Circulating miR-let7a levels predict future diagnosis of chronic thromboembolic pulmonary hypertension.

Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54-0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH.

Long-term mortality in patients with pulmonary embolism: results in a single-center registry.

Background: While numerous studies have investigated short-term outcomes after pulmonary embolism (PE), long-term mortality remains insufficiently studied. Objectives: To investigate long-term outcomes in an unselected cohort of patients with PE. Methods: A total of 896 consecutive patients with PE enrolled in a single-center registry between May 2005 and December 2017 were followed up for up to 14 years. The observed mortality rate was compared with the expected rate in the general population. Results: The total follow-up time was 3908 patient-years (median, 3.1 years). The 1- and 5-year mortality rates were 19.7% (95% CI, 17.2%-22.4%) and 37.1% (95% CI, 33.6%-40.5%), respectively. The most frequent causes of death were cancer (28.5%), PE (19.4%), infections (13.9%), and cardiovascular events (11.6%). Late mortality (after >30 days) was more frequent than expected in the general population, a finding that was consistent in patients without cancer (the 5-year standardized mortality ratios were 2.77 [95% CI, 2.41-3.16] and 1.80 [95% CI, 1.50-2.14], respectively). Active cancer was the strongest risk factor for death between 30 days and 3 years (hazard ratio [HR], 6.51; 95% CI, 4.67-9.08) but was not associated with later mortality. Death after >3 years was predicted by age (HR, 1.86; 95% CI, 1.51-2.29 per decade), chronic heart failure (HR, 1.66; 95% CI, 1.02-2.70), and anemia (HR, 1.62; 95% CI, 1.09-2.41). Conclusion: The risk of mortality in patients with PE remained elevated compared with that in the general population throughout the follow-up period. The main driver of long-term mortality during the first 3 years was cancer. After that, mortality was predicted by age, chronic heart failure, and anemia.

Circulating microRNAs predict recurrence and death following venous thromboembolism.

BACKGROUND: Recurrent events frequently occur after venous thromboembolism (VTE) and remain difficult to predict based on established genetic, clinical, and proteomic contributors. The role of circulating microRNAs (miRNAs) has yet to be explored in detail. OBJECTIVES: To identify circulating miRNAs predictive of recurrent VTE or death, and to interpret their mechanistic involvement. METHODS: Data from 181 participants of a cohort study of acute VTE and 302 individuals with a history of VTE from a population-based cohort were investigated. Next-generation sequencing was performed on EDTA plasma samples to detect circulating miRNAs. The endpoint of interest was recurrent VTE or death. Penalized regression was applied to identify an outcome-relevant miRNA signature, and results were validated in the population-based cohort. The involvement of miRNAs in coregulatory networks was assessed using principal component analysis, and the associated clinical and molecular phenotypes were investigated. Mechanistic insights were obtained from target gene and pathway enrichment analyses. RESULTS: A total of 1950 miRNAs were detected across cohorts after postprocessing. In the discovery cohort, 50 miRNAs were associated with recurrent VTE or death (cross-validated C-index, 0.65). A weighted miRNA score predicted outcome over an 8-year follow-up period (HRSD, 2.39; 95% CI, 1.98-2.88; P < .0001). The independent validation cohort validated 20 miRNAs (ORSD for score, 3.47; 95% CI, 2.37-5.07; P < .0001; cross-validated-area under the curve, 0.61). Principal component analysis revealed 5 miRNA networks with distinct relationships to clinical phenotype and outcome. Mapping of target genes indicated regulation via transcription factors and kinases involved in signaling pathways associated with fibrinolysis. CONCLUSION: Circulating miRNAs predicted the risk of recurrence or death after VTE over several years, both in the acute and chronic phases.

Acute Infections and Inflammatory Biomarkers in Patients with Acute Pulmonary Embolism.

