; I², 0%). The prevalence of VTE and the yield of D-dimer were 7.4% (95% CI, 3.8-12; I², 83%) and 34.2% (95% CI, 15.9-55.23; I², 89%) respectively., Conclusion: Our results suggest that D-dimer allows to safely rule out VTE in pregnant women with suspected VTE and a disease prevalence consistent with a low/intermediate or unlikely pretest probability., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: The International Society on Thrombosis and Haemostasis (ISTH)'s Scientific and Standardization Committee (SSC) recently proposed a definition of pulmonary embolism (PE)-related death., Objectives: To evaluate the accuracy and interrater reliability of the ISTH definition of PE-related death in an autopsy cohort., Methods: We reviewed reports of 1064 consecutive adult autopsies that were performed at the NewYork-Presbyterian Hospital from January 2010 until July 2019. We included all patients with autopsy-confirmed PE-related death (cases) during that time frame, combined with patients who died in 2018 from a cause other than PE (controls). Based on clinical summaries, two adjudicators independently adjudicated the cause of death in each patient using the ISTH classification for the cause of death, blinded to the case/control status and ratio. The primary outcome was autopsy-confirmed PE-related death. We determined the sensitivity and specificity of the ISTH definition to identify autopsy-confirmed PE-related death, and its interrater reliability using the percentage agreement and Cohen's kappa., Results: A total of 126 patients who underwent autopsy were included in the analysis (median age, 68 years [range, 21-94], 60 [48%] women), of which 29 (23%) had died from PE as confirmed by autopsy. The ISTH definition's sensitivity and specificity for autopsy-confirmed PE-related death were 45% (95% CI, 26-64) and 99% (95% CI, 94-100), respectively. Interrater reliability for PE-related death was substantial (percentage agreement, 94% [95% CI, 89-97]; kappa, 0.73 [95% CI, 0.55-0.97])., Conclusion: Adjudication of the cause of death using the ISTH definition resulted in very high specificity, moderate sensitivity, and good interrater reliability for PE-related death., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Diagnosis of heparin-induced thrombocytopenia (HIT) requires pretest probability assessment and dedicated laboratory assays., Objective: To develop a pretest score for HIT., Design: Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839)., Setting: Thirty-one tertiary hospitals in France, Switzerland, and Belgium., Patients: Patients tested for HIT antibodies (2280 evaluable), randomly allocated to derivation and validation cohorts., Measurements: Independent adjudicators diagnosed HIT based on the prospectively collected data and serotonin release assay results., Results: Heparin-induced thrombocytopenia was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); ≥40% decrease in platelet count over ≤6 days (3); thrombotic event, arterial (3) or venous (3). The C-statistic was 0.79 (95% CI, 0.76-0.82). In the validation cohort, the area under the receiver operating characteristic curve was 0.77 (95% CI, 0.74-0.80). Three groups of scores were defined; HIT prevalence reached almost 30% in the high-probability group., Limitation: The performance of the score may depend on settings and practices., Conclusion: The objective, easy-to-collect, clinical features of HIT we evidenced were incorporated into a pretest score, which may guide clinical decisions regarding diagnostic testing and anticoagulation., (© 2021 International Society on Thrombosis and Haemostasis.)

Introduction: The risk of recurrent venous thromboembolism (VTE) after combined oral contraceptive (COC) use is variably reported. We assessed the long-term risk of recurrent VTE in women on COC at the time of a first VTE, in comparison to women without COC use. Our secondary aim assessed the impact of COC use on the recurrent VTE risk in high-risk and low-risk hyperpigmentation, edema, or redness in either leg; D-dimer level ≥250 μg/L; obesity with body mass index ≥30; or older age, ≥65 years (HERDOO2) subgroups., Methods: The REVERSE cohort study derived the HERDOO2 clinical decision rule to predict recurrent VTE in patients who discontinued anticoagulation after 5-7 months for a first unprovoked VTE. Incidence rates of recurrent VTE among women with and without COC exposure were calculated as the number of recurrent VTE over the number of person-years of follow-up, and Cox proportional hazards model was used to compare risks between groups., Results: The risk of recurrent VTE among COC users was 1.1% (95% confidence interval [CI] 0.3-2.9) per patient-year as compared with 3.2% per patient-year (95% CI 2.4-4.3) among nonusers (hazard ratio 0.37; 95% CI 0.1-1.0). Women who were COC users and high risk by HERDOO2 score had a recurrence rate of 3.5% (95% CI 0.4-12.5) compared with 6.1% (95% CI 4.3-8.5) among women who were non-COC users and at high risk by HERDOO2 score (HR 0.6, 95% CI 0.1-2.5)., Conclusions: Women who were COC users at the time of an otherwise unprovoked VTE event had a lower VTE recurrence rate during long-term follow-up, compared with nonusers. The use of HERDOO2 rule may help identify higher risk women with COC use., (© 2021 International Society on Thrombosis and Haemostasis.)

