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Introduction: Patients with pulmonary embolism (PE) experience impaired functional ability and reduced quality of life long after discharge from the hospital. However, there are no structured follow-up programmes in Denmark for these patients, and there is considerable variation in practice patterns of post-PE management. No studies have investigated the effectiveness of structured follow-up care models in patients with PE. This study aims to investigate the effect and cost-effectiveness of a structured integrated post-pulmonary embolism follow-up care model (Attend-PE) compared with usual care. The Attend-PE model outlines a structured approach for in-hospital follow-up, involving group-based patient education, individual consultations and systematic use of patient-reported outcome measures to assess the patient's physical and psychological well-being., Methods and Analysis: The study is conducted in Denmark, where the healthcare system is tax-funded and services are freely available for all citizens, with an expected inclusion of 2000 patients in total. A pre-post-intervention study design is used to compare outcomes in the post-implementation cohort with the pre-implementation cohort. The co-primary outcomes are (1) health-related quality of life (patient-reported outcome, PRO) and (2) adherence to medical treatment (register-based data). Secondary outcomes include PROs on disability, treatment satisfaction, self-management, anxiety, depression and work productivity, and register-based outcomes, including recurrent PE, bleeding, mortality and healthcare use. Register-based data will be assessed at baseline (date of PE event), 6 and 12 months, while PRO-data will be assessed at 6 and 12 months after the PE event. The health economic evaluation of the Attend-PE model will include a cost-effectiveness analysis and a cost-utility analysis., Ethics and Dissemination: The project will be conducted by the Declaration of Helsinki. In accordance with the Danish Act on Health Research Ethics §14, the study is exempt from approval. The use of survey responses in research (in anonymous form) is, however, contingent on participants' consent, and the invitation letter therefore included information about the purpose of the study and participants' rights to withdraw consent at any time, and that completion of the questionnaire is considered as consent to their survey data to be included in research.Study findings will be disseminated in scientific peer-reviewed journals, at national and international conferences, and for staff and decision-makers at participating hospitals and patients and relatives via the Danish Heart Association., Trial Registration Number: Clinicaltrials.gov NCT06037096., Competing Interests: Competing interests: AAH has received research grants from The Danish Heart Foundation and The Novo Nordisk Foundation, consulting fees from Bayer and The Bristol-Myers Squibb-Pfizer Alliance, and speaker bureaus from Bayer, The Bristol-Myers Squibb-Pfizer Alliance. NR has given talks about pulmonary embolism and physical rehabilitation on postgraduate courses for nurses and physicians within thrombosis and participated in development and production of patient information material on the same subject, both sponsored by Bayer and Bristol-Myers Squibb-Pfizer Alliance. ELG has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Novo Nordisk, Organon and Lundbeck Pharma. He is investigator in clinical trials sponsored by AstraZeneca, Idorsia and Bayer has received unrestricted research grants from Boehringer Ingelheim. SFL has no conflicts of interest to declare. SPJ has received consultancy fees from Bristol-Myers Squibb and Pfizer and has worked on institutional grants from Bristol-Myers Squibb, Pfizer and Novo Nordisk., (© 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.)

Recent advances in therapy and the promulgation of multidisciplinary pulmonary embolism teams show great promise to improve management and outcomes of acute pulmonary embolism (PE). However, the absence of randomized evidence and lack of consensus leads to tremendous variations in treatment and compromises the wide implementation of new innovations. Moreover, the changing landscape of health care, where quality, cost, and accountability are increasingly relevant, dictates that a broad spectrum of outcomes of care must be routinely monitored to fully capture the impact of modern PE treatment. We set out to standardize data collection in patients with PE undergoing evaluation and treatment, and thus establish the foundation for an expanding evidence base that will address gaps in evidence and inform future care for acute PE. To do so, >100 international PE thought leaders convened in Washington, DC, in April 2022 to form the Pulmonary Embolism Research Collaborative. Participants included physician experts, key members of the US Food and Drug Administration, patient representatives, and industry leaders. Recognizing the multidisciplinary nature of PE care, the Pulmonary Embolism Research Collaborative was created with representative experts from stakeholder medical subspecialties, including cardiology, pulmonology, vascular medicine, critical care, hematology, cardiac surgery, emergency medicine, hospital medicine, and pharmacology. A list of critical evidence gaps was composed with a matching comprehensive set of standardized data elements; these data points will provide a foundation for productive research, knowledge enhancement, and advancement of clinical care within the field of acute PE, and contribute to answering urgent unmet needs in PE management. Evidence produced through the Pulmonary Embolism Research Collaborative, as it is applied to data collection, promises to provide crucial knowledge that will ultimately produce a robust evidence base that will lead to standardization and harmonization of PE management and improved outcomes., Competing Interests: Dr Rosenfield reports consulting fees from Abbott Vascular, Boston Scientific, Contego, Imperative Care, Johnson & Johnson, Biosense Webster, Medtronic, Neptune Medical, and Philips; board membership for the PERT (Pulmonary Embolism Response Team) Consortium; and stock or stock options in Access Vascular, Althea Medical, Auxetics, Contego, Endospan, Imperative Care, Innova Vascular, InspireMD, JanaCare, Magneto, MedAlliance, Neptune Medical, Orchestra, Sealonix, Shockwave, Skydance, Summa Therapeutics, Thrombolex, Vantis Vascular, Vasorum, Viz.ai, and Vumedi. Dr Bowers reports consulting fees from Truvic, Inc, lecture fees from Janssen and Bristol Myers Squibb (BMS)-Pfizer, payment for expert testimony, and participation on Advisory Board of Truvic, Inc. Dr Barnett reports payment for expert testimony. Dr Davis reports travel support for attending the Pulmonary Embolism Research Collaborative meeting. Dr Giri reports research support from Boston Scientific, Inc, and Inari Medical; consulting fees from Boston Scientific, Inc, Cordis, and Abbott Vascular; support for attending meetings from Inari Medical; participation on an advisory board for Angiodynamics, Inc, and Boston Scientific, Inc; participation in leadership at Society for Cardiac Angiography and Intervention and the PERT Consortium; and stock or stock options in Endovascular Engineering. Dr Horowitz reports research support from Inari Medical; consultation and personal lecture fees from Inari Medical and Penumbra, Inc; and support for attending meetings from Inari Medical. Dr Keeling reports consulting fees from Angiodynamics, Inc, Penumbra, Inc, Viz.ai, and Dexcom. Dr Klok reports institutional research support from Bayer, Bristol Myers Squibb, Actelion, Boston Scientific, Inc, Leo Pharma, the Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Association, the Dutch Heart Foundation, and the Horizon Europe program; service on the Board of the Rembrandt Institute of Cardiovascular Science; Chair of the Board of the Dutch Society of Vascular Medicine; nucleus member of the European Society of Cardiology work group on pulmonary circulation and RV function; nucleus member of ISTH SSC diagnostic and predictive variables; Chair of the Board of the Dutch Thrombosis Network; and medical lead, Anticoagulation Clinic Leiden. Dr Konstantinides reports personal and institutional consulting fees from Bayer AG, Daiichi-Sankyo, and Boston Scientific, Inc, and personal lecture fees from Bayer AG, Daiichi-Sankyo, Pfizer–Bristol Myers Squibb, and Boston Scientific, Inc. Dr Lookstein reports consulting fees from Penumbra, Inc, Boston Scientific, Inc, Medtronic, Cordis, Becton Dickinson, Abbott Vascular, Neptune Medical, Imperative Care, and Aidoc; payment for expert testimony; participation on advisory boards for Magneto, Boston Scientific, Inc, Medtronic, and Trireme; leadership roles at the PERT Consortium, Critical Limb Ischemia Global Society, and Society of Interventional Radiology; and stock or stock options in Imperative Vascular, Thrombolex, Innova Vascular, and Summa Vascular. Dr Moriarty reports research support from Angiodynamics, Inc, and Penumbra, Inc; consulting fees from Angiodynamics, Inc, Penumbra Inc, Inquis Medical, Innova Vascular, Boston Scientific Inc, Auxetics, and Retriever Medical; and participation on the data safety monitoring board for Penumbra, Inc. Dr Ní Áinle reports institutional research support from Sanofi, Daiichi-Sankyo, the Irish Health Research Board, Bayer, and Boston Scientific, Inc; patents pending for European Application No. 20166826.6; past member of World Thrombosis Day International Steering Committee; Director at Large and Member, International Network of Venous ThromboEmbolism Research Networks Council; Co-Director, InVite; Co-Founder and member of Executive Committee of Venous Thromboembolism Ireland; Advisory Committee for Human Medicines; member of “Preventing Venous Thromboembolism in Hospitals” Collaborative Advisory Group; Board Member, Thrombosis Ireland Patient Organization and Charity; and National Lead, Irish Venous Thromboembolism Patient Safety Programme. Dr Rosovsky reports research support from BMS and Janssen; consulting fees from Abbott, BMS, Dova, Inari Medical, Janssen, and Penumbra, Inc; participation on the data safety monitoring board for the Pepper Trial and Harvard Cancer Center; unpaid President-Elect of the PERT Consortium; and unpaid member of ASH Committee on Quality. Dr Secemsky reports research support from NIH/NHLBINIH/NHBLI K23HL150290, Food and Drug Administration, Becton-Dickinson, Boston Scientific, Inc, Cook Medical, Cardiovascular Systems Inc., Laminate Medical, Medtronic, and Philip; consulting fees and personal lecture fees from Abbott, Bayer, Becton-Dickinson, Boston Scientific, Inc, Cook, Cardiovascular Systems Inc., Inari Medical, Medtronic, Philips, Shockwave, and VentureMed; and participation on data safety monitoring boards for LIFE BTK, BIOMIMCS3D, HI-PEITHO, and Transcend. Dr Sharp reports consulting and lecture fees from Medtronic, Boston Scientific, Inc, Philips, Recor Medical, and Penumbra, Inc. Dr Sista reports research support from NIH/NHLBI as principal investigator of U34 and UG3 awards, unpaid participation on data safety monitoring boards for Angiodynamics, Inc, and Thrombolex, Inc; and participation on the Board of Directors for the Society of Interventional Radiology. Dr Wells reports participation on the data safety monitoring board for Anthos. The other authors report no conflicts.

Acute pulmonary embolism (PE) remains a critical medical condition requiring prompt and accurate management. The introduction and growing significance of pulmonary embolism response teams (PERT), also termed EXPERT-PE teams, signify a paradigm shift toward a collaborative, multidisciplinary approach in managing this complex entity. As the understanding of acute PE continues to evolve, PERTs stand as a linkage of optimized care, offering personalized and evidence-based management strategies for patients afflicted by this life-threatening condition. The evolving role of PERTs globally is evident in their increasing integration into the standard care pathways for acute PE. These teams have demonstrated benefits such as reducing time to diagnosis and treatment initiation, optimizing resource utilization, and improving patient outcomes., Competing Interests: L.H. received lecture/consultant fees from MSD, INARI, Johnson & Johnson, and Boston Scientific, outside the submitted work. L.H. also reports personal fees from MSD, personal fees from Johnson & Johnson, personal fees from INARI, and personal fees from Boston Scientific, outside the submitted work. I.T.F. reports no conflict of interest. D.D. received speaker's honoraria from Boston Scientific, Bayer, Daiichi Sankyo, BMS, and Pfizer. D.D. also reports grants from DFG, grants from DZHK, during the conduct of the study; personal fees from Boston Scientific, personal fees from Bayer, personal fees from Daiichi Sankyo, personal fees from BMS, and personal fees from Pfizer, outside the submitted work. K.K. reports no conflict of interest., (Thieme. All rights reserved.)