Although infections are frequent in patients with pulmonary embolism (PE), its effect on adverse outcome risk remains unclear. We investigated the incidence and prognostic impact of infections requiring antibiotic treatment and of inflammatory biomarkers (C-reactive protein [CRP] and procalcitonin [PCT]) on in-hospital adverse outcomes (all-cause mortality or hemodynamic insufficiency) in 749 consecutive PE patients enrolled in a single-centre registry. Adverse outcomes occurred in 65 patients. Clinically relevant infections were observed in 46.3% of patients and there was an increased adverse outcome risk with an odds ratio (OR) of 3.12 (95% confidence interval [CI] 1.70-5.74), comparable to an increase in one risk class of the European Society of Cardiology (ESC) risk stratification algorithm (OR 3.45 [95% CI 2.24-5.30]). CRP > 124 mg/dL and PCT > 0.25 µg/L predicted patient outcome independent of other risk factors and were associated with respective ORs for an adverse outcome of 4.87 (95% CI 2.55-9.33) and 5.91 (95% CI 2.74-12.76). In conclusion, clinically relevant infections requiring antibiotic treatment were observed in almost half of patients with acute PE and carried a similar prognostic effect to an increase in one risk class of the ESC risk stratification algorithm. Furthermore, elevated levels of CRP and PCT seemed to be independent predictors of adverse outcome.

Optimized definition of right ventricular dysfunction on computed tomography for risk stratification of pulmonary embolism.

OBJECTIVES: There is an ongoing discussion on the optimal right to left (RV/LV) diameter ratio threshold and the best definition of RV dysfunction on computed tomography pulmonary angiography (CTPA) for risk assessment of pulmonary embolism (PE). METHODS: On routine diagnostic CTPA, volumetric and diameter measurements (axial and reconstructed views) of the ventricles and reflux of contrast medium into the inferior vena cava (IVC) and hepatic veins were assessed in consecutive PE patients enrolled in a prospective single-center registry. In-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration. RESULTS: Of 609 patients (median age, 69 [IQR, 56-77] years; 47 % male) included in the analysis, 68 patients (11.2 %) had an adverse outcome and 35 (5.7 %) died. While neither a RV/LV volume ratio ≥1.0 nor RV/LV diameter ratios ≥1.0 were able to predict an adverse outcome, higher thresholds increased specificity. Further, neither volumetric measurements nor reconstruction of images provided superior prognostic information compared to RV/LV ratios measured in axial planes. The combination of an axial RV/LV diameter ratio ≥1.5 with substantial reflux of contrast medium was present in 134 patients (22 %) and associated with the best prognostic performance to predict an adverse outcome in unselected (OR 3.7 [95 % CI, 2.0-6.6]) and normotensive (OR 2.8 [95 % CI, 1.1-6.7]) patients. CONCLUSION: A new definition of RV dysfunction (axial RV/LV diameter ratio ≥1.5 and substantial reflux of contrast medium to the IVC and hepatic veins) allows an optimized CTPA-based prediction of PE-related adverse outcome.

Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: the FOCUS study.

AIMS: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria. METHODS AND RESULTS: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI. CONCLUSION: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care.

Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension.

BACKGROUND: A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. METHODS: Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery. RESULTS: A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. CONCLUSIONS: Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.

Impact of thyroid dysfunction on short-term outcomes and long-term mortality in patients with pulmonary embolism.

BACKGROUND: A large body of evidence suggest an impact of thyroid function on outcomes of cardiovascular diseases, but results for acute pulmonary embolism (PE) are sparse. METHODS: We analysed the impact of hypothyroidism as well as hyperthyroidism on the short and long-term outcomes of patients with acute PE. The impact was compared to the group of euthyroid PE patients as reference group. RESULTS: Overall, 831 PE patients (median age 69 [IQR 56-77] years; 52.2% females) were analysed. Among these, 734 patients (88.3%) were classified as euthyroid, 40 (4.8%) as hypothyroid and 57 (6.9%) as hyperthyroid. PE patients with hypothyroidism had higher rates of adverse in-hospital outcomes (37.5% vs. 11.6%, P < 0.001), PE-related (22.5% vs. 4.8%, P < 0.001) and all-cause in-hospital death (25.0% vs. 6.8%, P < 0.001), whereas hyperthyroidism did not affect in-hospital outcomes. Long-term mortality was higher in hypothyroidism (52.5% vs. 28.9%, P = 0.002) and hyperthyroidism (43.9% vs. 28.9%, P = 0.018) compared to euthyroid function. In the 750 normotensive PE patients, hyperthyroidism affected adverse in-hospital outcome (OR 2.58 [95%CI 1.12-5.97], P = 0.026) and PE-related in-hospital mortality (OR 3.50 [95%CI 1.10-11.17], P = 0.035) in comparison to euthyroid PE patients, while hypothyroidism showed no influence. Elevated fT4 (HR 1.75 [95%CI 1.16-2.63], P = 0.007) and reduced fT3 values (HR 2.51 [95%CI 1.48-4.28], P = 0.001) were associated with increased long-term mortality. CONCLUSION: Thyroid dysfunction had a substantial impact on short and long-term outcomes of patients with acute PE. Elevated fT4 and reduced fT3 values were significantly associated with increased long-term mortality in normotensive PE patients.

