External validation of AF-BLEED for predicting major bleeding and for tailoring NOAC dose in AF patients: A post hoc analysis in the ENGAGE AF-TIMI 48.

OBJECTIVE: AF-BLEED, a simple bleeding risk classifier, was found to predict major bleeding (MB) in patients with atrial fibrillation (AF) and identify AF patients at high risk of MB who might potentially benefit from a lower direct oral anticoagulant dose. This post hoc study aimed to externally validate these findings in the ENGAGE AF-TIMI 48 (Effective aNticoaGulation with factor Xa next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction study 48) trial. METHODS: The ENGAGE AF-TIMI 48 trial randomized AF patients to higher-dose edoxaban regimen (HDER 60/30 mg) versus lower-dose edoxaban regimen (LDER 30/15 mg), with prespecified dose reduction criteria. AF-BLEED was calculated in the modified intention-to-treat cohort (n = 21,026 patients) used for primary outcome analysis. Annualized event rates and hazard ratios (HRs) were obtained for the primary composite outcome (PCO) and its single components (MB, ischemic stroke/systemic embolism and death) to compare LDER 30 mg with HDER 60 mg in both AF-BLEED classes. RESULTS: AF-BLEED classified 2882 patients (13.7 %) as high-risk, characterized by a two- to three-fold higher MB risk than AF-BLEED classified low-risk patients. AF-BLEED classified high-risk patients randomized to LDER 30 mg demonstrated a 3.3 % reduction in MB at the cost of a 0.5 % increase in ischemic stroke/systemic embolism. LDER 30 mg resulted in a 3.1 % reduction of PCO compared to HDER 60 mg (HR of 0.81; 95%CI 0.65-1.01). Additional to existing dose reduction criteria, another 6 % of patients could potentially benefit of this dose adjustment strategy. CONCLUSION: AF-BLEED could identify AF patients to be at high risk of major bleeding. Our findings support the hypothesis that LDER 30 mg might provide a reasonable option in AF patients with legitimate bleeding concerns.

Towards optimal use of antithrombotic therapy of people with cancer at the end of life: A research protocol for the development and implementation of the SERENITY shared decision support tool.

BACKGROUND: Even though antithrombotic therapy has probably little or even negative effects on the well-being of people with cancer during their last year of life, deprescribing antithrombotic therapy at the end of life is rare in practice. It is often continued until death, possibly resulting in excess bleeding, an increased disease burden and higher healthcare costs. METHODS: The SERENITY consortium comprises researchers and clinicians from eight European countries with specialties in different clinical fields, epidemiology and psychology. SERENITY will use a comprehensive approach combining a realist review, flash mob research, epidemiological studies, and qualitative interviews. The results of these studies will be used in a Delphi process to reach a consensus on the optimal design of the shared decision support tool. Next, the shared decision support tool will be tested in a randomised controlled trial. A targeted implementation and dissemination plan will be developed to enable the use of the SERENITY tool across Europe, as well as its incorporation in clinical guidelines and policies. The entire project is funded by Horizon Europe. RESULTS: SERENITY will develop an information-driven shared decision support tool that will facilitate treatment decisions regarding the appropriate use of antithrombotic therapy in people with cancer at the end of life. CONCLUSIONS: We aim to develop an intervention that guides the appropriate use of antithrombotic therapy, prevents bleeding complications, and saves healthcare costs. Hopefully, usage of the tool leads to enhanced empowerment and improved quality of life and treatment satisfaction of people with advanced cancer and their care givers.

Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases.

BACKGROUND: Lemierre syndrome is characterized by head/neck vein thrombosis and septic embolism usually complicating an acute oropharyngeal bacterial infection in adolescents and young adults. We described the course of Lemierre syndrome in the contemporary era. METHODS: In our individual-level analysis of 712 patients (2000-2017), we included cases described as Lemierre syndrome if these criteria were met: (i) primary site of bacterial infection in the head/neck; (ii) objectively confirmed local thrombotic complications or septic embolism. The study outcomes were new or recurrent venous thromboembolism or peripheral septic lesions, major bleeding, all-cause death and clinical sequelae. RESULTS: The median age was 21 (Q1-Q3: 17-33) years, and 295 (41%) were female. At diagnosis, acute thrombosis of head/neck veins was detected in 597 (84%) patients, septic embolism in 582 (82%) and both in 468 (80%). After diagnosis and during in-hospital follow-up, new venous thromboembolism occurred in 34 (5.2%, 95% CI 3.8-7.2%) patients, new peripheral septic lesions became evident in 76 (11.7%; 9.4-14.3%). The rate of either was lower in patients who received anticoagulation (OR: 0.59; 0.36-0.94), higher in those with initial intracranial involvement (OR: 2.35; 1.45-3.80). Major bleeding occurred in 19 patients (2.9%; 1.9-4.5%), and 26 died (4.0%; 2.7-5.8%). Clinical sequelae were reported in 65 (10.4%, 8.2-13.0%) individuals, often consisting of cranial nerve palsy (n = 24) and orthopaedic limitations (n = 19). CONCLUSIONS: Patients with Lemierre syndrome were characterized by a substantial risk of new thromboembolic complications and death. This risk was higher in the presence of initial intracranial involvement. One-tenth of survivors suffered major clinical sequelae.

