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Background: Pulmonary embolism (PE) is a potentially life-threatening condition. Admission and treatment in the intensive care unit (ICU) is an important element in critically ill PE patients. Objectives: We aimed to identify risk factors for ICU admission and differences in patient profiles regarding risk factors and comorbidities between PE patients who had to be admitted to an ICU and those who were treated in a normal ward without ICU. Methods: We used the German nationwide inpatient sample to analyze all hospitalizations of PE patients in Germany from 2016 to 2020 stratified for ICU admission. Results: Overall, 484,859 hospitalized PE patients were treated in German hospitals from 2016 to 2020. Among these, 92,313 (19.0%) were admitted to ICU. Patients treated in ICU were younger (69.0 [IQR, 58.0-78.0] vs 72.0 [IQR, 60.0-80.0] years; P < .001) and had higher prevalence of cardiovascular risk factors and comorbidities. In-hospital case fatality rate was elevated in PE patients treated in ICU (22.7% vs 10.7%; P < .001), and ICU admission was independently associated with increased in-hospital case fatality (odds ratio [OR], 2.54; 95% CI, 2.49-2.59; P < .001). Independent risk factors for ICU admission comprised PE with imminent or present decompensation (OR, 3.30; 95% CI, 3.25-3.35; P < .001), hemodynamic instability (OR, 4.49; 95% CI, 4.39-4.59; P < .001), arterial hypertension (OR, 1.20; 95% CI, 1.18-1.22; P < .001), diabetes mellitus (OR, 1.16; 95% CI, 1.14-1.18; P < .001), obesity (OR, 1.300; 95% CI, 1.27-1.33; P < .001), surgery (OR, 2.55; 95% CI, 2.50-2.59; P < .001), stroke (OR, 2.86; 95% CI, 2.76-2.96; P < .001), pregnancy (OR, 1.45; 95% CI, 1.21-1.74; P < .001), heart failure (OR, 1.74; 95% CI, 1.71-1.77; P < .001), atrial fibrillation/flutter (OR, 1.69; 95% CI, 1.66-1.73; P < .001), chronic obstructive pulmonary disease (OR, 1.21; 95% CI, 1.18-1.24; P < .001), and renal failure (OR, 1.92; 95% CI, 1.88-1.95; P < .001). Conclusion: ICU treatment is an important element in the treatment of PE patients. Besides hemodynamic compromise, cardiovascular risk factors, stroke, pregnancy, and cardiopulmonary as well as renal comorbidities were independent predictors of ICU admission. Necessity of ICU admission was afflicted by increased case fatality.

Introduction: Up to 50% of pulmonary embolism (PE) patients have perfusion defects or residual vascular obstruction during follow-up despite adequate anticoagulant treatment, and a similar percentage experience chronic functional limitations and/or dyspnoea post-PE. We aimed to evaluate the association between pulmonary perfusion defects or residual vascular obstruction and functional recovery after PE. Methods: We performed a systematic review and meta-analysis including studies assessing both the presence of perfusion defects or residual vascular obstruction and functional recovery (i.e. persistent symptoms, quality of life, exercise endurance). An odds ratio was pooled for perfusion defects or residual vascular obstruction and persistent symptoms using a random-effect model. Results: 12 studies were included totalling 1888 PE patients; at a median of 6 months after PE (range 2–72 months), 34% had perfusion defects or residual vascular obstruction and 37% reported persistent symptoms. Among patients with perfusion defects or residual vascular obstruction, 48% (95% CI 37–60%, I2=82%) remained symptomatic during follow-up, compared to 34% (95% CI 20–51%, I2=96%) of patients without such defects. Presence of perfusion defects or residual vascular obstruction was associated with persistent symptoms (OR 2.15, 95% CI 1.66–2.78; I2=0%, τ=0). Notably, there was no association between these defects and quality of life or cardiopulmonary exercise test parameters. Conclusion: While the odds of having persistent symptoms was higher in patients with perfusion defects or residual vascular obstruction after acute PE, a significant proportion of these patients reported no limitations. A possible causality between perfusion defects or residual vascular obstruction and residual functional limitation therefore remains to be proven.

