Final Study Report of Andexanet Alfa for Major Bleeding With Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented. METHODS: Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome. RESULTS: There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94-93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95-93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82-65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79-67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75-84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54-0.70]) and correlated with lower mortality in patients <75 years of age (adjusted P=0.022; unadjusted P=0.003). Median endogenous thrombin potential was within the normal range by the end of andexanet alfa bolus through 24 hours for all FXa inhibitors. CONCLUSIONS: In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02329327.

S100B vs. "GFAP and UCH-L1" assays in the management of mTBI patients.

OBJECTIVES: To compare for the first time the performance of "GFAP and UCH-L1" vs. S100B in a cohort of patients managed for mild traumatic brain injury (mTBI) according to actualized French guidelines. METHODS: A prospective study was recently carried at the Emergency Department of Clermont-Ferrand University Hospital in France. Patients with mTBI presenting a medium risk of complications were enrolled. Blood S100B and "GFAP and UCHL-1" were sampled and measured according to French guidelines. S100B was measured in patients with samples within 3 h of trauma (Cobas®, Roche Diagnostics), while GFAP and UCHL-1 were measured in all patients (samples <3 h and 3-12 h) using another automated assay (i-STAT® Alinity, Abbott). RESULTS: For sampling <3 h, serum S100B correctly identifies intracranial lesions with a specificity of 25.7 % (95 % CI; 19.5-32.6 %), a sensitivity of 100 % (95 % CI; 66.4-100 %), and a negative predictive value of 100 % (95 % CI; 92.5-100 %). For sampling <12 h, plasma "GFAP and UCH-L1" levels correctly identify intracranial lesions with a specificity of 31.7 % (95 % CI; 25.7-38.2 %), a sensitivity of 100 % (95 % CI; 73.5-100 %), and a negative predictive value of 100 % (95 % CI; 95-100 %). Comparison of specificities (25.7 vs. 31.7 %) did not reveal a statistically significant difference (p=0.16). CONCLUSIONS: We highlight the usefulness of measuring plasma "GFAP and UCH-L1" levels to target mTBI patients (sampling within 12 h post-injury) and optimize the reduction of CT scans.

Simple Aspiration versus Drainage for Complete Pneumothorax: A Randomized Noninferiority Trial.

Rationale: Management of first episodes of primary spontaneous pneumothorax remains the subject of debate. Objectives: To determine whether first-line simple aspiration is noninferior to first-line chest tube drainage for lung expansion in patients with complete primary spontaneous pneumothorax. Methods: We conducted a prospective, open-label, randomized noninferiority trial. Adults aged 18-50 years with complete primary spontaneous pneumothorax (total separation of the lung from the chest wall), recruited at 31 French hospitals from 2009 to 2015, received simple aspiration (n = 200) or chest tube drainage (n = 202) as first-line treatment. The primary outcome was pulmonary expansion 24 hours after the procedure. Secondary outcomes were tolerance of treatment, occurrence of adverse events, and recurrence of pneumothorax within 1 year. Substantial discordance in the numerical inputs used for trial planning and the actual trial rates of the primary outcome resulted in a reevaluation of the trial analysis plan. Measurement and Main Results: Treatment failure occurred in 29% in the aspiration group and 18% in the chest tube drainage group (difference in failure rate, 0.113; 95% confidence interval [CI], 0.026-0.200). The aspiration group experienced less pain overall (mean difference, -1.4; 95% CI, -1.89, -0.91), less pain limiting breathing (frequency difference, -0.18; 95% CI, -0.27, -0.09), and less kinking of the device (frequency difference, -0.05; 95% CI, -0.09, -0.01). Recurrence of pneumothorax was 20% in this group versus 27% in the drainage group (frequency difference, -0.07; 95% CI, -0.16, +0.02). Conclusions: First-line management of complete primary spontaneous pneumothorax with simple aspiration had a higher failure rate than chest tube drainage but was better tolerated with fewer adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT01008228).