Atrial fibrillation is frequent but does not affect risk stratification in pulmonary embolism.

BACKGROUND: Although prior studies indicate a high prevalence of atrial fibrillation (AF) in patients with pulmonary embolism (PE), the exact prevalence and prognostic impact are unknown. METHODS: We aimed to investigate the prevalence, risk factors and prognostic impact of AF on risk stratification, in-hospital adverse outcomes and mortality in 528 consecutive PE patients enrolled in a single-centre registry between 09/2008 and 09/2017. RESULTS: Overall, 52 patients (9.8%) had known AF and 57 (10.8%) presented with AF on admission; of those, 34 (59.6%) were newly diagnosed with AF. Compared to patients with no AF, overt hyperthyroidism was associated with newly diagnosed AF (OR 7.89 [2.99-20.86]), whilst cardiovascular risk comorbidities were more frequently observed in patients with known AF. Patients with AF on admission had more comorbidities, presented more frequently with tachycardia and elevated cardiac biomarkers and were hence stratified to higher risk classes. However, AF on admission had no impact on in-hospital adverse outcome (8.3%) and in-hospital mortality (4.5%). In multivariate logistic regression analyses corrected for AF on admission, NT-proBNP and troponin elevation as well as higher risk classes in risk assessment models remained independent predictors of an in-hospital adverse outcome. CONCLUSION: Atrial fibrillation is a frequent finding in PE, affecting more than 10% of patients. However, AF was not associated with a higher risk of in-hospital adverse outcomes and did not affect the prognostic performance of risk assessment strategies. Thus, our data support the use of risk stratification tools for patients with acute PE irrespective of the heart rhythm on admission.

A prospective cohort study to identify and evaluate endotypes of venous thromboembolism: Rationale and design of the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism project (GMP-VTE).

Several clinical, genetic and acquired risk factors for venous thromboembolism (VTE) have been identified. However, the molecular pathophysiology and mechanisms of disease progression remain poorly understood. This is reflected by uncertainties regarding the primary and secondary prevention of VTE and the optimal duration of antithrombotic therapy. A growing body of literature points to clinically relevant differences between VTE phenotypes (e.g. deep vein thrombosis (DVT) versus pulmonary embolism (PE), unprovoked versus provoked VTE). Extensive links to cardiovascular, inflammatory and immune-related morbidities are testament to the complexity of the disease. The GMP-VTE project is a prospective, multi-center cohort study on individuals with objectively confirmed VTE. Sequential data sampling was performed at the time of the acute event and during serial follow-up investigations. Various data levels (e.g. clinical, genetic, proteomic and platelet data) are available for multi-dimensional data analyses by means of advanced statistical, bioinformatic and machine learning methods. The GMP-VTE project comprises n = 663 individuals with acute VTE (mean age: 60.3 ±â€¯15.9 years; female sex: 42.8%). In detail, 28.4% individuals (n = 188) had acute isolated DVT, whereas 71.6% subjects (n = 475) had PE with or without concomitant DVT. In the study sample, 28.9% (n = 129) of individuals with PE and 30.1% (n = 55) of individuals with isolated DVT had a recurrent VTE event at the time of study enrolment. The systems-oriented approach for the comprehensive dataset of the GMP-VTE project may generate new biological insights into the pathophysiology of VTE and refine our current understanding and management of VTE.

Perivascular adipose tissue: epiphenomenon or local risk factor?