Background: Early thromboprophylaxis does not prevent hospital admissions and death among outpatients with symptomatic COVID-19. Its impact on long-term outcomes, including long COVID symptoms and performance status, is unknown. Objectives: To assess the long-term effects of thromboprophylaxis given at the time of acute COVID-19 in outpatients. Methods: The OVID (enoxaparin for outpatients with COVID-19) trial randomized outpatients older than 50 years with acute COVID-19 to receive either subcutaneous enoxaparin 40 mg once daily for 14 days or standard of care (no thromboprophylaxis). In this follow-up study, we assessed the 2-year outcomes, including all-cause hospitalization and death, cardiovascular events, long COVID symptoms, and functional limitations based on the Post–COVID-19 Functional Status (PCFS) scale and EuroQol-5 Dimensions-5 Levels scale. Results: Of 469 potentially eligible patients, 468 survived, of whom 439 (mean age 59 years; 54% men) participated in the Post-OVID study. There was no difference in terms of hospitalization and death (8.3% in the treatment group vs 10% in controls; relative risk, 0.83; 95% CI, 0.5-1.5) and of cardiovascular events between groups. The risk of presenting with long COVID symptoms was similar in the 2 groups (44% in the treatment group vs 47% in the standard of care group), with no difference between groups also concerning individual symptoms. A PCFS grade of 1 to 3, indicating light-to-moderate functional limitation, was recorded in 15% of patients in each group (odds ratio, 0.98; 95% CI, 0.6-1.7). No patients reported severe limitations (PCFS grade 4). Median EuroQol visual analog scale score was 85 on 100 points (IQR, 80-90 for the standard of care group and 75-90 for the enoxaparin group). Conclusion: Early thromboprophylaxis does not improve long-term, 2-year clinical and functional outcomes among symptomatic ambulatory patients with acute COVID-19.

Introduction: Intravenous drug use continues to pose a substantial burden worldwide and little is known about the risk of venous thromboembolism (VTE) and its sequelae in people who inject drugs (PWID). Methods: A systematic literature search was conducted on the prevalence of VTE and chronic venous disease in intravenous drug users, as well as on the prevalence of intravenous drug use among selected VTE patients. Two reviewers independently selected the articles and appraised their quality. A random-effect meta-analysis was performed to pool risks across studies. Results: We included 18 studies with a total of 7691 patients. The overall prevalence of VTE among PWID was 29% (95%CI: 19–40%). Among patients diagnosed with VTE, 15% (95%CI: 10–20%) were PWID. Similar rates were confirmed in more recent studies published in the past decade, although these studies are often based on the general population from higher-risk areas. Reported rates of chronic venous disease ranged between 58% and 61%. The majority of the included studies had a low to moderate quality of evidence. We could not exclude a selection bias in the studies in geographical regions with high intravenous drug use prevalence. Conclusion: VTE and chronic venous disease appear to be common and understudied complications of injective drug use. National programs for PWID patients should also focus on early and late VTE-associated complications.