Clinical research in venous thromboembolism (VTE) is hindered by variability in the collection and reporting of data and outcomes. A consistent data language facilitates efficiencies, leads to higher quality data, and permits between-study comparisons and evidence synthesis. The International Society on Thrombosis and Haemostasis (ISTH) launched an international task force of more than 50 researchers to develop common data elements for clinical research in venous thromboembolism. The project was organized in seven working groups, each focusing on a topic area: General Core Data Elements; Anticoagulation and Other Therapies; Chronic VTE and Functional Outcomes; Diagnosis of VTE; Malignancy; Perioperative; and Predictors of VTE. The groups met via teleconference to collaboratively identify key data elements and develop definitions and data standards that were structured in a project-specific taxonomy. A Steering Committee met by teleconference and in-person to determine the overall scope of the project and resolve questions arising from the working groups. ISTH held an open public comment period to enable broader stakeholder involvement and feedback. The common data elements were then refined by the working groups to create a set of 512 unique data elements that are publicly available at http://isth.breakthrough.healthcare. The ISTH VTE Common Data Elements are intended to be a living project with ongoing curation, future expansion, and adaptation to meet the needs of the thrombosis and hemostasis research community., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Validated diagnostic algorithms are used to manage patients with suspected pulmonary embolism (PE). The recently published YEARS study proposed a simplified diagnostic strategy to reduce the use of computed tomography pulmonary angiography., Objectives: To externally validate this strategy in an independent cohort., Methods: We analyzed data from three previous prospective cohort studies of outpatients with suspected PE. We retrospectively applied the YEARS algorithm. The three YEARS clinical criteria are: clinical signs of deep vein thrombosis, hemoptysis, and PE as the most likely diagnosis. If zero YEARS criteria are met, a D-dimer < 1000 ng/mL will rule out PE. If ≥1 YEARS criteria are met, a D-dimer < 500 ng/mL will rule out PE., Results: Of the 3314 patients, 731 (22.1%) had PE. Applying the YEARS diagnostic algorithm, 1423 (42.9%) patients could have had PE ruled out without imaging. Of these patients, 17 (1.2%; 95% confidence interval 0.8-1.9) were diagnosed with PE at initial testing. All 17 had no YEARS item and a D-dimer < 1000 ng/mL. All 17 had a D-dimer level above their age-adjusted cutoff. Among the 272 patients with no YEARS criteria and a D-dimer < 1000 ng/mL but above their age-adjusted D-dimer cutoff, PE was diagnosed in 6.3% (17/272; 95% confidence interval 3.9-9.8)., Conclusion: We provide external validation of the YEARS diagnostic algorithm in an independent cohort. The rule appears to safely exclude PE. However, caution is required in patients with no YEARS item and a D-dimer < 1000 ng/mL but above their age-adjusted D-dimer cutoff., (© 2020 International Society on Thrombosis and Haemostasis.)