Assessment of discordance between radiologists and emergency physicians of RADIOgraphs among discharged patients in an emergency department: the RADIO-ED study.

BACKGROUND: The possibility to perform standard X-rays is mandatory for all French Emergency Department (ED). Initial interpretation is under the prescriber emergency physician-who continually works under extreme conditions, but a radiologist needs to describe a report as soon as possible. We decided to assess the rate of discordance between emergency physicians and radiologists among discharged patients. METHODS: We performed a monocentric study on an adult ED among discharged patients who had at least one X-ray during their consult. We used an automatic electronic system that classified interpretation as concordant or discordant. We review all discordant interpretation, which were classified as false negative, false positive, or more exam needed. RESULTS: For 1 year, 8988 patients had 12,666 X-rays. We found a total of 742 (5.9%) discordant X-rays, but only 277 (2.2%) discordance had a consequence (new consult or exam not initially scheduled). We found some factors associated with discordance such as male sex, or ankle, foot, knee, finger, wrist, ribs, and elbow locations. CONCLUSIONS: On discharged patients, using a systematic second interpretation of X-ray by a radiologist, we found a total of 2.2% discordance that had an impact on the initial care.

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.

Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism.

BACKGROUND: Pulmonary embolism is one of the leading causes of maternal death in the Western world. Because of the low specificity and sensitivity of the d-dimer test, all pregnant women with suspected pulmonary embolism undergo computed tomographic (CT) pulmonary angiography or ventilation-perfusion scanning, both of which involve radiation exposure to the mother and fetus. Whether a pregnancy-adapted algorithm could be used to safely avoid diagnostic imaging in pregnant women with suspected pulmonary embolism is unknown. METHODS: In a prospective study involving pregnant women with suspected pulmonary embolism, we assessed three criteria from the YEARS algorithm (clinical signs of deep-vein thrombosis, hemoptysis, and pulmonary embolism as the most likely diagnosis) and measured the d-dimer level. Pulmonary embolism was ruled out if none of the three criteria were met and the d-dimer level was less than 1000 ng per milliliter or if one or more of the three criteria were met and the d-dimer level was less than 500 ng per milliliter. Adaptation of the YEARS algorithm for pregnant women involved compression ultrasonography for women with symptoms of deep-vein thrombosis; if the results were positive (i.e., a clot was present), CT pulmonary angiography was not performed. All patients in whom pulmonary embolism had not been ruled out underwent CT pulmonary angiography. The primary outcome was the incidence of venous thromboembolism at 3 months. The secondary outcome was the proportion of patients in whom CT pulmonary angiography was not indicated to safely rule out pulmonary embolism. RESULTS: A total of 510 women were screened, of whom 12 (2.4%) were excluded. Pulmonary embolism was diagnosed in 20 patients (4.0%) at baseline. During follow-up, popliteal deep-vein thrombosis was diagnosed in 1 patient (0.21%; 95% confidence interval [CI], 0.04 to 1.2); no patient had pulmonary embolism. CT pulmonary angiography was not indicated, and thus was avoided, in 195 patients (39%; 95% CI, 35 to 44). The efficiency of the algorithm was highest during the first trimester of pregnancy and lowest during the third trimester; CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester and in 32% who began the study in the third trimester. CONCLUSIONS: Pulmonary embolism was safely ruled out by the pregnancy-adapted YEARS diagnostic algorithm across all trimesters of pregnancy. CT pulmonary angiography was avoided in 32 to 65% of patients. (Funded by Leiden University Medical Center and 17 other participating hospitals; Artemis Netherlands Trial Register number, NL5726.).

Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. METHODS: We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin). RESULTS: Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage. CONCLUSIONS: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).

Evaluation of serum neurofilament light in the early management of mTBI patients.

