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The holy grail of anticoagulation in patients with intracardiac devices, such as mechanical heart valves (MHVs) and left ventricular assist devices (LVADs), comprises safe prevention of thrombosis without interrupting normal hemostasis. Device-induced thrombosis and anticoagulant-related bleeding problems are dreaded complications that may cause a significantly reduced quality of life and increased morbidity and mortality. Vitamin K antagonists are the current standard for oral anticoagulation therapy in patients with MHVs and LVADs. Even within the therapeutic range, hemorrhage is the primary complication of these drugs, which emphasizes the need for safer anticoagulants for the prevention of device-induced thrombosis. Device-induced thrombosis is a complex multifactorial phenomenon that likely requires anticoagulant therapy targeting multiple pathways. Here, we review the preclinical and clinical data describing the efficacy of a variety of anticoagulants as thromboprophylaxis after implantation of intracardiac devices., Competing Interests: None declared., (Thieme. All rights reserved.)

COVID-19 is associated with a high incidence of thrombotic complications, which can be explained by the complex and unique interplay between coronaviruses and endothelial cells, the local and systemic inflammatory response, and the coagulation system. Empirically, an intensified dose of thrombosis prophylaxis is being used in patients admitted to hospital with COVID-19 and several guidelines on this topic have been published, although the insufficiency of high quality and direct evidence has led to weak recommendations. In this Viewpoint we summarise the pathophysiology of COVID-19 coagulopathy in the context of patients who are ambulant, admitted to hospital, and critically ill or non-critically ill, and those post-discharge from hospital. We also review data from randomised controlled trials in the past year of antithrombotic therapy in patients who are critically ill. These data provide the first high-quality evidence on optimal use of antithrombotic therapy in patients with COVID-19. Pharmacological thromboprophylaxis is not routinely recommended for patients who are ambulant and post-discharge. A first ever trial in non-critically ill patients who were admitted to hospital has shown that a therapeutic dose of low-molecular-weight heparin might improve clinical outcomes in this population. In critically ill patients, this same treatment does not improve outcomes and prophylactic dose anticoagulant thromboprophylaxis is recommended. In the upcoming months we expect numerous data from the ongoing antithrombotic COVID-19 studies to guide clinicians at different stages of the disease., Competing Interests: Declaration of interests JL and TFvH declare no competing interests. PFW reports personal fees from Sanofi, Bayer, Boehringer Ingelheim, Pfizer, and Sandoz. REGS reports grants from CSL Behring, Pfizer, Sanquin, and Sobi; grants and personal fees from Bayer and Novonordisk; and is a member of the scientific advisory board of Freeline, Boehringer Ingelheim, Roche, and Sobi. SM reports grants and personal fees from Daiichi Sankyo, Bayer, Pfizer, and Boehringer Ingelheim; and personal fees from Portola, Abbvie, and Bristol-Myers Squibb-Pfizer. SM is a steering committee member of the RAPID COVID COAG trial. SM and REGS are members of the anticoagulation domain of the REMAP-CAP trial., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Patients with unprovoked (i.e., without the presence of apparent transient risk factors such as recent surgery) venous thromboembolism (VTE) are at risk of recurrence if anticoagulants are stopped after 3-6 months, yet their risk remains heterogeneous. Thus, prolonging anticoagulant treatment should be considered in high-risk patients, whereas stopping is likely preferred in those with a low predicted risk. The Vienna Prediction Model (VPM) could aid clinicians in estimating this risk, yet its clinical effects and external validity are currently unknown. The aim of this study was to investigate the clinical impact of this model on reducing recurrence risk in patients with unprovoked VTE, compared to usual care., Methods and Findings: In a randomized controlled trial, the decision to