Does Age Matter? Pulmonary Endarterectomy in the Elderly Patient with CTEPH.

BACKGROUND: The gold standard treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). Little is known about the influence of advanced age on surgical outcome. Therefore, the aim of this study was to investigate the impact of patient's age on postoperative morbidity, mortality, and quality of life in a German referral center. METHODS: Prospectively collected data from 386 consecutive patients undergoing PEA between 01/2014 and 12/2016 were analyzed. Patients were divided into three groups according to their age: group 1: ≤ 50 years, group 2: > 50 ≤ 70 years, group 3: > 70 years. RESULTS: After PEA, distinct improvements in pulmonary hemodynamics, physical capacity (World Health Organization [WHO] functional class and 6-minute walking distance) and quality of life were found in all groups. There were more complications in elderly patients with longer time of invasive ventilation, intensive care, and in-hospital stay. However, the in-hospital mortality was comparable (0% in group 1, 2.6% in group 2, and 2.1% in group 3 [p = 0.326]). Furthermore, the all-cause mortality at 1 year was 1.1% in group 1, 3.2% in group 2, and 6.3% in group 3 (p = 0.122). CONCLUSIONS: PEA is an effective treatment for CTEPH patients of all ages accompanied by low perioperative and 1-year mortality. CTEPH patients in advanced age carefully selected by thorough preoperative evaluation should be offered PEA in expert centers to improve quality of life, symptoms, and pulmonary hemodynamics.

Impact of Systemic Atherosclerosis on Clinical Characteristics and Short-Term Outcomes in Patients with Deep Venous Thrombosis or Thrombophlebitis.

BACKGROUND: Venous thromboembolism (VTE) and atherosclerosis are accompanied by substantial cardiovascular mortality; links between both disease entities were reported. We aimed to investigate the impact of systemic atherosclerosis on adverse outcomes in patients with deep venous thrombosis or thrombophlebitis (DVT) and to identify differences in DVT patients with and without systemic atherosclerosis. METHODS: The German nationwide inpatient sample was used for this analysis. Patients admitted for DVT were included in this study and stratified by systemic atherosclerosis (composite of coronary artery disease, myocardial infarction, ischemic stroke, and/or atherosclerotic arterial diseases). We compared DVT patients with (DVT+Athero) and without (DVT-Athero) systemic atherosclerosis and analysed the impact of systemic atherosclerosis on adverse outcomes. RESULTS: Overall, 489,679 patients with DVT (55.7% females) were included in this analysis. Among these, 53,309 (10.9%) were coded with concomitant systemic atherosclerosis with age-dependent incline. Concomitant PE (4.1% vs.3.8%, P=0.001) was more frequently in DVT-Athero and risk for PE in DVT patients was independently associated with absence of systemic atherosclerosis (OR 0.87 [95%CI 0.83-0.91], P<0.001). In-hospital mortality (3.4% vs.1.4%, P<0.001) and adverse in-hospital events (2.2% vs.0.8%, P<0.001) were more prevalent in DVT+Athero compared to DVT-Athero; both, in-hospital mortality (OR 1.52 [95%CI 1.41-1.63], P<0.001) and adverse in-hospital events (OR 1.49 [95%CI 1.40-1.58], P<0.001) were affected independently of sex, age and comorbidities by systemic atherosclerosis. CONCLUSIONS: Systemic atherosclerosis in DVT patients was accompanied by poorer outcomes. Systemic atherosclerosis was associated with higher bleeding rate and with isolated DVT (without concomitant PE).

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.

A Comparison of GFR Calculated by Cockcroft-Gault vs. MDRD Formula in the Prognostic Assessment of Patients with Acute Pulmonary Embolism.

