Optimal follow-up after acute pulmonary embolism: a position paper of the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function, in collaboration with the European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology, endorsed by the European Respiratory Society.

This position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a practical guide to treating patients with acute PE complementary to the formal 2019 European Society of Cardiology guidelines developed with the European Respiratory Society. We propose a holistic approach considering the whole spectrum of serious adverse events that patients with acute PE may encounter on the short and long run. We underline the relevance of assessment of modifiable risk factors for bleeding, of acquired thrombophilia and limited cancer screening (unprovoked PE) as well as a dedicated surveillance for the potential development of chronic thromboembolic pulmonary hypertension as part of routine practice; routine testing for genetic thrombophilia should be avoided. We advocate the use of outcome measures for functional outcome and quality of life to quantify the impact of the PE diagnosis and identify patients with the post-PE syndrome early. Counselling patients on maintaining a healthy lifestyle mitigates the risk of the post-PE syndrome and improves cardiovascular prognosis. Therefore, we consider it important to discuss when and how to resume sporting activities soon after diagnosing PE. Additional patient-relevant topics that require Focused counselling are travel and birth control.

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.

Pharmacokinetics of dabigatran etexilate and rivaroxaban in patients with short bowel syndrome requiring parenteral nutrition: The PDER PAN study.

BACKGROUND AND AIMS: Patients on parenteral nutrition for short bowel syndrome (SBS) have a high risk of thrombotic complications and are often treated with parenteral anticoagulation. Direct oral anticoagulants are absorbed proximally in the digestive tract and may represent alternative regimens in selected SBS patients. In our pilot study, we provided pharmacokinetics parameters of dabigatran etexilate and rivaroxaban in this setting and compared peak (Cmax), trough (Ctrough) concentrations, and areas-under-the-concentration-time-curve (AUC0-t) to reference values retrieved from phase I-III studies. METHODS: We enrolled 6 adults with a remaining small bowel length≤200cm, normal renal/hepatic function, and intact stomach. In our crossover study, patients were exposed to twice-daily dabigatran etexilate 150mg and once-daily rivaroxaban 20mg. RESULTS: After 5days of dabigatran dosing, Ctrough and Cmax geometric means were 39µg/L (90% CI: 23-66) and 88µg/L (90% CI: 56-137), respectively; AUC0-12h was 958µg∗h/L (90% CI: 635-1445). After 5days of rivaroxaban dosing, Ctrough and Cmax geometric means were 9µg/L (90% CI: 1-71) and 167µg/L (90% CI: 102-276), respectively; AUC0-24h was 1720µg∗h/L (90% CI: 899-3300). Absorption was negligible in one patient with ultra-short (~15cm) bowel. For dabigatran, Cmax ratio was 0.57 (SD 0.33) and Ctrough ratio was 0.35 (SD 0.44). For rivaroxaban, the mean observed-to-reference ratios AUC0-24h and Cmax ratios were 0.73 (SD 0.32) and 0.76 (SD 0.34), respectively. CONCLUSIONS: While in SBS patients there is some absorption of the oral anticoagulants dabigatran etexilate and rivaroxaban, it appears to be lower than reference values. Plasma drug levels showed significant inter-individual variability.

Anticoagulants for the prevention and treatment of catheter-related thrombosis in adults and children on parenteral nutrition: a systematic review and critical appraisal.

BACKGROUND: Patients on parenteral nutrition require a central venous access and are at risk of catheter-related thrombosis, pulmonary embolism, and vena cava syndrome. Parenteral nutrition guidelines suggest anticoagulation for the primary prevention of catheter-related thrombosis during long-term parenteral nutrition. We conducted a systematic review of the efficacy, safety and feasibility of anticoagulant use for preventing and treating catheter-related thrombosis during parenteral nutrition. MATERIALS AND METHODS: We searched for interventional and observational studies on adults and children receiving systemic anticoagulants during either short- or long-term parenteral nutrition delivered via central venous access. Primary outcomes were: objectively-confirmed catheter-related thrombosis, pulmonary embolism and bleeding. Secondary outcomes were: heparin-induced thrombocytopenia, prevalence of anticoagulation, and quality of International Normalised Ratio management in vitamin K antagonist-treated patients. RESULTS: We identified 1,199 studies, of which 23 were included. Seven interventional studies of short-term parenteral nutrition (adult population, n=5) were classified as low-quality: in those, intravenous unfractionated heparin did not prevent catheter-related thrombosis if compared to saline. No interventional studies were conducted in patients on long-term parenteral nutrition. Observational data were sparse, rarely focusing on anticoagulation, and overall of low quality. The reported use of anticoagulants was between 22 and 66% in recent multicentre cohorts. DISCUSSION: The amount and quality of data in this area are very suboptimal: most studies are outdated and involved heterogeneous populations. Currently, there is insufficient evidence to allow conclusions to be reached regarding the efficacy and safety of anticoagulants in this setting.

Home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban. Rationale and design of the HoT-PE Trial.

Pulmonary embolism (PE) is a potentially life-threatening acute cardiovascular syndrome. However, more than 95 % of patients are haemodynamically stable at presentation, and among them are patients at truly low risk who may qualify for immediate or early discharge. The Home Treatment of Pulmonary Embolism (HoT-PE) study is a prospective international multicentre single-arm phase 4 management (cohort) trial aiming to determine whether home treatment of acute low-risk PE with the oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe. Patients with confirmed PE, who have no right ventricular dysfunction or free floating thrombi in the right atrium or ventricle, are eligible if they meet none of the exclusion criteria indicating haemodynamic instability, serious comorbidity or any condition mandating hospitalisation, or a familial/social environment unable to support home treatment. The first dose of rivaroxaban is given in hospital, and patients are discharged within 48 hours of presentation. Rivaroxaban is taken for at least three months. The primary outcome is symptomatic recurrent venous thromboembolism or PE-related death within three months of enrolment. Secondary outcomes include quality of life and patient satisfaction, and health care resource utilisation compared to existing data on standard-duration hospital treatment. HoT-PE is planned to analyse 1,050 enrolled patients, providing 80 % power to reject the null hypothesis that the recurrence rate of venous thromboembolism is >3 % with α≤0.05. If the hypothesis of HoT-PE is confirmed, early discharge and out-of-hospital treatment may become an attractive, potentially cost-saving option for a significant proportion of patients with acute PE.

New oral anticoagulants in elderly patients.

The new oral anticoagulants (NOACs) dabigatran etexilate, rivaroxaban, and apixaban have been extensively studied for prevention and treatment of venous thromboembolic disease and for stroke prevention in atrial fibrillation. Elderly patients have the highest incidence of thrombotic complications but also have the highest risk of anticoagulant associated bleeding. In this review we critically examine the balance between risks and benefits of NOACs compared with vitamin K antagonists in elderly patients enrolled in phase 3 randomized controlled trials for the management of venous thrombosis and stroke prevention in atrial fibrillation. Results show that the favourable balance between risks and benefits of NOACs is preserved in the elderly population.