BackgroundIntensive care units (ICU) capacities are one of the most critical determinants in health-care management of the COVID-19 pandemic. Therefore, we aimed to analyze the ICU-admission and case-fatality rate as well as characteristics and outcomes of patient admitted to ICU in order to identify predictors and associated conditions for worsening and case-fatality in this critical ill patient-group.MethodsWe used the German nationwide inpatient sample to analyze all hospitalized patients with confirmed COVID-19 diagnosis in Germany between January and December 2020. All hospitalized patients with confirmed COVID-19 infection during the year 2020 were included in the present study and were stratified according ICU-admission.ResultsOverall, 176,137 hospitalizations of patients with COVID-19-infection (52.3% males; 53.6% aged ≥70 years) were reported in Germany during 2020. Among them, 27,053 (15.4%) were treated in ICU. COVID-19-patients treated on ICU were younger [70.0 (interquartile range (IQR) 59.0–79.0) vs. 72.0 (IQR 55.0–82.0) years, P < 0.001], more often males (66.3 vs. 48.8%, P < 0.001), had more frequently cardiovascular diseases (CVD) and cardiovascular risk-factors with increased in-hospital case-fatality (38.4 vs. 14.2%, P < 0.001). ICU-admission was independently associated with in-hospital death [OR 5.49 (95% CI 5.30–5.68), P < 0.001]. Male sex [OR 1.96 (95% CI 1.90–2.01), P < 0.001], obesity [OR 2.20 (95% CI 2.10–2.31), P < 0.001], diabetes mellitus [OR 1.48 (95% CI 1.44–1.53), P < 0.001], atrial fibrillation/flutter [OR 1.57 (95% CI 1.51–1.62), P < 0.001], and heart failure [OR 1.72 (95% CI 1.66–1.78), P < 0.001] were independently associated with ICU-admission.ConclusionDuring 2020, 15.4% of the hospitalized COVID-19-patients were treated on ICUs with high case-fatality. Male sex, CVD and cardiovascular risk-factors were independent risk-factors for ICU admission.

Abstract Background Peripheral arterial disease is a progressive atherosclerotic disease with symptoms ranging from an intermittent claudication to acute critical limb ischemia and amputations. Drug-coated balloons and stents were developed to prevent neo-intimal proliferation and restenosis after percutaneous transluminal angioplasty. Randomized controlled trials showed that drug-coated, notably paclitaxel-coated, devices reduce restenosis, late lumen loss, and the need for target lesion re-vascularization compared with uncoated ones. However, the size of these trials was too small to prove superiority for “hard” clinical outcomes. Moreover, available studies were characterized by too restrictive eligibility criteria. Finally, it remains unclear whether paclitaxel-coated balloons may impair long-term survival. Alternative drug-coated balloons, the so-called limus-based analogs, have been approved for clinical use in patients with peripheral arterial disease. By encapsulating sirolimus in phospholipid drug nanocarriers, they optimize adhesion properties of sirolimus and provide better bioavailability. Methods In this investigator-initiated all-comer open-label phase III randomized controlled trial, we will evaluate whether sirolimus-coated balloon angioplasty is non-inferior and eventually superior, according to a predefined hierarchical analysis, to uncoated balloon angioplasty in adults with infra-inguinal peripheral arterial disease requiring endovascular angioplasty. Key exclusion criteria are pregnancy or breastfeeding, known intolerance or allergy to sirolimus, and participation in a clinical trial during the previous 3 months. The primary efficacy outcome is the composite of two clinically relevant non-subjective “hard” outcomes: unplanned major amputation of the target limb and endovascular or surgical target lesion re-vascularization for critical limb ischemia occurring within 1 year of randomization. The primary safety outcome includes death from all causes. Discussion By focusing on clinically relevant outcomes, this study will provide useful information on the efficacy and safety of sirolimus-coated balloon catheters for infra-inguinal peripheral arterial disease in a representative (“all-comer”) population of unselected patients. As regulatory agencies had raised safety concerns in patients exposed to paclitaxel-coated devices (versus uncoated ones), collect mortality data up to 5 years after randomization will be collected. Trial registration ClinicalTrials.gov NCT04238546