Obesity is associated with an increased cardiovascular risk, but the mechanisms underlying the link between increased body weight and vascular disease are incompletely understood. Over the past 15 years, perivascular adipose tissue has emerged as active component of the vessel wall involved in vascular homeostasis. However, perivascular adipose tissue can adopt detrimental properties under the influence of obesity and other factors and contribute actively to the pathophysiology of cardiovascular disease. Conversely, changes of the vessel wall may negatively affect perivascular adipose tissue qualities. In this review, we will discuss the recent literature on the possible direct and indirect connections between perivascular fat alterations and cardiovascular pathologies. In addition to clinical evidence on the association between perivascular fat mass and morphology and anthropometric measures of obesity or the reciprocal connection between perivascular fat and cardiometabolic risk factors and disease, special emphasis will be placed on results in rodent and other models and the possible direct contribution of local fat depots to vascular dysfunction, neointima formation or atherosclerosis. We will briefly highlight results from human and murine genome, miRNome and proteome-wide expression analyses of potential candidate mediators involved in its paracrine activities and present data on how the cardiovascular risk factors obesity, age or diabetes, but also the preventive measures weight loss or exercise impact on perivascular expression patterns. A better understanding of this unique adipose tissue depot, its properties and regulatory mechanisms, may create opportunities for novel diagnostic and therapeutic strategies to combat the cardiovascular consequences of increased body weight.

Survival and recurrent venous thromboembolism in patients with first proximal or isolated distal deep vein thrombosis and no pulmonary embolism.

Essentials The long-term risk of recurrence and death after distal deep vein thrombosis (DVT) is uncertain. We included subjects with first proximal or isolated distal DVT (IDDVT) and no pulmonary embolism. The risk of symptomatic and asymptomatic recurrence is lower after IDDVT (vs. proximal). IDDVT may be associated with a lower long-term risk of death, especially after unprovoked DVT. SUMMARY: Background A few studies have focused on the risk of recurrence after first acute isolated distal deep vein thrombosis (IDDVT) compared with proximal DVT (PDVT), whereas the incremental risk of death has never been explored beyond the first 3 years after acute event. Methods Our single-center cohort study included patients with first symptomatic acute PDVT or IDDVT. Patients were excluded if they had concomitant pulmonary embolism (PE) or prior venous thromboembolism. The primary outcomes were symptomatic objectively diagnosed recurrent PDVT or PE and all-cause death. Results In total, 4759 records were screened and 831 subjects included: 202 had symptomatic IDDVT and 629 had PDVT. The median age was 66 years and 50.5% were women. A total of 125 patients had recurrent PDVT or PE during 3175 patient-years of follow-up: 109 events occurred after PDVT (17.3%) and 16 after IDDVT (7.9%). Annual recurrence rates were 4.5% (95% confidence interval [CI], 3.7-5.4%) and 2.0% (95% CI, 1.1-3.2%), respectively, for an adjusted hazard ratio (aHR) for IDDVT patients of 0.32 (95% CI, 0.19-0.55). Death occurred in 263 patients (31.6% [95% CI, 28.6-34.9%]) during 5469 patient-years of follow-up for an overall annual incidence rate of 4.8% (95% CI, 4.2-5.4%). The mortality rate was 33.5% (n = 211) in PDVT patients and 25.7% (n = 52) in IDDVT patients. The long-term hazard of death appeared lower for IDDVT patients (aHR, 0.75 [95% CI, 0.55-1.02]), especially after unprovoked events (aHR, 0.58 [95% CI, 0.26-1.31]). Conclusions Compared with PDVT, IDDVT patients were at a lower risk of recurrent VTE. The risk of death appeared lower after IDDVT during a median follow-up of 7.6 years.

[Chronic thromboembolic pulmonary hypertension: Recommendations of the Cologne Consensus Conference 2016]. / Chronisch thromboembolische pulmonale Hypertonie: Empfehlungen der Kölner Konsensus Konferenz 2016.

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH), but also other significant subgroups of pulmonary hypertension (PH). In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). In every patient with PH of unknown cause CTEPH should be excluded. The primary treatment option is surgical pulmonary endarterectomy (PEA) in a specialized multidisciplinary CTEPH center. Inoperable patients or patients with persistent or recurrent CTEPH after PEA are candidates for targeted drug therapy. For balloon pulmonary angioplasty (BPA), there is currently only limited experience. This option - as PEA - is reserved to specialized centers with expertise for this treatment method. In addition, a brief overview is given on pulmonary artery sarcoma, since its surgical treatment is often analogous to PEA. The recommendations of this working group are summarized in the present paper.

Derivation of a clinical prediction score for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism.

