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Background/Aims Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy. Methods We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios. Results Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis. Conclusion The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Venous thromboembolism (VTE) includes the diagnosis of either deep venous thrombosis (DVT) and/or pulmonary embolism (PE). This review discusses an evidence-based approach to the outpatient treatment of VTE in the emergency care setting. Main findings: The majority of patients diagnosed with VTE in the acute care setting are at low risk for an adverse event. Outpatient treatment for patients deemed low-risk by validated clinical decision tools leads to safe, efficacious, patient-centered, and cost-effective care. From a patient perspective, outpatient treatment of VTE can been simplified by the use of direct oral anticoagulant (DOACs) medications, and is supported by clinical trial evidence, and clinical practice guidelines from international societies. Outpatient treatment of patients with DVT has been more widely accepted as a best practice, while adoption of outpatient treatment of low-risk patients with acute PE has lagged. Many acute care clinicians remain wary of discharging patients with PE, concerned about drug access, adherence, and follow-up. Patients with VTE should be risk stratified identically as emerging evidence has demonstrated efficacy and safety in the interdependence of acute care protocols for the outpatient treatment of low-risk DVT and PE. Clinicians who practice in the acute care setting should be comfortable with risk stratification, anticoagulation, and discharge of low-risk VTE.

The use of fibrinolytic agents in acute pulmonary embolism (PE), first described over 50 years ago, hastens the resolution of RV stain, leading to earlier hemodynamic improvement. However, this benefit comes at the increased risk of bleeding. The strongest indication for fibrinolysis is in high-risk PE, or that characterized by sustained hypotension, while its use in patients with intermediate-risk PE remains controversial. Fibrinolysis is generally not recommended for routine use in intermediate-risk PE, although most guidelines advise that it may be considered in patients with signs of acute decompensation and an overall low bleeding risk. The efficacy of fibrinolysis often varies significantly between patients, which may be at least partially explained by several factors found to promote resistance to fibrinolysis. Ultimately, treatment decisions should carefully weigh the risks and benefits of the individual clinical scenario at hand, including the overall severity, the patient's bleeding risk, and the presence of factors known to promote resistance to fibrinolysis. This review aims to further explore the use of fibrinolytic agents in the treatment of PE including specific indications, outcomes, and special considerations.

Background Clinical guidelines have supported outpatient treatment of low-risk pulmonary embolism (PE) since 2014, but adoption of this practice has been slow. Direct oral anticoagulant (DOAC) therapy for venous thromboembolism (VTE) is now as common as vitamin K antagonist treatment, but data are sparse regarding outcomes for patients with low-risk PE treated with DOACs as outpatients. We conducted a systematic review of literature on outcomes of outpatient management for PE, including comparisons to inpatient treatment and differences by anticoagulant class. Methods We searched Medline, Embase, PubMed, CENTRAL, clinicaltrials.gov, and ICTRN for studies published from January 1980 through February 2019 using a predefined strategy developed with a medical librarian. We included English-language randomized controlled trials (RCTs) and prospective nonrandomized trials (NRTs) of adult patients diagnosed with acute, symptomatic PE, and discharged from the emergency department or within 48 hours. Our primary outcome included four major adverse outcomes (all-cause mortality, PE-related mortality, recurrent VTE, and major bleeding) within 30 and 90 days. A preplanned subanalysis of high-quality studies assessed outcomes associated with different anticoagulation treatment classes. Results Our initial search identified 6,818 records, of which 12 studies (four RCT, eight NRT) with a total of 3,191 patients were included in the review. All RCTs and six NRTs were determined to have low to moderate risk of bias and were classified as high quality. Outpatients in these studies (n = 1,814) had rates of 90-day major adverse outcomes below 1%, including all-cause mortality (0.7%, 95% confidence interval [CI] = 0.4% to 1.2%), PE-related mortality (0.06%, 95% CI = 0.01% to 0.3%), recurrent VTE (0.8%, 95% CI = 0.5% to 1.4%), and major bleeding (0.8%, 95% CI = 0.5% to 1.4%). Exploratory analysis revealed no association between anticoagulant treatment class and rates of major adverse outcomes. Conclusion Among patients with low-risk PE treated as outpatients, few patients experienced major adverse outcomes such as mortality, recurrent VTE, or major bleeding within 90 days.

Background Pulmonary embolism (PE) in children carries a significant morbidity and mortality. We examined previously described factors in 2 cohorts of children tested for PE and identified novel factors. Methods We combined data from 2 retrospective cohorts. Patients up to age 21 years were included who underwent imaging or D‐dimer testing for PE, with positive radiologic testing being the gold standard. Combined predictor variables were examined by univariate analysis and then forward stepwise multivariable logistic regression. Results The combined data set yielded 1103 patients with 42 unique predictor variables, and 93 PE‐positive patients (8.4%), with a median age of 16 years. Univariate analysis retained 17 variables, and multivariable logistic regression found 9 significant variables with increased probability of PE diagnosis: age‐adjusted tachycardia, tachypnea, hypoxia, unilateral limb swelling, trauma/surgery requiring hospitalization in previous 4 weeks, prior thromboembolism, cancer, anemia, and leukocytosis. Conclusion This combined data set of children with suspected PE discovered factors that may contribute to a diagnosis of PE: hypoxia, unilateral limb swelling, trauma/surgery requiring hospitalization in previous 4 weeks, prior thromboembolism, and cancer, age‐adjusted tachycardia, tachypnea, anemia, and leukocytosis. Prospective testing is needed to determine which criteria should be used to initiate diagnostic testing for PE in children.

Background The 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 findings We 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. Conclusions The 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.

Acute pulmonary embolism (PE) does not always resolve after treatment and can progress to chronic thromboembolic disease (CTED) or the more severe chronic thromboembolic pulmonary hypertension (CTEPH). The mechanisms surrounding the likelihood of PE resolution or progress to CTED/CTEPH remain largely unknown. We have developed a rat model of CTEPH that closely resembles the human disease in terms of hemodynamics and cardiac manifestations. Embolization of rats with polystyrene microspheres followed by suppression of angiogenesis with the inhibitor of vascular endothelial growth factor receptor 2 (VEGF‐R2) SU5416 results in transient, acute pulmonary hypertension that progresses into chronic PE with PH with sustained right ventricular systolic pressures exceeding 70 mmHg (chronic pulmonary embolism [CPE] model). This model is similar to the widely utilized hypoxia/SU5416 model with the exception that the “first hit” is PE. Rats with CPE have impaired right heart function characterized by reduced VO2Max, reduced cardiac output, and increased Fulton index. None of these metrics are adversely affected by PE alone. Contrast‐mediated CT imaging of lungs from rats with PE minus SU5416 show large increases in pulmonary vascular volume, presumably due to an angiogenic response to acute PE/PH. Co‐treatment with SU5416 suppresses angiogenesis and produces the CTEPH‐like phenotype. We report here that treatment of CPE rats with agonists for soluble guanylate cyclase, a source of cGMP which is in turn a signal for angiogenesis, markedly increases angiogenesis in lungs, and ameliorates the cardiac deficiencies in the CPE model. These results have implications for future development of therapies for human CTEPH., Pulmonary embolism (PE) results increased pulmonary vascular angiogenesis. Blocking endogenous angiogenesis with the vascular endothelial growth factor receptor inhibitor SU5416 causes chronic progressive pulmonary hypertension. Stimulating angiogenesis with the soluble guanylate cyclase agonist cinaciguat or riociguat ameliorates chronic PE/hypertension.

