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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 Pulmonary embolism (PE) is a challenge to diagnose and when missed, exposes patients to potentially fatal recurrent events. Beyond CT pulmonary angiography (CTPA) and planar ventilation/perfusion (V/Q) scan, single photon emission CT (SPECT) V/Q emerged a new diagnostic modality of scintigraphic acquisition that has been reported to improve diagnostic performances. To date, no management outcome study or randomised trial evaluated an algorithm based on SPECT V/Q for PE diagnosis. We present the design of a randomised multicentre, international management study comparing SPECT V/Q with validated strategies.Material and methods We will include a total of 3672 patients with suspected PE requiring chest imaging, randomised into three different groups, each using a different diagnostic strategy based on SPECT V/Q, CTPA and planar V/Q scan. Randomisation will be unbalanced (2:1:1), with twice as many patients in SPECT V/Q arm (n=1836) as in CTPA and planar V/Q arms (n=918 in each). Our primary objective will be to determine whether a diagnostic strategy based on SPECT V/Q is non-inferior to previously validated strategies in terms of diagnostic exclusion safety as assessed by the 3-month risk of thromboembolism in patients with a negative diagnostic workup. Secondary outcomes will be the proportion of patients diagnosed with PE in each arm, patients requiring additional tests, the incidence of major and clinically relevant non-major bleeding and the incidence and cause of death in each arm.Ethics and dissemination This trial is funded by a grant from Brest University Hospital and by INVENT. The study protocol was approved by Biomedical Research Ethics Committee. The investigator or delegate will obtain signed informed consent from all patients prior to inclusion in the trial. Our results will inform future clinical practice guidelines and solve the current discrepancy between nuclear medicine guidelines and clinical scientific society guidelines.Trial registration number NCT02983760

Transient perivascular inflammation of the carotid artery (TIPIC) syndrome, historically named idiopathic carotidynia or Fay syndrome, is a rare condition characterized by inflammation and pain in the carotid artery. The diagnosis requires a specific clinical–radiological presentation. We describe a 37-year-old female who presented with headaches and left neck pain and was diagnosed with TIPIC syndrome with temporary perivascular infiltration.

BACKGROUND: Venous thromboembolism is a dreaded complication of hospitalised patients, with associated morbidity, mortality and increased healthcare costs. Previous studies have shown that pharmacological thromboprophylaxis, though effective, is inadequately administered in a large proportion of medical inpatients. STUDY AIMS: Our primary aim was to evaluate the contemporary adequacy of thromboprophylaxis in medical inpatients admitted to two Swiss hospitals (a university hospital and a regional hospital). The secondary aim was to estimate the 90-day incidence of relevant thrombotic and bleeding events. METHODS: In this prospective cohort, patients were recruited at the University Hospital of Geneva and the Regional Hospital of Lugano between September 2020 and February 2021 and followed for 90 days for venous thromboembolism and bleeding events. The adequacy of thromboprophylaxis (pharmacological and/or mechanical) at 24h after hospital admission was evaluated according to the simplified Geneva risk score for hospital-associated venous thromboembolism. RESULTS: Among 200 participants (100 at each site, mean age of 65 years), 57.5% were deemed at high risk of venous thromboembolism at admission. Thromboprophylaxis was adequate in 59.5% (95% CI 52.3–66.4%). Among high-risk and low-risk inpatients, thromboprophylaxis was adequate in 71.3% and 43.5%, respectively, with differences between sites. At 90 days, risks of adjudicated venous thromboembolism, major bleeding and mortality were 1.5%, 1.5% and 6.0%, respectively. CONCLUSION: Despite the extensive literature on thromboprophylaxis, the adequacy of thromboprophylaxis has not improved and remains insufficient among medical inpatients. Implementation and evaluation of clinical decision support systems are critically needed in this field. clinicaltrials.gov number: NCT05306821