OBJECTIVES: Serum S100B allows a one-third reduction of computed tomography (CT) scans performed for mild traumatic brain injury (mTBI) patients. In this study, we evaluated the diagnostic performance of serum NF-L in the detection of intracranial lesions induced by mTBI. METHODS: One hundred seventy-nine adult mTBI patients presenting to the emergency department of Clermont-Ferrand University Hospital with a Glasgow Coma Scale (GCS) score of 14-15 were included. S100B assays were performed for clinical routine while NF-L samples were stored at -80 °C until analysis. CT scans were performed for patients with S100B levels above the decision threshold of 0.10 µg/L. Later, NF-L and S100B levels were compared to CT scan findings to evaluate the biomarkers' performances. RESULTS: The area under the ROC curve (AUC) evaluating the diagnostic ability in the prediction of intracranial lesions was 0.72 (95% CI; 0.58-0.87) for S100B and 0.58 (95% CI; 0.45-0.71) for NF-L, the specificities (at a threshold allowing a 100% sensitivity) were 35.7% for S100B, and 28% for NF-L (p=0.096). AUCs of NF-L and S100B for the identification of patients with neurological disorders were statistically different (p<0.001). The AUCs were 0.87 (95% CI; 0.82-0.93) for NF-L and 0.57 (95% CI; 0.48-0.66) for S100B. There was a poor correlation between NF-L and S100B, and NF-L levels were correlated to patients' age (Spearman coefficient of 0.79). CONCLUSIONS: NF-L showed poor performances in the early management of mTBI patients. NF-L levels are strongly correlated to neurodegeneration, whether physiological, age-related, or pathological.

Assessment of sick building syndrome using visual analog scales.

BACKGROUND: Despite there is no recommendations for assessing symptoms of sick building syndrome, the use of visual analog scales (VAS) seems attractive and appropriate. We aimed to demonstrate the benefits of using VAS for evaluating subjective symptoms of sick building syndrome. METHOD: We compared an exposed group to a control group with a one-year follow-up. To assess chronology of symptoms, employees were asked to complete four VAS at different times: after vacations (time 1), beginning of the week-beginning of the day (time 2), beginning of the week-end of the day (time 3), and end of the week-end of the day (time 4). Measurements were repeated before and after ventilation work for the exposed group and at the same time in the control group without intervention. Confounding factors were assessed. RESULTS: We included 36 employees (21 in the exposed group and 15 in the control group). Both groups were comparable. Prior to ventilation work, the exposed group had more subjective symptoms than the control group with a chronology of symptoms. After ventilation work, symptoms did not differ between groups, and most symptoms decreased within the exposed group. PRACTICAL IMPLICATION: The use of VAS provided reliable data for assessing sick building syndrome and showed a dose-response relationship between occupational exposure and symptoms.

Triaging acute pulmonary embolism for home treatment by Hestia or simplified PESI criteria: the HOME-PE randomized trial.

AIMS: The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment. METHODS AND RESULTS: Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm. CONCLUSIONS: For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.

Prevalence of Pulmonary Embolism Among Patients With COPD Hospitalized With Acutely Worsening Respiratory Symptoms.

IMPORTANCE: The prevalence of pulmonary embolism in patients with chronic obstructive pulmonary disease (COPD) and acutely worsening respiratory symptoms remains uncertain. OBJECTIVE: To determine the prevalence of pulmonary embolism in patients with COPD admitted to the hospital for acutely worsening respiratory symptoms. DESIGN, SETTING, AND PARTICIPANTS: Multicenter cross-sectional study with prospective follow-up conducted in 7 French hospitals. A predefined pulmonary embolism diagnostic algorithm based on Geneva score, D-dimer levels, and spiral computed tomographic pulmonary angiography plus leg compression ultrasound was applied within 48 hours of admission; all patients had 3-month follow-up. Patients were recruited from January 2014 to May 2017 and the final date of follow-up was August 22, 2017. EXPOSURES: Acutely worsening respiratory symptoms in patients with COPD. MAIN OUTCOMES AND MEASURES: The primary outcome was pulmonary embolism diagnosed within 48 hours of admission. Key secondary outcome was pulmonary embolism during a 3-month follow-up among patients deemed not to have venous thromboembolism at admission and who did not receive anticoagulant treatment. Other outcomes were venous thromboembolism (pulmonary embolism and/or deep vein thrombosis) at admission and during follow-up, and 3-month mortality, whether venous thromboembolism was clinically suspected or not. RESULTS: Among 740 included patients (mean age, 68.2 years [SD, 10.9 years]; 274 women [37.0%]), pulmonary embolism was confirmed within 48 hours of admission in 44 patients (5.9%; 95% CI, 4.5%-7.9%). Among the 670 patients deemed not to have venous thromboembolism at admission and who did not receive anticoagulation, pulmonary embolism occurred in 5 patients (0.7%; 95% CI, 0.3%-1.7%) during follow-up, including 3 deaths related to pulmonary embolism. The overall 3-month mortality rate was 6.8% (50 of 740; 95% CI, 5.2%-8.8%). The proportion of patients who died during follow-up was higher among those with venous thromboembolism at admission than the proportion of those without it at admission (14 [25.9%] of 54 patients vs 36 [5.2%] of 686; risk difference, 20.7%, 95% CI, 10.7%-33.8%; P < .001). The prevalence of venous thromboembolism was 11.7% (95% CI, 8.6%-15.9%) among patients in whom pulmonary embolism was suspected (n = 299) and was 4.3% (95% CI, 2.8%-6.6%) among those in whom pulmonary embolism was not suspected (n = 441). CONCLUSIONS AND RELEVANCE: Among patients with chronic obstructive pulmonary disease admitted to the hospital with an acute worsening of respiratory symptoms, pulmonary embolism was detected in 5.9% of patients using a predefined diagnostic algorithm. Further research is needed to understand the possible role of systematic screening for pulmonary embolism in this patient population.

Large concomitant outbreaks of acute gastroenteritis emergency visits in adults and food-borne events suspected to be linked to raw shellfish, France, December 2019 to January 2020.

On 27 December 2019, the French Public Health Agency identified a large increase in the number of acute gastroenteritis and vomiting visits, both in emergency departments and in emergency general practitioners' associations providing house-calls. In parallel, on 26 and 27 December, an unusual number of food-borne events suspected to be linked to the consumption of raw shellfish were reported through the mandatory reporting surveillance system. This paper describes these concomitant outbreaks and the investigations' results.

Impact of take-home messages written into slide presentations delivered during lectures on the retention of messages and the residents' knowledge: a randomized controlled study.

BACKGROUND: Lectures with slide presentations are widely used to teach evidence-based medicine to large groups. Take-home messages (THMs) are poorly identified and recollected by students. We investigated whether an instruction to list THMs in written form on slides would improve the retention thereof by residents, and the residents' level of knowledge, 1 month after lectures. METHODS: Prospective blinded randomized controlled study was conducted. Twelve lectures (6 control and 6 intervention lectures) were delivered to 73 residents. For the intervention lectures, the lecturers were instructed to incorporate clear written THMs into their slide presentations. The outcomes were ability of resident to recollect THMs delivered during a lecture (as assessed by accordance rate between the lecturers' and residents' THMs) and knowledge (as assessed by multiple choice questions (MCQs)). RESULTS: Data for 3738 residents' THMs and 3410 MCQs were analyzed. The intervention did not significantly increase the number of THMs written on slides (77% (n = 20/26), 95% CI 56-91 vs 64% (n = 18/28), 95% CI 44-81, p = 0.31) nor THMs retention (13% (n = 238/1791), 95% CI 12-15 vs 17% (n = 326/1947), 95% 15-18, p = 0.40) nor knowledge (63.8 ± 26.2 vs 61.1 ± 31.4 /100 points, p = 0.75). In multivariable analyses performed with all THMs written on slides from the two groups, a superior knowledge was associated with notetaking during lectures (OR 1.88, 95% CI 1.41-2.51) and THMs retention (OR 2.17, 95% CI 1.54-3.04); and THMs retention was associated with written THMs (OR 2.94, 95% CI 2.20-3.93). CONCLUSIONS: In lectures delivered to residents, a third of the THMs were not in written form. An intervention based on an explicit instruction to lecturers to provide THMs in written form in their slide presentations did not result in increased use of written THMs into the slide presentation or improvement of the THMs retention or level of knowledge. However, we showed that there was a strong positive association between writing THMs on a slide, retention of THMs and residents' knowledge. Further researches are needed to assess interventions to increase written THMs in lectures by faculty. TRIAL REGISTRATION: ClinicalTrials.gov NCT01795651 (Fev 21, 2013).

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study.

Background: Data on the optimal diagnostic management of pregnant women with suspected pulmonary embolism (PE) are limited, and guidelines provide inconsistent recommendations on use of diagnostic tests. Objective: To prospectively validate a diagnostic strategy in pregnant women with suspected PE. Design: Multicenter, multinational, prospective diagnostic management outcome study involving pretest clinical probability assessment, high-sensitivity D-dimer testing, bilateral lower limb compression ultrasonography (CUS), and computed tomography pulmonary angiography (CTPA). (ClinicalTrials.gov: NCT00740454). Setting: 11 centers in France and Switzerland between August 2008 and July 2016. Patients: Pregnant women with clinically suspected PE in emergency departments. Intervention: Pulmonary embolism was excluded in patients with a low or intermediate pretest clinical probability and a negative D-dimer result. All others underwent lower limb CUS and, if results were negative, CTPA. A ventilation-perfusion (V/Q) scan was done if CTPA results were inconclusive. Pulmonary embolism was excluded if results of the diagnostic work-up were negative, and untreated pregnant women had clinical follow-up at 3 months. Measurements: The primary outcome was the rate of adjudicated venous thromboembolic events during the 3-month follow-up. Results: 441 women were assessed for eligibility, and 395 were included in the study. Among these, PE was diagnosed in 28 (7.1%) (proximal deep venous thrombosis found on ultrasonography [n = 7], positive CTPA result [n = 19], and high-probability V/Q scan [n = 2]) and excluded in 367 (clinical probability and negative D-dimer result [n = 46], negative CTPA result [n = 290], normal or low-probability V/Q scan [n = 17], and other reason [n = 14]). Twenty-two women received extended anticoagulation during follow-up, mainly for previous venous thromboembolic disease. The rate of symptomatic venous thromboembolic events was 0.0% (95% CI, 0.0% to 1.0%) among untreated women after exclusion of PE on the basis of negative results on the diagnostic work-up. Limitation: There were several protocol deviations, reflecting the difficulty of performing studies in pregnant women with suspected PE. Conclusion: A diagnostic strategy based on assessment of clinical probability, D-dimer measurement, CUS, and CTPA can safely rule out PE in pregnant women. Primary Funding Source: Swiss National Foundation for Scientific Research, Groupe d'Etude de la Thrombose de Bretagne Occidentale, and International Society on Thrombosis and Haemostasis.

Clinical validation of S100B in the management of a mild traumatic brain injury: issues from an interventional cohort of 1449 adult patients.

BACKGROUND: This study's primary objective was to validate the routine use of S100B via a prospective study. The aim was a reduction of cranial computed tomography (CCT) scans by 30%. The secondary goal was to investigate the influence of age and associated risk factors on the reduction of CCT. METHODS: S100B (sampling within 3 h postinjury) was used for patients with mild traumatic brain injury (mTBIs) presenting a medium risk of complications and requiring a CCT scan. Patients with negative S100B (S100B-) were discharged without a CCT scan. RESULTS: Of the 1449 patients included in this study, 468 (32.3%) had S100B- with a sensitivity of 96.4% (95% CI: 87.5%-99.6%), a specificity of 33.4% (95% CI: 31%-36%) and a negative predictive value of 99.6% (95% CI: 98.5%-99.9%). No significant difference in serum levels or the S100B+ rate was observed if patients had retrograde amnesia (0.16 µg/L; 63.8%), loss of consciousness (0.13; 63.6%) or antiplatelet therapy (0.20; 77.9%). Significant differences were found between the S100B concentrations and S100B positivity rates in patients >65 years old and all the groups with patients <55 years old (18-25, 26-35, 36-45 and 46-55). From 18 to 65 years old (n=874), the specificity is 39.3% (95% CI: 36%-42.6%) compared to 18.7% (95% CI: 15.3%-22.3%) for patients >65 years old (n=504). CONCLUSIONS: The clinical use of S100B in mTBI management reduces the use of CCTs by approximately one-third; furthermore, the percentage of CCTs reduction is influenced by the age of the patient.

Maximal tachycardia and high cardiac strain during night shifts of emergency physicians.

PURPOSE: To compare tachycardia and cardiac strain between 24-hour shifts (24hS) and 14-hour night shifts (14hS) in emergency physicians (EPs), and to investigate key factors influencing tachycardia and cardiac strain. METHODS: We monitored heart rate (HR) with Holter-ECG in a shift-randomized trial comparing a 24hS, a 14hS, and a control day, within a potential for 19 EPs. We also measured 24-h HR the third day (D3) after both shifts. We measured perceived stress by visual analog scale and the number of life-and-death emergencies. RESULTS: The 17 EPs completing the whole protocol reached maximal HR (180.9 ± 6.9 bpm) during both shifts. Minutes of tachycardia >100 bpm were higher in 24hS (208.3 ± 63.8) than in any other days (14hS: 142.3 ± 36.9; D3/14hS: 64.8 ± 31.4; D3/24hS: 57.6 ± 19.1; control day: 39.2 ± 11.6 min, p < .05). Shifts induced a cardiac strain twice higher than in days not involving patients contact. Each life-and-death emergency enhanced 26 min of tachycardia ≥100 bpm (p < .001), 7 min ≥ 110 bpm (p < .001), 2 min ≥ 120 bpm (p < .001) and 19 min of cardiac strain ≥30% (p = .014). Stress was associated with greater duration of tachycardia ≥100, 110 and 120 bpm, and of cardiac strain ≥30% (p < .001). CONCLUSION: We demonstrated several incidences of maximal HR during shifts combined with a high cardiac strain. Duration of tachycardia were the highest in 24hS and lasted several hours. Such values are comparable to those of workers exposed to high physical demanding tasks or heat. Therefore, we suggest that EPs limit their exposure to 24hS. We, furthermore, demonstrated benefits of HR monitoring for identifying stressful events. ClinicalTrials.gov identifier: NCT01874704.

Intervention Study with Algoplus® : A Pain Behavioral Scale for Older Patients in the Emergency Department.

OBJECTIVES: Evaluation of acute pain is often difficult in older patients admitted to the Emergency Department (ED), and self-evaluation of pain is not always possible. This observational study evaluates how the systematic use of Algoplus® , a validated behavioral scale, could improve pain management of older persons admitted to the ED. METHOD: The intervention study (NCT 02258503) took place in 4 steps in the ED, University Hospital Clermont-Ferrand, France. Pain assessment and analgesics prescription were collected from medical files for 3 months. For 6 months, the whole staff of the ED were trained on pain assessment and to use Algoplus® scale (3-same as step 1). To evaluate the intervention, pain assessment and analgesics prescription were compared before and after implementation by 2-sided tests with a type I error set at α = 0.05. RESULTS: The intervention led to systematic pain evaluation with Algoplus® in 100% of patients (≥ 75 years old, n = 434) and was completed by numeric rating scale (NRS) and other evaluations. Pearson's correlation between NRS ≥ 3 and Algoplus® < 2 was 0.61. Prescription of analgesics (+6%) especially opioids increased nonsignificantly but was similar for all patients whatever the evaluation. CONCLUSIONS: The systematic introduction of Algoplus® scale in the ED allowed a change in practice by improving evaluation and management of pain in patients ≥ 75 years old, especially when difficult to be evaluated. Algoplus® allowed an objective levelling of analgesics prescription in all admitted patients. It also promoted field action to improve pain management in ED.