Background: How diagnostic strategies for suspected pulmonary embolism (PE) perform in relevant patient subgroups defined by sex, age, cancer, and previous venous thromboembolism (VTE) is unknown. Purpose: To evaluate the safety and efficiency of the Wells and revised Geneva scores combined with fixed and adapted D-dimer thresholds, as well as the YEARS algorithm, for ruling out acute PE in these subgroups. Data Sources: MEDLINE from 1 January 1995 until 1 January 2021. Study Selection: 16 studies assessing at least 1 diagnostic strategy. Data Extraction: Individual-patient data from 20553 patients. Data Synthesis: Safety was defined as the diagnostic failure rate (the predicted 3-month VTE incidence after exclusion of PE without imaging at baseline). Efficiency was defined as the proportion of individuals classified by the strategy as "PE con -sidered excluded" without imaging tests. Across all strategies, efficiency was highest in patients younger than 40 years (47% to 68%) and lowest in patients aged 80 years or older (6.0% to 23%) or patients with cancer (9.6% to 26%). However, efficiency improved considerably in these subgroups when pretest probabil-ity-dependent D-dimer thresholds were applied. Predicted failure rates were highest for strategies with adapted D-dimer thresh-olds, with failure rates varying between 2% and 4% in the pre-defined patient subgroups. Limitations: Between-study differences in scoring predictor items and D-dimer assays, as well as the presence of differential verifica-tion bias, in particular for classifying fatal events and subsegmental PE cases, all of which may have led to an overestimation of the predicted failure rates of adapted D-dimer thresholds. Conclusion: Overall, all strategies showed acceptable safety, with pretest probability-dependent D-dimer thresholds having not only the highest efficiency but also the highest predicted failure rate. From an efficiency perspective, this individual-patient data meta-analysis supports application of adapted D-dimer thresholds. Primary Funding Source: Dutch Research Council. (PROSPERO: CRD42018089366)

Background: The objective was to test if low-risk emergency department patients with vitamin K antagonist (venous thromboembolism [VTE]; including venous thrombosis and pulmonary embolism [PE]) can be safely and effectively treated at home with direct acting oral (monotherapy) anticoagulation in a large-scale, real-world pragmatic effectiveness trial. Methods: This was a single-arm trial, conducted from 2016 to 2019 in accordance with the Standards for Reporting Implementation Studies guideline in 33 emergency departments in the United States. Participants had newly diagnosed VTE with low risk of death based upon either the modified Hestia criteria, or physician judgment plus the simplified PE severity index score of zero, together with nonhigh bleeding risk were eligible. Patients had to be discharged within 24 hours of triage and treated with either apixaban or rivaroxaban. Effectiveness was defined by the primary efficacy and safety outcomes, image-proven recurrent VTE and bleeding requiring hospitalization >24 hours, respectively, with an upper limit of the 95% CI for the 30-day frequency of VTE recurrence below 2.0% for both outcomes. Results: We enrolled 1421 patients with complete outcomes data, including 903 with venous thrombosis and 518 with PE. The recurrent VTE requiring hospitalization occurred in 14/1421 (1.0% [95% CI, 0.5%–1.7%]), and bleeding requiring hospitalization occurred in 12/1421 (0.8% [0.4%–1.5%). The rate of severe bleeding using International Society for Thrombosis and Haemostasis criteria was 2/1421 (0.1% [0%–0.5%]). No patient died, and serious adverse events occurred in 2.5% of venous thrombosis patients and 2.3% of patients with PE. Medication nonadherence was reported by patients in 8.0% (6.6%–9.5%) and was associated with a risk ratio of 6.0 (2.3–15.2) for VTE recurrence. Among all patients diagnosed with VTE in the emergency department during the period of study, 18% of venous thrombosis patients and 10% of patients with PE were enrolled. Conclusions: Monotherapy treatment of low-risk patients with venous thrombosis or PE in the emergency department setting produced a low rate of bleeding and VTE recurrence, but may be underused. Patients with venous thrombosis and PE should undergo risk-stratification before home treatment. Improved patient adherence may reduce rate of recurrent VTE. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03404635

This paper summarizes the methodology for the registry of suspected COVID‐19 in emergency care (RECOVER), a large clinical registry of patients from 155 United States (US) emergency departments (EDs) in 27 states tested for SARS‐CoV‐2 from March–September 2020. The initial goals are to derive and test: (1) a pretest probability instrument for prediction of SARS‐CoV‐2 test results, and from this instrument, a set of simple criteria to exclude COVID‐19 (the COVID‐19 Rule‐Out Criteria—the CORC rule), and (2) a prognostic instrument for those with COVID‐19. Patient eligibility included any ED patient tested for SARS‐CoV‐2 with a nasal or oropharyngeal swab. Abstracted clinical data included 204 variables representing the earliest manifestation of infection, including week of testing, demographics, symptoms, exposure risk, past medical history, test results, admission status, and outcomes 30 days later. In addition to the primary goals, the registry will provide a vital platform for characterizing the course, epidemiology, clinical features, and prognosis of patients tested for COVID‐19 in the ED setting.

IntroductionIn the USA, many emergency departments (EDs) have established protocols to treat patients with newly diagnosed deep vein thrombosis (DVT) as outpatients. Similar treatment of patients with pulmonary embolism (PE) has been proposed, but no large-scale study has been published to evaluate a comprehensive, integrated protocol that employs monotherapy anticoagulation to treat patients diagnosed with DVT and PE in the ED.Methods and analysisThis protocol describes the implementation of the Monotherapy Anticoagulation To expedite Home treatment of Venous ThromboEmbolism (MATH-VTE) study at 33 hospitals in the USA. The study was designed and executed to meet the requirements for the Standards for Reporting Implementation Studies guideline. The study was funded by investigator-initiated awards from industry, with Indiana University as the sponsor. The study principal investigator and study associates travelled to each site to provide on-site training. The protocol identically screens patients with both DVT or PE to determine low risk of death using either the modified Hestia criteria or physician judgement plus a negative result from the simplified PE severity index. Patients must be discharged from the ED within 24 hours of triage and treated with either apixaban or rivaroxaban. Overall effectiveness is based upon the primary efficacy and safety outcomes of recurrent VTE and bleeding requiring hospitalisation respectively. Target enrolment of 1300 patients was estimated with efficacy success defined as the upper limit of the 95% CI for the 30-day frequency of VTE recurrence below 2.0%. Thirty-three hospitals in 17 states were initiated in 2016–2017.Ethics and disseminationAll sites had Institutional Review Board approval. We anticipate completion of enrolment in June 2020; study data will be available after peer-reviewed publication. MATH-VTE will provide information from a large multicentre sample of US patients about the efficacy and safety of home treatment of VTE with monotherapy anticoagulation.

Pulmonary embolism (PE) is a common, potentially life-threatening yet treatable condition. Prompt diagnosis and expeditious therapeutic intervention is of paramount importance for optimal patient management. Our objective was to systematically review the accuracy of D-dimer assay, compression ultrasonography (CUS), computed tomography pulmonary angiography (CTPA), and ventilation-perfusion (V/Q) scanning for the diagnosis of suspected first and recurrent PE. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. 2 investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 61 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.97 (95% confidence interval [CI], 0.96-0.98) and 0.41 (95% CI, 0.36-0.46) respectively, whereas CTPA sensitivity and specificity were 0.94 (95% CI, 0.89-0.97) and 0.98 (95% CI, 0.97-0.99), respectively, and CUS sensitivity and specificity were 0.49 (95% CI, 0.31-0.66) and 0.96 (95% CI, 0.95-0.98), respectively. Three variations of pooled estimates for sensitivity and specificity of V/Q scan were carried out, based on interpretation of test results. D-dimer had the highest sensitivity when compared with imaging. CTPA and V/Q scans (high probability scan as a positive and low/non-diagnostic/normal scan as negative) both had the highest specificity. This systematic review was registered on PROSPERO as CRD42018084669.