UNLABELLED: Essentials Predicting chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism is hard. We studied 772 patients with pulmonary embolism who were followed for CTEPH (incidence 2.8%). Logistic regression analysis revealed 7 easily collectable clinical variables that combined predict CTEPH. Our score identifies patients at low (0.38%) or higher (10%) risk of CTEPH. SUMMARY: Introduction Validated risk factors for the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE) are currently lacking. Methods This is a post hoc patient-level analysis of three large prospective cohorts with a total of 772 consecutive patients with acute PE, without major cardiopulmonary or malignant comorbidities. All underwent echocardiography after a median of 1.5 years. In cases with signs of pulmonary hypertension, additional diagnostic tests to confirm CTEPH were performed. Baseline demographics and clinical characteristics of the acute PE event were included in a multivariable regression analysis. Independent predictors were combined in a clinical prediction score. Results CTEPH was confirmed in 22 patients (2.8%) by right heart catheterization. Unprovoked PE, known hypothyroidism, symptom onset > 2 weeks before PE diagnosis, right ventricular dysfunction on computed tomography or echocardiography, known diabetes mellitus and thrombolytic therapy or embolectomy were independently associated with a CTEPH diagnosis during follow-up. The area under the receiver operating charateristic curve (AUC) of the prediction score including those six variables was 0.89 (95% confidence interval [CI] 0.84-0.94). Sensitivity analysis and bootstrap internal validation confirmed this AUC. Seventy-three per cent of patients were in the low-risk category (CTEPH incidence of 0.38%, 95% CI 0-1.5%) and 27% were in the high-risk category (CTEPH incidence of 10%, 95% CI 6.5-15%). Conclusion The 'CTEPH prediction score' allows for the identification of PE patients with a high risk of CTEPH diagnosis after PE. If externally validated, the score may guide targeting of CTEPH screening to at-risk patients.

Performance of five different bleeding-prediction scores in patients with acute pulmonary embolism.

Bleeding-prediction scores may help guiding management of patients with pulmonary embolism (PE), although no such score has been validated. We aimed to externally validate and compare two bleeding-prediction scores for venous thromboembolism to three scores developed for patients with atrial fibrillation in a real-world cohort of PE patients. We performed a prospective observational cohort study in 448 consecutive PE patients who were treated with heparins followed by vitamin-K-antagonists. The Kuijer, RIETE, HEMORR2HAGES, HAS-BLED and ATRIA scores were assessed at baseline. All patients were followed for the occurrence of major bleeding over a 30-day period. The accuracies of both the overall, original 3-level and newly defined optimal 2-level outcome of the scores were evaluated and compared, both for the 30-day period as well as for bleeding occurring in versus after the first week of treatment. 20 of 448 patients suffered major bleeding resulting in a cumulative incidence of 4.5 % (95 % CI 2.5-6.5). The predictive power of all five scores for bleeding was poor (c-statistics 0.57-0.64), both for the 3-level and 2-level score outcomes. No individual score was found to be superior. The HAS-BLED score had a good c-statistic for bleedings occurring after the first week of treatment (0.75, 95 % CI 0.47-1.0). Current available scoring systems have insufficient accuracy to predict overall anticoagulation-associated bleeding in patients treated for acute PE. To optimally target bleeding-prevention strategies, the development of a high quality PE-specific risk score is urgently needed.

External validation of a simple non-invasive algorithm to rule out chronic thromboembolic pulmonary hypertension after acute pulmonary embolism.

PURPOSE: International guidelines do not provide strong recommendations on the duration and intensity of follow-up after acute pulmonary embolism (PE), nor on screening-programs for chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to address this gab by performing an external validation of the easy "CTEPH rule-out-criteria" based on a normal NT-proBNP level and the absence of 3 ECG characteristics. METHODS: 134 patients underwent clinical follow-up 6months after PE. Predefined transthoracic echocardiographic (TTE) criteria were used to categorize patients as "PH unlikely" or "PH possible/likely". The latter patients underwent further (invasive) diagnostic procedures to confirm and classify the diagnosis of pulmonary hypertension. NT-proBNP and ECGs, both assessed at the day of echocardiography, were evaluated post-hoc. RESULTS: Sixty-three patients (47%) scored none of the "CTEPH rule-out criteria" positive, of whom 61 had normal TTE (97%). Twenty-five patients (19%) were categorized by TTE as "PH possible/likely"; of those, 6 were diagnosed with CTEPH. The sensitivity of rule-out criteria for CTEPH was 100% (95%CI 56-100%; 6/6 patients identified), and for "PH possible/likely" on TTE 92% (95%CI 74-99%; 23/25 patients identified): 2 asymptomatic patients with estimated systolic pulmonary arterial pressure of 36mmHg and 38mmHg, respectively, who remained stable during further 2-year follow-up, were not identified. Inter-observer agreement for the adjudication of the ECG characteristics was excellent (kappa-statistic 0.97). CONCLUSIONS: In this external validation cohort, we confirmed the diagnostic accuracy and reproducibility of the "CTEPH rule-out criteria". These results provide a solid ground for future outcome trials applying this algorithm.

Thrombosis: a major contributor to global disease burden.