Abstract Background The magnitude of venous thromboembolism (VTE) risk in severe COVID‐19 is a matter of debate because of study heterogeneity, changes in VTE management, and scarce evidence of VTE risk in critically ill patients with pneumonia in the pre‐COVID‐19 era. Objectives To evaluate VTE risk in the pre‐COVID‐19 era in a large intensive care unit (ICU) database. Patients/Methods Data from consecutive pneumonia patients admitted to the ICU were retrieved from the Medical Information Mart for Intensive Care III. VTE risk was described in the entire cohort and in subgroups. Results Among 6842 pneumonia patients admitted to the ICU, 486 patients were diagnosed with VTE after a median of 3 (IQR 1–11) days in the ICU. The 30‐day cumulative incidence of VTE was 7% and remained at this level across different age groups, sex, and type of ICU. After adjusting for death, the overall cumulative incidence of VTE was 5%. A total of 1788 patients received thromboprophylaxis (of 2958 for whom that data were available). VTE occurred in 10.7% (95% CI 9.0–12.6) of patients without thromboprophylaxis and in 6.4% (95% CI 5.4–7.6) of those with thromboprophylaxis. Mortality was 20.6% among patients with VTE and 19.2% among those without VTE. Conclusions In the pre‐COVID‐19 era, VTE risk in ICU patients with pneumonia was high and decreased with thromboprophylaxis. These findings can serve as comparators for future studies aiming at evaluating the impact of COVID‐19 or other emerging infections on VTE risk.

Background As mortality from pulmonary embolism (PE) decreases, the personal and societal costs among survivors are receiving increasing attention. Detailing this burden would support an efficient public health resource allocation. We aimed to provide estimates for the economic and disease burden of PE also accounting for long‐term health care use and both direct and indirect costs beyond the acute phase. Methods and Results This is a cost‐of‐illness analysis with a bottom‐up approach based on data from the PREFER in VTE registry (Prevention of Thromboembolic Events—European Registry in Venous Thromboembolism). We calculated direct (clinical events and anticoagulation) and indirect costs (loss of productivity) of an acute PE event and its 12‐month follow‐up in 2020 Euros. We estimated a disability weight for the 12‐month post‐PE status and corresponding disability adjusted life years presumably owing to PE. Disease‐specific costs in the first year of follow‐up after an incident PE case ranged between 9135 Euros and 10 620 Euros. The proportion of indirect costs was 42% to 49% of total costs. Costs were lowest in patients with ongoing cancer, mainly because productivity loss was less evident in this already burdened population. The calculated disability weight for survivors who were cancer free 12 months post‐PE was 0.017, and the estimated disability adjusted life years per incident case were 1.17. Conclusions The economic burden imposed by PE to society and affected patients is considerable, and productivity loss is its main driver. The disease burden from PE is remarkable and translates to the loss of roughly 1.2 years of healthy life per incident PE case.

Abstract Background An increasing number of subjects are recovering from COVID-19, raising the need for tools to adequately assess the course of the disease and its impact on functional status. We aimed to assess the construct validity of the Post-COVID-19 Functional Status (PCFS) Scale among adult subjects with confirmed and presumed COVID-19. Methods Adult subjects with confirmed and presumed COVID-19, who were members of an online panel and two Facebook groups for subjects with COVID-19 with persistent symptoms, completed an online survey after the onset of infection-related symptoms. The number and intensity of symptoms were evaluated with the Utrecht Symptom Diary, health-related quality of life (HrQoL) with the 5-level EQ-5D questionnaire, impairment in work and activities with the Work Productivity and Activity Impairment questionnaire and functional status with the PCFS Scale. Results 1939 subjects were included in the analyses (85% women, 95% non-hospitalized during infection) about 3 months after the onset of infection-related symptoms. Subjects classified as experiencing ‘slight’, ‘moderate’ and ‘severe’ functional limitations presented a gradual increase in the number/intensity of symptoms, reduction of HrQoL and impairment in work and usual activities. No differences were found regarding the number and intensity of symptoms, HrQoL and impairment in work and usual activities between subjects classified as experiencing ‘negligible’ and ‘no’ functional limitations. We found weak-to-strong statistical associations between functional status and all domains of HrQoL (r: 0.233–0.661). Notably, the strongest association found was with the ‘usual activities’ domain of the 5-level EQ-5D questionnaire. Conclusion We demonstrated the construct validity of the PCFS Scale in highly-symptomatic adult subjects with confirmed and presumed COVID-19, 3 months after the onset of symptoms.