Prompt evaluation and therapeutic intervention of suspected pulmonary embolism (PE) are of paramount importance for improvement in outcomes. We systematically reviewed outcomes in patients with suspected PE, including mortality, incidence of recurrent PE, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. We included 22 studies with 15 865 patients. Among patients who were diagnosed with PE and discharged with anticoagulation, 3-month follow-up revealed that all-cause mortality was 5.69% (91/1599; 95% confidence interval [CI], 4.56-6.83), mortality from PE was 1.19% (19/1597; 95% CI, 0.66-1.72), recurrent venous thromboembolism (VTE) occurred in 1.38% (22/1597; 95% CI: 0.81-1.95), and major bleeding occurred in 0.90% (2/221%; 95% CI, 0-2.15). In patients with a low pretest probability (PTP) and negative D-dimer, 3-month follow-up revealed mortality from PE was 0% (0/808) and incidence of VTE was 0.37% (4/1094; 95% CI: 0.007-0.72). In patients with intermediate PTP and negative D-dimer, 3-month follow-up revealed that mortality from PE was 0% (0/2747) and incidence of VTE was 0.46% (14/3015; 95% CI: 0.22-0.71). In patients with high PTP and negative computed tomography (CT) scan, 3-month follow-up revealed mortality from PE was 0% (0/651) and incidence of VTE was 0.84% (11/1302; 95% CI: 0.35-1.34). We further summarize outcomes evaluated by various diagnostic tests and diagnostic pathways (ie, D-dimer followed by CT scan).

Acute pulmonary embolism is the third most common cause of cardiovascular death. Pulmonary embolism increases right ventricularafterload, which causes right ventricular failure, circulatory collapse and death. Most treatments focus on removal of themechanical obstruction caused by the embolism, but pulmonary vasoconstriction is a significant contributor to the increased rightventricular afterload and is often left untreated. Pulmonary thromboembolism causes mechanical obstruction of the pulmonaryvasculature coupled with a complex interaction between humoral factors from the activated platelets, endothelial effects, reflexesand hypoxia to cause pulmonary vasoconstriction that worsens right ventricular afterload. Vasoconstrictors include serotonin,thromboxane, prostaglandins and endothelins, counterbalanced by vasodilators such as nitric oxide and prostacyclins. Exogenousadministration of pulmonary vasodilators in acute pulmonary embolism seems attractive but all come with a risk of systemicvasodilation or worsening of pulmonary ventilation-perfusion mismatch. In animal models of acute pulmonary embolism, modulatorsof the nitric oxide-cyclic guanosine monophosphate-protein kinase G pathway, endothelin pathway and prostaglandinpathway have been investigated. But only a small number of clinical case reports and prospective clinical trials exist. The aim ofthis review is to give an overview of the causes of pulmonary embolism-induced pulmonary vasoconstriction and of experimentaland human investigations of pulmonary vasodilation in acute pulmonary embolism.

Thrombolytic agents have a long history of use in the treatment of thrombotic disorders including myocardial infarction and stroke, with their specific use in pulmonary embolism first reported over 50 years ago. All clinically available thrombolytic agents activate native plasminogen to plasmin, which hydrolyzes fibrin. Systemic fibrinolysis accelerates clot lysis, hastening the resolution of RV strain from acute PE and resulting in a reduced probability of shock in the short term but without clear mortality benefit. Systemic fibrinolysis increases the risk of bleeding, which can be life-threatening. The efficacy of fibrinolysis and bleeding risk can vary significantly between patients, depending upon concentrations and activities of fibrinolysis inhibitors such as plasminogen activator inhibitor-1 and antiplasmin. Guidelines generally agree that the benefit of thrombolysis outweighs the risk in patients with sustained hypotension –termed “high-risk” PE. Systemic thrombolysis is not recommended for routine use in “intermediate-risk” PE, although it may be considered in cases with a higher risk of acute decompensation, evidenced by high-circulating levels of troponin together with right ventricular dilation observed on computed tomography or echocardiography. More research is needed to further elucidate which patients in this largely heterogeneous “intermediate-risk” category are most likely to benefit from thrombolytic therapy.

Background: No recent data have investigated rates of diagnostic testing for pulmonary embolism (PE) in US emergency departments (EDs), and no data have examined computed tomographic pulmonary angiography (CTPA) rates in subgroups at high risk for adverse imaging outcomes, including young women and children. We hypothesized that over-testing for PE remains a problem. Methods and Results: We used electronic health record and billing data for 16 EDs in Indiana and 11 hospitals in the Dallas-Fort Worth area from 2016 to 2019 to locate ED patients who had any of the following: D-dimer, CTPA, scintillation ventilation perfusion lung scanning or formal pulmonary angiography. The primary outcomes were ED encounter volume-adjusted CTPA rate, PE yield rate with subgroup reporting for children (2 =0.43; P Conclusions: Over-testing for PE in American EDs remains a major public health problem. Centers with higher D-dimer ordering had higher yield of PE on CTPA. These data suggest the potential for implementation of D-dimer based protocols to reduce low-yield CTPA ordering.

Objective To derive and validate a D-dimer cutoff for ruling out pulmonary embolism (PE) in COVID-19 patients presenting to the emergency department (ED). Methods A retrospective cohort study was performed in an integrated healthcare system including 22 adult ED's between March 1, 2020, and January 31, 2021. Results were validated among patients enrolled in the RECOVER Registry, representing data from 154 ED's from 26 US states. Consecutive ED patients with laboratory confirmed COVID-19, a D-dimer performed within 48 h of ED arrival, and with objectively confirmed PE were compared to those without PE. After identifying a D-dimer threshold at which the 95% confidence lower bound of the negative predictive value for PE was higher than 98% in the derivation cohort, it was validated using RECOVER registry data. Results Among 3978 patients with a D-dimer result, 3583 with confirmed COVID-19 infection were included in the derivation cohort. Overall, PE incidence was 4.1% and a D-dimer cutoff of Conclusion A D-dimer cutoff of

Recommended strategy for venous thromboembolism (VTE) diagnosis includes the use of sensitive D-dimer (DDi) assays along with pretest probability (PTP) assessment. The Clinical and Laboratory Standards Institute (CLSI) recently issued a guideline (US FDA endorsed) on DDi in VTE exclusion. Such guideline specifies the ideal D-dimer assay characteristics and target population. Demonstrate STA-LiatestD-Di performance combined with a PTP score for proximal deep vein thrombosis (pDVT) exclusion in a CLSI compliant study. International, multicenter, prospective nonrandomized, noninterventional clinical outcome management study conducted in a standard-of-care setting. DDi was measured in DVT-suspected consecutive low/moderate PTP outpatients, without conditions possibly impacting DDi values independently of thrombosis presence (age >80, pregnancy, postoperative, cancer) using a 0.5 μg/ml (FEU) threshold for DVT exclusion. Results were used to determine test performance. One thousand two hundred and thirty-four patients (17 centers) signed informed consent. Nine hundred and eighty (mean age: 55) with valid results (494 negative DDi) completed the study (DVT prevalence: 8.7%). STA-LiatestD-Di performance exceeded CLSI/FDA requirements: sensitivity: 100% (95% CI 95.8-100%), NPV: 100% (95% CI 99.3-100%). STA-LiatestD-Di associated with PTP score showed excellent performance for pDVT exclusion, as recently demonstrated for pulmonary embolism. The assay allows safe VTE exclusion, avoiding unnecessary imaging tests.