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed., Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate., Results: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials., Discussion: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Ventilation/perfusion (V/Q) single-photon emission computed tomography (SPECT) has largely replaced conventional planar V/Q scan in nuclear medicine departments for pulmonary embolism (PE) diagnosis. However, the diagnostic performance of the test and its role in the diagnostic management of acute PE are still a matter of debate., Objective: The primary aim was to establish the diagnostic accuracy (sensitivity, specificity) of V/Q SPECT for PE diagnosis. The secondary aim was to review the clinical outcomes of patients investigated for PE suspicion with a standardized algorithm based on V/Q SPECT., Methods: We conducted a systematic review of diagnostic accuracy and management outcome studies involving patients evaluated with V/Q SPECT for suspected acute PE. We searched from inception to June 23, 2020, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for diagnostic accuracy studies, randomized controlled trials, and observational cohort studies. The methodological quality and risk of bias of eligible studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and the Risk of Bias in Nonrandomized Studies of Interventions tools., Results: We identified 13 accuracy studies and one prospective outcome study. Eleven diagnostic accuracy studies were deemed at high risk of bias in at least two of the four domains of QUADAS-2 evaluation and a further two studies raised concerns regarding the applicability of results, precluding the meta-analysis for accuracy indices. The only prospective cohort study demonstrated critical risk of bias., Conclusions: Although V/Q SPECT has been widely implemented in daily clinical practice, the exact diagnostic performance of V/Q SPECT for PE is still unknown. This systematic review clearly identifies knowledge gaps and sets the agenda for future research., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: The Registro Informatizado de Pacientes con Enfermedad TromboEmbólica (RIETE) score and the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) risk scores aim to identify patients with acute unprovoked venous thromboembolism (VTE) at high risk of occult cancer, but their predictive performance is unclear., Methods: The scores were evaluated in an individual patient data meta-analysis. Studies were eligible if enrolling consecutive adults with unprovoked VTE who underwent protocol-mandated screening for cancer. The primary outcome was a cancer diagnosis between 30 days and 2 years of follow-up. The discriminatory performance was evaluated by computing the area under the receiver (ROC) curve in random-effects meta-analyses., Results: The RIETE score could be calculated in 1753 patients, of whom 63 (3.6%) were diagnosed with cancer. The pooled area under the ROC curve was 0.59 (95% confidence interval [CI], 0.52-0.66; I 2  = 0%). Of the 427 patients (24%) classified as high risk, 25 (5.9%) were diagnosed with cancer compared with 38 of 1326 (2.9%) low-risk patients (hazard ratio [HR], 2.0; 95% CI, 1.3-3.4). The SOME score was calculated in 925 patients, of whom 37 (4.0%) were diagnosed with cancer. The pooled area under the ROC curve was 0.56 (95% CI, 0.46-0.65; I 2  = 46%). Of the 161 patients (17%) classified as high risk (≥2 points), eight (5.0%) were diagnosed with cancer compared with 29 of 764 (3.8%) low-risk patients (HR, 1.2; 95% CI, 0.55-2.7)., Conclusions: The predictive discriminatory performance of both scores is poor. When used dichotomously, the RIETE score is able to discriminate between low- and high-risk patients. Because this is largely driven by advanced age, these results do not support the use of these scores in daily clinical practice., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Improved imaging techniques have increased the incidence of subsegmental pulmonary embolism (ssPE). Indirect evidence is suggesting that ssPE may represent a more benign presentation of venous thromboembolism not necessarily requiring anticoagulant treatment. However, correctly diagnosing ssPE is challenging with reported low interobserver agreement, partly due to the lack of widely accepted diagnostic criteria., Objectives: We sought to derive uniform diagnostic criteria for ssPE, guided by expert consensus., Methods: Based on an extensive literature review and expert opinion of a Delphi steering committee, two surveys including statements regarding diagnostic criteria and management options for ssPE were established. These surveys were conducted electronically among two panels, respectively: expert thoracic radiologists and clinical venous thromboembolism specialists. The Delphi method was used to achieve consensus after multiple survey rounds. Consensus was defined as a level of agreement >70%., Results: Twenty-nine of 40 invited radiologists (73%) and 40 of 51 clinicians (78%) participated. Following two survey rounds by the expert radiologists, consensus was achieved on 15 of 16 statements, including on the established diagnostic criteria for ssPE (96% agreement): a contrast defect in a subsegmental artery, that is, the first arterial branch division of any segmental artery independent of artery diameter, visible in at least two subsequent axial slices, using a computed tomography scanner with a desired maximum collimator width of ≤1 mm. These criteria were approved by 83% of the clinical venous thromboembolism (VTE) specialists. The clinical expert panel favored anticoagulant treatment in case of prior VTE, antiphospholipid syndrome, pregnancy, cancer, and proximal deep vein thrombosis., Conclusion: The results of this analysis provide standard radiological criteria for ssPE that may be applicable in both clinical trials and practice., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE. This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE., Methods: A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process., Results: The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements., Conclusions: The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving., (Published by Elsevier Inc.)