Abstract Background COVID-19 appears to be associated with a high risk of venous thromboembolism (VTE). We aimed to systematically review and meta-analyze the risk of clinically relevant VTE in patients hospitalized for COVID-19. Methods This meta-analysis included original articles in English published from January 1st, 2020 to June 15th, 2020 in Pubmed/MEDLINE, Embase, Web of science, and Cochrane. Outcomes were major VTE, defined as any objectively diagnosed pulmonary embolism (PE) and/or proximal deep vein thrombosis (DVT). Primary analysis estimated the risk of VTE, stratified by acutely and critically ill inpatients. Secondary analyses explored the separate risk of proximal DVT and of PE; the risk of major VTE stratified by screening and by type of anticoagulation. Results In 33 studies (n = 4009 inpatients) with heterogeneous thrombotic risk factors, VTE incidence was 9% (95%CI 5–13%, I 2 = 92.5) overall, and 21% (95%CI 14–28%, I 2 = 87.6%) for patients hospitalized in the ICU. Proximal lower limb DVT incidence was 3% (95%CI 1–5%, I 2 = 87.0%) and 8% (95%CI 3–14%, I 2 = 87.6%), respectively. PE incidence was 8% (95%CI 4–13%, I 2 = 92.1%) and 17% (95%CI 11–25%, I 2 = 89.3%), respectively. Screening and absence of anticoagulation were associated with a higher VTE incidence. When restricting to medically ill inpatients, the VTE incidence was 2% (95%CI 0–6%). Conclusions The risk of major VTE among COVID-19 inpatients is high but varies greatly with severity of the disease. These findings reinforce the need for the use of thromboprophylaxis in all COVID-19 inpatients and for clinical trials testing different thromboprophylaxis regimens in subgroups of COVID-19 inpatients. Trial registration The review protocol was registered in PROSPERO International Prospective Register of Systematic Reviews ( CRD42020193369 ).

Abstract Background Hospital‐associated venous thromboembolism (HA‐VTE) can be prevented by pharmacologic thromboprophylaxis. Thrombotic risk assessment models (RAMs) are essential tools to improve inadequately prescribed thromboprophylaxis. Among cases of HA‐VTE, our study objectives are to explore the classifications of available thrombosis RAMs, the adequacy of thromboprophylaxis and risk factors for inadequate thromboprophylaxis. Methods We identified cases of HA‐VTE occurring during medical hospitalizations within a multicenter Swiss venous thromboembolism (VTE) cohort (2009‐2013). We calculated the proportion of VTE cases deemed at high risk with 4 VTE RAMs (Geneva, Simplified Geneva, Padua, and Improve) and the adequacy of administered pharmacologic thromboprophylaxis, and explored risk factors for underprescription of thromboprophylaxis in high‐risk inpatients. Results Among 66 medical inpatients with HA‐VTE, 60.6% had pulmonary embolism. The sensitivities of the Geneva, Simplified Geneva, Padua, and Improve RAMs were 86.4%, 80.3%, 72.7%, and 57.6%, respectively. The proportion of inadequate thromboprophylaxis was high, as 62.5%‐71.1% of high‐risk inpatients had not received it. Among the high‐risk group according to the Simplified Geneva RAM, absence of immobilization was the only variable significantly associated with an inadequate use of thromboprophylaxis (odds ratio, 3.59; 95% confidence interval, 1.08‐11.88). Conclusions We found a dramatically high proportion of inadequate medical thromboprophylaxis among inpatients who suffered from HA‐VTE. This reinforces the need for global and local quality‐improvement efforts to promote adequate use of thromboprophylaxis in elderly inpatients. Mobility may favor the underuse of thromboprophylaxis, and clinicians should stay alert to other thrombotic risk factors in mobile inpatients.

