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.

Activated Endothelial TGFß1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1: Potential Role for Chronic Thromboembolic Pulmonary Hypertension.

RATIONALE: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by defective thrombus resolution, pulmonary artery obstruction, and vasculopathy. TGFß (transforming growth factor-ß) signaling mutations have been implicated in pulmonary arterial hypertension, whereas the role of TGFß in the pathophysiology of CTEPH is unknown. OBJECTIVE: To determine whether defective TGFß signaling in endothelial cells contributes to thrombus nonresolution and fibrosis. METHODS AND RESULTS: Venous thrombosis was induced by inferior vena cava ligation in mice with genetic deletion of TGFß1 in platelets (Plt.TGFß-KO) or TGFß type II receptors in endothelial cells (End.TGFßRII-KO). Pulmonary endarterectomy specimens from CTEPH patients were analyzed using immunohistochemistry. Primary human and mouse endothelial cells were studied using confocal microscopy, quantitative polymerase chain reaction, and Western blot. Absence of TGFß1 in platelets did not alter platelet number or function but was associated with faster venous thrombus resolution, whereas endothelial TGFßRII deletion resulted in larger, more fibrotic and higher vascularized venous thrombi. Increased circulating active TGFß1 levels, endothelial TGFßRI/ALK1 (activin receptor-like kinase), and TGFßRI/ALK5 expression were detected in End.TGFßRII-KO mice, and activated TGFß signaling was present in vessel-rich areas of CTEPH specimens. CTEPH-endothelial cells and murine endothelial cells lacking TGFßRII simultaneously expressed endothelial and mesenchymal markers and transcription factors regulating endothelial-to-mesenchymal transition, similar to TGFß1-stimulated endothelial cells. Mechanistically, increased endothelin-1 levels were detected in TGFßRII-KO endothelial cells, murine venous thrombi, or endarterectomy specimens and plasma of CTEPH patients, and endothelin-1 overexpression was prevented by inhibition of ALK5, and to a lesser extent of ALK1. ALK5 inhibition and endothelin receptor antagonization inhibited mesenchymal lineage conversion in TGFß1-exposed human and murine endothelial cells and improved venous thrombus resolution and pulmonary vaso-occlusions in End.TGFßRII-KO mice. CONCLUSIONS: Endothelial TGFß1 signaling via type I receptors and endothelin-1 contribute to mesenchymal lineage transition and thrombofibrosis, which were prevented by blocking endothelin receptors. Our findings may have relevant implications for the prevention and management of CTEPH.

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.

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.

Survival and quality of life after early discharge in low-risk pulmonary embolism.

INTRODUCTION: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes. METHODS: The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism. RESULTS: The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001). CONCLUSIONS: Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.

Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany.

AIMS: Pulmonary embolism (PE) is the third most common cardiovascular cause of death; systemic thrombolysis is potentially lifesaving treatment in patients presenting with haemodynamic instability. We investigated trends in the use of systemic thrombolysis and the outcome of patients with acute PE. METHODS AND RESULTS: We analysed data on the characteristics, comorbidities, treatment, and in-hospital outcome of 885 806 PE patients in Germany between 2005 and 2015. Incidence of acute PE was 99/100 000 population/year and increased from 85/100 000 in 2005 to 109/100 000 in 2015 [ß 0.32 (0.26-0.38), P < 0.001]. During the same period, in-hospital case fatality rates decreased from 20.4% to 13.9% [ß -0.51 (-0.52 to -0.49), P < 0.001]. The overall proportion of patients treated with systemic thrombolysis increased from 3.1% in 2005 to 4.4% in 2015 [ß 0.28 (0.25-0.31), P < 0.001]. Thrombolysis was associated with lower in-hospital mortality rates in patients with haemodynamic instability, both in those with shock not necessitating cardiopulmonary resuscitation (CPR) or mechanical ventilation [odds ratio (OR) 0.42 (0.37-0.48), P < 0.001], and in those who underwent CPR [OR 0.92 (0.87-0.97), P = 0.002]. This association was independent from age, sex, and comorbidities. However, systemic thrombolysis was administered to only 23.1% of haemodynamically unstable patients. CONCLUSION: Although the proportion of PE patients treated with systemic thrombolysis increased slightly in Germany between 2005 and 2015, only the minority of haemodynamically unstable patients currently receive this treatment. In the nationwide inpatient cohort, thrombolytic therapy was associated with reduced in-hospital mortality rates in PE patients with shock, and also in those who underwent CPR.

Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial.

AIMS: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. METHODS AND RESULTS: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). CONCLUSION: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.

[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.

Impact of obesity on adverse in-hospital outcomes in patients undergoing percutaneous mitral valve edge-to-edge repair using MitraClip® procedure - Results from the German nationwide inpatient sample.

BACKGROUND AND AIM: The number of percutaneous edge-to-edge mitral regurgitation (MR) valve repairs with MitraClip® implantations increased exponentially in recent years. Studies have suggested an obesity survival paradox in patients with cardiovascular diseases. We investigated the influence of obesity on adverse in-hospital outcomes in patients with MitraClip® implantation. METHODS AND RESULTS: We analyzed data on characteristics of patients and in-hospital outcomes for all percutaneous mitral valve repairs using the edge-to-edge MitraClip®-technique in Germany 2011-2015 stratified for obesity vs. normal-weight/over-weight. The nationwide inpatient sample comprised 13,563 inpatients undergoing MitraClip® implantations. Among them, 1017 (7.5%) patients were coded with obesity. Obese patients were younger (75 vs.77 years,P < 0.001), more often female (45.4% vs.39.5%,P < 0.001), had more often heart failure (87.1% vs.79.2%,P < 0.001) and renal insufficiency (67.0% vs.56.4%,P < 0.001). Obese and non-obese patients were comparable regarding major adverse cardiac and cerebrovascular events (MACCE) and in-hospital death. The combined endpoint of cardio-pulmonary resuscitation (CPR), mechanical ventilation and death was more often reached in non-obese than in obese patients with a trend towards significance (20.6%vs.18.2%,P = 0.066). Obesity was an independent predictor of reduced events regarding the combined endpoint of CPR, mechanical ventilation and death (OR 0.75, 95%CI 0.64-0.89,P < 0.001), but not for reduced in-hospital mortality (P = 0.355) or reduced MACCE rate (P = 0.108). Obesity class III was associated with an elevated risk for pulmonary embolism (OR 5.66, 95%CI 1.35-23.77,P = 0.018). CONCLUSIONS: We observed an obesity paradox regarding the combined endpoint of CPR, mechanical ventilation and in-hospital death in patients undergoing MitraClip® implantation, but our results failed to confirm an impact of obesity on in-hospital survival or MACCE.

Differential impact of syncope on the prognosis of patients with acute pulmonary embolism: a systematic review and meta-analysis.

Aims: Controversial reports exist in the literature regarding the prognostic role and therapeutic implications of syncope in patients with acute pulmonary embolism (PE). We conducted a systematic review and meta-analysis to investigate the association between syncope and short-term adverse outcomes, taking into account the presence or absence of haemodynamic compromise at acute PE presentation. Methods and results: The literature search identified 1664 studies, 29 of which were included for a total of 21 956 patients with PE (n = 3706 with syncope). Syncope was associated with higher prevalence of haemodynamic instability [odds ratio (OR) 3.50; 95% confidence interval (CI) 2.67-4.58], as well as with echocardiographic signs of right ventricular (RV) dysfunction (OR 2.10; CI 1.60-2.77) at presentation. Patients with syncope had a higher risks of all-cause early (either in-hospital or within 30 days) death (OR 1.73; CI 1.22-2.47) and PE-related 30-day adverse outcomes (OR 2.00; CI 1.11-3.60). The absolute risk difference (95% CI) for all-cause death was +6% (+1% to +10%) in studies including unselected patients, but it was -1% (-2% to +1%) in studies restricted to normotensive patients. We observed no prognostic impact of syncope in studies with a lower score at formal quality assessment and in those conducted retrospectively. Conclusion: Syncope as a manifestation of acute PE was associated with a higher prevalence of haemodynamic instability and RV dysfunction at presentation, and an elevated risk for early PE-related adverse outcomes. The association with an increased risk of early death appeared more prominent in studies including unselected patients, when compared with those focusing on normotensive patients only.