Introduction: Pulmonary embolism (PE)-related death is often part of the primary outcome in venous thromboembolism (VTE) studies. The Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis developed a definition for PE-related death and classification of the cause of death. The present survey evaluated a preliminary version of this definition and classification., Methods: Sixty-nine VTE experts from nine countries were invited for a cross-sectional online survey on January 15, 2019, including multiple-choice and open-ended questions on a seven-subcategory classification of the cause of death. Descriptive statistics were used to describe the results; qualitative comments were summarized., Results: Forty of 69 (58%) invitees completed the survey. All respondents agreed that guidance on classification of the cause of death in VTE studies is required. There was high agreement on the proposal (median overall score, 6; interquartile range, 6-7; scale from 1 [poor] to 7 [excellent]). All respondents approved the wording and content of the seven subcategories, except for one disagreeing vote for two subcategories (A3: "PE is not objectively confirmed, but is most likely the main cause of death" and C1: "Another cause of death is more likely than PE but has not been objectively confirmed"). Suggestions for improvement mainly concerned the extensiveness of the criteria and clinical situations described to define the cause of death., Conclusion: Acceptance of the proposal was excellent. Suggestions for improvement were incorporated in the SSC communication on the definition of PE-related death and classification of the cause of death in VTE studies., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Because hospital-acquired venous thromboembolism (VTE) represents a frequent cause of preventable deaths in medical inpatients, identifying at-risk patients requiring thromboprophylaxis is critical. We aimed to externally assess the Caprini, IMPROVE, and Padua VTE risk scores and to compare their performance to advanced age as a stand-alone predictor., Methods: We performed a retrospective analysis of patients prospectively enrolled in the PREVENU trial. Patients aged 40 years and older, hospitalized for at least 2 days on a medical ward were consecutively enrolled and followed for 3 months. Critical ill patients were not recruited. Patients diagnosed with VTE within 48 hours from admission, or receiving full dose anticoagulant treatment or who underwent surgery were excluded. All suspected VTE and deaths occurring during the 3-month follow-up were adjudicated by an independent committee. The three scores were retrospectively assessed. Body mass index, needed for the Padua and Caprini scores, was missing in 44% of patients., Results: Among 14 910 eligible patients, 14 660 were evaluable, of which 1.8% experienced symptomatic VTE or sudden unexplained death during the 3-month follow-up. The area under the receiver operating characteristic curves (AUC) were 0.60 (95% confidence interval [CI] 0.57-0.63), 0.63 (95% CI 0.60-0.66) and 0.64 (95% CI 0.61-0.67) for Caprini, IMPROVE, and Padua scores, respectively. None of these scores performed significantly better than advanced age as a single predictor (AUC 0.61, 95% CI 0.58-0.64)., Conclusion: In our study, Caprini, IMPROVE, and Padua VTE risk scores have poor discriminative ability to identify not critically ill medical inpatients at risk of VTE, and do not perform better than a risk evaluation based on patient's age alone., (© 2020 International Society on Thrombosis and Haemostasis.)

Pulmonary embolism (PE)-related death is often a component of the primary outcome in venous thromboembolism (VTE) clinical studies. Definitions for PE-related death vary widely, which may lead to biased risk estimates of clinical outcomes, thereby affecting both internal and external validity of study results. We here provide a standardized definition of PE-related death and propose guidance for classification and reporting of the cause of death for clinical studies in VTE. The proposal was developed in a four-step process, including a systematic review of definitions used for PE-related death in previous studies, two subsequent surveys with VTE experts, and meetings held within the Scientific and Standardization Committee (SSC) working group until consensus on the proposal was reached. The proposed classification comprises three categories: Category A: PE-related death, category B: undetermined cause of death, and category C: cause of death other than PE. Category A includes A1: autopsy-confirmed PE in the absence of another more likely cause of death; A2: objectively confirmed PE before death in the absence of another more likely cause of death; and A3: PE is not objectively confirmed, but is most likely the main cause of death. Category B includes B1: cause of death is undetermined, despite available information; and B2: insufficient clinical information available to determine the cause of death. The use of the proposed definition will hopefully improve the accuracy of study outcomes, between-study comparisons, meta-analyses, and validity of future clinical VTE studies., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: In patients with suspected pulmonary embolism (PE) and a non-high pretest probability, the use of an age-adjusted D-dimer cutoff (AADD, <500 ng/mL up to 50 years, then $200 000/lost QALY was 79.4%. In sensitivity analyses, the DCER became <+$200 000/lost QALY only if, among patients with D-dimer below the AADD cutoff, the mortality of an undiagnosed PE was >6% or the prevalence of PE was >0.6%., Conclusions: The AADD cutoff results in a clinically nonsignificant