INTRODUCTION: Risk stratification is mandatory for optimal management of patients with acute pulmonary embolism (APE). Previous studies indicated that renal dysfunction predicts outcome and can improve risk assessment in APE. AIM: The aim of the study was a comparison of estimated glomerular filtration rate (eGFR) formulas, MDRD, and Cockcroft-Gault (CG), in the prognostic assessment of patients with APE. MATERIALS AND METHODS: Data from 2274 (1147 M/1127 F, median 71 years) hospitalised patients with APE prospectively included in a multicenter, observational, cohort study were analysed. A serum creatinine measurement as a routine laboratory parameter at the cooperating centers and eGFR calculation were performed on admission. Patients were followed for 180 days. The primary outcome was death from any cause within 30 days. RESULTS: The eGFR levels assessed by both, MDRD (eGFRMDRD) and CG formula (eGFRCG), were highest in patients with low-risk APE and lowest in high-risk APE. The eGFR (using both methods) was significantly lower in nonsurvivors compared to survivors. Using a threshold of <60 ml/min/1.73 m2, eGFRMDRD revealed the primary outcome with sensitivity 67%, specificity 52%, PPV 8%, and NPV 97%, while eGFRCG had a sensitivity 62%, specificity 62%, PPV 8.6%, and NPV 96%. The area under the ROC curve for eGFRCG tended to be higher than that for eGFRMDRD: 0.658 (95% CI: 0.608-0.709) vs. 0.631 (95% CI: 0.578-0.683), p = 0.12. A subanalysis of ROC curves in a population above 65 yrs showed a higher AUC for eGFRCG than based on MDRD. Kaplan-Meier analysis showed a worse long-term outcome in patients with impaired renal function. CONCLUSION: eGFRMDRD and eGFRCG assessed on admission significant short- and long-term mortality predictors in patients with APE. The eGFRCG seems to be a slightly better 30-day mortality predictor than eGFRMDRD in the elderly.

[Pulmonary Embolism]. / Lungenembolie.

Pulmonary embolism (PE) is a life-threatening disease and the third most frequent cardiovascular cause of death after stroke and myocardial infarction. The annual incidence is increasing (in Germany from 85 cases per 100000 population in the year 2005 to 109 cases per 100000 population in the year 2015). The individual risk for PE-related complications and death increases with the number of comorbidities and severity of right ventricular dysfunction. Using clinical, laboratory and imaging parameters, patients with PE can be stratified to four risk classes (high, intermediate-high, intermediate-low and low risk). This risk stratification has concrete therapeutic consequences ranging from out-of-hospital treatment of low-risk patients to reperfusion treatment of (intermediate)-high-risk patients. For haemodynamically unstable patients, treatment decision should preferably be made in interdisciplinary "Pulmonary Embolism Response Teams" (PERT). Due to their comparable efficacy and preferable safety profile compared to vitamin-K antagonists (VKAs), non-vitamin K-dependent oral anticoagulants (NOACs) are increasingly considered the treatment of choice for initial and prolonged anticoagulation of patients with pulmonary embolism. Use of low molecular weight heparins (LMWHs) is recommended for PE patients with cancer; however, recent studies indicate that treatment with factor Xa-inhibitors may be effective and safe (in patients without gastrointestinal cancer). Only prolonged anticoagulation (in reduced dosage) will ensure reduction of VTE recurrence and should thus be considered for all patients with unprovoked events.

Temporal trends and predictors of inhospital death in patients hospitalised for heart failure in Germany.

AIMS: We investigated trends in incidence, case fatality rate, patient characteristics and adverse inhospital events of patients hospitalised for heart failure in Germany. METHODS AND RESULTS: The German nationwide inpatient sample (2005-2016) was used for this analysis. Patients hospitalised due to heart failure were selected for analysis. Temporal trends in the incidence of hospitalisations, case fatality rate and treatments were analysed and predictors of inhospital death were identified. The analysis comprised a total number of 4,539,140 hospitalisations (52.0% women, 81.0% aged ≥70 years) due to heart failure. Although hospitalisations increased from 381 (2005) to 539 per 100,000 population (2016) (ß estimate 0.06, 95% confidence interval (CI) 0.06 to 0.07, P < 0.001) in parallel with median age and prevalence of comorbidities, the inhospital case fatality rate decreased from 11.1% to 8.1% (ß estimate -0.36, 95% CI -0.37 to -0.35, P < 0.001) and the rate of major adverse cardiovascular and cerebrovascular events (ß estimate -0.24, 95% CI -0.25 to -0.23, P < 0.001) decreased from 12.7% to 10.3%. Age 70 years and older (odds ratio (OR) 2.60, 95% CI 2.57 to 2.63, P < 0.001) and cancer (OR 1.93, 95% CI 1.91 to 1.96, P < 0.001) were independent predictors of inhospital death. CONCLUSION: Hospitalisations for heart failure increased in Germany from 2005 to 2016, whereas the major adverse cardiovascular and cerebrovascular event rate and inhospital case fatality rate decreased during this period despite higher patient age and increasing prevalence of comorbidities.