Age-Dependent and -Independent Effects of Perivascular Adipose Tissue and Its Paracrine Activities during Neointima Formation.

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks ("middle-aged") were compared to tissue or cells from mice aged 16 weeks ("adult"). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat.

Prognostic impact of copeptin in pulmonary embolism: a multicentre validation study.

To externally validate the prognostic impact of copeptin, either alone or integrated in risk stratification models, in pulmonary embolism (PE), we performed a post hoc analysis of 843 normotensive PE patients prospectively included in three European cohorts.Within the first 30 days, 21 patients (2.5%, 95% CI 1.5-3.8) had an adverse outcome and 12 (1.4%, 95% CI 0.7-2.5) died due to PE. Patients with copeptin ≥24 pmol·L-1 had a 6.3-fold increased risk for an adverse outcome (95% CI 2.6-15.5, p<0.001) and a 7.6-fold increased risk for PE-related death (95% CI 2.3-25.6, p=0.001). Risk classification according to the 2014 European Society of Cardiology (ESC) guideline algorithm identified 248 intermediate-high-risk patients (29.4%) with 5.6% (95% CI 3.1-9.3) at risk of adverse outcomes. A stepwise biomarker-based risk assessment strategy (based on high-sensitivity troponin T, N-terminal pro-brain natriuretic peptide and copeptin) identified 123 intermediate-high-risk patients (14.6%) with 8.9% (95% CI 4.5-15.4) at risk of adverse outcomes. The identification of patients at higher risk was even better when copeptin was measured on top of the 2014 ESC algorithm in intermediate-high-risk patients (adverse outcome OR 11.1, 95% CI 4.6-27.1, p<0.001; and PE-related death OR 13.5, 95% CI 4.2-43.6, p<0.001; highest risk group versus all other risk groups). This identified 85 patients (10.1%) with 12.9% (95% CI 6.6-22.0) at risk of adverse outcomes and 8.2% (95% CI 3.4-16.2) at risk of PE-related deaths.Copeptin improves risk stratification of normotensive PE patients, especially when identifying patients with an increased risk of an adverse outcome.

Fibrinolysis for patients with intermediate-risk pulmonary embolism.

BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Comparison of risk assessment strategies for not-high-risk pulmonary embolism.

We compared the prognostic performance of the 2014 European Society of Cardiology (ESC) risk stratification algorithm with the previous 2008 ESC algorithm, the Bova score and the modified FAST score (based on a positive heart-type fatty acid-binding protein (H-FABP) test, syncope and tachycardia, modified using high-sensitivity troponin T instead of H-FABP) in 388 normotensive pulmonary embolism patients included in a single-centre cohort study.Overall, 25 patients (6.4%) had an adverse 30-day outcome. Regardless of the score or algorithm used, the rate of an adverse outcome was highest in the intermediate-high-risk classes, while all patients classified as low-risk had a favourable outcome (no pulmonary embolism-related deaths, 0-1.4% adverse outcome). The area under the curve for predicting an adverse outcome was higher for the 2014 ESC algorithm (0.76, 95% CI 0.68-0.84) compared with the 2008 ESC algorithm (0.65, 95% CI 0.56-0.73) and highest for the modified FAST score (0.82, 95% CI 0.75-0.89). Patients classified as intermediate-high-risk by the 2014 ESC algorithm had a 8.9-fold increased risk for an adverse outcome (3.2-24.2, p<0.001 compared with intermediate-low- and low-risk patients), while the highest OR was observed for a modified FAST score ≥3 points (OR 15.9, 95% CI 5.3-47.6, p<0.001).The 2014 ESC algorithm improves risk stratification of not-high-risk pulmonary embolism compared with the 2008 ESC algorithm. All scores and algorithms accurately identified low-risk patients, while the modified FAST score appears more suitable to identify intermediate-high-risk patients.

Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment.

Attempts at identifying patients with an elevated risk of bleeding while on anticoagulation following acute venous thromboembolism (VTE) have largely been unsuccessful thus far. We sought to develop a clinical prediction score for bleeding during stable anticoagulation treatment after acute VTE.We performed a post hoc analysis of the pooled RE-COVER studies, two double-blind randomised "sister" trials evaluating dabigatran versus standard treatment in 5107 VTE patients.A score was derived from patients randomised to dabigatran using logistic regression analysis covering the complete follow-up period. The final model, named VTE-BLEED, included six variables and yielded a c-statistic of 0.72 (95% CI 0.67-0.76). Patients from the derivation cohort in the low-risk group (<2 points; 74% of the derivation population) had a bleeding incidence of 2.8% compared to 12.6% in the elevated-risk group (OR 5.0; 95% CI 3.5-7.1). The score proved accurate for our primary end-point, i.e. prediction of major bleeding after day 30 ("stable" anticoagulation), both in patients on dabigatran (c-statistic 0.75, 95% CI 0.61-0.89) and those on warfarin (0.78, 95% CI 0.68-0.86; p=0.77 for difference).The new VTE-BLEED score accurately predicted major bleeding events in VTE patients on stable anticoagulation with both dabigatran and warfarin.

Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model.

The European Society of Cardiology (ESC) has proposed an updated risk stratification model for death in patients with acute pulmonary embolism based on clinical scores (Pulmonary Embolism Severity Index (PESI) or simplified PESI (sPESI)), right ventricle dysfunction (RVD) and elevated serum troponin (2014 ESC model).We assessed the ability of the 2014 ESC model to predict 30-day death after acute pulmonary embolism. Consecutive patients with symptomatic, confirmed pulmonary embolism included in prospective cohorts were merged in a collaborative database. Patients' risk was classified as high (shock or hypotension), intermediate-high (RVD and elevated troponin), intermediate-low (RVD or increased troponin or none) and low (sPESI 0). Study outcomes were death and pulmonary embolism-related death at 30 days.Among 906 patients (mean±sd age 68±16, 489 females), death and pulmonary embolism-related death occurred in 7.2% and 4.1%, respectively. Death rate was 22% in "high-risk" (95% CI 14.0-29.8), 7.7% in "intermediate-high-risk" (95% CI 4.5-10.9) and 6.0% in "intermediate-low-risk" patients (95% CI 3.4-8.6). One of the 196 "low-risk" patients died (0.5%, 95% CI 0-1.0; negative predictive value 99.5%).By using the 2014 ESC model, RVD or troponin tests would be avoided in about 20% of patients (sPESI 0), preserving a high negative predictive value. Risk stratification in patients at intermediate risk requires further improvement.

Outcome of patients with right heart thrombi: the Right Heart Thrombi European Registry.