Abstract Patients undergoing knee joint replacement (KJR) are at high risk of postoperative venous thromboembolism (VTE), but data on the time trends of VTE rate in this population are sparse. In this analysis of the German nationwide inpatient sample, we included all hospitalizations for elective primary KJR in Germany 2005–2016. Overall, 1,804,496 hospitalized patients with elective primary KJR (65.1% women, 70.0 years [IQR 63.0–76.0]) were included in the analysis. During hospitalization, VTE was documented in 23,297 (1.3%) patients. Total numbers of primary KJR increased from 129,832 in 2005 to 167,881 in 2016 (β-(slope)-estimate 1,978 [95% CI 1,951 to 2,004], P

Abstract 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.

Background Diagnostic delay of chronic thromboembolic pulmonary hypertension (CTEPH) exceeds 1 year, contributing to higher mortality. Health economic consequences of late CTEPH diagnosis are unknown. We aimed to develop a model for quantifying the impact of diagnosing CTEPH earlier on survival, quality-adjusted life-years (QALYs) and healthcare costs. Material and methods A Markov model was developed to estimate lifelong outcomes, depending on the degree of delay. Data on survival and quality of life were obtained from published literature. Hospital costs were assessed from patient records (n=498) at the Amsterdam UMC – VUmc, which is a Dutch CTEPH referral center. Medication costs were based on a mix of standard medication regimens. Results For 63-year-old CTEPH patients with a 14-month diagnostic delay of CTEPH (median age and delay of patients in the European CTEPH Registry), lifelong healthcare costs were estimated at EUR 117 100 for a mix of treatment options. In a hypothetical scenario of maximal reduction of current delay, improved survival was estimated at a gain of 3.01 life-years and 2.04 QALYs. The associated cost increase was EUR 44 654, of which 87% was due to prolonged medication use. This accounts for an incremental cost–utility ratio of EUR 21 900/QALY. Conclusion Our constructed model based on the Dutch healthcare setting demonstrates a substantial health gain when CTEPH is diagnosed earlier. According to Dutch health economic standards, additional costs remain below the deemed acceptable limit of EUR 50 000/QALY for the particular disease burden. This model can be used for evaluating cost-effectiveness of diagnostic strategies aimed at reducing the diagnostic delay.

Abstract Introduction Pulmonary embolism (PE) has not been accounted for as a cause of death contributing to cause‐specific mortality in global reports. Methods We analyzed global PE‐related mortality by focusing on the latest year available for each member state in the World Health Organization (WHO) mortality database, which provides age‐sex–specific aggregated mortality data transmitted by national authorities for each underlying cause of death. PE‐related deaths were defined by International Classification of Diseases, Tenth Revision codes for acute PE or nonfatal manifestations of venous thromboembolism (VTE). The 2001 WHO standard population served for standardization. Results We obtained data from 123 countries covering a total population of 2 602 561 422. Overall, 50 (40.6%) were European, 39 (31.7%) American, 13 (10.6%) Eastern Mediterranean, 13 (10.6%) Western Pacific, 3 (2.4%) Southeast Asian, and 2 (1.6%) African. Of 116 countries classifiable according to population income, 57 (49.1%) were high income, 42 (36.2%) upper‐middle income, 14 (12.1%) lower‐middle income, and 3 (2.6%) low income. A total of 18 726 382 deaths were recorded, of which 86 930 (0.46%) were attributed to PE. PE‐related mortality rate increased with age in most countries. The reporting of PE‐related deaths was heterogeneous, with an age‐standardized mortality rate ranging from 0 to 24 deaths per 100 000 population‐years. Income status only partially explained this heterogeneity. Conclusions Reporting of PE‐related mortality in official national vital registration was characterized by extreme heterogeneity across countries. These findings mandate enhanced efforts toward systematic and uniform coverage of PE‐related mortality and provides a case for full recognition of PE and VTE as a primary cause of death.

