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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

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

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.

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.

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.