Our aim was the assessment of the prognostic significance of right heart thrombi (RiHT) and their characteristics in pulmonary embolism in relation to established prognostic factors.138 patients (69 females) aged (mean±sd) 62±19 years with RiHT were included into a multicenter registry. A control group of 276 patients without RiHT was created by propensity scoring from a cohort of 963 contemporary patients. The primary end-point was 30-day pulmonary embolism-related mortality; the secondary end-point included 30-day all-cause mortality. In RiHT patients, pulmonary embolism mortality was higher in 31 patients with systolic blood pressure <90 mmHg than in 107 normotensives (42% versus 12%, p=0.0002) and was higher in the 83 normotensives with right ventricular dysfunction (RVD) than in the 24 normotensives without RVD (16% versus 0%, p=0.038). In multivariable analysis the simplified Pulmonary Embolism Severity Index predicted mortality (hazard ratio 2.43, 95% CI 1.58-3.73; p<0.0001), while RiHT characteristics did not. Patients with RiHT had higher pulmonary embolism mortality than controls (19% versus 8%, p=0.003), especially normotensive patients with RVD (16% versus 7%, p=0.02).30-day mortality in patients with RiHT is related to haemodynamic consequences of pulmonary embolism and not to RiHT characteristics. However, patients with RiHT and pulmonary embolism resulting in RVD seem to have worse prognosis than propensity score-matched controls.

Late outcomes after acute pulmonary embolism: rationale and design of FOCUS, a prospective observational multicenter cohort study.

Acute pulmonary embolism (PE) is a frequent cause of death and serious disability. The risk of PE-associated mortality and morbidity extends far beyond the acute phase of the disease. In earlier follow-up studies, as many as 30 % of the patients died during a follow-up period of up to 3 years, and up to 50 % of patients continued to complain of dyspnea and/or poor physical performance 6 months to 3 years after the index event. The most feared 'late sequela' of PE is chronic thromboembolic pulmonary hypertension (CTEPH), the true incidence of which remains obscure due to the large margin of error in the rates reported by mostly small, single-center studies. Moreover, the functional and hemodynamic changes corresponding to early, possibly reversible stages of CTEPH, have not been systematically investigated. The ongoing Follow-Up after acute pulmonary embolism (FOCUS) study will prospectively enroll and systematically follow, over a 2-year period and with a standardized comprehensive program of clinical, echocardiographic, functional and laboratory testing, a large multicenter prospective cohort of 1000 unselected patients (all-comers) with acute symptomatic PE. FOCUS will possess adequate power to provide answers to relevant remaining questions regarding the patients' long-term morbidity and mortality, and the temporal pattern of post-PE abnormalities. It will hopefully provide evidence for future guideline recommendations regarding the selection of patients for long-term follow-up after PE, the modalities which this follow-up should include, and the findings that should be interpreted as indicating progressive functional and hemodynamic post-PE impairment, or the development of CTEPH.

Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis.

AIM: Thrombolytic therapy induces faster clot dissolution than anticoagulation in patients with acute pulmonary embolism (PE) but is associated with an increased risk of haemorrhage. We reviewed the risks and benefits of thrombolytic therapy in the management of patients with acute PE. METHODS AND RESULTS: We systematically reviewed randomized controlled studies comparing systemic thrombolytic therapy plus anticoagulation with anticoagulation alone in patients with acute PE. Fifteen trials involving 2057 patients were included in our meta-analysis. Compared with heparin, thrombolytic therapy was associated with a significant reduction of overall mortality (OR; 0.59, 95% CI: 0.36-0.96). This reduction was not statistically significant after exclusion of studies including high-risk PE (OR; 0.64, 95% CI: 0.35-1.17). Thrombolytic therapy was associated with a significant reduction in the combined endpoint of death or treatment escalation (OR: 0.34, 95% CI: 0.22-0.53), PE-related mortality (OR: 0.29; 95% CI: 0.14-0.60) and PE recurrence (OR: 0.50; 95% CI: 0.27-0.94). Major haemorrhage (OR; 2.91, 95% CI: 1.95-4.36) and fatal or intracranial bleeding (OR: 3.18, 95% CI: 1.25-8.11) were significantly more frequent among patients receiving thrombolysis. CONCLUSIONS: Thrombolytic therapy reduces total mortality, PE recurrence, and PE-related mortality in patients with acute PE. The decrease in overall mortality is, however, not significant in haemodynamically stable patients with acute PE. Thrombolytic therapy is associated with an increase of major and fatal or intracranial haemorrhage.