Background: Over the last few years, the concept of multidisciplinary pulmonary embolism response teams (PERTs) has emerged to encounter the increasing variety and complexity in managing acute pulmonary embolism (PE)., Purpose: To investigate PERT's composition and added clinical value in a university center in Germany., Methods: Over 4 years (01/2019-11/2022), patients with confirmed PE were enrolled in a prospective single-center cohort study (PERT Mainz). We investigated the composition of PERT and compared, after propensity score matching, patients with acute PE before and after the initiation of PERT at our Medical University Centre. The primary outcome was in-hospital PE-related mortality., Results: From 2019 to 2022, 88 patients with acute PE with a PERT decision were registered. Of those, 13 (14.8%) patients died during the in-hospital stay. Patients evaluated by a PERT had a median age of 68; 48.9% were females, and 21.7% suffered from malignancy. Right ventricular dysfunction was present in 76.1% of all patients. In total, 42.0% were classified as intermediate-high-risk PE and 11.4% as high-risk PE. First PERT contact mainly originated from emergency departments (33.3%) and intensive care units (30.0%), followed by chest pain units (21.3%) and regular wards (12.0%). The participation rate of medical specialties demonstrated that cardiologists (100%) or cardiac/vascular surgeons (98.6%) were included in almost all PERT consultations, followed by radiologists (95.9%) and anesthesiologists (87.8%). Compared to the PERT era, more patients in the pre-PERT era were classified as simplified pulmonary embolism severity index (sPESI) ≥ 1 (78.4% vs 71.6%) and as high-risk PE according to ESC 2019 guidelines (18.2% vs. 11.4%). In the pre-PERT era, low- and intermediate-low patients with PE received more frequently advanced reperfusion therapies such as systemic thrombolysis or surgical embolectomy compared to the PERT era (10.7% vs. 2.5%). Patients in the pre-PERT were found to have a considerably higher all-cause mortality and PE-related mortality rate (31.8% vs. 14.8%) compared to patients in the PERT era (22.7% vs. 13.6%). After propensity matching (1:1) by including parameters as age, sex, sPESI, and ESC risk classes, univariate regression analyses demonstrated that the PE management based on a PERT decision was associated with lower risk of all-cause mortality (OR, 0.37 [95%CI 0.18-0.77]; p = 0.009). For PE-related mortality, a tendency for reduction was observed (OR, 0.54 [95%CI 0.24-1.18]; p = 0.121)., Conclusion: PERT implementation was associated with a lower risk of all-cause mortality rate in patients with acute PE. Large prospective studies are needed further to explore the impact of PERTs on clinical outcomes., (© 2023. The Author(s).)

Background: Prior clinical trials have demonstrated the efficacy of ultrasound-facilitated catheter-directed thrombolysis (USCDT) for the treatment of acute intermediate-risk pulmonary embolism (PE) using reduced thrombolytic doses and shorter infusion durations. However, utilization and safety of such strategies in broader PE populations remain unclear. The KNOCOUT PE (The EKoSoNic Registry of the Treatment and Clinical Outcomes of Patients With Pulmonary Embolism) registry is a multicenter international registry designed to study the treatment of acute PE with USCDT, with focus on safety outcomes., Methods: The KNOCOUT PE prospective cohort included 489 patients (64 sites internationally) with acute intermediate-high or high-risk PE treated with USCDT between March 2018 and June 2020. Principal safety outcomes were independently adjudicated International Society on Thrombosis and Haemostasis major bleeding at 72 hours post-treatment and mortality within 12 months of treatment. Additional outcomes included change in right ventricular/left ventricular ratio and quality of life measures over 12 months., Results: Mean alteplase (r-tPA [recombinant tissue-type plasminogen activator]) infusion duration was 10.5 hours. Mean total r-tPA dose was 18.1 mg, with 31.0% of patients receiving ≤12 mg. Major bleeding events within 72 hours occurred in 1.6% (8/489) of patients. One patient experienced worsening of a preexisting subdural hematoma after USCDT and therapeutic anticoagulation, which ultimately required surgery. All-cause mortality at 30 days was 1.0% (5/489). Improvement in PE quality of life score was observed with a 41.1% (243/489, 49.7%) and 44.2% (153/489, 31.3%) mean relative reduction by 3 and 12 months, respectively., Conclusions: In a prospective observational cohort study of patients with intermediate-high and high-risk PE undergoing USCDT, mean r-tPA dose was 18 mg, and the rates of major bleeding and mortality were low., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03426124., Competing Interests: At the time of KNOCOUT (The EKoSoNic Registry of the Treatment and Clinical Outcomes of Patients With Pulmonary Embolism) and writing of this article, Dr Sterling was a consultant to Boston Scientific, Access Vascular Inc, and vizai. Dr Sterling is now an employee of Boston Scientific. Dr Piazza has received research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific Corporation, Janssen, NAMSA, Penumbra, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. Dr Sharp was a Consultant to Medtronic, Boston Scientific, Recor Medical, Penumbra, Philips. Dr Kucher received consulting and lecture fees from Concept Medical, Boston Scientific, Bayer, and INARI; institutional grants from the Swiss National Foundation, Bard, Bayer, Boston Scientific, Concept Medical, and Sanofi; not related to the present work. Dr Goldhaber received Research Support from Bayer, BMS, Boston Scientific, Janssen, NHLBI, and Pfizer. Dr Meneveau was a consultant at Abbott Medical, Bayer Health Care, Bristol-Myers Squibb, Edwards Lifesciences, Terumo, Inari, Boston Scientific. Fees: Abbott Medical, AstraZeneca, Bayer Health Care, Bristol-Myers Squibb, Pfizer, Terumo. Dr Zlotnick participated in Speaker’s Bureau: Abiomed, Inari Medical; Consultant/Speaker’s Bureau: Angiodynamics. Dr Sayfo was consultant with Boston Scientific. Dr Konstantinides received institutional grants from Bayer AG, Daiichi-Sankyo, and Boston Scientific; consulting or lecture fees from Bayer AG, Daiichi Sankyo, Boston Scientific, Penumbra, MSD, Pfizer, and Bristol-Myers Squibb. The other authors report no conflicts.

Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54-0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH., (© 2024. The Author(s).)

Background: Deep venous thrombosis (DVT) poses a substantial disease burden. Lymphedema may present with similar symptoms making the diagnosis process more difficult. Data on the epidemiology of lymphedema are lacking. Methods: The German nationwide inpatient sample served to analyze all patients hospitalized owing to DVT and/or thrombophlebitis (referred to as DVT) of the legs in Germany between 2005 and 2020. We stratified these patients for additional lymphedema and analyzed the impact of lymphedema on adverse in-hospital events. Results: Overall, 1,136,574 hospitalizations related to DVT were recorded in Germany during 2005-2020 (53.3% women; 51.3% aged ≥70 years). Lymphedema was coded in 9974 (0.9%) patient-cases (82.0% not elsewhere classified, 17.7% secondary lymphedema). Annual numbers of hospitalizations with lymphedema among DVT patients increased from 450 (2005) to 613 (2016) (β 0.57; 95% confidence interval [CI]: 0.48-0.66], p  < 0.001) and decreased thereafter. Despite similar age, DVT patients with lymphedema had higher prevalence of cardiovascular diseases, chronic organ failure, and all types of investigated cancer. Prevalence of pulmonary embolism (PE) with shock/CPR (4.1% vs. 1.5%), acute renal failure (6.7% vs. 2.5%), and stroke (5.2% vs. 4.2%) was higher in DVT patients with lymphedema than without. Lymphedema was independently associated with PE with shock/CPR (OR: 2.1; 95% CI: 1.9-2.3) as well as death (OR: 1.3; 95% CI: 1.2-1.4). Conclusions: Comorbidity conditions like cancer, obesity, and cardiovascular risk factors, and also infectious complications, were more prevalent in DVT patients with lymphedema than in those without. Lymphedema was independently associated with severe in-hospital complications, particularly when its genesis was related to severe comorbidities.