BACKGROUND: Thrombosis is the common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused 1 in 4 deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. OBJECTIVE: To review the literature on the global burden of disease caused by VTE. APPROACH AND RESULTS: We performed a systematic review of the literature on the global disease burden because of VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged ≥70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years lost in low- and middle-income countries, and second in high-income countries, responsible for more disability-adjusted life-years lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. CONCLUSIONS: VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems and to evaluate whether improved use of preventive measures will reduce the burden.

The post-PE syndrome: a new concept for chronic complications of pulmonary embolism.

Long-term follow-up studies have consistently demonstrated that after an episode of acute pulmonary embolism (PE), half of patients report functional limitations and/or decreased quality of life up to many years after the acute event. Incomplete thrombus resolution occurs in one-fourth to one-third of patients. Further, pulmonary artery pressure and right ventricular function remain abnormal despite adequate anticoagulant treatment in 10-30% of patients, and 0.5-4% is diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH) which represents the most severe long term complication of acute PE. From these numbers, it seems that CTEPH itself is the extreme manifestation of a much more common phenomenon of permanent changes in pulmonary artery flow, pulmonary gas exchange and/or cardiac function caused by the acute PE and associated with dyspnea and decreased exercise capacity, which in analogy to post-thrombotic syndrome after deep vein thrombosis could be referred to as the post-pulmonary embolism syndrome. The acknowledgement of this syndrome would both be relevant for daily clinical practice and also provide a concept that aids in further understanding of the pathophysiology of CTEPH. In this clinically oriented review, we discuss the established associations and hypotheses between the process of thrombus resolution or persistence, lasting hemodynamic changes following acute PE as well as the consequences of a PE diagnosis on long-term physical performance and quality of life.

[Chronic thromboembolic pulmonary hypertension--a position paper]. / Chronisch thromboembolische pulmonale Hypertonie (CTEPH) 2014. Ein Positionspapier.

This position paper summarises current developments in chronic thromboembolic pulmonary hypertension (CTEPH) including diagnostic approaches and treatment options. Based on the guidelines of the task force of CTEPH experts at the 5th World Symposium on Pulmonary Hypertension in Nice 2013. Open questions arising during the treatment of patients with CTEPH are addressed. Patients with suspected CTEPH should undergo echocardiography and cardiopulmonary exercise testing. A ventilation/perfusion scan is the recommended imaging test for screening in the diagnostic algorithm for the evaluation of CTEPH. CTEPH-patients should be discussed in an expert center with an interdisciplinary team and an experienced PEA surgeon to decide the further treatment. Pulmonary endarterectomy (PEA) is the treatment of choice for patients with CTEPH. Medical therapy with PH-targeted medications for inoperable CTEPH and residual disease after PEA should only be initiated if evaluation reveals that the patient is no candidate for a PEA. Current data suggest that CTEPH patients treated with PEA have a better long-term survival rate and quality of life than patients treated with medical therapy.

Pulmonary embolism hotline 2012. Recent and expected trials.

Management of acute pulmonary embolism (PE) has advanced considerably in the past year, and progress is expected to continue in 2013. To help determine the optimal management strategy for normotensive patients with intermediate-risk PE, the Pulmonary Embolism Thrombolysis (PEITHO) study completed enrolment of 1006 patients with evidence of right ventricular dysfunction (by echocardiography or computed tomography) plus a positive troponin test. Patients have been randomised to thrombolytic treatment with tenecteplase versus placebo, and the effects on clinical end points (death or haemodynamic collapse) assessed at 7 and 30 days. The results are expected in spring 2013; long-term follow-up is also being performed. The results of a randomised trial on ultrasound-enhanced low-dose catheter-delivered thrombolysis will also become available soon. While optimisation of treatment with vitamin K antagonists incorporating pharmacogenetic testing is still being pursued, new oral anticoagulants are entering the field of PE treatment and secondary prophylaxis. Following the successful use of rivaroxaban as single oral drug therapy in the EINSTEIN-PE trial, the approval of this drug has recently been extended to cover, apart from deep vein thrombosis, PE as well. The apixaban (AMPLIFY) and edoxaban (HOKUSAI) trials have finished recruitment of PE patients, and their results will become available shortly. In the meantime, the AMPLIFY-EXT trial showed that both the therapeutic (5 mg twice daily) and the prophylactic dose (2.5 mg twice daily) of apixaban are effective and safe for long-term secondary prophylaxis after PE. For the extended prophylaxis (after the reommended initial anticoagulation period) of the (few) patients who are unable to tolerate any form of anticoagulation, low-dose asprin may be a safe albeit moderately efficacious option, as indicated by two recent investigator-initiated trials with a total of 1224 patients.