decrease in QALY but important costs reductions. It is a decrementally cost-effective innovation, with a potential of cost savings of >$80 million per year for the United States health care system., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Antiphospholipid syndrome (APS) is an acquired thrombophilia disorder with prevalence not completely known in patients with first unprovoked venous thromboembolic events (VTE). Recent data suggest that the management of some APS patients should be different from that of patients with other thrombophilia. Our aim was to estimate the prevalence of APS in a community-based cohort of patients with a first unprovoked VTE., Methods: We conducted a cross-sectional study analyzing data from our computer assisted oral anticoagulant dosage program. Data of all consecutive patients aged 18 to 50 years who were seen between January 1, 2002 and December 31, 2011 for a first proximal unprovoked VTE were extracted. The prevalence and main features of patients who fulfilled the Sapporo revised criteria for APS were collected., Results and Discussion: A total of 524 incident patients aged 18 to 50 years were included in the anticoagulation clinic during the study period. Of them, 491 were tested for APS and 44 (9.0%; 95% confidence interval [CI]: 6.7-11.8) fulfilled APS criteria. Of 26 APS women, 8 (30.8%) were on combined oral contraceptive pill at the time of VTE, versus 108 (55.1%) in non-APS women (P = .02). No difference was observed between APS and non-APS patients in terms of gender or type of VTE. The prevalence of APS is high in young patients with a first unprovoked VTE. In the direct oral anticoagulant era, when and how to test for APS is challenging and deserves further investigation., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: There is a paucity of studies comparing postoperative thromboembolic and major bleeding complications following perioperative interruption of the direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs)., Objective/methods: We conducted a retrospective cohort study to compare postoperative thromboembolic and major bleeding outcomes following perioperative interruption of DOACs and VKAs in patients with atrial fibrillation. The primary efficacy and safety outcomes were the 30-day postoperative rates of arterial thromboembolic events (ATEs) and major bleeding, respectively. The secondary outcomes included the 30-day rates of clinically relevant nonmajor bleeding (CRNMB) and overall mortality. Thromboembolic, major bleeding, and mortality outcomes were independently adjudicated. Multivariable mixed-effects logistic-regression models were used to adjust for potential confounding variables between the DOAC and VKA cohorts., Results: A total of 325 DOAC patients undergoing 351 procedures and 199 VKA patients undergoing 221 procedures were included. The 30-day ATE rate was 0.57% (95% confidence interval [CI], 0.27-0.8) in the DOAC cohort. There were no ATEs in the VKA cohort. The 30-day rates of major bleeding were 0.57% (95% CI, 0.27-0.8) and 3.62% (95% CI, 0-7.3) in the DOAC and the VKA cohorts, respectively. There were significantly more postoperative major bleeding events in the VKA cohort. The 30-day rate of CRNMB was 4.27% (95% CI, 4.15-4.42) in the DOAC cohort and 4.52% (95% CI, 3.67-5.38) in the VKA cohort. There were 2 deaths in the VKA cohort, one of which was deemed to be a fatal nonsurgical bleeding event., Conclusions: The perioperative interruption of VKAs may be associated with higher postoperative major bleeding rates as compared to DOACs. Careful postoperative reinitiation and monitoring of VKA anticoagulation may be warranted following surgical procedures., (© 2019 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Background: Pulmonary embolism (PE)-related death is a component of the primary outcome in many venous thromboembolism (VTE) studies. The absence of a standardized definition for PE-related death hampers study outcome evaluation and between-study comparisons., Objectives: To summarize definitions for PE-related death used in recent VTE studies and to assess the PE-related death rate., Patients/methods: A systematic literature search was conducted on 26 April 2018 from 1 January 2014 up to the search date in MEDLINE, Embase, and CENTRAL. Cohort studies and randomized trials in which PE-related death was included in the primary outcome were eligible. Screening of titles, abstracts, and full-text articles, and data extraction were independently performed in duplicate by two authors. Study outcomes included the definition for PE-related death, VTE case-fatality rate, and death due to PE rate. Descriptive statistics were used to analyze the data., Results: Of the 6807 identified citations, 83 studies were included of which 27% were randomized trials, 31% were prospective, and 42% retrospective cohort studies. Thirty-five studies (42%) had a central adjudication committee. Thirty-eight (46%) reported a definition for PE-related death of which the most frequently used components were "autopsy-confirmed PE" (50%), "objectively confirmed PE before death" (55%), and "unexplained death" (58%). Median VTE case-fatality rate was 1.8% (interquartile range, 0.0-13)., Conclusions: Only half of the included studies reported definitions for PE-related death, which were very heterogeneous. Case-fatality rate of VTE events varied widely across studies. Standardization of the definition and guidance on adjudication and reporting of PE-related death is needed., (© 2019 Amsterdam University Medical Center, AMC. Journal of Thrombosis and Haemostasis © 2019 International Society on Thrombosis and Haemostasis.)