Background: Ultrasound-assisted catheter-directed thrombolysis (USAT) may reverse right ventricular dysfunction due to acute pulmonary embolism (PE) with a favorable safety profile., Methods: We studied intermediate-high- and high-risk acute PE patients who underwent USAT at the University Hospital Zurich, 2018-2022. The USAT regimen included alteplase 10 mg per catheter over 15 h, therapeutic-dosed heparin, and dosage adaptations based on routinely monitored coagulation parameters, notably anti-factor Xa activity and fibrinogen. We focused on the mean pulmonary arterial pressure (mPAP) and the National Early Warning Score (NEWS) before and after USAT, and reported the incidence of hemodynamic decompensation, PE recurrence, major bleeding, and death over 30 days., Results: We included 161 patients: 96 (59.6 %) were men and the mean age was 67.8 (SD 14.6) years. Mean PAP decreased from a mean of 35.6 (SD 9.8) to 25.6 (SD 8.2) mmHg, whereas the NEWS decreased from a median of 5 (Q1-Q3 4-6) to 3 (Q1-Q3 2-4) points. No cases of hemodynamic decompensation occurred. One (0.6 %) patient had an episode of recurrent PE. Two (1.2 %) major bleeding events occurred, including one (0.6 %) intracranial, fatal hemorrhage in a patient with high-risk PE, severe heparin overdosing, and a recent head trauma (with negative CT scan of the brain performed at baseline). No other deaths occurred., Conclusions: USAT resulted in a rapid improvement of hemodynamic parameters among patients with intermediate-high risk acute PE and selected ones with high-risk acute PE, without any recorded deaths related to PE itself. A strategy including USAT, therapeutic-dosed heparin, and routinely monitored coagulation parameters may partly explain the overall very low rate of major bleeding., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The study was conducted at the Department of Angiology of the University Hospital Zurich and was supported by an unrestricted grant from Boston Scientific., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Catheter-directed interventions have slowly been gaining ground in the treatment of pulmonary embolism (PE), especially in patients with increased risk of bleeding. The goal of this study is to summarize the evidence for the efficacy and safety of percutaneous thrombectomy (PT) in patients with contraindications to systemic and local thrombolysis. We performed a systematic review and meta-analysis using MEDLINE, Cochrane, Scopus and the Web of Science databases for studies from inception to March 2022. We included patients with intermediate- and high-risk PE with contraindications to thrombolysis; patients who received systematic or local thrombolysis were excluded. Primary endpoint was in-hospital and 30-day mortality, with secondary outcomes based on hemodynamic and radiographic changes. Major bleeding events were assessed as a safety endpoint. Seventeen studies enrolled 455 patients, with a mean age of 58.6 years and encompassing 50.4% females. In-hospital and 30-day mortality rates were 4% (95% CI 3-6%) and 5% (95% CI 3-9%) for all-comers, respectively. We found a post-procedural reduction in systolic and mean pulmonary arterial pressures by 15.4 mmHg (95% CI 7-23.7) and 10.3 mmHg (95% CI 3.1-17.5) respectively. The RV/LV ratio and Miller Index were reduced by 0.42 (95% CI 0.38-46) and 7.8 (95% CI 5.2-10.5). Major bleeding events occurred in 4% (95% CI 3-6%). This is the first meta-analysis to report pooled outcomes on PT in intermediate- and high-risk PE patients without the use of systemic or local thrombolytics. The overall mortality rate is comparable to other contemporary treatments, and is an important modality particularly in those with contraindications for adjunctive thrombolytic therapy. Further studies are needed to understand the interplay of anticoagulation with PT and catheter-directed thrombolysis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pulmonary embolism (PE) is a life-threatening acute disease accompanied by high morbidity and mortality. Regarding hospitalizations of patients with PE, risk stratification of these patients is crucial. Thus, risk stratification tools like risk scores are of key interest., Methods: The nationwide German inpatient sample of the years 2005-2018 was used for this present analysis. Hospitalized PE patients were stratified according to Mansoor's Self-Report Tool for Cardiovascular Risk Assessment class, and the performance of this score was evaluated to predict adverse in-hospital events., Results: Overall, 1 174 196 hospitalizations of PE patients (53.5% females; 56.4% ≥70 years) were registered in Germany between 2005 and 2018. According to the Mansoor's self-report tool for cardiovascular risk assessment, 346 126 (29.5%) PE patients were classified as high risk. Higher Mansoor's Self-Report Tool for Cardiovascular Risk Assessment class was predictive for in-hospital death (OR 1.129 [95%CI 1.117-1.141], P < 0.001), shock (OR 1.117 [95%CI 1.095-1.140], P < 0.001), cardiopulmonary resuscitation (OR 1.109 [95%CI 1.092-1.126], P < 0.001), right ventricular dysfunction (OR 1.039 [95%CI 1.030-1.048], P < 0.001), intracerebral bleeding (OR 1.316 [95%CI 1.275-1.358], P < 0.001), and gastro-intestinal bleeding (OR 1.316 [95%CI 1.275-1.358], P < 0.001). Systemic thrombolysis was not associated with lower in-hospital mortality in high-risk class (OR 5.139 [95%CI 4.961-5.323], P < 0.001)., Conclusions: Prognostic performance of the Mansoor's Self-Report Tool for Cardiovascular Risk Assessment for risk stratification of PE patients was poor and not able to identify those PE patients, who might benefit from systemic thrombolysis. However, the Mansoor's Self-Report Tool for Cardiovascular Risk Assessment was moderately helpful to identify PE patients at higher risk for bleeding events., (© 2022 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Pulmonary embolism is one of the leading causes of cardiovascular death in Europe. Rapid diagnosis and treatment initiation are essential, especially in hemodynamically unstable patients. For normotensive patients, the diagnostic workflow is based on the clinical probability of pulmonary embolism. Due to numerous differential diagnoses and a highly variable clinical presentation, diagnosis of acute pulmonary embolism still remains a clinical challenge. Computed tomography angiography is the common gold standard to confirm pulmonary embolism and bedside echocardiography adds a major impact in clinical decision making. The European Society of Cardiology guidelines serve as a framework for a standardized diagnostic approach and risk prediction. Based on vital signs, clinical scores, biomarkers and imaging results, four risk categories can be defined and treatment is accordingly. To optimize the individual management of critical patients, multidisciplinary pulmonary embolism response teams are increasingly designated in specialized centers. This article provides an overview of the current risk-adapted management of patients with acute pulmonary embolism., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Aim of this narrative review is to summarize the functional and hemodynamic implications of acute PE and PE sequelae, namely the post-PE syndrome. Briefly, we will first describe the epidemiology, diagnostic procedures, and therapeutic approaches of acute PE. Then, we will provide a definition of the post-PE syndrome and present the so far accumulated evidence regarding its epidemiology and the implications that arise for further diagnosis and treatment. Lastly, we will explore the most devastating long-term complication of PE, namely chronic thromboembolic pulmonary hypertension (CTEPH), and recent advances in its management.

Background: Pulmonary embolism is a leading cause of maternal morbidity and mortality in Western countries. In the United States, pulmonary embolism-related mortality rates have plateaued in the general population after an initial decrease in the past 20 years., Objective: This study aimed to describe the changes in pulmonary embolism-related maternal mortality rates in the United States over the past 2 decades., Study Design: In this epidemiologic study of public vital registration data (death certificates encompassing underlying and contributing causes of death) from the Centers for Disease Control and Prevention Multiple Cause of Death database (2003-2020), we identified all maternal deaths with a pulmonary embolism code listed in any position of the death certificates. We investigated the changes in annual crude pulmonary embolism-related maternal mortality rates for the years 2003 to 2020, considering the effect of the introduction of the pregnancy checkbox in death certificates on the pulmonary embolism-related maternal mortality rates., Results: Overall, 735 pulmonary embolism-related maternal deaths out of 12,871 total maternal deaths (5.7%) were recorded between 2003 and 2020; the overall pulmonary embolism-related maternal mortality rate was 1.02 (95% confidence interval, 0.95-1.10) per 100,000 live births. The pulmonary embolism-related maternal mortality rate increased from 0.93 in 2003 to 1.96 in 2020; however, when accounting for the implementation of the pregnancy checkbox in the death certificates, the trends in pulmonary embolism-related maternal mortality were largely unchanged from 2003 to 2020. The crude pulmonary embolism-related maternal mortality rates differed across maternal age groups (overall 0.61, 1.09, and 3.83 maternal deaths per 100,000 live births for those aged ≤24, 25-39, and ≥40 years, respectively) and racial/ethnicity groups (2.89, 0.47, 0.77, and 0.63 maternal deaths per 100,000 live births for Black non-Hispanics, other non-Hispanics, White non-Hispanics, and Hispanics, respectively)., Conclusion: Maternal mortality rates related to pulmonary embolism did not decrease during the period from 2003 to 2020, as opposed to mortality rates related to pulmonary embolism in the general population. More research is required to assess whether improvement in venous thromboembolism prevention and pulmonary embolism diagnosis and management strategies might reduce death owing to pulmonary embolism in this vulnerable population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Although the two manifestations of venous thromboembolism (VTE), deep vein thrombosis (DVT) and pulmonary embolism (PE), vary considerably, the consensus guidelines recommend similar algorithms for therapeutic anticoagulation in both conditions. Real-world data assessing contemporary management strategies in PE and DVT alone may help tailoring future recommendations towards more individualized patient care., Methods: In the present analysis, we compared demographics, comorbidities, treatment patterns, and clinical outcomes of PE versus DVT only among 2062 consecutive patients with confirmed VTE enrolled by 11 acute care hospitals between November 2012 and February 2015 in the SWIss Venous ThromboEmbolism Registry (SWIVTER)., Results: Overall, 1246 (60 %) patients were diagnosed with PE. In comparison to DVT alone, PE patients were older (66 vs. 59 years; p < 0.001), more frequently had acute and chronic comorbidities, less frequently had prior VTE and hormone replacement, and were less often pregnant. VTE was considered similarly often provoked in patients with PE and DVT alone (33.8 % vs. 33.5 %; p = 0.88). Anticoagulation for an indefinite duration was more often prescribed to patients with PE than those with DVT alone (45.7 vs. 19.6 %; p < 0.001), and PE diagnosis was the strongest independent predictor of indefinite anticoagulation (OR 3.21; 95 % CI 2.55-4.06; p < 0.001). Diagnosis of PE was associated with both increased risk of 90-day mortality (HR 2.31, 95 % CI 1.44-3.71; p = 0.001) and major bleeding (HR 3.88, 95 % CI 1.63-9.22; p = 0.002)., Conclusions: Our analysis affirms differences in demographics, risk factors, and clinical outcomes of PE versus DVT alone. In routine clinical practice, duration of anticoagulation is being managed differently between the two manifestations of VTE, in contrast to recommendations of the current consensus guidelines., Competing Interests: Conflict of interest JHB reports grants from the Swiss National Science Foundation and the Swiss Heart Foundation, grants, and personal fees from Boehringer Ingelheim, Pfizer, Bayer, and Daiichi-Sankyo, outside the submitted work. RPE reports personal fees from Bayer, Daiichi-Sankyo and Sanofi-Aventis, outside the submitted work. WK reports personal fees and non-financial support from Bayer, Pfizer, Shire/Takeda, Roche, Daiichi-Sankyo, and Novo Nordisk, outside the submitted work. NK reports personal fees from Bayer, Boston Scientific, Optimed, Bard, and BTG, outside the submitted work. SB reports personal fees from BTG Pharmaceuticals and Leo Pharma, personal fees and non-financial support from Bayer HealthCare, and non-financial support from Daiichi-Sankyo, outside the submitted work. DS is an employee of Sanofi-Aventis (Suisse) SA, Vernier, Switzerland., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: There is an ongoing discussion on the optimal right to left (RV/LV) diameter ratio threshold and the best definition of RV dysfunction on computed tomography pulmonary angiography (CTPA) for risk assessment of pulmonary embolism (PE)., Methods: On routine diagnostic CTPA, volumetric and diameter measurements (axial and reconstructed views) of the ventricles and reflux of contrast medium into the inferior vena cava (IVC) and hepatic veins were assessed in consecutive PE patients enrolled in a prospective single-center registry. In-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration., Results: Of 609 patients (median age, 69 [IQR, 56-77] years; 47 % male) included in the analysis, 68 patients (11.2 %) had an adverse outcome and 35 (5.7 %) died. While neither a RV/LV volume ratio ≥1.0 nor RV/LV diameter ratios ≥1.0 were able to predict an adverse outcome, higher thresholds increased specificity. Further, neither volumetric measurements nor reconstruction of images provided superior prognostic information compared to RV/LV ratios measured in axial planes. The combination of an axial RV/LV diameter ratio ≥1.5 with substantial reflux of contrast medium was present in 134 patients (22 %) and associated with the best prognostic performance to predict an adverse outcome in unselected (OR 3.7 [95 % CI, 2.0-6.6]) and normotensive (OR 2.8 [95 % CI, 1.1-6.7]) patients., Conclusion: A new definition of RV dysfunction (axial RV/LV diameter ratio ≥1.5 and substantial reflux of contrast medium to the IVC and hepatic veins) allows an optimized CTPA-based prediction of PE-related adverse outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The gold standard treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). Little is known about the influence of advanced age on surgical outcome. Therefore, the aim of this study was to investigate the impact of patient's age on postoperative morbidity, mortality, and quality of life in a German referral center., Methods: Prospectively collected data from 386 consecutive patients undergoing PEA between 01/2014 and 12/2016 were analyzed. Patients were divided into three groups according to their age: group 1: ≤ 50 years, group 2: > 50 ≤ 70 years, group 3: > 70 years., Results: After PEA, distinct improvements in pulmonary hemodynamics, physical capacity (World Health Organization [WHO] functional class and 6-minute walking distance) and quality of life were found in all groups. There were more complications in elderly patients with longer time of invasive ventilation, intensive care, and in-hospital stay. However, the in-hospital mortality was comparable (0% in group 1, 2.6% in group 2, and 2.1% in group 3 [ p  = 0.326]). Furthermore, the all-cause mortality at 1 year was 1.1% in group 1, 3.2% in group 2, and 6.3% in group 3 ( p  = 0.122)., Conclusions: PEA is an effective treatment for CTEPH patients of all ages accompanied by low perioperative and 1-year mortality. CTEPH patients in advanced age carefully selected by thorough preoperative evaluation should be offered PEA in expert centers to improve quality of life, symptoms, and pulmonary hemodynamics., Competing Interests: CBW has received speaker fees and/or consultant honoraria from Actelion, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, and Pfizer.DB has nothing to disclose.KA has nothing to disclose.HAG has reported receiving fees for serving as a board member for Bellerophon Pulse Technologies, Medscape, OMT, UCB Celltech, and Web MD Global; receiving consultancy fees and fees for serving on a steering committee for Actelion Pharmaceuticals, Bayer, Gilead Sciences, GlaxoSmithKline, Merck, Novartis, and Pfizer; receiving lecture fees from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer; and receiving grant support from Actelion Pharmaceuticals, Bayer, Novartis, and Pfizer.ML reports consultant and speaker fees from Actelion, Bayer, Thermo Fisher Scientific, Daiichi-Sankyo, MSD and Bristol-Myers Squibb-Pfizer, project funding from Thermo Fisher Scientific and institutional funding from the German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503).CL has received speaker fees from Abbott, Astra Zeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Elixir Medical, and Pfizer.DP has received speaker fees from AstraZeneca, and Kerckhoff-Forschungs GmbH, and received grant support from Johnson & Johnson and Medtronic.EM has received speaker fees and/or honoraria for consultations from Actelion, Bayer, GSK, MSD, and Pfizer.SDK has nothing to disclose.SG has received speaker fees from Actelion, Bayer, GSK, MSD and Pfizer., (Thieme. All rights reserved.)