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

BACKGROUND: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe. METHODS: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555). FINDINGS: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran. INTERPRETATION: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation. FUNDING: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.

Outcome of patients with different clinical presentations of high-risk pulmonary embolism.

AIMS: The 2019 European Society of Cardiology (ESC) guidelines provide a revised definition of high-risk pulmonary embolism (PE) encompassing three clinical presentations: Cardiac arrest, obstructive shock, and persistent hypotension. This study investigated the prognostic implications of this new definition. METHODS AND RESULTS: Data from 784 consecutive PE patients prospectively enrolled in a single-centre registry were analysed. Study outcomes include an in-hospital adverse outcome (PE-related death or cardiopulmonary resuscitation) and in-hospital all-cause mortality. Overall, 86 patients (11.0%) presented with high-risk PE and more often had an adverse outcome (43.0%) compared to intermediate-high-risk patients (6.1%; P < 0.001). Patients with cardiac arrest had the highest rate of an in-hospital adverse outcome (78.4%) and mortality (59.5%; both P < 0.001 compared to intermediate-high-risk patients). Obstructive shock and persistent hypotension had similar rates of adverse outcomes (15.8% and 18.2%, respectively; P = 0.46), but the only obstructive shock was associated with an increased all-cause mortality risk. Use of an optimised venous lactate cut-off value (3.8 mmol/L) to diagnose obstructive shock allowed differentiation of adverse outcome risk between patients with shock (21.4%) and persistent hypotension (9.5%), resulting in a net reclassification improvement (0.24 ± 0.08; P = 0.002). CONCLUSION: The revised ESC 2019 guidelines definition of high-risk PE stratifies subgroups at different risk of in-hospital adverse outcomes and all-cause mortality. Risk prediction can be improved by using an optimised venous lactate cut-off value to diagnose obstructive shock, which might help to better assess the risk-to-benefit ratio of systemic thrombolysis in different subgroups of high-risk patients.

Prognostic value of right atrial dilation in patients with pulmonary embolism.

AIMS: Right atrial (RA) dilation and stretch provide prognostic information in patients with cardiovascular diseases. We investigated the prevalence, confounding factors and prognostic relevance of RA dilation in patients with pulmonary embolism (PE). METHODS: Overall, 609 PE patients were consecutively included in a prospective single-centre registry between September 2008 and August 2017. Volumetric measurements of heart chambers were performed on routine non-electrocardiographic-gated computed tomography and plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) measured on admission. An in-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration. RESULTS: Patients with an adverse outcome (11.2%) had larger RA volumes (median 120 (interquartile range 84-152) versus 102 (78-134) mL; p=0.013), RA/left atrial (LA) volume ratios (1.7 (1.2-2.4) versus 1.3 (1.1-1.7); p<0.001) and MR-proANP levels (282 (157-481) versus 129 (64-238) pmol·L-1; p<0.001) compared to patients with a favourable outcome. Overall, 499 patients (81.9%) had a RA/LA volume ratio ≥1.0 and a calculated cut-off value of 1.8 (area under the curve 0.64, 95% CI 0.56-0.71) predicted an adverse outcome, both in unselected (OR 3.1, 95% CI 1.9-5.2) and normotensive patients (OR 2.7, 95% CI 1.3-5.6). MR-proANP ≥120 pmol·L-1 was identified as an independent predictor of an adverse outcome, both in unselected (OR 4.6, 95% CI 2.3-9.3) and normotensive patients (OR 5.1, 95% CI 1.5-17.6). CONCLUSIONS: RA dilation is a frequent finding in patients with PE. However, the prognostic performance of RA dilation appears inferior compared to established risk stratification markers. MR-proANP predicted an in-hospital adverse outcome, both in unselected and normotensive PE patients, integrating different prognostic relevant information from comorbidities.