Introduction: The recently proposed YEARS algorithm was shown to safely exclude pulmonary embolism (PE) and reduce the use of computed tomography pulmonary angiography (CTPA) among pregnant women with suspected PE. Our aim was to externally validate this finding., Methods: We performed a post hoc analysis of a prospective management outcome study for PE diagnosis in pregnant women. PE was diagnosed with an algorithm that combined the revised Geneva score, D-dimer testing, bilateral lower-limb compression ultrasonography, and CTPA. All women had a 3-month follow-up. All of the items necessary to use the YEARS algorithm were prospectively collected at the time of the study., Results: Of the 395 women included in the original study, 371 were available for the present analysis. The PE prevalence was 6.5%. Ninety-one women had no YEARS items, and 280 had one or more items. When the YEARS items were combined with D-dimer levels (<1000 ng/mL in women with no items, and <500 ng/mL in women with one or more items), 77 women (21%) met the criteria for PE exclusion and would not have undergone CTPA as per the YEARS algorithm. None of these 77 women had PE diagnosed during the initial work-up or 3-month follow-up. Therefore, the failure rate of the YEARS algorithm in our pregnant women population was 0/77 (95% confidence interval 0.0-3.9)., Conclusion: In our study, application of the YEARS algorithm would have resulted in safe exclusion of PE in one of five pregnant women without the need for radiation exposure, further supporting the use of the algorithm in this population., (© 2019 International Society on Thrombosis and Haemostasis.)

Essentials Patients with cancer-associated VTE frequently undergo invasive procedures. Data on the perioperative interruption of anticoagulation for cancer-associated VTE are lacking. Patients with cancer-associated VTE experience high post-operative VTE and major bleeding rates. This patient population may warrant close follow-up after invasive procedures., Background: Patients with cancer are at high risk for venous thromboembolic events. Venous thromboembolism (VTE) can lead to significant morbidity among patients with cancer, and is estimated to be one of the leading causes of death among cancer patients. Patients with cancer often require invasive procedures for biopsy or therapeutic purposes. There is a lack of data on postoperative outcomes following interruption of anticoagulation in this population., Objective: To assess 30-day postoperative thromboembolic and major bleeding complication rates following the perioperative interruption of anticoagulation in patients with cancer-associated VTE., Methods: We conducted a retrospective self-controlled case series study with patients with cancer-associated VTE undergoing perioperative interruption of anticoagulation at a dedicated tertiary-care anticoagulation clinic for invasive procedures between January 2013 and March 2018. The primary efficacy and safety outcomes were the 30-day postoperative rates of VTE and major bleeding, respectively. The secondary outcomes included the 30-day rates of clinically relevant non-major bleeding (CRNMB) and overall mortality. Patients undergoing multiple perioperative anticoagulation interruptions were included., Results: One hundred and forty-six patients undergoing 171 periprocedural interruptions were included in our cohort. The 30-day rates of VTE and major bleeding were both 4.1% (95% confidence interval [CI] 2.0-8.2). The 30-day rate of CRNMB was 2.9% (95% CI 1.3-6.7) and the 30-day overall mortality rate was 0.6% (95% CI 0.1-3.4). There were no fatal postoperative VTE or major bleeding events., Conclusions: The periprocedural interruption of anticoagulation in patients with cancer-associated VTE is associated with high postoperative rates of VTE and major bleeding. Patients with cancer-associated VTE may require closer follow-up for VTE and bleeding complications after invasive procedures., (© 2019 International Society on Thrombosis and Haemostasis.)