Competing Interests: O.S. has received institutional research grants from Bayer, Leo Pharma, Bristol-Myers Squibb, Merck Sharp and Dome, Daiichi-Sankyo, Boehringer Ingelheim, and Sanofi, and personal consultancy/speaker fees from Bayer, Bristol-Myers Squibb, Pfizer, Boston Scientific, Merck Sharp and Dome, Boehringer Ingelheim, Sanofi, and Chiesi. S.V.K. reports institutional research grants and personal consultancy/speaker fees from Actelion/Janssen, Bayer AG, Daiichi-Sankyo, and Boston Scientific; institutional research grants from Boehringer Ingelheim and Servier; and personal consultancy/speaker fees from Bristol-Myers Squibb/Pfizer and Novartis.

Background: Crohn's disease (CD) is associated with an increased risk for venous thromboembolism (VTE). Beside higher VTE risk, data on impact of VTE on survival and risk factors for the occurrence of VTE in CD are sparse., Methods: The German nationwide inpatient sample was screened for patients admitted due to CD (ICD-code K50). CD hospitalizations were stratified for VTE and risk-factors for VTE and impact of VTE on in-hospital case-fatality rate were investigated., Results: Overall, 333,975 hospitalizations of patients due to CD were counted in Germany (median age 38.0 [IQR 24.0-52.0] years, 56.0 % females) during the observational period 2005-2018. VTE rate increased slightly from 0.6 % (2005) to 0.7 % (2018) (β 0.000097 [95%CI 0.000027 to 0.000167], P = 0.007) 2005-2018 and with age-decade (β 0.0017 [95%CI 0.0016 to 0.0019], P < 0.001). In total, 0.7 % (2295) of the CD inpatients had a VTE event. Patients with VTE were in median 12 years older (49.0 [34.0-62.0] vs. 37.0 [24.0-52.0] years, P < 0.001) and colon-involvement was in those patients more prevalent (32.0 % vs.27.7 %, P < 0.001). Age ≥ 70 years, obesity, colon-involvement, cancer, surgery, thrombophilia, and heart failure were strongly associated with higher risk of VTE in CD patients. In-hospital death occurred 15-times more often in CD with VTE than without (4.5 % vs. 0.3 %, P < 0.001). VTE was independently associated with increased in-hospital case-fatality rate (OR 9.31 [95%CI 7.54-11.50], P < 0.001)., Conclusions: VTE is a life-threatening event in hospitalized CD patients associated with 9.3-fold increased case-fatality rate. Older age, obesity, colon involvement, cancer, surgery, thrombophilia and heart failure were strong risk factors for VTE in CD., Competing Interests: Declaration of competing interest KK, VS, VHS, MAO, TM report no conflict of interests. TM is PI of the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. CEK reports having from Amarin Germany, Amgen GmbH, Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, MSD Sharp & Dohme, Novartis Pharma, Pfizer Pharma GmbH, Sanofi-Aventis GmbH. LH received lecture/consultant fees from MSD and Actelion, outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

There is a growing clinical and scientific interest in catheter-directed therapy (CDT) of acute pulmonary embolism (PE). Currently, CDT should be considered for patients with high-risk PE, in whom thrombolysis is contraindicated or has failed. Also, CDT is a treatment option for initially stable patients in whom anticoagulant treatment fails, i.e., those who experience haemodynamic deterioration despite adequately dosed anticoagulation. However, the definition of treatment failure (primary reperfusion therapy or anticoagulation alone) remains an important area of uncertainty. Moreover, several techniques for CDT are available without evidence supporting one over the other, and variation in practice with regard to periprocedural anticoagulation is considerable. The aim of this position paper is to describe the currently available CDT approaches in PE patients and to standardise patient selection, the timing and technique of the procedure itself as well as anticoagulation regimens during CDT. We discuss several clinical scenarios of the clinical evaluation of the "efficacy" of thrombolysis and anticoagulation, including treatment failure with haemodynamic deterioration and treatment failure based on a lack of improvement. This clinical consensus statement serves as a practical guide for CDT, complementary to the formal guidelines.

Background: Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) results in respiratory syndromes but also in vascular complications such as thromboembolism (TE). In this regard, immunothrombosis, resulting from inflammation in SARS-CoV-2 infected tissues, has been described. Data on TE in COVID-19 are mainly based on clinical observational and/or incomplete autopsy studies. The true burden of TE and the relevance of genetic predisposition, however, have not been resolved., Objectives: Here, we report on a consecutive cohort of 100 fully autopsied patients deceased by SARS-CoV-2 infections during the first wave of the pandemic (March to April 2020). We investigated the localization of TE, potential clinical risk factors, and the prothrombotic gene mutations, factor V Leiden and prothrombin G20210A, in postmortem blood or tissue samples., Results: TE was found in 43/100 autopsies. 93 % of TE events were venous occlusions, with 23 patients having pulmonary thromboembolism (PT) with or without lower-extremity deep vein thrombosis. Of these, 70 % showed PT restricted to (sub)segmental arteries, consistent with in situ immunothrombosis. Patients with TE had a significantly higher BMI and died more frequently at an intensive care unit. Hereditary thrombophilia factors were not associated with TE., Conclusions: Our autopsy results show that a significant proportion of SARS-CoV-2 infected patients suffer from TE, affecting predominantly the venous system. Orthotopic peripheral PT was the most frequent finding. Hereditary thrombophilia appears not to be a determinant for TE in COVID-19. However, obesity and the need for intensive care increase the risk of TE in these patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations., Competing Interests: O.S. has received institutional research grants from Bayer, Leo Pharma, Bristol-Myers Squibb, Merck Sharp and Dome, Daiichi-Sankyo, Boehringer Ingelheim, and Sanofi, and personal consultancy/speaker fees from Bayer, Bristol-Myers Squibb, Pfizer, Boston Scientific, Merck Sharp and Dome, Boehringer Ingelheim, Sanofi, and Chiesi. S.B. has received congress and travel payments from Daiichi-Sankyo and Bayer AG, honoraria from BTG Pharmaceuticals, Boston Scientific, Bayer HealthCare, and Leo Pharma, and institutional grants from Sanofi, outside the submitted work. W.A. reports research support from Bayer; activity in advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo, Portola, Janssen, Aspen, and Sanofi. D.D. has received speaker's honoraria from Bayer Vital, Daiichi-Sankyo, and Pfizer/Bristol-Myers Squibb, and consulting fees from Bayer Vital and Daiichi-Sankyo. In addition, D.D. is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation #422681845). K.E. reports lecture fees from AstraZeneca, Bayer Vital, Berlin Chemie, Boehringer Ingelheim, and Novartis, and consulting fees from Bayer Vital, Boehringer Ingelheim, Novartis, and Novo Nordisk. M.F. reports lecture fees and travel grants from Bayer, Bristol-Myers Squibb, and Pfizer, and travel grants from Daiichi-Sankyo and Leo Pharma. M.V.H. reports grants from ZonMW Dutch Healthcare Fund, and grants and personal fees to the hospital from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Bayer Health Care, Aspen, and Daiichi-Sankyo, all outside the submitted work. D.J. has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; served as a speaker or a member of a speakers' bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Leo Pharma, ROVI, and Sanofi; received grants for clinical research from Daiichi-Sankyo, Sanofi, and ROVI. M.K. reports speaker fees from Pfizer, Boehringer Ingelheim, and Bayer AG, outside the submitted work. M.L. reports consultant and speaker fees from Actelion, Bayer, Thermo Fisher Scientific, Daiichi-Sankyo, MSD, and Bristol-Myers Squibb-Pfizer, and project funding from Thermo Fisher Scientific. N.M. reports consulting fees, speaker fees, and project funding from Bayer AG and Bristol-Myers Squibb/Pfizer; speaker fees from AstraZeneca and Boehringer Ingelheim; and consulting fees from Abbott and Terumo. A.P. reports speaker fees from S.C. Pfizer Romania SRL, Servier Pharma SRL, Novartis Pharma Services Romania SRL, Bayer SRL, and SC Sanience SRL.S.R. received honoraria for lectures and/or consultancy from Abbott, Acceleron, Actelion, Arena, Bayer, BMS, Ferrer, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor, and institutional research grants from Actelion, AstraZeneca, Bayer, Janssen, and Novartis. S.S. has received consulting fees and speaker fees from Aspen and Boehringer Ingelheim, speaker fees from Bayer AG and Daiichi-Sankyo, and project funding and speaker fees from Pfizer/Bristol-Myers Squibb. P.V. received honoraria for lectures and/or consultancy from Anthos Therapeutics, Bayer, Boehringer, Daiichi-Sankyo, BMS, and Pfizer, and research support from Bayer, Daiichi-Sankyo, BMS, and Pfizer. S.K. reports institutional research grants and personal consultancy/speaker fees from Actelion/Janssen, Bayer AG, Daiichi-Sankyo, and Boston Scientific; institutional research grants from Boehringer Ingelheim and Servier; and personal consultancy/speaker fees from Bristol-Myers Squibb/Pfizer and Novartis. All other authors report no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Despite evidence of ongoing epidemiological changes in deaths from venous thromboembolism in high-income countries, little recent information is available on the time trends in mortality related to pulmonary embolism (PE) as underlying or concomitant cause of death in Europe., Methods: We accessed the regional database of death certificates of Veneto Region (Northern Italy, population 4,900,000) from 2008 to 2019. We analyzed the trends in crude and age-adjusted annual rates of mortality related to PE (reported either as underlying cause or in any position in the death certificate) using Joinpoint regression; in the contribution of PE to mortality (proportionate mortality); and, using logistic regression, in the association between PE and cancer at death., Results: Between 2008 and 2019, the annual age-standardized mortality rate related to PE in Veneto decreased from 20.7 to 12.6 deaths per 100,000 population for PE in any position of the death certificate, and from 4.6 to 2.2 deaths per 100,000 population for PE as underlying cause of death. PE-related proportionate mortality remained up to twice as high in women. The age- and sex-adjusted odds ratio for cancer in deaths with versus without PE constantly increased from 1.01 (95% confidence interval [CI]: 0.88-1.16) in 2008 to 1.58 (95% CI: 1.35-1.83) in 2019., Conclusion: The descending trends in PE-related mortality reported for Europe up to 2015 for both sexes continued thereafter in this high-income region of Northern Italy. However, sex differences in proportionate mortality persist. The increasing strength in the association between cancer and PE may indicate a change in risk factor distribution, calling for tailored management practices in this patient group., Competing Interests: None declared., (Thieme. All rights reserved.)