Abstract Background Hospitalized patients with COVID‐19 suffered initially from high rates of venous thromboembolism (VTE), with possible associations between therapeutic anticoagulation and better clinical outcomes in observational studies. Objective To test whether therapeutic anticoagulation improves clinical outcomes in severe COVID‐19. Patients/Methods In this multicenter, open‐label, randomized controlled trial, we recruited acutely ill medical COVID‐19 patients with D‐dimer >1000 ng/ml or critically ill COVID‐19 patients in four Swiss hospitals, from April 2020 until June 2021, with a 30‐day follow‐up. Participants were randomized to in‐hospital therapeutic anticoagulation versus low‐dose anticoagulation in acutely ill participants/intermediate‐dose anticoagulation in critically ill participants, with enoxaparin or unfractionated heparins. The primary outcome was a centrally adjudicated composite of 30‐day all‐cause mortality, VTE, arterial thrombosis, and disseminated intravascular coagulopathy (DIC), with screening for proximal deep vein thrombosis. Results Among 159 participants, 55.3% were critically ill and 94.3% received corticosteroids. Before study inclusion, pulmonary embolism had been excluded in 71.7%. The primary outcome occurred in 4/79 participants randomized to therapeutic anticoagulation and 4/80 to low/intermediate anticoagulation (5.4% vs. 5.0%; risk difference +0.4%; adjusted hazard ratio 0.76, 95% confidence interval 0.18–3.21), including three deaths in each group. All primary outcomes and major bleeding (n = 3) occurred in critically ill participants. There was no asymptomatic proximal deep vein thrombosis and no difference in major bleeding. Conclusions Among patients with severe COVID‐19 treated with corticosteroids and with exclusion of pulmonary embolism at hospital admission for most, risks of mortality, thrombotic outcomes, and DIC were low at 30 days. The lack of benefit of therapeutic anticoagulation was too imprecise for definite conclusions.

Pulmonary embolism (PE) is one of the most common causes of severe morbidity and mortality during pregnancy. PE diagnosis during pregnancy remains a true challenge for all physicians, as many of the symptoms and signs associated with PE are often reported during physiological pregnancy. The fear of missing a PE during pregnancy leads a low threshold of suspicion, hence to a low prevalence of confirmed PE among pregnant women with suspected PE. This means that most pregnant women with suspected PE do not have the disease. Until recently, international guidelines suggested thoracic imaging in all pregnant women with suspected PE. Two recent prospective management outcome studies based on clinical probability assessment, D-dimer measurement, venous compression ultrasonography of the lower limbs (CUS) and computed tomography pulmonary angiography (CTPA) proved the safety of such strategies, with a very low failure rate. For the first time, these studies also demonstrated that the association of a clinical prediction rule and D-dimer measurement allowed a safe exclusion of PE in a significant proportion of pregnant women, without the need for radiating imaging tests. These two prospective studies pave the way to further improvements in the diagnostic strategies. Indeed, both specific clinical prediction rules and possibly D-dimer cutoffs adapted to pregnant women could help to further reduce the proportion of patients needing thoracic imaging. As an imaging test will still ultimately be necessary in a significant proportion of women, further technical advances in CT scans protocols could reduce the radiation dose to both the fetus and the mother, an important step to reassure clinicians. Finally, educational efforts should be encouraged in the future to pass the challenge of implementing these validated diagnostic strategies in everyday clinical practice.

Abstract Background The rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), and coronavirus disease 2019 (COVID‐19), has caused more than 3.9 million cases worldwide. Currently, there is great interest to assess venous thrombosis prevalence, diagnosis, prevention, and management in patients with COVID‐19. Objectives To determine the prevalence of venous thromboembolism (VTE) in critically ill patients with COVID‐19, using lower limbs venous ultrasonography screening. Methods Beginning March 8, we enrolled 25 patients who were admitted to the intensive care unit (ICU) with confirmed SARS‐CoV‐2 infections. The presence of lower extremity deep vein thrombosis (DVT) was systematically assessed by ultrasonography between day 5 and 10 after admission. The data reported here are those available up to May 9, 2020. Results The mean (± standard deviation) age of the patients was 68 ± 11 years, and 64% were men. No patients had a history of VTE. During the ICU stay, 8 patients (32%) had a VTE; 6 (24%) a proximal DVT, and 5 (20%) a pulmonary embolism. The rate of symptomatic VTE was 24%, while 8% of patients had screen‐detected DVT. Only those patients with a documented VTE received a therapeutic anticoagulant regimen. As of May 9, 2020, 5 patients had died (20%), 2 remained in the ICU (8%), and 18 were discharged (72%). Conclusions In critically ill patients with SARS‐CoV‐2 infections, DVT screening at days 5‐10 of admission yielded a 32% prevalence of VTE. Seventy‐five percent of events occurred before screening. Earlier screening might be effective in optimizing care in ICU patients with COVID‐19.