Background Metabolic syndrome (MetS) has been associated with a procoagulant and hypofibrinolytic state. Current data exploring the role of MetS in venous thromboembolism (VTE) are limited. The objective was to measure the prevalence of MetS in patients with acute PE receiving catheter-directed thrombolysis (CDT) and to investigate its effect on mean pulmonary arterial pressure and overall treatment success. Methods We used a 3-year prospective registry of ED patients with acute PE with severity qualifying for activation of a PE response team (PERT). All patients had CDT with catheter-measured mPAP and angiography. The presence or absence of MetS components were extracted from chart review based on the following criteria: 1. body mass index (BMI) > 30 kg/m2; 2. diagnosed hypertension; 3. diabetes mellitus (including HbA1c > 6.5%) and; 4. dyslipidemia (including triglycerides > 150 mg/dL or high-density lipoprotein Results Of the 134 patients, 85% met the criteria for at least one of four MetS components, with obesity being most common, present in 71%. Results demonstrated a positive concordance between the number of criteria for MetS and MPAP, both pre- and post-fibrinolysis, as pressures tended to increase with each additional MetS criterion. Multivariate regression analysis determined age (-), BMI (+) and hypertension (+) to be significant independent predictor variables for mPAP. Conclusions MetS was common in patients with more severe manifestations of PE and was associated with higher mPAP values both at diagnosis and following treatment with CDT.

Background The pulmonary embolism rule out criteria (PERC) reliably predicts a low probability of PE in adults. We examine the diagnostic accuracy of the objective components of the PERC rule in children previously tested for PE. Methods Children aged 5–17 who had a D-dimer or pulmonary vascular imaging ordered from 2004 to 2014 in a large multicenter hospital network were identified by query of administrative databases. Using explicit, predefined methods, trained abstracters selected charts of children clearly tested for PE, collected the 8 objective variables for PERC, and determined PE criterion standard status (image or autopsy confirmed PE or deep vein thrombosis within 30 days by query of the Indiana Network for Patient Care (INPC)). Results We identified 543 patients, including 56 (10.3%, 95% CI: 7.8–13.1%) who were PE+, with a mean and median age of 15 years. All 8 objective criteria from PERC were negative in 170 patients (31%), including one with PE (false negative rate 0.6%, 0–3.2%). Diagnostic sensitivity and specificity were 98.2% (90.5–100%), and 34.7 (30.5–39.1%), respectively, leading to a likelihood ratio negative = 0.05 (0.1–0.27). When treated as a diagnostic test based upon sum of criteria positive, PERC had good discrimination between PE+ vs PE− with an area under receiver operating characteristic curve 0.81 (0.75–0.86). Conclusions In this sample of children and teenagers with suspected PE, the PERC rule was negative in 31%, and demonstrated good overall diagnostic accuracy, including a low false negative rate. These data support the need for a large, prospective diagnostic validation study of PERC in children.

International audience; Background: Diagnosing pulmonary embolism in suspected patients is notoriously difficult as signs and symptoms are non-specific. Different diagnostic strategies have been developed, usually combining clinical probability assessment with D-dimer testing. However, their predictive performance differs across different healthcare settings, patient subgroups, and clinical presentation, which are currently not accounted for in the available diagnostic approaches.Methods: This is a protocol for a large diagnostic individual patient data meta-analysis (IPDMA) of currently available diagnostic studies in the field of pulmonary embolism. We searched MEDLINE (search date January 1, 1995, till August 25, 2016) to retrieve all primary diagnostic studies that had evaluated diagnostic strategies for pulmonary embolism. Two authors independently screened titles, abstracts, and subsequently full-text articles for eligibility from 3145 individual studies. A total of 40 studies were deemed eligible for inclusion into our IPDMA set, and principal investigators from these studies were invited to participate in a meeting at the 2017 conference from the International Society on Thrombosis and Haemostasis. All authors agreed on data sharing and participation into this project. The process of data collection of available datasets as well as potential identification of additional new datasets based upon personal contacts and an updated search will be finalized early 2018. The aim is to evaluate diagnostic strategies across three research domains: (i) the optimal diagnostic approach for different healthcare settings, (ii) influence of comorbidity on the predictive performance of each diagnostic strategy, and (iii) optimize and tailor the efficiency and safety of ruling out PE across a broad spectrum of patients with a new, patient-tailored clinical decision model that combines clinical items with quantitative D-dimer testing.Discussion: This pre-planned individual patient data meta-analysis aims to contribute in resolving remaining diagnostic challenges of time-efficient diagnosis of pulmonary embolism by tailoring available diagnostic strategies for different healthcare settings and comorbidity.Systematic review registration: Prospero trial registration: ID 89366.

Background Hospitalization for low‐risk pulmonary embolism (PE) is common, expensive, and of questionable benefit. Objective The objective was to determine if low‐risk PE patients discharged from the emergency department (ED) on rivaroxaban require fewer hospital days compared to standard of care (SOC). Methods Multicenter, open‐label randomized trial in low‐risk PE defined by Hestia criteria. Adult subjects were randomized to early ED discharge on rivaroxaban or SOC. Primary outcome was total number of initial hospital hours, plus hours of hospitalization for bleeding or venous thromboembolism (VTE), 30 days after randomization. A 90‐day composite safety endpoint was defined as major bleeding, clinically relevant nonmajor bleeding, and mortality. Results Of 114 randomized subjects, 51 were early discharge and 63 were SOC. Of 112 (98.2%) receiving at least one dose of study drug, 99 (86.8%) completed the study. Initial hospital LOS was 4.8 hours versus 33.6 hours, with a mean difference of –28.8 hours (95% confidence interval [CI] = –42.55 to –15.12 hours) for early discharge versus SOC, respectively. At 90 days, mean total hospital days (for any reason) were less for early discharge than SOC, 19.2 hours versus 43.2 hours, with a mean difference of 26.4 hours (95% CI = –46.97 to –3.34 hours). At 90 days, there were no bleeding events, recurrent VTE, or deaths. The composite safety endpoint was similar in both groups, with a difference in proportions of 0.005 (95% CI = –0.18 to 0.19). Total costs were $1,496 for early discharge and $4,234 for SOC, with a median difference of $2,496 (95% CI = –$2,999 to –$2,151). Conclusions Low‐risk ED PE patients receiving early discharge on rivaroxaban have similar outcomes to SOC, but fewer total hospital days and lower costs over 30 days.

BACKGROUND This systematic review addresses the controversy over the decision to anticoagulate patients with subsegmental pulmonary embolism (SSPE). METHODS We searched Ovid MEDLINE, PubMed, Embase, the Cochrane Library, Scopus, Web of Science, ClinicalTrials.gov, Google Scholar, and bibliographies in March 2017. Two authors reviewed and retained papers with symptomatic patients who underwent computerized tomographic pulmonary angiography and had sufficient information to determine SSPE; decision to treat (or not) with systemic anticoagulation; and outcomes of bleeding, venous thromboembolism (VTE) recurrence, and death. Papers were assessed for selection and publication bias and heterogeneity, with Eggers and the inconsistency indexes (I2 ). RESULTS From 1,512 papers screened, we included 14 studies comprising 15,563 patients for full-length review and analysis. Pooled data demonstrated I2 = 99% with an Eggers p

Failure to test for pulmonary embolism (PE) can be a lethal mistake, but PE and produces symptoms similar to many other diseases. Overtesting for PE has negative consequences.Use published evidence to create a rationale and safe diagnostic approach for ambulatory and emergency patients with suspected PE in 2017.Pulmonary embolism need not be pursued in patients with no symptoms of PE in the present or recent history (dyspnea, chest pain, cough or syncope), and always normal vital signs. When clinicians have a low clinical suspicion for PE or a Wells score2, they can reasonably exclude PE with the Pulmonary Embolism Rule out Criteria (PERC rule). For patients with a "PE-unlikely" pretest probability (Wells or simplified revised Geneva score5), PE can be ruled out with a normal or age-adjusted D-dimer concentrations. Other patients should undergo pulmonary vascular imaging, and the choices are discussed, including computerized tomographic pulmonary angiography, planar and single-photon emission computed tomography (SPECT).A thoughtful algorithm for PE exclusion and diagnosis requires pretest probability assessment in all patients, followed by selective use of clinical criteria, the quantitative D-dimer, and pulmonary vascular imaging.