Aims/introduction: In patients with pulmonary embolism (PE), the impact of diabetes mellitus on patient profile and outcome is not well investigated., Material and Methods: The German nationwide inpatient sample of the years 2005-2018 was analyzed. Hospitalized PE patients were stratified for diabetes, and the impact of diabetes on in-hospital events was investigated., Results: Overall, 1,174,196 PE patients (53.8% aged ≥70 years, 53.5% women) and, among these, 219,550 (18.7%) diabetes patients were included. In-hospital mortality rate amounted to 15.8%, and was higher in diabetes patients than in non-diabetes patients (19.8% vs 14.8%, P < 0.001). PE patients with diabetes had a higher prevalence of cardiovascular risk factors, comorbidities, right ventricular dysfunction (31.8% vs 27.7%, P < 0.001), prolonged in-hospital stay (11.0 vs 9.0 days, P < 0.001) and higher rates of adverse in-hospital events. Remarkably, diabetes was independently associated with increased in-hospital mortality (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.20-1.23, P < 0.001) when adjusted for age, sex and comorbidities. Within the observation period of 2005-2018, a relevant decrease of in-hospital mortality in PE patients with diabetes was observed (25.5% to 16.8%). Systemic thrombolysis was more often administered to diabetes patients (OR 1.18, 95% CI 1.01-3.49, P < 0.001), and diabetes was associated with intracerebral (OR 1.19, 95% CI 1.12-1.26, P < 0.001), as well as gastrointestinal bleeding (OR 1.11, 95% CI 1.07-1.15, P < 0.001). Type 1 diabetes mellitus was shown to be a strong risk factor in PE patients for shock, right ventricular dysfunction, cardiopulmonary resuscitation and in-hospital death (OR 1.75, 95% CI 1.61-1.90, P < 0.001)., Conclusions: Despite the progress in diabetes treatments, diabetes is still associated with an unfavorable clinical patient profile and higher risk for adverse events, including substantially increased in-hospital mortality in acute PE., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

We aimed to evaluate the impact of age, sex, and their interactions with provoking risk factors for deep vein thrombosis (DVT). In addition, we intended to provide additional insights on risk factors associated with the isolated distal versus proximal presentation of first symptomatic acute DVT, both being characterized by different prognosis. In the present analysis from the SWIss Venous ThromboEmbolism Registry (SWIVTER), we compared demographic and baseline characteristics in patients with isolated distal (n = 184; 35%) versus proximal (n = 346) DVT of the lower limbs without symptomatic pulmonary embolism, and identified factors related with the presenting thrombosis location. In the overall population, mean age was 59 ± 19 years, 266 (50%) were women, 106 (20%) patients had cancer, 86 (16%) recent surgery, and 52 (10%) acute infection/sepsis. In a multivariable analysis, recent surgery [odds ratio (OR) 2.92, 95% confidence interval (CI) 1.80-4.73] was independently associated with a diagnosis of isolated distal DVT, whereas cancer (OR 2.01, 95% CI 1.20-3.35), male sex aged 41 to 75 years (OR 2.21, 95% CI 1.33-3.67), and acute infection/sepsis (OR 2.71, 95% CI 1.29-5.66) with a diagnosis of proximal DVT. In SWIVTER, age, sex, and several provoking risk factors for VTE appeared to be related with the presenting location of first symptomatic DVT. Cancer, male sex, and acute infection/sepsis were associated with a proximal location of DVT, whereas recent surgery was associated with a distal presentation, likely acting as confounders for the association between thrombosis location and prognosis., (© 2021. The Author(s).)

Background: A large body of evidence suggest an impact of thyroid function on outcomes of cardiovascular diseases, but results for acute pulmonary embolism (PE) are sparse., Methods: We analysed the impact of hypothyroidism as well as hyperthyroidism on the short and long-term outcomes of patients with acute PE. The impact was compared to the group of euthyroid PE patients as reference group., Results: Overall, 831 PE patients (median age 69 [IQR 56-77] years; 52.2% females) were analysed. Among these, 734 patients (88.3%) were classified as euthyroid, 40 (4.8%) as hypothyroid and 57 (6.9%) as hyperthyroid. PE patients with hypothyroidism had higher rates of adverse in-hospital outcomes (37.5% vs. 11.6%, P < 0.001), PE-related (22.5% vs. 4.8%, P < 0.001) and all-cause in-hospital death (25.0% vs. 6.8%, P < 0.001), whereas hyperthyroidism did not affect in-hospital outcomes. Long-term mortality was higher in hypothyroidism (52.5% vs. 28.9%, P = 0.002) and hyperthyroidism (43.9% vs. 28.9%, P = 0.018) compared to euthyroid function. In the 750 normotensive PE patients, hyperthyroidism affected adverse in-hospital outcome (OR 2.58 [95%CI 1.12-5.97], P = 0.026) and PE-related in-hospital mortality (OR 3.50 [95%CI 1.10-11.17], P = 0.035) in comparison to euthyroid PE patients, while hypothyroidism showed no influence. Elevated fT4 (HR 1.75 [95%CI 1.16-2.63], P = 0.007) and reduced fT3 values (HR 2.51 [95%CI 1.48-4.28], P = 0.001) were associated with increased long-term mortality., Conclusion: Thyroid dysfunction had a substantial impact on short and long-term outcomes of patients with acute PE. Elevated fT4 and reduced fT3 values were significantly associated with increased long-term mortality in normotensive PE patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Pulmonary embolism (PE) occurs frequently in patients with malignant melanoma (MM). The aim of this study is to determine the incidence of PE in patients with MM and to assess the clinical characteristics and mortality of MM patients with PE., Material and Methods: Medical records from 381 MM patients who underwent contrast-enhanced computed tomography were evaluated. Imaging parameters including location of PE and measurements of right heart dysfunction and clinical parameters including D-Dimer levels, local and distant tumor stage and time of death were analyzed., Results: PE was found in 23/381 (6%) MM patients, whereby 17/23 (74%) were detected incidentally and only 6/23 (26%) were symptomatic. The presence of PE significantly correlated with elevated D-Dimers (p < 0.001), right ventricular dysfunction (p = 0.04), higher local tumor stage (≥T3) (p = 0.05), presence of visceral (p = 0.02) or cerebral metastases (p = 0.03) and increased mortality (p = 0.05). Further, patients with central PE showed an increased mortality compared to peripheral PE (p = 0.03), but no correlation was found between the localization of PE and the occurrence of clinical symptoms (p = 0.36)., Conclusion: PE in patients with MM often occurs without clinical symptoms and is indicative for advanced disease and a poorer prognosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) and atherosclerosis are accompanied by substantial cardiovascular mortality; links between both disease entities were reported. We aimed to investigate the impact of systemic atherosclerosis on adverse outcomes in patients with deep venous thrombosis or thrombophlebitis (DVT) and to identify differences in DVT patients with and without systemic atherosclerosis., Methods: The German nationwide inpatient sample was used for this analysis. Patients admitted for DVT were included in this study and stratified by systemic atherosclerosis (composite of coronary artery disease, myocardial infarction, ischemic stroke, and/or atherosclerotic arterial diseases). We compared DVT patients with (DVT+Athero) and without (DVT-Athero) systemic atherosclerosis and analysed the impact of systemic atherosclerosis on adverse outcomes., Results: Overall, 489,679 patients with DVT (55.7% females) were included in this analysis. Among these, 53,309 (10.9%) were coded with concomitant systemic atherosclerosis with age-dependent incline. Concomitant PE (4.1% vs.3.8%, P=0.001) was more frequently in DVT-Athero and risk for PE in DVT patients was independently associated with absence of systemic atherosclerosis (OR 0.87 [95%CI 0.83-0.91], P<0.001). In-hospital mortality (3.4% vs.1.4%, P<0.001) and adverse in-hospital events (2.2% vs.0.8%, P<0.001) were more prevalent in DVT+Athero compared to DVT-Athero; both, in-hospital mortality (OR 1.52 [95%CI 1.41-1.63], P<0.001) and adverse in-hospital events (OR 1.49 [95%CI 1.40-1.58], P<0.001) were affected independently of sex, age and comorbidities by systemic atherosclerosis., Conclusions: Systemic atherosclerosis in DVT patients was accompanied by poorer outcomes. Systemic atherosclerosis was associated with higher bleeding rate and with isolated DVT (without concomitant PE)., Competing Interests: Declaration of Competing Interest KK, TM and MAO report no conflict of interest. TM is PI of the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. LH reports having received lecture honoraria from MSD. M.L. reports having received consultancy and lecture honoraria from Actelion, Bayer, Daiichi-Sankyo, MSD, Pfizer – Bristol-Myers Squibb and research funding from BRAHMS – Thermo Fisher scientific. S.K. reports having received consultancy and lecture honoraria from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, MSD and Pfizer – Bristol-Myers Squibb; and institutional grants from Actelion, Bayer, Boehringer Ingelheim, Daiichi-Sankyo and Pfizer – Bristol-Myers Squibb., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