ImportanceThe post-thrombotic syndrome (PTS) is the most common long-term complication of deep vein thrombosis (DVT), occurring in up to 40–50% of cases. There are limited evidence-based approaches for PTS clinical management.ObjectiveTo provide an expert consensus for PTS diagnosis, prevention, and treatment.Evidence-ReviewMEDLINE, Cochrane Database review, and GOOGLE SCHOLAR were searched with the terms “post-thrombotic syndrome” and “post-phlebitic syndrome” used in titles and abstracts up to September 2020.Filters WereEnglish, Controlled Clinical Trial / Systematic Review / Meta-Analysis / Guideline. The relevant literature regarding PTS diagnosis, prevention and treatment was reviewed and summarized by the evidence synthesis team. On the basis of this review, a panel of 15 practicing angiology/vascular medicine specialists assessed the appropriateness of several items regarding PTS management on a Likert-9 point scale, according to the RAND/UCLA method, with a two-round modified Delphi method.FindingsThe panelists rated the following as appropriate for diagnosis: 1-the Villalta scale; 2- pre-existing venous insufficiency evaluation; 3-assessment 3–6 months after diagnosis of iliofemoral or femoro-popliteal DVT, and afterwards periodically, according to a personalized schedule depending on the presence or absence of clinically relevant PTS. The items rated as appropriate for symptom relief and prevention were: 1- graduated compression stockings (GCS) or elastic bandages for symptomatic relief in acute DVT, either iliofemoral, popliteal or calf; 2-thigh-length GCS (30–40 mmHg at the ankle) after ilio-femoral DVT; 3- knee-length GCS (30–40 mmHg at the ankle) after popliteal DVT; 4-GCS for different length of times according to the severity of periodically assessed PTS; 5-catheter-directed thrombolysis, with or without mechanical thrombectomy, in patients with iliofemoral obstruction, severe symptoms, and low risk of bleeding. The items rated as appropriate for treatment were: 1- thigh-length GCS (30–40 mmHg at the ankle) after iliofemoral DVT; 2-compression therapy for ulcer treatment; 3- exercise training. The role of endovascular treatment (angioplasty and/or stenting) was rated as uncertain, but it could be considered for severe PTS only in case of stenosis or occlusion above the inguinal ligament, followed by oral anticoagulation.Conclusions and RelevanceThis position paper can help practicing clinicians in PTS management.

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

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.

Objective: Vitamin D deficiency is associated with increased risks of arte rial and venous cardiovascular events. Hypothetically, supplementation with vitamin D may lead to a less prothrombotic phenotype, as measured by global coagulation assa ys and fibrin clot structure. Methods: In this prospective cohort study, we enrolled adult outpatient s attending the Primary Care Division of the Geneva University Hospitals wi th a severe vitamin D deficiency (25-hydroxyvitamin-D3 (25-OHD)