Author(s): Akhter, Murtaza; Kline, Jeffrey; Bhattarai, Bikash; Courtney, Mark; Kabrhel, Christopher | Abstract: Introduction: The American College of Emergency Physicians guidelines recommend more aggressive workup beyond imaging alone in patients with a high pretest probability (PTP) of pulmonary embolism (PE). However, the ability of multiple tests to safely rule out PE in high PTP patients is not known. We sought to measure the ability of negative computed tomography pulmonary angiography (CTPA) along with negative D-dimer to rule out PE in these high-risk patients.Methods: We analyzed data from a previous prospective observational study conducted in 12 emergency departments (ED). Wells score criteria were entered by providers before final PE testing. PE was diagnosed by imaging on the index ED visit, or within 45 days, demonstrating either PE ordeep vein thrombosis (DVT), or if the patient died of PE during the 45-day, follow-up period. Testing threshold was set at 1.8%.Results: A total of 7,940 patients were enrolled and tested for PE, and 257 had high PTP (Wells g6). Sixteen of these high-risk patients had negative CTPA and negative D-dimer, of whom two were positive for PE (12.5% [95% confidence interval 2.2%-40.0%]). One of these patients had a DVT on CT venogram and the other was diagnosed at follow-up.Conclusion: Our analysis suggests that in patients with high PTP of PE, neither negative CTPA by itself nor a negative CTPA plus a negative D-dimer are sufficient to rule out PE. More aggressive workup strategies may be required for these patients.

Background The inflammatory response associated with acute pulmonary embolism (PE) contributes to the development of right ventricular (RV) dysfunction. Nonsteroidal anti-inflammatory drugs (NSAIDs) may facilitate the reversal of PE-associated RV dysfunction. Methods We randomly assigned normotensive patients who had acute PE associated with echocardiographic RV dysfunction and normal systemic blood pressure to receive intravenous (IV) diclofenac (two doses of 75 mg in the first 24 h after diagnosis) or IV placebo. All patients received standard anticoagulation with subcutaneous low-molecular-weight heparin (LMWH) and an oral vitamin K antagonist. RV dysfunction was defined by the presence of, at least, two of the following criteria: i) RV diastolic diameter > 30 mm in the parasternal window; ii) RV diameter > left ventricle diameter in the apical or subcostal space; iii) RV free wall hypokinesis; and iv) estimated pulmonary artery systolic pressure > 30 mm Hg. Persistence of RV dysfunction at 48 h and 7 days after randomization were the primary and secondary efficacy outcomes, respectively. The primary safety outcome was major bleeding within 7 days after randomization. Results Of the 34 patients randomly assigned to diclofenac or placebo, the intention-to-treat analysis showed persistent RV dysfunction at 48 h in 59% (95% confidence interval [CI], 33–82%) of the diclofenac group and in 76% (95% CI, 50–93%) of the placebo group (difference in risk [diclofenac minus standard anticoagulation], − 17 percentage points; 95% CI, − 47 to 17). Similar proportions (35%) of patients in the diclofenac and placebo groups had persistent RV dysfunction at 7 days. Major bleeding occurred in none of patients in the diclofenac group and in 5.9% (95% CI, 0.2–29%) of patient in the placebo group. Conclusions Due to slow recruitment, our study is inconclusive as to a potential benefit of diclofenac over placebo to reverse RV dysfunction in normotensive patients with acute PE. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01590342 .

Key Points Question Can a pretest probability score make it possible to rule out pulmonary embolism solely on clinical criteria and optimized D-dimer measurement to safely decrease imaging testing? Findings In this study, the 4-Level Pulmonary Embolism Clinical Probability Score (4PEPS) was derived and validated using databases from 3 merged management studies. The safety and the efficacy of the 4PEPS strategy was confirmed in 2 external validation cohorts (false-negative rates: 0.71% and 0.89%; absolute reductions in imaging testing: −19% and −22%, respectively). Meaning The 4PEPS strategy may lead to a substantial and safe reduction in imaging testing for patients with suspected pulmonary embolism., This study derives and validates a 4-level pretest probability rule that makes it possible to rule out pulmonary embolism solely on clinical criteria and optimized D-dimer measurement to safely decrease imaging testing for suspected pulmonary embolism., Importance In patients with suspected pulmonary embolism (PE), overuse of diagnostic imaging is an important point of concern. Objective To derive and validate a 4-level pretest probability rule (4-Level Pulmonary Embolism Clinical Probability Score [4PEPS]) that makes it possible to rule out PE solely on clinical criteria and optimized D-dimer measurement to safely decrease imaging testing for suspected PE. Design, Setting, and Participants This study included consecutive outpatients suspected of having PE from US and European emergency departments. Individual data from 3 merged management studies (n = 11 114; overall prevalence of PE, 11%) were used for the derivation cohort and internal validation cohort. The external validation cohorts were taken from 2 independent studies, the first with a high PE prevalence (n = 1548; prevalence, 21.5%) and the second with a moderate PE prevalence (n = 1669; prevalence, 11.7%). A prior definition of pretest probability target values to achieve a posttest probability less than 2% was used on the basis of the negative likelihood ratios of D-dimer. Data were collected from January 2003 to April 2016, and data were analyzed from June 2018 to August 2019. Main Outcomes and Measures The rate of PE diagnosed during the initial workup or during follow-up and the rate of imaging testing. Results Of the 5588 patients in the derivation cohort, 3441 (61.8%) were female, and the mean (SD) age was 52 (18.5) years. The 4PEPS comprises 13 clinical variables scored from −2 to 5. It results in the following strategy: (1) very low probability of PE if 4PEPS is less than 0: PE ruled out without testing; (2) low probability of PE if 4PEPS is 0 to 5: PE ruled out if D-dimer level is less than 1.0 μg/mL; (3) moderate probability of PE if 4PEPS is 6 to 12: PE ruled out if D-dimer level is less than the age-adjusted cutoff value; (4) high probability of PE if 4PEPS is greater than 12: PE ruled out by imaging without preceding D-dimer test. In the first and the second external validation cohorts, the area under the receiver operator characteristic curves were 0.79 (95% CI, 0.76 to 0.82) and 0.78 (95% CI, 0.74 to 0.81), respectively. The false-negative testing rates if the 4PEPS strategy had been applied were 0.71% (95% CI, 0.37 to 1.23) and 0.89% (95% CI, 0.53 to 1.49), respectively. The absolute reductions in imaging testing were −22% (95% CI, −26 to −19) and −19% (95% CI, −22 to −16) in the first and second external validation cohorts, respectively. The 4PEPS strategy compared favorably with all recent strategies in terms of imaging testing. Conclusions and Relevance The 4PEPS strategy may lead to a substantial and safe reduction in imaging testing for patients with suspected PE. It should now be tested in a formal outcome study.