This position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a practical guide to treating patients with acute PE complementary to the formal 2019 European Society of Cardiology guidelines developed with the European Respiratory Society. We propose a holistic approach considering the whole spectrum of serious adverse events that patients with acute PE may encounter on the short and long run. We underline the relevance of assessment of modifiable risk factors for bleeding, of acquired thrombophilia and limited cancer screening (unprovoked PE) as well as a dedicated surveillance for the potential development of chronic thromboembolic pulmonary hypertension as part of routine practice; routine testing for genetic thrombophilia should be avoided. We advocate the use of outcome measures for functional outcome and quality of life to quantify the impact of the PE diagnosis and identify patients with the post-PE syndrome early. Counselling patients on maintaining a healthy lifestyle mitigates the risk of the post-PE syndrome and improves cardiovascular prognosis. Therefore, we consider it important to discuss when and how to resume sporting activities soon after diagnosing PE. Additional patient-relevant topics that require Focused counselling are travel and birth control., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim of the Study: Extracorporeal membrane oxygenation (ECMO) is considered a life-saving treatment option for patients in cardiogenic shock or cardiac arrest undergoing cardiopulmonary resuscitation (CPR) due to acute pulmonary embolism (PE). We sought to analyze use and outcome of ECMO with or without adjunctive treatment strategies in patients with acute PE., Methods: We retrospectively analyzed data on patient characteristics, treatments, and in-hospital outcomes for all PE patients (ICD-code I26) undergoing ECMO in Germany between 2005 and 2018., Results: At total of 1,172,354 patients were hospitalized with PE; of those, 2,197 (0.2%) were treated with ECMO support. Cardiac arrest requiring cardiopulmonary resuscitation was present in 77,196 (6.5%) patients. While more than one fourth of those patients were treated with systemic thrombolysis alone (n = 20,839 patients; 27.0%), a minority of patients received thrombolysis and VA-ECMO (n = 165; 0.2%), embolectomy and VA-ECMO (n = 385; 0.5%) or VA-ECMOalone (n = 588; 0.8%). A multivariable logistic regression analysis indicated the lowest risk for in-hospital death in patients who received embolectomy in combination with VA-ECMO (OR, 0.50 [95% CI, 0.41-0.61], p < 0.001), thrombolysis and VA-ECMO (0.60 [0.43-0.85], p = 0.003) or VA-ECMO alone (0.68 [0.57-0.82], p < 0.001) compared to thrombolysis alone (1.04 [0.99-1.01], p = 0.116)., Conclusion: Our findings suggest that the use of VA-ECMO alone or as part of a multi-pronged reperfusion approach including embolectomy or thrombolysis might offer survival advantages compared to thrombolysis alone in patients with PE deteriorating to cardiac arrest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown., Methods: ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute pulmonary embolism (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells., Results: Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were elevated in patients with pulmonary embolism and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and transforming growth factor-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels., Conclusion: Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from pulmonary embolism to CTEPH., Competing Interests: Conflict of interest: L. Hobohm reports personal fees for lectures from MSD and Actelion, outside the submitted work. Conflict of interest: S. Kölmel has nothing to disclose. Conflict of interest: C. Niemann has nothing to disclose. Conflict of interest: P. Kümpers has nothing to disclose. Conflict of interest: V.J. Krieg has nothing to disclose. Conflict of interest: M.L. Bochenek has nothing to disclose. Conflict of interest: A.H. Lukasz has nothing to disclose. Conflict of interest: Y. Reiss has nothing to disclose. Conflict of interest: K-H. Plate has nothing to disclose. Conflict of interest: C. Liebetrau reports personal fees for lectures and consultancy from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Daiichi-Sankyo, Pfizer–Bristol-Myers Squibb and Thermo-Fisher, outside the submitted work. Conflict of interest: C.B. Wiedenroth reports personal fees for lectures and consultancy from Actelion, Bayer, Pfizer, BTG and MSD, outside the submitted work. Conflict of interest: S. Guth reports personal fees for lectures and consultancy from Actelion, Bayer, GlaxoSmithKline, Pfizer and MSD, outside the submitted work. Conflict of interest: T. Münzel has nothing to disclose. Conflict of interest: G. Hasenfuß reports personal fees for lectures and consultancy from AstraZeneca, Corvia, Impulse Dynamics, Novartis, Servier, Berlin Chemie and Vifor Pharma; and editor honoraria from Springer International Publishing AG. Conflict of interest: P. Wenzel has nothing to disclose. Conflict of interest: E. Mayer reports personal fees for lectures and consultancy from Actelion, Bayer, MSD and Pfizer, outside the submitted work. Conflict of interest: S.V. Konstantinides reports grants from German Federal Ministry of Education and Research (BMBF 01EO1003 and BMBF 01EO1503), during the conduct of the study; personal fees for consultancy and lectures from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, MSD and Pfizer–Bristol-Myers Squibb; and institutional grants from Actelion, Bayer, Boehringer Ingelheim, Daiichi-Sankyo and Pfizer–Bristol-Myers Squibb, outside the submitted work. Conflict of interest: K. Schäfer has nothing to disclose. Conflict of interest: M. Lankeit reports grants from German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503), during the conduct of the study; personal fees for consultancy and lectures from Actelion, Bayer, BRAHMS–Thermo-Fisher Scientific, Daiichi-Sankyo, MSD and Pfizer–Bristol-Myers Squibb, and research funding from BRAHMS–Thermo-Fisher Scientific., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: An increased risk for venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep venous thrombosis, has been reported in psoriasis patients. The impact of psoriasis on prognosis of VTE patients is widely unknown., Methods: Hospitalized PE patients were stratified for psoriasis and the impact of psoriasis on outcome was investigated in the German nationwide inpatient sample of the years 2005-2017., Results: Overall, 1,076,384 hospitalizations of PE patients (53.7% females, median age 72.0 [60.0-80.0] years) were recorded in Germany 2005-2017. Among these, 3145 patients had psoriasis (0.3%). Psoriatic PE patients were younger (68.0 [57.0-76.0] vs. 72.0 [60.0-80.0] years,P < 0.001) and more often male (64.1% vs. 46.3%,P < 0.001). The prevalence of VTE risk factors, traditional cardiovascular risk factors and cardiovascular comorbidities was higher in psoriatic than in non-psoriatic individuals. Psoriatic PE patients showed a lower in-hospital case-fatality rate (11.1% vs. 16.0%,P < 0.001), confirmed by logistic regressions showing an independent association of psoriasis with reduced case-fatality rate (OR 0.73 [95%CI 0.65-0.82],P < 0.001), despite higher prevalence of pneumonia (24.8% vs. 23.2%,P = 0.029). Psoriasis was an independent predictor for gastro-intestinal bleeding (OR 1.35 [95%CI 1.04-1.75],P = 0.023) and transfusion of blood constituents (OR 1.23 [95%CI 1.11-1.36],P < 0.001)., Conclusions: PE patients with psoriasis were hospitalized in median four years earlier than those without. Although psoriasis was associated with an unfavorable cardiovascular-risk and VTE-risk profile in PE patients, our data demonstrate a lower in-hospital mortality in psoriatic PE, which might be mainly driven by younger age. Our findings may improve the clinical management of these patients and contribute evidence for relevant systemic manifestation of psoriasis., Translational Perspective: An increased risk for venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep venous thrombosis, has been reported in psoriasis patients, but the impact of psoriasis on prognosis of VTE patients is widely unknown. PE patients with psoriasis were younger and psoriasis was associated with an unfavorable cardiovascular-risk and VTE-risk profile. In-hospital mortality was lower in psoriatic PE patients, which might be mainly driven by younger age. Our findings improve the clinical management of PE patients and contribute evidence for relevant systemic manifestation of psoriasis., One Sentence Summary: Psoriasis with chronic inflammation promotes PE development, is associated with an unfavorable cardiovascular and VTE-risk profile, but lower in-hospital mortality., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The Post-Pulmonary Embolism Syndrome (PPES) comprises heterogeneous entities, including chronic thromboembolic disease with/without pulmonary hypertension (CTEPH/CTEPD), and deconditioning., Objectives: To assess underlying physiological determinants of PPES, and efficacy and safety of rehabilitation training in these patients., Methods: 56 consecutive PE patients with persistent dyspnea and/or functional limitations despite ≥3 months of anticoagulation underwent standardized diagnostic work-up including exercise testing as part of routine practice. All diagnostic (imaging and cardiopulmonary function) tests were interpreted by a core group of experienced clinicians. A subgroup of patients without CTEPH or other treatable conditions was referred for a 12-week personalized rehabilitation program, studying changes in physical condition and patient-reported outcome measures., Results: Persistent vascular occlusions were observed in 21/56 patients (38%) and CTEPH was confirmed in ten (18%). Regarding those without CTEPH, impaired cardiopulmonary responses were evident in 18/39 patients with available CPET data (46%), unrelated to chronic thrombi. Rehabilitation was completed by 27 patients after excluding 29 (patients with CTEPH or treatable comorbidities, refusal, ineligibility, or training elsewhere). Training intensity, PE-specific quality of life (PEmb-QoL) and fatigue (CIS) improved with a median difference of 20 W (p = 0.001), 3.9 points (p < 0.001) and 16 points (p = 0.003), respectively. Functional status (Post-VTE Functional Status Scale) improved ≥1 grade in 18 (67%) patients, and declined in one (3.7%)., Conclusions: Our findings suggest that abnormal cardiopulmonary responses to exercise are common in patients with PPES and are not limited to those with chronic thrombi. Offering pulmonary rehabilitation to patients not treated otherwise seems safe and promising., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: The 2019 European Society of Cardiology (ESC) guidelines provide a revised definition of high-risk pulmonary embolism (PE) encompassing three clinical presentations: Cardiac arrest, obstructive shock, and persistent hypotension. This study investigated the prognostic implications of this new definition., Methods and Results: Data from 784 consecutive PE patients prospectively enrolled in a single-centre registry were analysed. Study outcomes include an in-hospital adverse outcome (PE-related death or cardiopulmonary resuscitation) and in-hospital all-cause mortality. Overall, 86 patients (11.0%) presented with high-risk PE and more often had an adverse outcome (43.0%) compared to intermediate-high-risk patients (6.1%; P < 0.001). Patients with cardiac arrest had the highest rate of an in-hospital adverse outcome (78.4%) and mortality (59.5%; both P < 0.001 compared to intermediate-high-risk patients). Obstructive shock and persistent hypotension had similar rates of adverse outcomes (15.8% and 18.2%, respectively; P = 0.46), but the only obstructive shock was associated with an increased all-cause mortality risk. Use of an optimised venous lactate cut-off value (3.8 mmol/L) to diagnose obstructive shock allowed differentiation of adverse outcome risk between patients with shock (21.4%) and persistent hypotension (9.5%), resulting in a net reclassification improvement (0.24 ± 0.08; P = 0.002)., Conclusion: The revised ESC 2019 guidelines definition of high-risk PE stratifies subgroups at different risk of in-hospital adverse outcomes and all-cause mortality. Risk prediction can be improved by using an optimised venous lactate cut-off value to diagnose obstructive shock, which might help to better assess the risk-to-benefit ratio of systemic thrombolysis in different subgroups of high-risk patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe., Methods: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555)., Findings: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran., Interpretation: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation., Funding: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim., Competing Interests: Declaration of interests FAK reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharpe & Dohme, the Netherlands Organisation for Health Research and Development, Actelion, the Dutch Heart foundation, and the Dutch Thrombosis Association, all outside the submitted work. SB reports congress and travel payments from Daiichi Sankyo and Bayer; honoraria from BTG Pharmaceuticals, Boston Scientific, Bayer HealthCare, and LeoPharma; and institutional grants from Sanofi, all outside the submitted work. WA reports research support from Bayer, and participating in advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo, Portola, Janssen, Aspen, and Sanofi all outside the submitted work. MB reports consulting and speaker fees from Bayer Healthcare, Daiichi Sankyo, and Sanofi Aventis outside the submitted work. FC reports research grant support from Bristol-Myers Squibb-Pfizer Alliance; fees for board memberships or symposia from Bayer, Bristol-Myers Squibb-Pfizer Alliance, and Astra Zeneca; and travel support from Bayer, Bristol-Myers Squibb-Pfizer Alliance, Leo Pharma, and Actelion all outside the submitted work. KD reports unrestricted research support and speaker or consultant fees from Janssen outside the submitted work. DD reports speaker's honoraria from Bayer Vital, Daiichi Sankyo, and Bristol-Myers Squibb-Pfizer Alliance; and consulting fees from Bayer Vital and Daiichi Sankyo all outside the submitted work. KE reports lecture fees from AstraZeneca, Bayer Vital, Berlin Chemie, Boehringer Ingelheim, and Novartis; and consulting fees from Bayer Vital, Boehringer Ingelheim, Novartis, and Novo Nordisk all outside the submitted work. GG reports personal fees or research grants, or both, from Bayer, Boehringer Ingelheim, Leo, Merck Sharpe & Dohme, and Pfizer outside the submitted work. MVH reports grants from the ZonMW Dutch Healthcare Fund; and grants and personal fees to the Leiden University Medical Center from Boehringer Ingelheim, Bristol-Myers Squibb-Pfizer Alliance, Bayer Health Care, Aspen, and Daiichi Sankyo, all outside the submitted work. DJ reports serving as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; serving as a speaker or a member of a speakers' bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, ROVI, and Sanofi; and receiving grants for clinical research from Daiichi Sankyo, Sanofi, and ROVI all outside the submitted work. MK reports speaker fees from Pfizer, Boehringer Ingelheim, and Bayer outside the submitted work. IML reports receiving consulting fees and research grants from, and being a member of scientific advisory boards for AOPOrphan Pharmaceuticals, Actelion-Janssen, Merck Sharpe & Dohme, United Therapeutics, Medtronic, Neutrolis, and Ferrer, in addition to being an investigator in trials involving these companies. ML reports consultant and speaker fees from Actelion, Bayer, Thermo Fisher Scientific, Daiichi Sankyo, Merck Sharpe & Dohme, and Bristol-Myers Squibb-Pfizer Alliance; and project funding from Thermo Fisher Scientific all outside the submitted work. NM reports consulting fees, speaker fees, and project funding from Bayer and Bristol-Myers Squibb-Pfizer Alliance; speaker fees from AstraZeneca and Boehringer Ingelheim; and consulting fees from Abbott and Terumo all outside the submitted work. AOP reports speaker fees from SC Pfizer Romania, Servier Pharma, Novartis Pharma Services Romania, Bayer, and SC Sanience outside the submitted work. AS reports consulting fees from Pfizer outside the submitted work. SS reports consulting fees and speaker fees from Aspen and Boehringer Ingelheim; speaker fees from Bayer and Daiichi Sankyo; and project funding and speaker fees from Bristol-Myers Squibb-Pfizer Alliance all outside the submitted work. K-HS reports speaker and consulting fees from Merck Sharpe & Dohme, Janssen-Cilag, and Abbott outside the submitted work. FV reports research grants from Daiichi Sanyo, Boehringer-Ingelheim, Radiometer, and Biomerieux, outside the submitted work. SVK reports institutional research grants and personal consultancy or speaker fees from Actelion/Janssen, Bayer, Daiichi Sankyo, and Boston Scientific; institutional research grants from Boehringer Ingelheim and Servier; and personal consultancy or speaker fees from Bristol-Myers Squibb-Pfizer Alliance and Novartis all outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aims: Catheter-directed treatment of acute pulmonary embolism (PE) is technically advancing. Recent guidelines acknowledge this treatment option for patients with overt or imminent haemodynamic decompensation, particularly when systemic thrombolysis is contraindicated. We investigated patients with PE who underwent catheter-directed thrombolysis (CDT) in the German nationwide inpatient cohort., Methods and Results: Data from hospitalizations with PE (International Classification of Disease code I26) between 2005 and 2016 were collected by the Federal Office of Statistics in Germany. Patients with PE who underwent CDT (OPS 8-838.60 or OPS code 8-83b.j) were compared with patients receiving systemic thrombolysis (OPS code 8-020.8), and those without thrombolytic or other reperfusion treatment. The analysis was not prespecified; therefore, our findings can only be considered to be hypothesis generating. We analysed data from 978 094 hospitalized patients with PE. Of these, 41 903 (4.3%) patients received thrombolytic treatment [systemic thrombolysis in 4.2%, CDT in 0.1% (1175 patients)]. Among patients with shock, CDT was associated with lower in-hospital mortality compared to systemic thrombolysis [odds ratios (OR) 0.30 (95% 0.14-0.67); P = 0.003]. Intracranial bleeding occurred in 14 (1.2%) patients who received CDT. Among haemodynamically stable patients with right ventricular dysfunction (intermediate-risk PE), CDT also was associated with a lower risk of in-hospital mortality compared to systemic thrombolysis {OR 0.55 [95% confidence interval (CI) 0.40-0.75]; P < 0.001} or no thrombolytic treatment [0.45 (95% CI 0.33-0.62); P < 0.001]., Conclusion: In the German nationwide inpatient cohort, based on administrative data, CDT was associated with lower in-hospital mortality rates compared to systemic thrombolysis, but the overall rate of intracranial bleeding in patients who received CDT was not negligible. Prospective controlled data are urgently needed to determine the true value of this treatment option in acute PE., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Arterial lactate is an established risk marker in patients with pulmonary embolism (PE). However, its clinical applicability is limited by the need of an arterial puncture. In contrast, venous lactate can easily be measured from blood samples obtained via routine peripheral venepuncture., Methods: We investigated the prognostic value of venous lactate with regard to in-hospital adverse outcomes and mortality in 419 consecutive PE patients enrolled in a single-center registry between 09/2008 and 09/2017., Results: An optimised venous lactate cut-off value of 3.3 mmol/l predicted both, in-hospital adverse outcome (OR 11.0 [95% CI 4.6-26.3]) and all-cause mortality (OR 3.8 [95%CI 1.3-11.3]). The established cut-off value for arterial lactate (2.0 mmol/l) and the upper limit of normal for venous lactate (2.3 mmol/l) had lower prognostic value for adverse outcomes (OR 3.6 [95% CI 1.5-8.7] and 5.7 [95% CI 2.4-13.6], respectively) and did not predict mortality. If added to the 2019 European Society of Cardiology (ESC) algorithm, venous lactate <2.3 mmol/l was associated with a high negative predictive value (0.99 [95% CI 0.97-1.00]) for adverse outcomes in intermediate-low-risk patients, whereas levels ≥3.3 mmol/l predicted adverse outcomes in the intermediate-high-risk group (OR 5.2 [95% CI 1.8-15.0])., Conclusion: Venous lactate above the upper limit of normal was associated with increased risk for adverse outcomes and an optimised cut-off value of 3.3 mmol/l predicted adverse outcome and mortality. Adding venous lactate to the 2019 ESC algorithm may improve risk stratification. Importantly, the established cut-off value for arterial lactate has limited specificity in venous samples and should not be used., (Copyright © 2021. Published by Elsevier B.V.)