prolong or stop anticoagulant treatment was guided by predicted recurrence risk using the VPM (n = 441), which was compared with usual care (n = 442). Patients with unprovoked VTE were recruited from local thrombosis services in the Netherlands (in Utrecht, Harderwijk, Ede, Amersfoort, Zwolle, Hilversum, Rotterdam, Deventer, and Enschede) between 22 July 2011 and 30 November 2015, with 24-month follow-up complete for all patients by early 2018. The primary outcome was recurrent VTE during 24 months of follow-up. Secondary outcomes included major bleeding and clinically relevant non-major (CRNM) bleeding. In the total study population of 883 patients, mean age was 55 years, and 507 (57.4%) were men. A total of 96 recurrent VTE events (10.9%) were observed, 46 in the intervention arm and 50 in the control arm (risk ratio 0.92, 95% CI 0.63-1.35, p = 0.67). Major bleeding occurred in 4 patients, 2 in each treatment arm, whereas CRNM bleeding occurred in 20 patients (12 in intervention arm versus 8 in control arm). The VPM showed good discriminative power (c-statistic 0.76, 95% CI 0.69-0.83) and moderate to good calibration, notably at the lower spectrum of predicted risk. For instance, in 284 patients with a predicted risk of >2% to 4%, the observed rate of recurrence was 2.5% (95% CI 0.7% to 4.3%). The main limitation of this study is that it did not enroll the preplanned number of 750 patients in each study arm due to declining recruitment rate., Conclusions: Our results show that application of the VPM in all patients with unprovoked VTE is unlikely to reduce overall recurrence risk. Yet, in those with a low predicted risk of recurrence, the observed rate was also low, suggesting that it might be safe to stop anticoagulant treatment in these patients., Trial Registration: Netherlands Trial Register NTR2680., Competing Interests: The authors have declared that no competing interests exist.

Background: There is a marked lack of evidence on the optimal prevention of ischaemic stroke and other thromboembolic events in patients with non-valvular atrial fibrillation and a recent intracerebral haemorrhage during treatment with oral anticoagulation. These patients are currently treated with oral anticoagulants, antiplatelet drugs, or no antithrombotic treatment, depending on personal and institutional preferences. Compared with warfarin, the direct oral anticoagulant apixaban reduces the risk of stroke or systemic embolism, intracranial haemorrhage, and case fatality in patients with atrial fibrillation. Compared with aspirin, apixaban reduces the risk of stroke or systemic embolism in patients with atrial fibrillation, and has a similar risk of intracerebral haemorrhage. Novel oral anticoagulants have not been evaluated in patients with atrial fibrillation and a recent intracerebral haemorrhage. To inform a phase III trial, the phase II Apixaban versus Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intraCerebral HaEmorrhage in patients with Atrial Fibrillation (APACHE-AF) trial aims to obtain estimates of the rates of vascular death or non-fatal stroke in patients with atrial fibrillation and a recent anticoagulation-associated intracerebral haemorrhage treated with apixaban and in those in whom oral anticoagulation is avoided., Methods/design: APACHE-AF is a phase II, multicentre, open-label, parallel-group, randomised clinical trial with masked outcome assessment. One hundred adults with a history of atrial fibrillation and a recent intracerebral haemorrhage during treatment with anticoagulation in whom clinical equipoise exists on the optimal stroke prevention strategy will be enrolled in 14 hospitals in The Netherlands. These patients will be randomly assigned in a 1:1 ratio to either apixaban or to avoiding oral anticoagulation. Patients in the control group may be treated with antiplatelet drugs at the discretion of the treating physician. The primary outcome is the composite of vascular death or non-fatal stroke during follow-up. We aim to include 100 patients in 2.5 years. All patients will be followed-up for the duration of the study, but at least for 1 year. Recruitment commenced in September 2014 and is ongoing. This trial is funded by the Dutch Heart Foundation (2012 T077) and ZonMW (015008048)., Trial Registration: NTR4526 (16 April 2014).

Introduction: Traditionally, patients with pulmonary embolism (PE) are treated in-hospital until they reach an adequate international normalized ratio (INR). Analogous to patients with a deep venous thrombosis, therapy with low-molecular-weight heparin facilitates out of hospital treatment of PE. We retrospectively analysed the current practice of early anticoagulant therapy in 86 acute PE patients with emphasis on the occurrence and safety of outpatient treatment., Methods: Data were collected from two large regional teaching hospitals and from a specialized anticoagulation clinical, where patients were followed in the period after hospital discharge. The course of hospitalization and LMWH transitioning therapy and the quality of treatment in the first three months after diagnosis were compared between patients discharged before and patients discharged after reaching adequate INR., Results: Forty-four patients (51.2%) were discharged early, before reaching an adequate INR, and 42 patients (48.8%) were discharged after reaching adequate INR. Early discharged patients needed more time to reach adequate INR compared to other patients (13 versus 6 days). In 28 patients (32.6%), the LMWH transitioning therapy was stopped prematurely; 21 patients were from the early discharged group. During the first 3 months, the mean individual times below, in and above the INR range were equal between the two groups., Conclusion: Enhanced compliance to existing guidelines and tools, and further development of guidelines, with focus on intensification of monitoring of INR values in an outpatient setting and preventing premature discontinuation of transitioning therapy, are warranted for a safe and early discharge of stable patients with PE., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Little is known about the differences between unfractionated heparin (UFH) and low molecular weight heparin (LMWH) with regard to their effects on coagulation activity during treatment for pulmonary embolism. The objective of this study was to compare UFH and LMWH (dalteparin) in the early treatment of pulmonary embolism in terms of control of coagulation markers and perfusion abnormalities. Thirty-seven patients with acute pulmonary embolism were randomized to receive intravenous UFH or subcutaneous dalteparin, each accompanied by acenocoumarol. Daily blood samples were obtained for the measurement of thrombin generation (fragments 1 and 2 [F1+2], thrombin-antithrombin (TAT) complexes and fibrin monomers [FMs]) and fibrinolysis (d-dimer concentrations and clot-lysis times). Ventilation-perfusion scintigraphies were performed, and with the data they yielded, percentage of vascular obstruction scores (PVOs) were calculated on days 0 and 5. The international normalized ratio was within the therapeutic range in both groups on day 3. F1+2 and TAT complexes rapidly normalized, without differences between the groups (P =.5 and.4, respectively). FM levels did not decrease and, in fact, showed an increase in the UFH group from day 3 on (P <.05 between groups). d-Dimer levels decreased over time, with no differences between groups (P =.6). Clot-lysis times were shorter in the UFH group (P <.05). PVOs on days 0 and 5 were not different (P =.5 and.8, respectively), but the decrease in PVOs over time was greater in the dalteparin group (P =.04). These results show that dalteparin is at least as effective as UFH in reducing coagulation activity and perfusion abnormalities in the early treatment of pulmonary embolism.

Background: There is a marked lack of evidence on the optimal prevention of ischaemic stroke and other thromboembolic events in patients with non-valvular atrial fibrillation and a recent intracerebral haemorrhage during treatment with oral anticoagulation. These patients are currently treated with oral anticoagulants, antiplatelet drugs, or no antithrombotic treatment, depending on personal and institutional preferences. Compared with warfarin, the direct oral anticoagulant apixaban reduces the risk of stroke or systemic embolism, intracranial haemorrhage, and case fatality in patients with atrial fibrillation. Compared with aspirin, apixaban reduces the risk of stroke or systemic embolism in patients with atrial fibrillation, and has a similar risk of intracerebral haemorrhage. Novel oral anticoagulants have not been evaluated in patients with atrial fibrillation and a recent intracerebral haemorrhage. To inform a phase III trial, the phase II Apixaban versus Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intraCerebral HaEmorrhage in patients with Atrial Fibrillation (APACHE-AF) trial aims to obtain estimates of the rates of vascular death or non-fatal stroke in patients with atrial fibrillation and a recent anticoagulation-associated intracerebral haemorrhage treated with apixaban and in those in whom oral anticoagulation is avoided. Methods/Design: APACHE-AF is a phase II, multicentre, open-label, parallel-group, randomised clinical trial with masked outcome assessment. One hundred adults with a history of atrial fibrillation and a recent intracerebral haemorrhage during treatment with anticoagulation in whom clinical equipoise exists on the optimal stroke prevention strategy will be enrolled in 14 hospitals in The Netherlands. These patients will be randomly assigned in a 1:1 ratio to either apixaban or to avoiding oral anticoagulation. Patients in the control group may be treated with antiplatelet drugs at the discretion of the treating physician. The primary outcome is the composite of vascular death or non-fatal stroke during follow-up. We aim to include 100 patients in 2.5 years. All patients will be followed-up for the duration of the study, but at least for 1 year. Recruitment commenced in September 2014 and is ongoing. This trial is funded by the Dutch Heart Foundation (2012 T077) and ZonMW (015008048). [ABSTRACT FROM AUTHOR]