The diagnosis of pulmonary embolism (PE) is nowadays based on the sequential use of several diagnostic tests rather than on a single test. These diagnostic strategies are safe and have been prospectively validated. The first step after identifying patients with suspicion of PE is to establish the pre-test clinical probability. Several scores are available in order to make a standardised and reproducible assessment of the clinical probability, and therefore represent precious diagnostic tools. Indeed, clinical probability guides further investigations. Indeed, in patients with a low or an intermediate clinical probability or an "unlikely" probability, PE can be safely ruled out by negative D-dimers in approximately one third of outpatients without additional imaging. In case of positive D-dimers and a high clinical probability or a "likely" clinical probability, CT pulmonary angiography is now the recommended imaging technique. However, lower limb venous compression ultrasound and ventilation/perfusion scans remain useful in patients with contra-indications to CT, mainly those with renal insufficiency. Finally, some novel diagnostic tests seem promising. For example, V/Q SPECT has arisen as a highly accurate test and a potential alternative to CTPA. However, prospective management outcome studies are still lacking and are warranted before its implementation in routine clinical practice., (Copyright © 2019 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Background: Multiple D-dimer cutoffs have been suggested for older patients to improve diagnostic specificity for venous thromboembolism. These approaches are better established for pulmonary embolism., Objectives: We evaluated the diagnostic performance and compared the health system cost for previously suggested cutoffs and a new D-dimer cutoff for low-risk emergency department (ED) deep venous thrombosis (DVT) patients., Methods: We conducted a retrospective cohort study in two large EDs involving patients aged > 50 years who had low pretest probability for DVT and had a D-dimer performed. The outcome was a diagnosis of DVT at 30 days. We evaluated the diagnostic accuracy and estimated the difference in cost for cutoffs of 500 ng/mL and the age-adjusted (age × 10) rule. A derived cutoff of 1000 ng/mL was also assessed., Results: Nine hundred and seventy-two patients were included (median age 66 years; 59.5% female); 63 (6.5%) patients were diagnosed with DVT. The conventional cutoff of < 500 ng/mL demonstrated a sensitivity of 100% (95% confidence interval [CI] 94.3-100%) and a specificity of 35.6% (95% CI 32.5-38.8%). The age-adjusted approach increased specificity while maintaining high sensitivity. A new cutoff of 1000 ng/mL demonstrated improved performance: sensitivity 100% (95% CI 94.3-00%) and specificity 66.3% (95% CI 63.2-69.4%). Compared to the conventional approach, both the 1000 ng/mL cutoff and the age-adjusted cutoffs could save healthcare dollars. A cutoff of 1000 ng/mL could have saved 310 ED length of stay hours and $166,909 (Canadian dollars) in our cohort, or an average savings of 0.32 h and $172 per patient., Conclusions: Among patients aged > 50 years with suspected DVT, the age-adjusted D-dimer and a cutoff of 1000 ng/mL improved specificity without compromising sensitivity, and lowered the health care system cost compared to that for the conventional approach., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Essentials Management of patients with calf deep vein thrombosis remains controversial. We conducted a post-hoc analysis of a placebo controlled LMWH randomized clinical trial. Pain was assessed using visual analogue scale at inclusion, one and six weeks. There was no difference in pain control between the two arms. SUMMARY: Background The optimal management of distal deep vein thrombosis (DVT) is highly debated. The only available placebo-controlled trial suggested the absence of clear benefit of anticoagulation. Many physicians feel that, beyond preventing thromboembolic complications, anticoagulation with low-molecular-weight heparin (LMWH) has the potential to improve pain control. Objectives To analyze whether LMWHs decrease pain in patients with distal deep vein thrombosis. Patients and methods Two-hundred and fifty-two patients included in a multicenter, placebo-controlled, randomized clinical trial of LMWH in patients with acute distal DVT and who were asked to rate their pain at inclusion and at each medical visit, using a visual analogue pain scale (VAS). Results One hundred and thirty patients were randomized in the therapeutic nadroparin arm and 122 patients were randomized in the placebo arm. Mean VAS values were 4.6 (standard deviation [SD] 2.5) at inclusion, 2.1 (SD 2.0) at 1 week and 0.4 (SD 1.2) at 6 weeks. We calculated the individual variation in VAS between inclusion and 1 week in patients in whom VAS was available at the two study time-points. There was no difference in the mean VAS reduction between patients treated with therapeutic nadroparin (n = 106) and with placebo (n = 109): -2.6 (SD 2.4) vs. -2.3 (SD 2.0) after 1 week and -4.4 (SD 2.8) vs. -4.0 (SD 2.4) after 6 weeks, respectively. The use of compression stockings was associated with a reduction in pain. Conclusion These data suggests that LMWH use does not improve pain control as compared with placebo in patients with acute distal DVT., (© 2019 International Society on Thrombosis and Haemostasis.)