Background: Pulmonary embolism (PE)-related mortality is decreasing in Europe. However, time trends in the USA and Canada remain uncertain because the most recent analyses of PE-related mortality were published in the early 2000s., Methods: For this retrospective epidemiological study, we accessed medically certified vital registration data from the WHO Mortality Database (USA and Canada, 2000-17) and the Multiple Cause of Death database produced by the Division of Vital Statistics of the US Centers for Disease Control and Prevention (CDC; US, 2000-18). We investigated contemporary time trends in PE-related mortality in the USA and Canada and the prevalence of conditions contributing to PE-related mortality reported on the death certificates. We also estimated PE-related mortality by age group and sex. A subgroup analysis by race was performed for the USA., Findings: In the USA, the age-standardised annual mortality rate (PE as the underlying cause) decreased from 6·0 deaths per 100 000 population (95% CI 5·9-6·1) in 2000 to 4·4 deaths per 100 000 population (4·3-4·5) in 2006. Thereafter, it continued to decrease to 4·1 deaths per 100 000 population (4·0-4·2) in women in 2017 and plateaued at 4·5 deaths per 100 000 population (4·4-4·7) in men in 2017. Among adults aged 25-64 years, it increased after 2006. The median age at death from PE decreased from 73 years to 68 years (2000-18). The prevalence of cancer, respiratory diseases, and infections as a contributing cause of PE-related death increased in all age categories from 2000 to 2018. The annual age-standardised PE-related mortality was consistently higher by up to 50% in Black individuals than in White individuals; these rates were approximately 50% higher in White individuals than in those of other races. In Canada, the annual age-standardised mortality rate from PE as the underlying cause of death decreased from 4·7 deaths per 100 000 population (4·4-5·0) in 2000 to 2·6 deaths per 100 000 population (2·4-2·8) in 2017; this decline slowed after 2006 across age groups and sexes., Interpretation: After 2006, the initially decreasing PE-related mortality rates in North America progressively reached a plateau in Canada, while a rebound increase was observed among young and middle-aged adults in the USA. These findings parallel recent upward trends in mortality from other cardiovascular diseases and might reflect increasing inequalities in the exposure to risk factors and access to health care., Funding: None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Since 2008, specialized chest pain units (CPUs) were implemented across Germany ensuring structured diagnostics in acute chest pain. This study aims to analyze the management of pulmonary embolism (PE) patients in such certified CPUs., Methods: Data were retrieved from 13,902 patients enrolled in the German CPU registry and analyzed for the diagnosis of PE including patient characteristics, critical time intervals, diagnostic workup, treatment, and prognosis. PE patients were compared to the overall CPU patient cohort. Only patients with a complete 3-month follow-up were included., Results: Overall, 1.1% of all CPU patients were diagnosed with PE. Chest pain and dyspnea were the leading symptoms. Patients with PE were older, presented with higher heart rates, and more frequently exhibited signs of heart failure, despite a normal left ventricular function. PE patients showed significantly longer time delays between symptom onset and the first medical contact, while PE patients with chest pain presented earlier than PE patients with dyspnea only. Whereas more PE patients had to be transferred to the intensive care unit, in-CPU mortality and event rates over 3 months were low., Discussion/conclusion: This study suggests a certain risk for underdiagnosis and consecutive potential undertreatment of PE patients in German Cardiac Society (GCS)-certified CPUs, which is thought to result from an anticipated focus on patients with acute coronary syndrome (ACS). Public awareness for PE beyond chest pain should be improved. Certified CPUs should be urged to implement strategic pathways for a better simultaneous diagnostic workup of differential diagnosis beyond ACS., (© 2021 S. Karger AG, Basel.)

Background: Pulmonary embolism (PE) is a frequent complication in immobile stroke patients and an important cause of death in stroke patients. We aimed to investigate predictors of PE and the impact of PE on survival of ischemic stroke patients., Methods: Patients were selected by screening the German nationwide inpatient sample (2005-2017) for ischemic stroke (ICD-code I63) and stratified for occurrence of PE (ICD-code I26). Impact of PE on mortality and predictors for PE in ischemic stroke patients were analysed., Results: Overall, 2,914,546 patients were hospitalized due to ischemic stroke (50.5% females; 69.3% aged ≥70 years) in Germany 2005-2017. Among these, 0.4% had PE and 7.2% died during hospitalization. In-hospital mortality rate of ischemic stroke patients with PE was substantially higher compared to those patients without PE (28.4% vs. 7.1%, P < 0.001). PE was strongly associated with in-hospital death (OR 5.786, 95%CI 5.515-6.070, P < 0.001). Important predictors of PE were cancer (OR 3.165, 95%CI 2.969-3.374, P < 0.001), coagulation abnormalities (OR 2.672, 95CI 2.481-2.878, P < 0.001), heart failure (OR 1.553, 95%CI 1.472-1.639, P < 0.001) and obesity (OR 1.559, 95%CI 1.453-1.672, P < 0.001). Systemic thrombolysis was not beneficial regarding survival in unselected ischemic stroke patients. In contrast, systemic thrombolysis was beneficial in ischemic stroke patients without PE, who had to undergo cardio-pulmonary resuscitation (OR 0.866, 95%CI 0.782-0.960, P = 0.006)., Conclusions: Patients with ischemic stroke revealed still a high in-hospital mortality of 7.2% in Germany. While only a minority of 0.4% of the ischemic stroke patients suffered from occurrence of PE, PE was accompanied by a substantial increase regarding in-hospital mortality. Systemic thrombolysis was beneficial regarding short-term survival in ischemic stroke patients without PE, who had to undergo cardio-pulmonary resuscitation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Data on the early course and use of systemic thrombolysis in pregnant women with pulmonary embolism associated or not with haemodynamic failure are scarce. We investigated these aspects using the information from the German Nationwide Inpatient Registry (years 2005-2016)., Methods and Results: In Germany, all diagnoses referring to hospitalized patients are coded according to the International Classification of Diseases and Related Health Problems, 10th Revision with German Modification. We analysed data of pregnant women aged 18-50 years for whom the following diagnoses were recorded during hospitalization: (i) pulmonary embolism (I26) during pregnancy or peripartum (O09) or (ii) obstetric thromboembolism (O88.2). Haemodynamic failure at any time during the in-hospital stay was defined as need for cardiopulmonary resuscitation (OPS code 8-77) or the presence of shock (International Classification of Diseases and Related Health Problems, 10th Revision with German Modification code R57). The primary study outcome was in-hospital death. A total of 8 271 327 births were registered in Germany from 2005 to 2016. During this 12 year time period, there were 1846 hospitalizations for pregnancy-associated pulmonary embolism in patients aged 18-50, corresponding to 2.2 [95% confidence interval (CI): 2.1-2.3] cases every 10 000 births and 0.2% of all hospitalizations for pulmonary embolism in Germany. The median age was 31 years, and the median length of hospitalization was 8 days. A total of 63 deaths were reported, corresponding to an overall in-hospital fatality rate of 3.4% (95% CI: 2.7-4.4) and a pulmonary embolism-related mortality rate of 0.8 (95% CI: 0.6-1.0) per 100 000 (live) births per year. Pulmonary embolism-related deaths in hospitalized pregnant women represented 14% of all maternal deaths recorded in Germany between 2005 and 2016. A total of 135 (7.3%) women had haemodynamic failure, of whom 51 (37.8%) received systemic thrombolysis and 50 (37.0%) died., Conclusions: Pulmonary embolism-related fatality remains substantial in pregnant women with pulmonary embolism and represents a frequent cause of maternal mortality. The use of systemic thrombolysis was reported in one third of pregnant women with pulmonary embolism and haemodynamic failure. Better preventive and management strategies should be urgently implemented in this vulnerable patient group., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Pulmonary embolism (PE) is a frequent cause of death and morbidity. A few studies suggest that clot burden in pulmonary artery bed is related to PE patients' survival, but the impact of concomitant deep venous thrombosis and/or thrombophlebitis (DVT) on short-term survival of PE patients remains unclear. Thus, we aimed to investigate the impact of DVT on adverse outcomes in PE patients., Methods: Patients of the nationwide inpatient sample with PE (ICD-code I26) were stratified for DVT (ICD-code I80) and compared for patient characteristics, risk stratification markers, treatments and outcomes. Impact of concomitant DVT on adverse in-hospital outcomes was tested., Results: Overall, 346,586 PE patients (53.3% females) were included in this analysis. Among these, in 126,477 (36.5%) DVT was coded. PE patients with DVT were younger, less often of female sex and VTE risk-factors (surgery, cancer) as well as cardiovascular and pulmonary diseases were less prevalent compared with isolated PE. PE patients with DVT showed a significant better survival (5.4% vs. 20.2%, P < .001) and lower adverse in-hospital event rate (9.7% vs. 27.4%, P < .001) compared to patients with isolated PE. Lower risk for in-hospital mortality (OR 0.238 [95%CI 0.232-0.245], P < .001) and adverse in-hospital events (OR 0.302 [95%CI 0.295-0.309], P < .001) were respectively independent of age, gender, comorbidities and reperfusion-treatments., Conclusions: Concomitant DVT affects survival of PE patients. Patients with an isolated PE had higher rate of in-hospital mortality and adverse in-hospital events. Our data suggest, that peripheral thrombus burden in PE with concomitant DVT might be less harmful in comparison to isolated PE with a probably larger thrombus burden., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pulmonary embolism (PE) is the third most frequent acute cardiovascular syndrome. Annual PE incidence and PE-related mortality rates rise exponentially with age, and consequently, the disease burden imposed by PE on the society continues to rise as the population ages worldwide. Recently published landmark trials provided the basis for new or changed recommendations included in the 2019 update of the European Society of Cardiology Guidelines (developed in cooperation with the European Respiratory Society). Refinements in diagnostic algorithms were proposed and validated, increasing the specificity of pre-test clinical probability and D-dimer testing, and thus helping to avoid unnecessary pulmonary angiograms. Improved diagnostic strategies were also successfully tested in pregnant women with suspected PE. Non-vitamin K antagonist oral anticoagulants (NOACs) are now the preferred agents for treating the majority of patients with PE, both in the acute phase (with or without a brief lead-in period of parenteral heparin or fondaparinux) and over the long term. Primary reperfusion is reserved for haemodynamically unstable patients. Besides, the 2019 Guidelines endorse multidisciplinary teams for coordinating the acute-phase management of high-risk and (in selected cases) intermediate-risk PE. For normotensive patients, physicians are advised to include the assessment of the right ventricle on top of clinical severity scores in further risk stratification, especially if early discharge of the patient is envisaged. Further important updates include guidance (1) on extended anticoagulation after PE, taking into account the improved safety profile of NOACs; and (2) on the overall care and follow-up of patients who have suffered PE, with the aim to prevent, detect and treat late sequelae of venous thromboembolism.

Background: Data regarding pulmonary embolism (PE)-related mortality in Italy are scarce. We assessed PE-related mortality and its time trend in Italy by using the World Health Organization (WHO) Mortality Database., Methods: The vital registration data of Italy from the WHO Mortality Database were analyzed for the period between 2003 and 2015, and compared with time trends in Southern Europe. Death was defined as PE-related when classified with specific codes for PE or limb vein thrombosis listed as the primary cause of death. This coding was based on the International Classification of Diseases, tenth revision., Results: Overall, 28 647 PE-related deaths (10 178 men and 18 469 women) were recorded between 2003 and 2015. The observed age-standardized annual PE-related mortality rates were 2.5 per 100 000 men and 2.8 per 100 000 women. Moreover, PE-related mortality increased with age with a seemingly exponential distribution. Joinpoint regression analysis demonstrated a statistically significant linear decrease in age-standardized PE-related mortality of -0.21 (95% confidence interval -0.27; -0.15) and -0.22 (95% confidence interval -0.28; -0.16) deaths per 100 000 population for men and women, respectively., Conclusions: The Italian age-adjusted mortality rates appeared lower compared to overall Southern Europe, despite a similar decreasing trend over time.

Introduction: Studies performed in the past decade suggested that evolving reperfusion strategies may improve early outcomes of patients with acute pulmonary embolism (PE) and hemodynamic decompensation. In this regard, catheter-directed treatment (CDT) options are receiving increasing attention., Areas Covered: A broad spectrum of CDT options exists for the treatment of patients with acute PE. Procedures include catheter-directed local thrombolysis with or without ultrasound assistance, catheter-directed mechanical or suction embolectomy, and combined pharmaco-mechanical approaches. We present here an overview of the available CDT techniques, focusing on the EkoSonic® endovascular system., Expert Commentary: CDT, particularly local ultrasound accelerated thrombolysis, continues to evolve. Its increasing popularity is the result of accumulating promising results, which suggest a relief of right ventricular (RV) pressure overload and improvement of RV function. These favorable effects on surrogate endpoints were accompanied by a low rate of procedure-related adverse events, notably intracranial hemorrhage. Although the overall risk of serious bleeding appears to be low in CDT, the lack of direct comparisons with other reperfusion options does not allow definitive conclusions. Prospective controlled trials with robust clinical outcomes are urgently needed to establish the postulated benefits of CDT in selected patients with acute PE.

Introduction: We recently proposed a scale for assessment of patient-relevant functional limitations following an episode of venous thromboembolism (VTE). Further development of this post-VTE functional status (PVFS) scale is still needed., Methods: Guided by the input of VTE experts and patients, we refined the PVFS scale and its accompanying manual, and attempted to acquire broad consensus on its use., Results: A Delphi analysis was performed involving 53 international VTE experts with diverse scientific and clinical backgrounds. In this process, the number of scale grades of the originally proposed PVFS scale was reduced and descriptions of the grades were improved. After these changes, a consensus was reached on the number/definitions of the grades, and method/timing of the scale assessment. The relevance and potential impact of the scale was confirmed in three focus groups totaling 18 VTE patients, who suggested additional changes to the manual, but not to the scale itself. Using the improved manual, the κ-statistics between PVFS scale self-reporting and its assessment via the structured interview was 0.75 (95%CI 0.58-1.0), and 1.0 (95%CI 0.83-1.0) between independent raters of the recorded interview of 16 focus groups members., Conclusion: We improved the PVFS scale and demonstrated broad consensus on its relevance, optimal grades, and methods of assessing among international VTE experts and patients. The interobserver agreement of scale grade assignment was shown to be good-to-excellent. The PVFS scale may become an important outcome measure of functional impairment for quality of patient care and in future VTE trials., Competing Interests: Declaration of competing interest All authors declare to have no relevant conflict of interests related to this work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Declaration of Competing Interests Stefano Barco has received congress and travel payments from Daiichi-Sankyo and Bayer HealthCare, and honoraria from BTG Pharmaceuticals, Bayer HealthCare, and LeoPharma. Tim Sebastian has no conflicts of interest to declare.