Abstract Direct oral anti–activated factor X and antithrombin agents have largely replaced vitamin K antagonists as the standard of care in treatment of venous thromboembolism. However, gaps in efficacy and safety persist, notably in end‐stage renal disease, implantable heart valves or assist devices, extracorporeal support of the circulation, and antiphospholipid syndrome. Inhibition of coagulation factor XI (FXI) emerges as a promising new therapeutic target. Antisense oligonucleotides offer potential advantages as a prophylactic or therapeutic modality, with one dose‐finding trial in orthopedic surgery already published. In addition, monoclonal antibodies blocking activation and/or activity of activated factor XI are investigated, as are small‐molecule inhibitors with rapid offset of action. Further potential targets include upstream components of the contact pathway such as factor XII, polyphosphates, or kallikrein. Finally, catheter‐directed, pharmacomechanical antithrombotic strategies have been developed for high‐ and intermediate‐risk pulmonary embolism, and large randomized trials aiming to validate their efficacy, safety, and prognostic impact are about to start.

Abstract Objectives The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. Trial design The OVID study is conducted as a multicentre open-label superiority randomised controlled trial. Participants Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study’s background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. 6. Ability to walk from car to study centre or reach it by wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. 7. Ability to self-administer prefilled enoxaparin injections after instructions received at the study centre or availability of a person living with the patient to administer enoxaparin. Exclusion Criteria 1. Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior venous thromboembolism (VTE), acute confirmed symptomatic VTE, acute coronary syndrome. 2. Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis: a. Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke, b. previous VTE, c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or recurrent, or metastatic, or inoperable. 3. Any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomization or sign of acute bleeding. 4. Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage. 5. Haemoglobin 70 years; and by study centre) with a randomization ratio of 1:1 with block sizes varying between 4 and 8. Randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria using the electronic data capture software (REDCAP, Vanderbilt University, v9.1.24). Blinding (masking) In this open-label study, no blinding procedures will be used. Numbers to be randomised (sample size) The sample size calculation is based on the parameters α = 0.05 (2-sided), power: 1−β = 0.8, event rate in experimental group, pexp = 0.09 and event rate in control group, pcon = 0.15. The resulting total sample size is 920. To account for potential dropouts, the total sample size was fixed to 1000 with 500 patients in the intervention group and 500 in the control group. Trial Status Protocol version 1.0, 14 April 2020. Protocol version 3.0, 18 May 2020 Recruiting start date: June 2020. Last Patient Last Visit: March 2021. Trial registration ClinicalTrials.gov Identifier: NCT04400799 First Posted: May 26, 2020 Last Update Posted: July 16, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Abstract The clinical spectrum of coronavirus disease 2019 (COVID‐19) is wide, ranging from minor, nonspecific symptoms to severe pneumonia, acute respiratory distress syndrome, multiorgan involvement, and shock. In severe cases, the acute systemic inflammatory response, coagulation activation, and diffuse endothelial damage may, in combination with hypoxia, immobilization, and underlying risk factors, result in potentially life‐threatening venous and arterial thrombotic events. The first data from single‐center retrospective studies suggest that thrombotic events are a key aspect of COVID‐19‐associated morbidity and mortality. We have planned and will be launching the COvid REgistry on THROMBOSIS (CORE‐THROMBOSIS), a large online registry of previously or currently hospitalized patients with COVID‐19. The study aims to (i) determine the rate of acute thrombotic events in consecutive hospitalized patients with coronavirus (COVID‐19); (ii) investigate the current use and trends in thromboprophylaxis regimens; and (iii) describe the use of imaging tests for the detection of cardiovascular events in patients with COVID‐19.

Abstract Introduction VTE‐BLEED is a validated score for identification of patients at increased risk of major bleeding during extended anticoagulation for venous thromboembolism (VTE). It is unknown whether VTE‐BLEED high‐risk patients also have an increased risk for recurrent VTE, which would limit the potential usefulness of the score. Methods This was a post hoc analysis of the randomized, double‐blind, placebo‐controlled PADIS‐PE trial that randomized patients with a first unprovoked pulmonary embolism (PE) initially treated during 6 months to receive an additional 18‐month of warfarin vs. placebo. The primary outcome of this analysis was recurrent VTE during 2‐year follow‐up after anticoagulant discontinuation, that is, after the initial 6‐month treatment in the placebo arm and after 24 months of anticoagulation in the active treatment arm. This rate, adjusted for study treatment allocation, was compared between patients in the high‐ vs. low‐risk VTE‐BLEED group. Results In complete case analysis (n = 308; 82.4% of total population), 89 (28.9%) patients were classified as high risk; 44 VTE events occurred after anticoagulant discontinuation during 668 patient‐years. The cumulative incidence of recurrent VTE was 16.4% (95% confidence interval [CI], 10.0%‐26.1%; 14 events) and 14.6% (95% CI, 10.4%‐20.3%; 30 events) in the high‐risk and low‐risk VTE‐BLEED groups, respectively, for an adjusted hazard ratio of 1.16 (95% CI, 0.62‐2.19). Conclusion In this study, patients with unprovoked PE classified at high risk of major bleeding by VTE‐BLEED did not have a higher incidence of recurrent VTE after cessation of anticoagulant therapy, supporting the potential yield of the score for making management decisions on the optimal duration of anticoagulant therapy.

Background. Fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT) rapidly improves hemodynamic parameters and reverses right ventricular dysfunction caused by acute pulmonary embolism (PE). The effectiveness of USAT for acute PE associated with coronavirus disease 2019 (COVID-19) is unknown. Methods and results. The study population of this cohort study consisted of 36 patients with an intermediate-high- or high-risk acute PE treated with a fixed low-dose USAT protocol (r-tPA 10–20 mg/15 h). Of these, 9 patients tested positive for COVID-19 and were age–sex-matched to 27 patients without COVID-19. The USAT protocol included, beyond the infusion of recombinant tissue plasminogen activator, anti-Xa-activity-adjusted unfractionated heparin therapy (target 0.3–0.7 U/mL). The study outcomes were the invasively measured mean pulmonary arterial pressure (mPAP) before and at completion of USAT, and the National Early Warning Score (NEWS), according to which more points indicate more severe hemodynamic impairment. Twenty-four (66.7%) patients were men; the mean age was 67 ± 14 years. Mean ± standard deviation mPAP decreased from 32.3 ± 8.3 to 22.4 ± 7.0 mmHg among COVID-19 patients and from 35.4 ± 9.7 to 24.6 ± 7.0 mmHg among unexposed, with no difference in the relative improvement between groups (p = 0.84). Within 12 h of USAT start, the median NEWS decreased from six (Q1–Q3: 4–8) to three (Q1–Q3: 2–4) points among COVID-19 patients and from four (Q1–Q3: 2–6) to two (Q1–Q3: 2–3) points among unexposed (p = 0.29). One COVID-19 patient died due to COVID-19-related complications 14 days after acute PE. No major bleeding events occurred. Conclusions. Among patients with COVID-19-associated acute PE, mPAP rapidly decreased during USAT with a concomitant progressive improvement of the NEWS. The magnitude of mPAP reduction was similar in patients with and without COVID-19.

Unselected data of nationwide studies of hospitalized patients with COVID-19 are still sparse, but these data are of outstanding interest to avoid exceeding hospital capacities and overloading national healthcare systems. Thus, we sought to analyze seasonal/regional trends, predictors of in-hospital case-fatality, and mechanical ventilation (MV) in patients with COVID-19 in Germany. We used the German nationwide inpatient samples to analyze all hospitalized patients with a confirmed COVID-19 diagnosis in Germany between 1 January and 31 December in 2020. We analyzed data of 176,137 hospitalizations of patients with confirmed COVID-19-infection. Among those, 31,607 (17.9%) died, whereby in-hospital case-fatality grew exponentially with age. Overall, age ≥ 70 years (OR 5.91, 95%CI 5.70–6.13, p < 0.001), pneumonia (OR 4.58, 95%CI 4.42–4.74, p < 0.001) and acute respiratory distress syndrome (OR 8.51, 95%CI 8.12–8.92, p < 0.001) were strong predictors of in-hospital death. Most COVID-19 patients were treated in hospitals in urban areas (n = 92,971) associated with the lowest case-fatality (17.5%), as compared to hospitals in suburban (18.3%) or rural areas (18.8%). MV demand was highest in November/December 2020 (32.3%, 20.3%) in patients between the 6th and 8th age decade. In the first age decade, 78 of 1861 children (4.2%) with COVID-19-infection were treated with MV, and five of them died (0.3%). The results of our study indicate seasonal and regional variations concerning the number of COVID-19 patients, necessity of MV, and case fatality in Germany. These findings may help to ensure the flexible allocation of intensive care (human) resources, which is essential for managing enormous societal challenges worldwide to avoid overloaded regional healthcare systems.

Background: Hemostatic abnormalities have been described in COVID-19, and pulmonary microthrombosis was consistently found at autopsy with concomitant severe lung damage. Methods: This is a retrospective observational cross-sectional study including consecutive patients with COVID-19 pneumonia who underwent unenhanced chest CT upon admittance at the emergency room (ER) in one large academic hospital. QCT was used for the calculation of compromised lung volume (%CL). Clinical data were retrieved from patients’ files. Laboratory data were obtained upon presentation at the ER. Aim: The aim of this study was to evaluate the correlation between hemostatic abnormalities and lung involvement in patients affected by COVID-19 pneumonia as described using computer-aided quantitative evaluation of chest CT (quantitative CT (QCT)). Results: A total of 510 consecutive patients (68% males), aged 67 years in median, diagnosed with COVID-19 pneumonia, who underwent unenhanced CT scan upon admission to the ER, were included. In all, 115 patients had %CL > 23%; compared to those with %CL < 23%, they showed higher levels of D-dimer, fibrinogen, and CRP, greater platelet count, and longer PT ratio. Via multivariate regression analysis, BMI ≥ 30 kg/m2, D-dimer levels > 500 ng/mL, CRP > 5.0 ng/mL and PT ratio > 1.2 were found to be independent predictors of a %CL > 23% (adjusted odds ratios (95% confidence intervals): 2.1 (1.1–4.0), 3.1 (1.6–5.8), 2.4 (1.3–4.5), and 3.4 (1.4–8.5), respectively). Conclusions: Hemostatic abnormalities in patients affected by COVID-19 correlate with the severity of lung injury as measured by %CL. Our results underline the pathogenetic role of hemostasis in COVID-19 pneumonia beyond the presence of clinically evident thromboembolic complications.

Abstract Background It remains unclear whether the distal location of deep vein thrombosis (DVT) is independently associated with a lower risk of recurrence in all patients, or represents a marker of the presence and severity of provoking factors for venous thromboembolism (VTE). Methods We investigated the impact of distal (vs. proximal) DVT location on the risk of developing symptomatic, objectively confirmed recurrent VTE in 831 patients with a first acute symptomatic DVT not associated with pulmonary embolism (PE), who were stratified by the presence of transient or persistent risk factors at baseline. The primary outcome was symptomatic, objectively diagnosed recurrent VTE, including proximal DVT and PE. Results A total of 205 (24.7%) patients presented with a transient risk factor, 189 (22.7%) with a minor persistent risk factor, 202 (24.3%) with unprovoked DVT, and 235 (28.3%) with cancer-associated DVT. One-hundred twenty-five patients (15.0%) experienced recurrent DVT or PE. The largest relative difference between patients with distal (vs. proximal) DVT was observed in the absence of identifiable risk factors (adjusted hazard ratio [aHR]: 0.11; 95% CI [confidence interval]: 0.03–0.45). In patients with cancer, distal and proximal DVT had a comparable risk of recurrence (aHR: 0.70; 95% CI: 0.28–1.78]). Conclusions The distal (vs. proximal) location of first acute symptomatic DVT represented, in the absence of any identifiable transient or persistent risk factors, a favorable prognostic factor for recurrence. In contrast, the prognostic impact of DVT location was weaker if persistent provoking risk factors for VTE were present, notably cancer.