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

Introduction The clinical significance of subsegmental pulmonary embolism (SSPE) is currently unclear. Although growing evidence from observational studies suggests that withholding anticoagulant treatment may be a safe option in selected patients with isolated SSPE, most patients with this condition receive anticoagulant treatment, which is associated with a 90-day risk of recurrent venous thromboembolism (VTE) of 0.8% and major bleeding of up to 5%. Given the ongoing controversy concerning the risk-benefit ratio of anticoagulation for isolated SSPE and the lack of evidence from randomised-controlled studies, the aim of this clinical trial is to evaluate the efficacy and safety of clinical surveillance without anticoagulation in low-risk patients with isolated SSPE.Methods and analysis SAFE-SSPE (Surveillance vs. Anticoagulation For low-risk patiEnts with isolated SubSegmental Pulmonary Embolism, a multicentre randomised placebo-controlled non-inferiority trial) is an international, multicentre, placebo-controlled, double-blind, parallel-group non-inferiority trial conducted in Switzerland, the Netherlands and Canada. Low-risk patients with isolated SSPE are randomised to receive clinical surveillance with either placebo (no anticoagulation) or anticoagulant treatment with rivaroxaban. All patients undergo bilateral whole-leg compression ultrasonography to exclude concomitant deep vein thrombosis before enrolment. Patients are followed for 90 days. The primary outcome is symptomatic recurrent VTE (efficacy). The secondary outcomes include clinically significant bleeding and all-cause mortality (safety). The ancillary outcomes are health-related quality of life, functional status and medical resource utilisation.Ethics and dissemination The local ethics committees in Switzerland have approved this protocol. Submission to the Ethical Committees in the Netherlands and Canada is underway. The results of this trial will be published in a peer-reviewed journal.Trial registration number NCT04263038.

AIMS OF THE STUDY Many centres have noticed a high number of venous thromboembolism (VTE) events among critically ill inpatients with COVID-19 pneumonia. The aims of this study were (1) to summarise the reported risk of VTE associated with COVID-19 infections and (2) to summarise guidance documents on thromboprophylaxis in COVID-19 patients, in a systematic review. METHODS We systematically searched for peer-reviewed evidence on the risk of VTE in patients with COVID-19, in PubMed, Embase and Twitter, and for guidelines or guidance documents for thromboprophylaxis, from international or national societies relevant to the field of thrombosis and haemostasis, up to April 30 2020. RESULTS We found 11 studies (1 clinical trial, 7 retrospective cohorts and 3 prospective cohorts), which included a range of 16 to 388 in patients with COVID-19 (total of 1369 inpatients). The diagnoses of COVID-19 and VTE were of high quality, but the follow-up was often unclear. Most studies reported universal in-hospital thromboprophylaxis. Among all inpatients and among intensive care unit (ICU) inpatients with COVID-19, reported risks of VTE were 4.4–8.2% (three studies) and 0–35.3% (six studies), respectively. Two studies at least partially screened for VTE in ICU inpatients with COVID-19, and found risks of 24.7–53.8%. We found 12 guidelines for thromboprophylaxis of COVID-19 patients. The majority suggested universal pharmacological thromboprophylaxis in all COVID-19 inpatients, but there was heterogeneity in the suggested intensity of thromboprophylaxis: seven advised considering intensified doses of heparin according to the clinical or biological severity of the disease, especially in the ICU setting. CONCLUSIONS Venous thromboembolism very commonly complicates the clinical course of inpatients with COVID-19, despite thromboprophylaxis. The risk appears highest among critically ill inpatients. We found no estimates of risks among outpatients. Many questions remain unresolved, as delineated by the heterogeneity of national and international guidelines. This situation calls for fast randomised clinical trials, comparing different schemes of thromboprophylaxis in COVID-19 inpatients.

UNLABELLED:Biomarkers unrelated to myocardial necrosis, such as cystatin C, copeptin, and mid-regional pro-adrenomedullin (MR-proADM), showed promise for cardiovascular risk prediction. Knowing whether they are comparable to cardiac biomarkers such as high-sensitive cardiac-troponin T (hs-cTnT) or N-terminal pro-Brain natriuretic peptide (NT-proBNP) in elderly patients with acute non-massive pulmonary embolism (NMPE) remains elusive. This study aims at comparing the prognostic accuracy of cardiac and non-cardiac biomarkers in patients with NMPE aged ≥65 years over time. In the context of the SWITCO65+ cohort, we evaluated 227 elderly patients with an available blood sample taken within one day from diagnosis. The primary study endpoint was defined as PE-related mortality and the secondary endpoint as PE-related complications. The biomarkers' predictive ability at 1, 3, 12 and 24 months was determined using C-statistics and Cox regression. For both study endpoints, C-statistics (95% confidence interval) were stable over time for all biomarkers, with the highest value for hs-cTnT, ranging between 0.84 (0.68-1.00) and 0.80 (0.70-0.90) for the primary endpoint, and between 0.74 (0.63-0.86) and 0.65 (0.57-0.73) for the secondary endpoint. For both study endpoints, cardiac biomarkers were found to be independently associated with risk, NT-proBNP displaying a negative predictive value of 100%. Among non-cardiac biomarkers, only copeptin and MR-proADM were independent predictors of PE-related mortality but they were not independent predictors of PE-related complications, and displayed lower negative predictive values. In elderly NMPE patients, cardiac biomarkers appear to be valuable prognostic to identify very low-risk individuals. TRIAL REGISTRATION:ClinicalTrials.gov NCT00973596.