Randomized controlled trials provide important evidence to guide clinical practice. These full-scale trials are expensive, time consuming and many are never successfully completed. Well conducted pilot studies help with full-scale trial design, assessment and optimization of feasibility, and can avoid the waste of resources associated with starting a full-scale trial that will not succeed. They also provide an opportunity for capacity growth and mentorship of new investigators. It is important to appreciate that the usual goal of a pilot trial is assessment of feasibility and refinement of trial design rather than to gain preliminary evidence of efficacy. Indeed, using event rates from a pilot trial to calculate sample sizes can be misleading in therapeutic trials. Misconceptions exist that pilot trials are just "small trials," are easy to perform, and are not worthy of publication. While, in the past, many pilot trials were poorly conducted and not followed by a full-scale trial, by following the recommendations in the "CONSORT 2010 statement: extension to randomized pilot and feasibility trials," high-quality pilot trials can be performed and reported that will greatly improve the chances of successfully completing a practice-changing trial. We propose that pilot trials are a valuable investment and describe the TRIM-Line pilot trial (NCT03506815), a pilot study assessing the feasibility of a randomized controlled trial investigating primary thromboprophylaxis with rivaroxaban in patients with malignancy and central venous catheters, as an illustrative example of how a pilot trial in the area of thrombosis should be designed.

After completing anticoagulation therapy for acute venous thromboembolism (VTE), patients with unprovoked VTE are at increased risk of recurrent thrombotic events. Recent studies suggest a risk of nearly 10% in the first year after stopping anticoagulants and 30% at 8 years. Therefore, it is important to consider extended anticoagulation for secondary prevention in these high-risk patients. While several oral anticoagulants are available for this purpose, there is limited information available regarding the optimal agent to minimize bleeding risks and maximize efficacy at VTE prevention. This review article summarizes the evidence available for Vitamin-K antagonists (VKAs) and direct oral anticoagulants (DOACs) for extended treatment of VTE. We also introduce the COVET trial, the first head-to-head comparison of VKAs to DOACs, rivaroxaban and apixaban, for extended management of unprovoked VTE.

Essentials Patients at high-risk of occult cancer may benefit from extensive screening. We validated the RIETE cancer score in the MVTEP study. One in three patients were classified as high-risk, 10% of whom had cancer diagnosed. The RIETE score identifies a subgroup at high risk for cancer., Summary: Background Most recent trials evaluating extensive screening strategies for occult cancer in patients with unprovoked venous thromboembolism have failed, because, among other reasons, of an overall low rate of occult cancer. The RIETE investigators recently proposed a score aimed at identifying a subgroup at higher risk. Methods We retrospectively computed the RIETE score for all patients included in the MVTEP study, which evaluated the accuracy of [¹⁸F]fluorodeoxyglucose-positron emission tomography in the screening of occult cancer in patients with unprovoked venous thromboembolism. Performance of the RIETE score was assessed according to the proportion of patients classified in each risk group, and the corresponding rates of cancer diagnosis. Results Among the 386 patients included in the analysis, 136 patients (35.3%) were classified as high risk by the RIETE score. Cancer was diagnosed in 16 (11.8%) of them, whereas it was diagnosed in nine (3.6%) of the 250 patients with a low RIETE cancer score: odds ratio of 3.6 (95% confidence interval [CI] 1.53-8.32). The area under the receiver operating characteristic curve was 0.63 (95% CI 0.51-0.74). Conclusion The RIETE score seems to be able to identify a subgroup at high risk for cancer (10%) in our specific dataset of patients with unprovoked venous thromboembolism., (© 2017 International Society on Thrombosis and Haemostasis.)