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.

[Medicinal treatment of tricuspid valve regurgitation]. / Medikamentöse Therapie der Trikuspidalklappeninsuffizienz.

The vast majority of tricuspid valve regurgitations are of low degree without prognostic relevance in healthy individuals; however, morbidity and mortality increase with the degree of regurgitation, which can be secondary to either primary (structural) or secondary (functional) alterations of the valve. Due to the frequent lack of symptoms, echocardiographic examinations should be annually performed in patients with higher degree (at least moderate) tricuspid valve regurgitation, in particular in the presence of risk factors. Individual therapeutic management strategies should consider the etiology of the tricuspid valve regurgitation, the degree of regurgitation, the valve pathology and the risk-to-benefit ratio of the envisaged therapeutic procedure. Medicinal treatment options for tricuspid valve regurgitation are limited and generalized recommendations cannot be provided due to the lack of conclusive clinical trials. Symptomatic therapeutic measures encompass especially (loop) diuretics for the reduction of preload and afterload of the right ventricle. Pharmaceutical reduction of the heart rate should be avoided in patients with right heart insufficiency. While symptomatic therapeutic measures are often associated with only moderate effects, the most effective therapy of tricuspid valve regurgitation consists in the treatment of underlying illnesses, in most cases pulmonary hypertension due to pulmonary arterial hypertension (PAH), left heart disease or acute pulmonary embolism. Based on a number of published clinical studies and licensing of new drugs, treatment options for patients with PAH and heart failure with reduced ejection fraction (HFrEF) have substantially improved during the past years allowing for a differentiated, individualized management.

[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.

[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.

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.

Long-term clinical course of acute pulmonary embolism.

The long-term clinical course of acute pulmonary embolism (PE) is complicated by high rates of serious adverse events, both before and after cessation of anticoagulant therapy. These adverse events include recurrent venous thromboembolism, chronic thromboembolic pulmonary hypertension, arterial thrombotic events and increased risk of death, all compared to patients without thromboembolic disease. Several pharmacological options are available that may beneficially influence patients' prognosis. Nonetheless, because of insufficient knowledge of the benefit-to-harm ratio of these pharmacological agents, unambiguous recommendations are scarcely available. This review will cover the epidemiological aspects of the various possible complications in the long-term clinical course of acute PE as well as the latest evidence on preventive strategies. In addition, the unresolved issues regarding frequency, duration and focus of medical follow-up after acute PE are discussed.

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.

BMI-independent inverse relationship of plasma leptin levels with outcome in patients with acute pulmonary embolism.

OBJECTIVE: The adipocytokine leptin is an independent cardiovascular risk factor and exerts prothrombotic effects, both in arterial and venous thrombosis. We therefore investigated the relationship between leptin levels and clinical outcome in patients with acute pulmonary embolism (PE). DESIGN: We prospectively studied consecutive patients with confirmed acute PE admitted at the University Hospital of Goettingen (Germany) between 2003 and 2009. SUBJECTS: The study subjects were a total of 264 patients with PE (median age, 68 years; interquartile range, 53-75; 60% women; body mass index (BMI) 27 kg m(-2) (24.1-31.2)). Leptin levels were determined by a commercially available enzyme-linked immunosorbent assay. Patients were followed for an adverse 30-day outcome, that is, death, circulatory collapse with need for catecholamines, intubation or resuscitation, and for long-term survival. RESULTS: The median leptin level was 10.1 ng ml(-1) (3.7-25.2). Patients (n=49; 18.6%) with a complicated 30-day course had significantly lower leptin levels (5.3 ng ml(-1) (1.8-19.7) compared with patients without complications (10.4 ng ml(-1) (4.7-25.5), P=0.02). When leptin was analyzed as a continuous variable, there was a significant 36% increase in the relative risk for early complications for every decrease in the natural logarithm of leptin by one s.d. (odds ratio (OR) 1.36 (1.06-1.76), P=0.017), independently of BMI (BMI-adjusted OR, 1.52 (1.13-2.05), P=0.006). In addition, patients within the lowest leptin tertile had a 2.8- and 2.3-fold increased risk for 30-day-complications, compared with those in the middle (P=0.011) and high tertile (P=0.030), and a worse probability of long-term survival (log-rank; P=0.018). CONCLUSION: Low plasma leptin concentration is a predictor for a complicated course and high mortality in patients with acute PE. This association is independent of known factors affecting leptin levels, including gender and obesity.

Heart-type fatty acid-binding protein for risk assessment of chronic thromboembolic pulmonary hypertension.

Heart-type fatty acid-binding protein (H-FABP) is a reliable marker of myocardial injury and was recently identified as a predictor of outcome in acute pulmonary embolism. The aim of the present study was to investigate the prognostic value of H-FABP in chronic thromboembolic pulmonary hypertension (CTEPH). In total, 93 consecutive patients with CTEPH were studied. During long-term follow-up (median duration 1,260 days, interquartile range (IQR) 708-2,460 days), 46 (49%) patients had an adverse outcome, defined as CTEPH-related death, lung transplantation or persistent pulmonary hypertension after pulmonary endarterectomy (PEA). Baseline H-FABP levels in plasma ranged from 0.69-24.3 ng x mL(-1) (median (IQR) 3.41 (2.28-4.86) ng x mL(-1)). Cox regression analysis revealed a hazard ratio of 1.10 (95% confidence interval 1.04-1.18) for each increase of H-FABP by 1 ng x mL(-1), and continuous elevations of H-FABP emerged as an independent predictor of adverse outcome by multivariable analysis. PEA was performed in 52 patients and favourably affected the long-term outcome. Kaplan-Meier analysis revealed that patients with baseline H-FABP concentrations >2.7 ng x mL(-1), the median value of the biomarker in the surgically treated population, had a lower probability of event-free survival after PEA. Heart-type fatty acid-binding protein is a promising novel biomarker for risk stratification of patients with chronic thromboembolic pulmonary hypertension.