Whether anticoagulation management practices are associated with improved outcomes in elderly patients with acute venous thromboembolism (VTE) is uncertain. Thus, we aimed to examine whether practices recommended by the American College of Chest Physicians guidelines are associated with outcomes in elderly patients with VTE. We studied 991 patients aged ≥65 years with acute VTE in a Swiss prospective multicenter cohort study and assessed the adherence to four management practices: parenteral anticoagulation ≥5 days, INR ≥2.0 for ≥24 hours before stopping parenteral anticoagulation, early start with vitamin K antagonists (VKA) ≤24 hours of VTE diagnosis, and the use of low-molecular-weight heparin (LMWH) or fondaparinux. The outcomes were all-cause mortality, VTE recurrence, and major bleeding at 6 months, and the length of hospital stay (LOS). We used Cox regression and lognormal survival models, adjusting for patient characteristics. Overall, 9% of patients died, 3% had VTE recurrence, and 7% major bleeding. Early start with VKA was associated with a lower risk of major bleeding (adjusted hazard ratio 0.37, 95% CI 0.20-0.71). Early start with VKA (adjusted time ratio [TR] 0.77, 95% CI 0.69-0.86) and use of LMWH/fondaparinux (adjusted TR 0.87, 95% CI 0.78-0.97) were associated with a shorter LOS. An INR ≥2.0 for ≥24 hours before stopping parenteral anticoagulants was associated with a longer LOS (adjusted TR 1.2, 95% CI 1.08-1.33). In elderly patients with VTE, the adherence to recommended anticoagulation management practices showed mixed results. In conclusion, only early start with VKA and use of parenteral LMWH/fondaparinux were associated with better outcomes.

Management of anticoagulation in elderly patients represents a particularly challenging issue. Indeed, this patient population is at high thromboembolic risk, but also at high hemorrhagic risk. Assessment of the benefit-risk balance of anticoagulation is the key point when decisions are made about introducing and/or continuing such treatments in the individual elderly patient. In order to maximise the safety of anticoagulation in the elderly, some specific considerations need to be taken into account, including renal insufficiency, modified pharmacodynamics of anticoagulants, especially vitamin K antagonists, and the presence of multiple comorbidities and concomitant medications. New anticoagulants could greatly simplify and possibly increase the safety of anticoagulation in the elderly in the near future.

Luca Masotti1, Marc Righini2, Nicolas Vuilleumier3, Fabio Antonelli4, Giancarlo Landini5, Roberto Cappelli6, Patrick Ray71Internal Medicine, 4Clinical Chemistry, Cecina Hospital, Cecina, Italy; 2Division of Angiology and Haemostasis, Department of Internal Medicine, Geneva University Hospital, Switzerland; 3Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals and University of Geneva, Switzerland; 5Internal Medicine, Santa Maria Nuova Hospital, Florence, Italy; 6Thrombosis Center, University of Siena, Siena, Italy; 7Department of Emergency Medicine, Centre Hospitalo-Universitaire Pitié-Salpêtrière, UPMC Paris 6, Paris, FranceAbstract: Pulmonary embolism (PE) represents a common disease in emergency medicine and guidelines for diagnosis and treatment have had wide diffusion. However, PE morbidity and mortality remain high, especially when associated to hemodynamic instability or right ventricular dysfunction. Prognostic stratification to identify high risk patients needing to receive more aggressive pharmacological and closer monitoring is of utmost importance. Modern guidelines for management of acute PE are based on risk stratification using either clinical, radiological, or laboratory findings. This article reviews the modern treatment of acute PE, which is customized upon patient prognosis. Accordingly the current risk stratification tools described in the literature such as clinical scores, echocardiography, helical computer tomography, and biomarkers will be reviewed.Keywords: pulmonary embolism, prognosis, troponin, BNP, NT-proBNP, echocardiography, computer tomography