Changes in systemic redox balance can alter platelet activation and aggregation. Acute pulmonary embolism (PE) is a systematic inflammatory disease associated with mechanical shear stress, increased thrombin, catecholamines, serotonin and hemolysis, which cumulatively can hyperactivate platelets and accelerate their turnover. We tested the hypothesis that platelets from patients with moderately severe PE will show hyperstimulation and a pre-apoptotic phenotype associated with microparticles (MPs) in plasma. Blood for platelet respiration and thromboelastography (TEG) was obtained at diagnosis and 24h later from patients (n=76) with image-proven PE, SBP>90mmHg and right ventricular dysfunction demonstrated by echocardiogram or elevated biomarkers. Controls (n=12) were healthy volunteers. At diagnosis, platelets from PE patients had significantly elevated baseline oxygen consumption compared with controls, explained primarily by accelerated electron transport and oxygen wasting with no measurable extramitochondrial oxygen consumption. On thromboelastography, unstimulated thrombin-independent maximum amplitude was increased with PE, 19±14.1 vs.10.5±7.8mm in controls (p=0.002). Compared with controls, platelets from PE patients showed elevated mitochondrial reactive oxygen species with decreased mitochondrial Bcl-2 protein content and increased cytosolic cytochrome C, coincident with strong annexin V binding, P selectin release from lysed platelets and in plasma MPs compared to controls (p

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor–dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.

The study hypothesis is that administration of inhaled nitric oxide (NO) plus oxygen to subjects with submassive pulmonary embolism (PE) will improve right ventricular (RV) systolic function and reduce RV strain and necrosis, while improving patient dyspnea, more than treatment with oxygen alone.This article describes the rationale and protocol for a registered (NCT01939301), nearly completed phase II, 3-center, randomized, double-blind, controlled trial. Eligible patients have pulmonary imaging-proven acute PE. Subjects must be normotensive, and have RV dysfunction on echocardiography or elevated troponin or brain natriuretic peptide and no fibrinolytics. Subjects receive NO plus oxygen or placebo for 24 hours (±3 hours) with blood sampling before and after treatment, and mandatory echocardiography and high-sensitivity troponin posttreatment to assess the composite primary end point. The sample size of N=78 was predicated on 30% more NO-treated patients having a normal high-sensitivity troponin (14 pg/mL) and a normal RV on echocardiography at 24 hours with α=.05 and β=.20. Safety was ensured by continuous spectrophotometric monitoring of percentage of methemoglobinemia and a predefined protocol to respond to emergent changes in condition. Blinding was ensured by identical tanks, software, and physical shielding of the device display and query of the clinical care team to assess blinding efficacy.We have enrolled 78 patients over a 31-month period. No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event related to NO.We present methods and a protocol for the first double-blinded, randomized trial of inhaled NO to treat PE.

Background In pulmonary embolism (PE) suspicion, several strategies based on clinical criteria and D-dimer (Dd) measurement have been developed in order to reduce resource utilization. However, they used different clinical probability (CP) assessment methods limiting their combination. Purpose To develop and validate a unique probability score integrating most of previous proposals to allow safely reduction of imaging testing. Methods 4 CP levels were previously defined in order to obtain a false negative rate Results PEPS comprised 13 variables: age Derivation Int. validation Ext. validation 1 Ext. validation 2 nPE/N % [95% CI] nPE/N % [95% CI] nPE/N % [95% CI] nPE/N % [95% CI] TOTAL 615/5588: 11.0% [10.2–11.9] 432/3726: 11.6% [10.6–12.7] 327/1546: 21.2% [19.2–23.2] 196/1669: 11.7% [10.3–13.4] Very low CP PEPS Conclusions A strategy based on the proposed score may lead to a safely substantial reduction of imaging testing. It should now be tested in an outcome interventional study.

OBJECTIVE: To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. METHODS: This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 hours. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration

BackgroundWe sought to measure the diagnostic accuracy of D-dimer in children with suspected pulmonary embolism (PE).MethodsWe queried our electronic medical record for quantitative D-dimer values obtained in all children ages 5–17 over 10 years in our 10-hospital system. Patients who had a D-dimer obtained in the evaluation of PE underwent supervised chart review to extract baseline demographics (age, sex, ethnicity), medical history, laboratory data and imaging results. PE was confirmed by imaging positive for deep vein thrombosis (DVT) or PE and excluded by imaging or no DVT or PE diagnosis within 90 days.ResultsOver a 10-year period, we identified 13 792 orders for D-dimer testing in 2554 unique patients. Chart review indicated that 526 (20.6%) unique patients had D-dimer testing performed in the evaluation of PE (Cohen’s kappa=0.95, 95% CI 0.85 to 1.0). Most D-dimers (465/526, 88%) were ordered in children aged >12 years. Of these 526 children, 34 (6.4%, 95% CI) had a criterion standard positive for new or recurrent PE. The mean D-dimer value was 2104±1394 ng/mL in the 34/34 PE+ children and 586±962 ng/mL in PE− children with a sensitivity of 34/34 (100%, 89% to 100%) and a specificity of 290/492 (58%, 54% to 63%). The area under the receiver operating characteristic curve was 0.90 ((0.9)87–0.94).ConclusionsD-dimer is currently ordered in children for suspected PE in the emergency care setting, mostly in teenagers. The observed lower limit 95% CIs of 89% and 54% for diagnostic sensitivity and the specificity, respectively, suggest if used in patients with low-clinical probability, a normal D-dimer can safely exclude PE in children.

Background: Modern diagnostic strategies for venous thromboembolism (VTE) incorporate pretest probability (PTP; prevalence) assessment. The ability of diagnostic tests to correctly identify or exclude VTE is influenced by VTE prevalence and test accuracy characteristics. Objective: These evidence-based guidelines are intended to support patients, clinicians, and health care professionals in VTE diagnosis. Diagnostic strategies were evaluated for pulmonary embolism (PE), deep vein thrombosis (DVT) of the lower and upper extremity, and recurrent VTE. Methods: The American Society of Hematology (ASH) formed a multidisciplinary panel including patient representatives. The McMaster University GRADE Centre completed systematic reviews up to 1 October 2017. The panel prioritized questions and outcomes and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations. Test accuracy estimates and VTE population prevalence were used to model expected outcomes in diagnostic pathways. Where modeling was not feasible, management and accuracy studies were used to formulate recommendations. Results: Ten recommendations are presented, by PTP for patients with suspected PE and lower extremity DVT, and for recurrent VTE and upper extremity DVT. Conclusions: For patients at low (unlikely) VTE risk, using D-dimer as the initial test reduces the need for diagnostic imaging. For patients at high (likely) VTE risk, imaging is warranted. For PE diagnosis, ventilation-perfusion scanning and computed tomography pulmonary angiography are the most validated tests, whereas lower or upper extremity DVT diagnosis uses ultrasonography. Research is needed on new diagnostic modalities and to validate clinical decision rules for patients with suspected recurrent VTE.

Long-term right ventricular (RV) function, functional capacity, exercise capacity, and quality of life following pulmonary embolism (PE), and the impact of thrombolysis, are unclear. A systematic review of studies that evaluated these outcomes with ⩾ 3-month mean follow-up after PE diagnosis was performed. For each outcome, random effects meta-analyses were performed. Twenty-six studies (3671 patients) with 18-month median follow-up were included. The pooled prevalence of RV dysfunction was 18.1%. Patients treated with thrombolysis had a lower, but not statistically significant, risk of RV dysfunction versus those treated with anticoagulation (odds ratio: 0.51, 95% CI: 0.24 to 1.13, p=0.10). Pooled prevalence of at least mild functional impairment (NYHA II–IV) was 33.2%, and at least moderate functional impairment (NYHA III–IV) was 11.3%. Patients treated with thrombolysis had a lower, but not statistically significant, risk of at least moderate functional impairment versus those treated with anticoagulation (odds ratio: 0.48, 95% CI: 0.15 to 1.49, p=0.20). Pooled 6-minute walk distance was 415 m (95% CI: 372 to 458 m), SF-36 Physical Component Score was 44.8 (95% CI: 43 to 46), and Pulmonary Embolism Quality of Life (QoL) Questionnaire total score was 9.1. Main limitations included heterogeneity among studies for many outcomes, variation in the completeness of data reported, and inclusion of data from non-randomized, non-controlled, and retrospective studies. Persistent RV dysfunction, impaired functional status, diminished exercise capacity, and reduced QoL are common in PE survivors. The effect of thrombolysis on RV function and functional status remains unclear.

Background Many clinicians use a global visual interpretation of patient appearance to decide if a patient looks sick or not. For patients with suspected acute pulmonary embolism (PE), we tested the relationship between visual appearance of a happy patient facial affect and probability of PE+ on CT pulmonary angiography (CTPA). Methods Eligible patients were selected by usual care to undergo CTPA, the criterion standard for PE+ or PE−. Prior to CTPA result, trained study personnel obtained physician pretest probability using the gestalt method (visual analogue scale, 0%–100%), the Wells score (0–12) and physicians’ impression of whether the patient smiled during the initial examination (smile+). Patients9 faces were also video recorded and analysed with an automated neural network-based algorithm (Noldus FaceReader) for happy affect. Results Of the 208 patients enrolled, 27 were PE+ and smile+ was more frequent in patients with PE+ than PE−, a finding confirmed by the Noldus. The diagnostic sensitivity and specificity of smile was low, and physicians overestimated presence of an alternative diagnosis more likely to PE with smile+ than smile− patients in patients with true PE. As a result, the area under the receiver operating characteristic curve (AUROC) was lower for the Wells score in smile+ patients. However, the physicians’ mean gestalt estimate of PE did not differ with smile status, nor did smile status affect the AUROC for gestalt. Conclusions In patients with suspected PE, physician recollection of patients’ smile+ was more common in PE+ patients, and was associated with a less accurate Wells score, primarily because physicians overestimated probability of alternative diagnosis. However, the overall diagnostic accuracy of physicians’ gestalt did not differ with perceived smile status. These data suggest that the patients’ smile had less effect on the numeric gestalt pretest probability assessment than on the binary decision about an alternative diagnosis.

Essentials When high probability of pulmonary embolism (PE), sensitivity of computed tomography (CT) is unclear. We investigated the sensitivity of multidetector CT among 134 patients with a high probability of PE. A normal CT alone may not safely exclude PE in patients with a high clinical pretest probability. In patients with no clear alternative diagnosis after CTPA, further testing should be strongly considered. Summary Background Whether patients with a negative multidetector computed tomographic pulmonary angiography (CTPA) result and a high clinical pretest probability of pulmonary embolism (PE) should be further investigated is controversial. Methods This was a prospective investigation of the sensitivity of multidetector CTPA among patients with a priori clinical assessment of a high probability of PE according to the Wells criteria. Among patients with a negative CTPA result, the diagnosis of PE required at least one of the following conditions: ventilation/perfusion lung scan showing a high probability of PE in a patient with no history of PE, abnormal findings on venous ultrasonography in a patient without previous deep vein thrombosis at that site, or the occurrence of venous thromboembolism (VTE) in a 3-month follow-up period after anticoagulation was withheld because of a negative multidetector CTPA result. Results We identified 498 patients with a priori clinical assessment of a high probability of PE and a completed CTPA study. CTPA excluded PE in 134 patients; in these patients, the pooled incidence of VTE was 5.2% (seven of 134 patients; 95% confidence interval [CI] 1.5–9.0). Five patients had VTEs that were confirmed by an additional imaging test despite a negative CTPA result (five of 48 patients; 10.4%; 95% CI 1.8–19.1), and two patients had objectively confirmed VTEs that occurred during clinical follow-up of at least 3 months (two of 86 patients; 2.3%; 95% CI 0–5.5). None of the patients had a fatal PE during follow-up. Conclusions A normal multidetector CTPA result alone may not safely exclude PE in patients with a high clinical pretest probability.

Objectives Outpatient treatment of acute venous thromboembolism (VTE) requires the selection of patients with a low risk of bleeding during the first few weeks of anticoagulation. The accuracy of four systems, originally derived for predicting bleeding in VTE treated with vitamin K antagonists (VKAs), was assessed in VTE patients treated with rivaroxaban. Methods All patients treated with rivaroxaban in the multinational EINSTEIN deep vein thrombosis (DVT) and pulmonary embolism (PE) trials were included. Major bleeding was defined as ≥2 g/dL drop in hemoglobin or ≥2-unit blood transfusion, bleeding in critical area, or bleeding contributing to death. The authors examined the incidence of major bleeding in patients with low-risk assignment by the systems of Ruiz-Gimenez et al. (score = 0 to 1), Beyth et al. (score = 0), Kuijer et al. (score = 0), and Landefeld and Goldman. (score = 0). For clinical relevance, the definition of low risk for all scores except Kuijer includes all patients

Statin therapy appears to reduce incidence of venous thromboembolism in secondary analyses of non-venous thromboembolism trials, but no evidence has shown effect of statins in large population samples. The objective of this study was to examine the magnitude of the effect of statin therapy on venous thromboembolism recurrence across a large statewide population.This was a retrospective analysis of the Indiana Network for Patient Care database. All patients with an International Classification of Diseases-defined diagnosis of either deep vein thrombosis or pulmonary embolism from 2004-2017 were included. We collected Generic Product Identifier codes to determine whether patients had been prescribed a statin medication and divided patients into 2 groups: + or - statin. We then performed a propensity-matching analysis to balance covariates and created a final logistic regression model with statin use as the predictor variable and venous thromboembolism recurrence as the dependent variable.This study included a total of 192,908 patients with documented statin use in 13.5%. Venous thromboembolism recurrence occurred in 16% of all patients over the study period. After propensity matching, patients not on a statin were found to have significantly higher rates of venous thromboembolism recurrence (20% vs 16%, P.0001). Logistic regression yielded an odds ratio of 0.75 (95% confidence interval, 0.72-0.79) for venous thromboembolism recurrence for those on statin therapy.We found that a statin prescription reduced risk of venous thromboembolism recurrence by approximately 25% after adjusting for risk factors, supporting the adjunctive role of statins in the prevention of venous thromboembolism recurrence.

BACKGROUND: Right ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies.METHODS: A multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations.RESULTS: This document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes.CONCLUSIONS: This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.

Objective Pulmonary embolism (PE) can cause intracardiac hemolysis and increased plasma hemoglobin and arginase-1, which can worsen pulmonary vasoconstriction. We test the hypothesis that patients with PE that causes tricuspid regurgitation (TR), indicative of higher pulmonary arterial pressures, have decreased leukocyte expression of hmox -1 compared with patients with PE and no TR and patients without PE. Design Prospective, noninterventional study. Patients Normotensive patients with suspected PE (n=87) who underwent CT pulmonary angiography and transthoracic Doppler-echocardiography. Measurements Significant TR was defined as a jet velocity >2.7m/s. Leukocyte expression of hmox -1, haptoglobin, haptoglobin related gene, the haptoglobin receptor, CD163 and cox -2 genes were assessed by quantitative rtPCR, and the hmox -1 promoter was examined for the −413 A→T SNP and GT repeat polymorphisms. Results Of the 44 (50%) with PE+, 22 had TR+, and their mean pulmonary vascular occlusion (39±32%) did not differ significantly from patients who were TR− (28±26%, P=0.15). Patients with PE+ and TR+ had significantly lower expression of hmox -1 and haptoglobin genes than patients without PE+ and no TR. Expression of hmox -1 varied inversely with TR velocity (r 2 =0.45, P Hmox -1 expression did not vary significantly with genotype. Cox -2 did not differ between groups and had no correlation with TR. Conclusions Severity of TR varied inversely with hmox -1 expression, suggesting that hmox -1 expression affects pulmonary vascular reactivity after PE.