Role of angiopoietin-2 in venous thrombus resolution and chronic thromboembolic disease.

BACKGROUND: Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown. METHODS: ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute pulmonary embolism (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells. RESULTS: Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were elevated in patients with pulmonary embolism and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and transforming growth factor-ß1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels. CONCLUSION: Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from pulmonary embolism to CTEPH.

Time trends of pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension is considered as a rare but severe complication after acute pulmonary embolism and is potentially curable by pulmonary endarterectomy. We aimed to evaluate, over an 11-year period, time trends of in-hospital outcomes of pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension patients and to investigate predictors of the in-hospital course. We analyzed data on the characteristics, comorbidities, treatments, and in-hospital outcomes for all chronic thromboembolic pulmonary hypertension patients treated with pulmonary endarterectomy in the German nationwide inpatient sample between 2006 and 2016. Overall, 1398 inpatients were included. Annual number of pulmonary endarterectomy increased from 67 in 2006 to 194 in 2016 (P < 0.001), in parallel with a significant decrease of in-hospital mortality (10.9% in 2008 to 1.5% in 2016; P < 0.001). Patients' characteristics shifted slightly toward older age and higher prevalence of chronic renal insufficiency and obesity over time, whereas duration of hospital stay decreased over time. Independent predictors of in-hospital mortality were age (OR 1.03 (95%CI: 1.01-1.05); P = 0.001), right heart failure (2.55 (1.37-4.76); P = 0.003), in-hospital complications such as ischemic stroke (6.87 (1.06-44.70); P = 0.044) and bleeding events like hemopneumothorax (24.93 (6.18-100.57); P < 0.001). Annual pulmonary endarterectomy volumes per center below 10 annual procedures were associated with higher rates of adverse in-hospital outcomes. Annual numbers of chronic thromboembolic pulmonary hypertension patients treated with pulmonary endarterectomy increased markedly in Germany between 2006 and 2016, in parallel with a decrease of in-hospital mortality. Our findings suggest that perioperative management of pulmonary endarterectomy, institutional experience, and patient selection is crucial and has improved over time.

In-hospital outcomes of catheter-directed thrombolysis in patients with pulmonary embolism.

AIMS: Catheter-directed treatment of acute pulmonary embolism (PE) is technically advancing. Recent guidelines acknowledge this treatment option for patients with overt or imminent haemodynamic decompensation, particularly when systemic thrombolysis is contraindicated. We investigated patients with PE who underwent catheter-directed thrombolysis (CDT) in the German nationwide inpatient cohort. METHODS AND RESULTS: Data from hospitalizations with PE (International Classification of Disease code I26) between 2005 and 2016 were collected by the Federal Office of Statistics in Germany. Patients with PE who underwent CDT (OPS 8-838.60 or OPS code 8-83b.j) were compared with patients receiving systemic thrombolysis (OPS code 8-020.8), and those without thrombolytic or other reperfusion treatment. The analysis was not prespecified; therefore, our findings can only be considered to be hypothesis generating. We analysed data from 978 094 hospitalized patients with PE. Of these, 41 903 (4.3%) patients received thrombolytic treatment [systemic thrombolysis in 4.2%, CDT in 0.1% (1175 patients)]. Among patients with shock, CDT was associated with lower in-hospital mortality compared to systemic thrombolysis [odds ratios (OR) 0.30 (95% 0.14-0.67); P = 0.003]. Intracranial bleeding occurred in 14 (1.2%) patients who received CDT. Among haemodynamically stable patients with right ventricular dysfunction (intermediate-risk PE), CDT also was associated with a lower risk of in-hospital mortality compared to systemic thrombolysis {OR 0.55 [95% confidence interval (CI) 0.40-0.75]; P < 0.001} or no thrombolytic treatment [0.45 (95% CI 0.33-0.62); P < 0.001]. CONCLUSION: In the German nationwide inpatient cohort, based on administrative data, CDT was associated with lower in-hospital mortality rates compared to systemic thrombolysis, but the overall rate of intracranial bleeding in patients who received CDT was not negligible. Prospective controlled data are urgently needed to determine the true value of this treatment option in acute PE.