Helia Robert-Ebadi, Grégoire Le Gal, Marc RighiniDivision of Angiology and Hemostasis (HRE, MR), Department of Internal Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland, and Department of Internal Medicine and Chest Diseases, EA 3878 (GETBO), Brest University Hospital, Brest, France (GLG)Abstract: Elderly people represent a patient population at high thromboembolic risk, but also at high hemorrhagic risk. There is a general tendency among physicians to underuse anticoagulants in the elderly, probably both because of underestimation of thromboembolic risk and overestimation of bleeding risk. The main indications for anticoagulation are venous thromboembolism (VTE) prophylaxis in medical and surgical settings, VTE treatment, atrial fibrillation (AF) and valvular heart disease. Available anticoagulants for VTE prophylaxis and initial treatment of VTE are low molecular weight heparins (LMWH), unfractionated heparin (UFH) or synthetic anti-factor Xa pentasaccharide fondaparinux. For long-term anticoagulation vitamin K antagonists (VKA) are the first choice and only available oral anticoagulants nowadays. Assessing the benefit-risk ratio of anticoagulation is one of the most challenging issues in the individual elderly patient, patients at highest hemorrhagic risk often being those who would have the greatest benefit from anticoagulants. Some specific considerations are of utmost importance when using anticoagulants in the elderly to maximize safety of these treatments, including decreased renal function, co-morbidities and risk of falls, altered pharmacodynamics of anticoagulants especially VKAs, association with antiplatelet agents, patient education. Newer anticoagulants that are currently under study could simplify the management and increase the safety of anticoagulation in the future.Keywords: anticoagulation, elderly patients, venous thromboembolism, hemorrhagic risk, atrial fibrillation, thrombin inhibitors, factor Xa inhibitor

Luca Masotti1,8, Patrick Ray2, Marc Righini3, Gregoire Le Gal4, Fabio Antonelli5, Giancarlo Landini1, Roberto Cappelli6, Domenico Prisco7, Paola Rottoli81Internal Medicine, Cecina Hospital, Cecina, Italy; 2Department of Emergency Medicine, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie-Paris 6, Paris, France; 3Division of Angiology and Hemostasis, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland; 4Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest, France; 5Clinical Chemistry, Cecina Hospital, Cecina, Italy; 6Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Siena, Italy; 7Department of Critical Care Medicine, Thrombosis Centre, Careggi Hospital, Florence, Italy; 8Departiment of Clinical Medicine and Immunological Sciences, Division of Respiratory Diseases, University of Siena, Siena, ItalyObjective: Diagnosis of pulmonary embolism (PE) remains difficult and is often missed in the elderly due to nonspecific and atypical presentation. Diagnostic algorithms able to rule out PE and validated in young adult patients may have reduced applicability in elderly patients, which increases the number of diagnostic tools use and costs. The aim of the present study was to analyze the reported clinical presentation of PE in patients aged 65 and more.Materials and Methods: Prospective and retrospective English language studies dealing with the clinical, instrumental and laboratory aspects of PE in patients more than 65 and published after January 1987 and indexed in MEDLINE using keywords as pulmonary embolism, elderly, old, venous thromboembolism (VTE) in the title, abstract or text, were reviewed.Results: Dyspnea (range 59%–91.5%), tachypnea (46%–74%), tachycardia (29%–76%), and chest pain (26%–57%) represented the most common clinical symptoms and signs. Bed rest was the most frequent risk factor for VTE (15%–67%); deep vein thrombosis was detected in 15%–50% of cases. Sinus tachycardia, right bundle branch block, and ST-T abnormalities were the most frequent ECG findings. Abnormalities of chest X-ray varied (less than 50% in one-half of the studies and more than 70% in the other one-half). Arterial blood gas analysis revealed severe hypoxemia and mild hypocapnia as the main findings. D-Dimer was higher than cut-off in 100% of patients in 75% of studies. Clinical usefulness of D-Dimer measurement decreases with age, although the strategies based on D-Dimer seem to be cost-effective at least until 80 years.Conclusion: Despite limitations due to pooling data of heterogeneous studies, our review could contribute to the knowledge of the presentation of PE in the elderly with its diagnostic difficulties. A diagnostic strategy based on reviewed data is proposed.Keywords: pulmonary embolism, diagnosis, elderly, symptoms