Objectives Treatment guidelines for acute pulmonary embolism (PE) recommend risk stratifying patients to assess PE severity, as those at higher risk should be considered for therapy in addition to standard anticoagulation to prevent right ventricular (RV) failure, which can cause hemodynamic collapse. The hypothesis was that 12-lead electrocardiography (ECG) can aid in this determination. The objective of this study was to measure the prognostic value of specific ECG findings (the Daniel score, which includes heart rate > 100 beats/min, presence of the S1Q3T3 pattern, incomplete and complete right bundle branch block [RBBB], and T-wave inversion in leads V1–V4, plus ST elevation in lead aVR and atrial fibrillation suggestive of RV strain from acute pulmonary hypertension), in patients with acute PE. Methods Studies were identified by a structured search of MEDLINE, PubMed, EMBASE, the Cochrane library, Google Scholar, Scopus, and bibliographies in October 2014. Case reports, non-English papers, and those that lacked either patient outcomes or ECG findings were excluded. Papers with evidence of a predefined reference standard for PE and the results of 12-lead ECG, stratified by outcome (hemodynamic collapse, defined as circulatory shock requiring vasopressors or mechanical ventilation, or in hospital or death within 30 days) were included. Papers were assessed for selection and publication bias. The authors also assessed heterogeneity (I2) and calculated the odds ratios (OR) for each ECG sign from the random effects model if I2 > 24% and fixed effects if I2 < 25%. Funnel plots were used to examine for publication bias. Results Forty-five full-length studies of 8,209 patients were analyzed. The most frequent ECG signs found in patients with acute PE were tachycardia (38%), T-wave inversion in lead V1 (38%), and ST elevation in lead aVR (36%). Ten studies with 3,007 patients were included for full analysis. Six ECG findings (heart rate > 100 beats/min, S1Q3T3, complete RBBB, inverted T waves in V1–V4, ST elevation in aVR, and atrial fibrillation) had likelihood and ORs with lower-limit 95% confidence intervals above unity, suggesting them to be significant predictors of hemodynamic collapse and 30-day mortality. OR data showed no evidence of publication bias, but the proportions of patients with hemodynamic collapse or death and S1Q3T3 and RBBB tended to be higher in smaller studies. Patients who were outcome-negative had a significantly lower mean ± SD Daniel score (2.6 ± 1.5) than patients with hemodynamic collapse (5.9 ± 3.9; p = 0.039, ANOVA with Dunnett's post hoc), but not patients with all-cause 30-day mortality (4.9 ± 3.3; p = 0.12). Conclusions This systematic review and meta-analysis revealed 10 studies, including 3,007 patients with acute PE, that demonstrate that six findings of RV strain on 12-lead ECG (heart rate > 100 beats/min, S1Q3T3, complete RBBB, inverted T waves in V1–V4, ST elevation in aVR, and atrial fibrillation) are associated with increased risk of circulatory shock and death.

Abstract—Background: In part 1 of this two-part review, we discussed which risk factors, historical features, and physical findings increase risk for pulmonary embolism (PE) in symptomatic emergency department (ED) patients. Objectives: Use published evidence to describe criteria that a reasonable and prudent clinician can use to initiate and guide the process of excluding and diagnosing PE. Discussion: Thecarefulanddiligentemergencyphysiciancanuse clinical criteria to safely obviate a formal evaluation of PE, including the use of gestalt reasoning and the pulmonary embolism rule-out criteria (PERC rule, Table 2, part 1). We present published clinical and radiographic features of patients with PE who eluded diagnosis in the ED. D-dimer can be used to exclude PE in many patients, and employing agebased adjustments to the threshold to define an abnormal value can further reduce patient exposure to pulmonary vascular imaging. Moreover, we discuss benefits, limitations, and potential harms of computed tomographic pulmonary vascularimagingrelevanttopatientsandthepracticeofemergency care. We present algorithms to guide exclusion and diagnosis ofPEinpatientswithsuspected PE, includingthose who are pregnant. Conclusions: Reasonable and prudent emergency clinicians can exclude PE in symptomatic ED patients on clinical grounds alone in many patients, and many more can have PE ruled out by use of the D-dimer. 2015 Elsevier Inc.

Background Pulmonary embolism (PE) can be fatal, but profligate testing for PE can harm patients. Objectives With consideration of potential medicolegal implications, this two-part review provides current evidence about the care of patients with suspected and diagnosed PE in the emergency department (ED) setting. Discussion In part 1, we review published evidence to describe the epidemiology, risk factors, and clinical presentation of PE in the ED setting. Older age, surgery requiring endotracheal intubation within the past 30 days, new use of oral contraceptives, and prior unprovoked venous thromboembolism in nonanticoagulated patients are clear risk factors for PE in ED patients. Recent history of unexplained dyspnea, pleuritic chest pain, and hemoptysis increase probability, but the effect of syncope is less clear. Treated and inactive cancer, smoking, obesity, and pregnancy have not been found to increase the probability of PE in symptomatic ED patients. Unexplained dyspnea, tachycardia, and a low pulse oximetry reading increase probability of PE. Finding of wheezing on lung auscultation reduces the probability of PE, and findings that suggest deep venous thrombosis increase the probability of PE. Conclusions Understanding of risk factors, historical data, and physical findings that have been found to increase or decrease the probability of PE in symptomatic ED patients can help create rational guidelines for the diagnostic approach to PE.

Objectives Quantitative pretest probability (qPTP) incorporated into a decision support tool with advice can reduce unnecessary diagnostic testing among patients with symptoms suggestive of acute coronary syndrome (ACS) and pulmonary embolism (PE), reducing 30-day costs without an increase in 90-day adverse outcomes. This study estimates long-term (beyond 90-day) costs and outcomes associated with qPTP. The authors hypothesized that qPTP reduces lifetime costs and improves outcomes in low-risk patients with symptoms suggestive of ACS and PE. Methods This was a cost-effectiveness analysis of a multicenter, randomized controlled trial of adult emergency patients with dyspnea and chest pain, in which a clinician encountering a low-risk patient with symptoms suggestive of ACS or PE conducted either the intervention (qPTP for ACS and PE with advice) or the sham (no qPTP and no advice). Effect of the intervention over a patient's lifetime was assessed using a Markov microsimulation model. Short-term costs and outcomes were from the trial; long-term outcomes and costs were from the literature. Outcomes included lifetime transition to PE, ACS, and intracranial hemorrhage (ICH); mortality from cancer, ICH, PE, ACS, renal failure, and ischemic stroke; quality-adjusted life-years (QALYs); and total medical costs compared between simulated intervention and sham groups. Results Markov microsimulation for a 40-year-old patient receiving qPTP found lifetime cost savings of $497 for women and $528 for men, associated with small gains in QALYs (2 and 6 days, respectively) and lower rates of cancer mortality in both sexes, but a reduction in ICH only in males. Sensitivity analysis for patients aged 60 years predicted that qPTP would continue to save costs and also reduce mortality from both ICH and cancer. Use of qPTP significantly reduced the lifetime probability of PE diagnosis, with lower probability of death from PE in both sexes aged 40 to 60 years. However, use of qPTP reduced the rate of ACS diagnosis and death from ACS at age 40, but increased the death rate from ACS at age 60 for both sexes. Conclusions Widespread use of a combined qPTP for both ACS and PE has the potential to decrease costs by reducing diagnostic testing, while improving most long-term outcomes in emergency patients with chest pain and dyspnea.