Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

BACKGROUND: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING: Eighteen sites between February 2011 and February 2021. PATIENTS: Patients with isolated subsegmental pulmonary embolism. INTERVENTION: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION: The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study.

IMPORTANCE: D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE: To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS: A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS: All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES: The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS: Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE: Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01134068.

Time to negative PCR conversion amongst high-risk patients with mild-to-moderate Omicron BA.1 and BA.2 COVID-19 treated with sotrovimab or nirmatrelvir.

OBJECTIVES: Our aim was to compare the clinical and virological outcomes in Omicron BA.1- and BA.2-infected patients who received sotrovimab with those in patients who received nirmatrelvir for the prevention of severe COVID-19. METHODS: In this multi-centric, prospective ANRS 0003S CoCoPrev cohort study, patients at a high risk of progression of mild-to-moderate BA.1 or BA.2 COVID-19 who received sotrovimab or nirmatrelvir were included. The proportion of patients with progression to severe COVID-19, time between the start of treatment to negative PCR conversion, SARS-CoV-2 viral decay, and characterization of resistance variants were determined. A multi-variable Cox proportional hazard model was used to determine the time to negative PCR conversion and a mixed-effect model for the dynamics of viral decay. RESULTS: Amongst 255 included patients, 199 (80%) received ≥3 vaccine doses, 195 (76%) received sotrovimab, and 60 (24%) received nirmatrelvir. On day 28, new COVID-19-related hospitalization occurred in 4 of 193 (2%; 95% CI, 1-5%) sotrovimab-treated patients and 0 of 55 nirmatrelvir-treated patients (p 0.24). One out of the 55 nirmatrelvir-treated patients died (2%; 95% CI, 0-10%). The median time to negative PCR conversion was 11.5 days (95% CI, 10.5-13) in the sotrovimab-treated patients vs. 4 days (95% CI, 4-9) in the nirmatrelvir-treated patients (p < 0.001). Viral decay was faster in the patients who received nirmatrelvir (p < 0.001). In the multi-variable analysis, nirmatrelvir and nasopharyngeal PCR cycle threshold values were independently associated with faster conversion to negative PCR (hazard ratio, 2.35; 95% CI, 1.56-3.56; p < 0.0001 and hazard ratio, 1.05; 95% CI, 1.01-1.08; p 0.01, respectively). CONCLUSIONS: Early administration of nirmatrelvir in high-risk patients compared with that of sotrovimab was associated with faster viral clearance. This may participate to decrease transmission and prevent viral resistance.

Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial.

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients. Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707). Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034). Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens. Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

Enoxaparin versus Placebo to Prevent Symptomatic Venous Thromboembolism in Hospitalized Older Adult Medical Patients.

BACKGROUND: Admission to the hospital is a major risk factor for the development of venous thromboembolism (VTE). Whether thromboprophylaxis with low-molecular-weight heparin prevents symptomatic VTE in medically ill, hospitalized older adults remains debated. METHODS: In a prospective, randomized, placebo-controlled, double-blind, multicenter trial, older adults (>70 years of age) hospitalized for acute medical conditions were randomly assigned to receive 40 mg a day of low-molecular-weight heparin (enoxaparin) or placebo for 6 to 14 days. The primary efficacy outcome was the cumulative incidence of symptomatic VTE (distal or proximal deep vein thrombosis, fatal or nonfatal pulmonary embolism) at 30 days. The primary safety outcome was major bleeding. Secondary outcomes included efficacy and safety outcomes at 90 days. RESULTS: The trial was prematurely discontinued in September 2020, 5 years after enrollment began, because of drug supply issues. By the time of trial discontinuation, 2559 patients had been randomly assigned at 47 centers. Median age was 82 years and 60% of patients were female. In the intention-to-treat population, the primary efficacy outcome occurred in 22 out of 1278 (cumulative incidence, 1.8%) patients in the enoxaparin group and in 27 out of 1263 (cumulative incidence, 2.2%) patients in the placebo group (cumulative incidence difference, −0.4 percentage points; 95% confidence interval, −1.5 to 0.7), with no significant difference in time to VTE (P=0.46). The incidence of major bleeding was 0.9% in the enoxaparin group and 1.0% in the placebo group. At 90 days there were 14 symptomatic pulmonary emboli in the enoxaparin group and 25 in the placebo group; all 39 pulmonary embolism events resulted in hospital readmission and/or death, with 5 deaths from pulmonary embolism in the enoxaparin group and 11 deaths in the placebo group. CONCLUSIONS: This trial of thromboprophylaxis in medically ill, hospitalized older adults did not demonstrate that enoxaparin reduced the risk of symptomatic VTE after 1 month. Because the trial was prematurely discontinued, larger trials are needed to definitively address this question. (Funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique, grant number PHRC-N-13-0283; ClinicalTrials.gov number, NCT02379806.)

Thromboembolic risk stratification by TRiP(cast) score to rationalise thromboprophylaxis in patients with lower leg trauma requiring immobilisation: a study protocol of the casting stepped-wedge cluster randomised trial.

INTRODUCTION: Patients with lower limb trauma requiring orthopaedic immobilisation may be at risk of venous thromboembolism but opinions differ about who may benefit from thromboprophylactic anticoagulant treatment.The aim of this CASTING study is to demonstrate the safety of thromboprophylaxis based on the Thrombosis Risk Prediction for patients with cast immobilisation (TRiP(cast) score with regards to the 3-month incidence of symptomatic venous thromboembolism events in low-risk patients not receiving thromboprophylaxis, as well as the usefulness of this strategy on the rate of patients receiving anticoagulant treatment in comparison to current practice. METHODS AND ANALYSIS: CASTING will be a stepped-wedge cluster randomised controlled clinical trial, performed in 15 emergency departments in France and Belgium. With their informed consent, outpatients admitted to one of the participating emergency departments for a lower limb trauma requiring orthopaedic immobilisation without surgery will be included. All centres will begin the trial with the 'observational period' and, every 2 weeks, 1 centre will be randomly assigned to switch to the 'interventional period' and to apply the TRiP(cast) score, in which only patients with a score ≥7 will receive thromboprophylactic anticoagulant treatment. The primary endpoint is the rate of clinical thromboembolic events within 90 days following the inclusion of low-risk patients not receiving thromboprophylaxis. ETHICS AND DISSEMINATION: The protocol has been approved by the Comité de Protection des Personnes Sud I (Ethics Review ID-RCB: 2019-A01829-48) for France and the Comité d'éthique hôpital-facultaire Saint Luc (N° B403201941338) for Belgium. It is carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The findings of this study will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: NCT04064489.

Comparison of the Wells score and the revised Geneva score as a tool to predict pulmonary embolism in outpatients over age 65.

TITLE: Comparison of the Wells score and the revised Geneva score as a tool to predict pulmonary embolism in outpatients over 65 years of age. INTRODUCTION: The incidence and mortality of pulmonary embolism (PE) is high in the elderly. The Wells score (SW) and the revised Geneva score (RGS) have been validated in patient populations with a large age range. The aim of this study was to compare the predictive accuracy of these two scores in diagnosis of PE in patients over 65 years of age. METHOD: A prospective multicentre study (nine French and three Belgian centres) was conducted at the same time as the PERCEPIC study. A total of 1757 patients admitted with suspected PE were included and divided into two groups according to age (≥65 years or <65 years). The pre-test probability of PE was assessed prospectively for the RGS. The SW was calculated retrospectively. The predictive accuracy of the two scores was compared by the area under the curve (AUC) of the ROC curves. RESULTS: The overall prevalence of PE was 11.3%. The prevalence among patients aged ≥65 in the low, moderate and high pre-test probability groups, evaluated using the WS and was respectively 13.5% (CI 95%: CI 9.9-17.3), 28.2% (CI 22.1-34.3), 50% (CI 26-74) and 8.1% (CI 3.2-12.9), 22.3% (CI 18.2-26.3), 43.7% (CI 25.6-61.9) using the RGS. The AUC for the WS and RGS for patients aged ≥65 was 0.632 (CI 0.574-0.691) and 0.610 (CI 0.555-0.666). The difference between the AUCs was not statistically significant (p = .441). CONCLUSION: In the population for this study, the WS and RGS have the same PE diagnostic accuracy in patients over age 65. This result should be validated in a prospective study that directly compares these scores.

Major ischaemic and bleeding risks following current drug-eluting stent implantation: Are there differences across current drug-eluting stent types in real life?

BACKGROUND: Current drug-eluting stents (c-DESs) reduce the occurrence of ischaemic events, but expose recipients to stent thrombosis and bleeding secondary to preventive antiplatelet therapy. To date, comparative data on the relative effectiveness and safety of the various c-DESs in real life are limited. AIM: To compare ischaemic and bleeding risks across the major c-DESs used in France. METHODS: French national health insurance reimbursement and hospitalization databases were used. Patients implanted with a c-DES in 2014 were followed for 1 year. The risks of ischaemic events (revascularization, myocardial infarction and/or stroke), major bleeding events and death were compared across six c-DESs (XIENCE®, PROMUS®, RESOLUTE®, BIOMATRIX®, NOBORI® and ORSIRO®), using multilevel Cox models adjusted for baseline individual and hospital characteristics. RESULTS: A total of 52,891 subjects were included: 34.4% with XIENCE®; 27.6% with PROMUS®; 24.0% with RESOLUTE®; 8.0% with BIOMATRIX®; 5.0% with NOBORI®; and 1.0% with ORSIRO®. Among them, 9378 had at least one event (ischaemic, 6064; major bleeding, 1968; death, 2411), resulting in an overall incidence rate of 19 per 100 person-years. In the multivariable analysis, the risk of ischaemic events, major bleeding events or death did not differ between the c-DESs overall (adjusted hazard ratios between 0.85 [95% confidence interval 0.68-1.07] and 1.04 [95% confidence interval 0.98-1.10] compared with XIENCE® used as the reference) and when each outcome was considered separately. CONCLUSIONS: In real life, major ischaemic and bleeding risks do not differ across the various c-DESs over the first year following implantation. Future studies are needed to assess comparative c-DES effectiveness and safety longer term.

[Admissions of elderly to French emergency departments related to adverse drug events]. / Admissions des sujets âgés aux Services d'Accueil des Urgences pour effets indésirables médicamenteux.

AIMS: To investigate the characteristics of adverse drug events (ADE) causing emergency medical admissions in the elderly. METHODS: Data were obtained from two prospective cross sectional studies with similar experimental design which were carried out in seven French emergency departments in 1999 and 2003. The proportion of ADE leading to admission, their severity and preventability were assessed in patients aged > or =70 (group A) and compared to those of patients < 70 years (group B). RESULTS: Out of a total of 2907 patients, 1158 (39.8%) were > or =70 years of age. Among these, 17.1% were admitted as a result of an ADE vs. 13.2% in group B (p = 0.004). ADE appeared to be more severe in group A than in group B. The part of preventable ADE did not significantly differ between the two groups (48.9% vs. 43.7%, respectively). CONCLUSION: ADE are a common preventable cause of unplanned admissions, especially in the elderly.

[Not Available]. / Admissions des sujets âgés aux Services d'Accueil des Urgences pour effets indésirables médicamenteux.

AIMS: To investigate the characteristics of adverse drug events (ADE) causing emergency medical admissions in the elderly. METHODS: Data were obtained from two prospective cross sectional studies with similar experimental design which were carried out in seven French emergency departments in 1999 and 2003. The proportion of ADE leading to admission, their severity and preventability were assessed in patients aged ≥70 (group A) and compared to those of patients <70years (group B). RESULTS: Out of a total of 2907 patients, 1158 (39.8%) were ≥70years of age. Among these, 17.1% were admitted as a result of an ADE vs. 13.2% in group B (p=0.004). ADE appeared to be more severe in group A than in group B. The part of preventable ADE did not significantly differ between the two groups (48.9% vs. 43.7%, respectively). CONCLUSION: ADE are a common preventable cause of unplanned admissions, especially in the elderly.

Pulmonary embolism rule-out criteria (PERC) rule in European patients with low implicit clinical probability (PERCEPIC): a multicentre, prospective, observational study.

BACKGROUND: The ability of the pulmonary embolism rule-out criteria (PERC) to exclude pulmonary embolism without further testing remains debated outside the USA, especially in the population with suspected pulmonary embolism who have a high prevalence of the condition. Our main objective was to prospectively assess the predictive value of negative PERC to rule out pulmonary embolism among European patients with low implicit clinical probability. METHODS: We did a multicentre, prospective, observational study in 12 emergency departments in France and Belgium. We included consecutive patients aged 18 years or older with suspected pulmonary embolism. Patients were excluded if they had already been hospitalised for more than 2 days, had curative anticoagulant therapy in progress for more than 48 h, or had a diagnosis of thromboembolic disease documented before admission to emergency department. Physicians completed a standardised case report form comprising implicit clinical probability assessment (low, moderate, or high) and a list of risk factors including criteria of the PERC rule. They were asked to follow international recommendations for diagnostic strategy, masked to PERC assessment. The primary endpoint was the proportion of patients with low implicit clinical probability and negative PERC who had venous thromboembolic events, diagnosed during initial diagnostic work-up or during 3-month follow-up, as externally adjudicated by an independent committee masked to the PERC and clinical probability assessment. The upper limit of the 95% CI around the 3-month thromboembolic risk was set at 3%. We did all analyses by intention to treat, including all patients with complete follow-up. This trial is registered with ClinicalTrials.gov, number NCT02360540. FINDINGS: Between May 1, 2015, and April 30, 2016, 1773 consecutive patients with suspected pulmonary embolism were prospectively assessed for inclusion, of whom 1757 were included. 1052 (60%) patients were classed as having low clinical probability, 49 (4·7%, 95% CI 3·5-6·1) of whom had a venous thromboembolic event. In patients with a low implicit clinical probability, 337 (32%) patients had negative PERC, of whom four (1·2%; 95% CI 0·4-2·9) went on to have a pulmonary embolism. INTERPRETATION: In European patients with low implicit clinical probability, PERC can exclude pulmonary embolism with a low percentage of false-negative results. The results of our prospective, observational study allow and justify an implementation study of the PERC rule in Europe. FUNDING: French Ministry of Health.