We aimed to assess whether elderly patients with acute venous thromboembolism (VTE) receive recommended initial processes of care and to identify predictors of process adherence.We prospectively studied in- and outpatients aged ≥65 years with acute symptomatic VTE in a multicenter cohort study from nine Swiss university- and non-university hospitals between September 2009 and March 2011. We systematically assessed whether initial processes of care, which are recommended by the 2008 American College of Chest Physicians guidelines, were performed in each patient. We used multivariable logistic models to identify patient factors independently associated with process adherence.Our cohort comprised 950 patients (mean age 76 years). Of these, 86% (645/750) received parenteral anticoagulation for ≥5 days, 54% (405/750) had oral anticoagulation started on the first treatment day, and 37% (274/750) had an international normalized ratio (INR) ≥2 for ≥24 hours before parenteral anticoagulation was discontinued. Overall, 35% (53/153) of patients with cancer received low-molecular-weight heparin monotherapy and 72% (304/423) of patients with symptomatic deep vein thrombosis were prescribed compression stockings. In multivariate analyses, symptomatic pulmonary embolism, hospital-acquired VTE, and concomitant antiplatelet therapy were associated with a significantly lower anticoagulation-related process adherence.Adherence to several recommended processes of care was suboptimal in elderly patients with VTE. Quality of care interventions should particularly focus on processes with low adherence, such as the prescription of continued low-molecular-weight heparin therapy in patients with cancer and the achievement of an INR ≥2 for ≥24 hours before parenteral anticoagulants are stopped.

The assessment of clinical probability represents an important step in the diagnostic strategy of patients with suspected deep vein thrombosis. The recently derived LEFt clinical prediction rule for pregnant women combines three variables: symptoms in the left leg (L), calf circumference difference of 2 centimeters or over (E for edema) and first trimester presentation (Ft) but is lacking an external validation. The LEFt rule was computed among pregnant women with suspected deep vein thrombosis who were included in a multicenter prospective diagnostic management outcome study. We calculated the proportion of women and the prevalence of deep vein thrombosis in each probability group, along with the diagnostic performances of the LEFt rule. All variables needed to compute the rule could be retrieved in 157 of the 167 pregnant women with suspected deep vein thrombosis. The prevalence of confirmed deep vein thrombosis was 13 of 157 (8.3%). The LEFt rule was negative in 46 (29%) women. A deep vein thrombosis was diagnosed in 13 of 111 (11.7%, 95% Confidence Interval (CI): 8.3-20.9%) of women with at least one of the LEFt criteria, as compared with none of 46 (0.0%, 95%CI: 0.0-7.9%) of women with none of the LEFt criteria. These results suggest that a negative LEFt rule accurately identifies pregnant women in whom the proportion of confirmed deep vein thrombosis appears to be very low. The rule should not be used as stand-alone test for excluding DVT during pregnancy, but might rather be implemented in a diagnostic strategy in association with D-dimer measurement and compression ultrasonography. The original trial was registered at clinicaltrials.gov (NCT 00740454).

Background D-dimer testing to rule out deep vein thrombosis is less useful in older patients because of a lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut-off combined with clinical probability for the exclusion of deep vein thrombosis.Design and Methods Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability of deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 μg/L) and the age-adjusted D-dimer cut-off (patient's age x 10 μg/L in patients >50 years).Results In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) patients with the age-adjusted cut-off value versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted cut-off value and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non-high probability.Conclusions The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded.