edoxaban and Venous-Thrombosis

Venous thromboembolism is a feared frequent complication of cancer with a 2-way relationship. Low molecular weight heparin is the mainstay of treatment. The use of direct oral anticoagulants is supported by established evidence for the treatment of deep vein thrombosis also in active cancer and they are prioritized over low molecular weight heparin for cancer-associated thrombosis according to current guidelines. However, upper limb deep vein thrombosis is poorly studied with scant data on the use of direct oral anticoagulants in noncatheter-related deep vein thrombosis. We report the case of a patient with noncatheter-related deep vein thrombosis and a rare tumor site effectively and safely treated with a direct oral anticoagulant, edoxaban, after lack of efficacy with low molecular weight heparin.. A 35-year-old man with primitive mediastinal seminoma presented at our Cardio-Oncology Unit for prechemotherapy assessment.. Persistent brachiocephalic deep vein thrombosis, despite full-dose enoxaparin, was detected at ultrasonography.. We decided to switch the anticoagulant treatment from enoxaparin to edoxaban.. The 3-month ultrasonography showed almost total regression of the deep vein thrombosis without any adverse effects and a good patient compliance.. We conducted a literature review on upper limb deep vein thrombosis, since its management is challenging due to inconsistency of evidence. This report highlights the benefits of direct oral anticoagulants compared to low molecular weight heparins in cancer-associated thrombosis therapy in terms of efficacy, safety and ease of use.

Topics: Adult; Anticoagulants; Brachiocephalic Veins; Enoxaparin; Heparin, Low-Molecular-Weight; Humans; Male; Pyridines; Seminoma; Testicular Neoplasms; Thiazoles; Thrombosis; Venous Thrombosis

Venous thromboembolism (VTE) is a common disease with high risk for death and recurrence and can severely impair patients' quality of life. Despite decades of study on this troublesome disease, there are still many unsolved problems in terms of pathogenesis, diagnosis and treatment. Hundreds of articles with various study methods and controversial research results are published every year. Thus it is crucial to keep track of reliable recent studies and articles on VTE in order to better understand it and to handle intricate related clinical events more reasonably. We reviewed high-qualified articles and guidelines from recent years and summarized VTE-related progresses in this review.

Topics: Anticoagulants; Blood Coagulation Factors; Computed Tomography Angiography; Dabigatran; Genetic Predisposition to Disease; Heparin; Humans; Phlebography; Practice Guidelines as Topic; Pulmonary Embolism; Pyridines; Quality of Life; Recurrence; Risk Factors; Thiazoles; Venous Thromboembolism; Venous Thrombosis

New oral anticoagulants (NOACs) are likely to have a major impact in the next few years, changing clinical practice of anticoagulation therapy. Evidence on its efficacy and superiority to vitamin K antagonists (VKAs) in treating non-cancer patients have been reported in a few clinical trials. However, patients with cancer are complicated by the prothrombotic nature of the disease, need for potentially invasive surgery and interventions, and altered drug handling. This chapter examines the available evidence and guidelines on the use of NOAC in patients with cancer.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Catheters, Indwelling; Dabigatran; Drug Administration Schedule; Drug Dosage Calculations; Humans; Neoplasms; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis

To review clinical data on direct oral anticoagulants (DOACs) used in the acute treatment of venous thromboembolism (VTE) as well as practical considerations when using these products.. Searches of PubMed and Google Scholar for VTE, deep vein thrombosis, pulmonary embolism, and relevant drug international nonproprietary names were conducted. Additional online searches were conducted for prescribing information.. Relevant articles on dabigatran, rivaroxaban, apixaban, and edoxaban for the management of VTE compared with oral vitamin K antagonists (VKAs; published between 1966 and December 2015) were reviewed and summarized, together with information on dosing, pharmacokinetics/pharmacodynamics, and drug-drug interactions.. The DOACs have the potential to circumvent many of the disadvantages of VKAs. At a minimum, they greatly increase the available therapeutic options, thus providing a greater opportunity for clinicians to select a management option that best fits the needs of individual patients. Despite the significant advance that DOACs represent, they are not without risk and require careful consideration of a number of clinical issues to optimize safety and efficacy.. The emergence of DOACs for the management of thromboembolic disorders represents a paradigm shift from oral VKAs. The DOACs provide similar efficacy and improved safety in selected patients as compared with VKAs. Clinicians treating VTE need to be familiar with the intricacies involved in using these agents, including the appropriate dose selection for the relevant indication, avoidance of drug-drug and drug-disease interactions, and consideration of dose adjustments in specific clinical situations, such as organ dysfunction.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Drug Interactions; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

Four target-specific oral anticoagulants (TSOA's) have been compared to a vitamin K antagonist for the treatment of acute venous thromboembolism (VTE): dabigatran (D), rivaroxaban (R), apixaban (A) and edoxaban (E). We performed an indirect comparison of the TSOA's, based on the six phase III trials identified (RE-COVER I, RE-COVER II, EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY and Hokusai-VTE). There was no statistically significant difference in risk of recurrent VTE or all-cause mortality between the TSOA's. For major bleeding, the RR of an event was 0.42 (95% CI 0.21-0.87, p = 0.02) for A versus D, compared with 0.57 (95% CI 0.29-1.15, p = 0.12) for A versus R, 0.37 (95% CI 0.19-0.73, p < 0.001) for A versus E, 0.74 (95% CI 0.42-1.30, p = 0.30) for R versus D, 0.64 (95% CI 0.38-1.08, p = 0.10) for R versus E and 1.15 (95% CI 0.66-2.00, p = 0.62) for E versus D. For the composite endpoint of major or clinically relevant nonmajor bleeding, the RR was 0.71 (95% CI 0.53-0.96, p = 0.02) for A versus D, 0.47 (95% CI 0.37-0.61, p < 0.001) for A versus R, 0.54 (95% CI 0.42-0.70, p < 0.001) for A versus E, 1.50 (95% CI 1.17-1.92, p = 0.001) for R versus D, 1.15 (95% CI 0.95-1.39, p = 0.16) for R versus E and 1.31 (95% CI 1.02-1.68, p = 0.04) for E versus D. Overall, apixaban appears to be associated with a lower risk of bleeding than the other TSOA's. This analysis may be helpful to the clinician in trying to balance risk versus benefit in selecting a new anticoagulant. A dedicated randomized trial directly comparing the new agents would be required to confirm these results.

Topics: Acute Disease; Adult; Aged; Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Recurrence; Risk Assessment; Rivaroxaban; Survival Analysis; Thiazoles; Venous Thrombosis

As a class, the target-specific oral anticoagulants (TSOACs) are at least as effective as warfarin, often with superior safety for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and the treatment of acute venous thromboembolism (VTE) and prevention of recurrent VTE. Currently, dabigatran, the direct thrombin inhibitor, along with rivaroxaban and apixaban, direct factor Xa inhibitors, has been approved in multiple countries for these indications. Edoxaban, which has received approval for the abovementioned indications in Japan, has demonstrated efficacy and safety comparable to or better than warfarin in Phase III clinical trials and is under further regulatory consideration. It is anticipated that the use of TSOACs will increase as practitioners and healthcare systems gain familiarity with these drugs and adopt their use into clinical practice. This review will provide a brief overview of the TSOAC Phase III clinical trials for prevention of stroke and systemic embolic events in patients with AF and the Phase III clinical trials for the prevention of recurrent VTE, discuss current treatment guidelines, address how TSOACs may help meet national safety goals, and provide clinical decision-making guidance regarding the use of TSOACs for hospitalists.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Hospitalists; Humans; International Normalized Ratio; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thrombosis; Warfarin

Venous thromboembolism (VTE), manifesting as either deep vein thrombosis or pulmonary embolism, is common worldwide including in Japan. The number of patients clinically diagnosed with VTE is increasing with the majority of cases occurring out-of-hospital and of milder severity. Cancer is the largest risk factor for VTE and VTE in cancer patients confers an increased 1-year mortality rate. However, the majority of VTE cases are considered "idiopathic" or "unprovoked." The limited efficacies of unfractionated heparin and warfarin have stimulated the development of new anticoagulant therapies. Recently, parenteral and oral administration of the Xa inhibitors fondaparinux and edoxaban, respectively, was approved in Japan. These agents have the potential to provide safer and more efficacious treatment options for VTE. Although further randomized studies are required to validate the utility of these agents, they are expected to substantially improve quality of life in VTE patients. This review summarizes the current status of VTE management in Japan focusing on current epidemiology and recent advances in anticoagulant therapy.

Topics: Anticoagulants; Fondaparinux; Heparin; Humans; Japan; Polysaccharides; Pulmonary Embolism; Pyridines; Quality of Life; Risk Factors; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Warfarin

Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately 1 in 1,000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of novel oral anticoagulants (NOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the treatment of DVT.. To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT.. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations.. We included randomised controlled trials in which people with a DVT confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT.. Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third review author (PK). We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and PE. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI).. We included 11 randomised controlled trials of 27,945 participants. Three studies tested oral DTIs (two dabigatran and one ximelagatran), while eight tested oral factor Xa inhibitors (four rivaroxaban, two apixaban and two edoxaban). We deemed all included studies to be of high methodological quality and low risk of bias. The quality of the evidence was graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the ORs. Meta-analysis of three studies (7596 participants) comparing oral DTIs with standard anticoagulation groups showed no difference in the rate of recurrent VTE (OR 1.09; 95% CI 0.80 to 1.49), recurrent DVT (OR 1.08; 95% CI 0.74 to 1.58), fatal PE (OR 1.00; 95% CI 0.27 to 3.70), non-fatal PE (OR 1.12; 95% CI 0.66 to 1.90) or all-cause mortality (OR 0.82; 95% CI 0.60 to 1.13). However, oral DTIs were associated with reduced bleeding (OR 0.68; 95% CI 0.47 to 0.98). Meta-analysis of eight studies (16,356 participants) comparing oral factor Xa inhibitors with standard anticoagulation demonstrated a similar rate of recurrent VTE between the two treatments (OR 0.89; 95% CI 0.73 to 1.07). Oral factor Xa inhibitors were associated with a lower rate of recurrent DVT (OR 0.75; 95% CI 0.57 to 0.98). However, this was a weak association, heavily dependent on one study. The rate of fatal (OR 1.20; 95% CI 0.71 to 2.03), non-fatal PE (OR 0.94; 95% CI 0.68 to 1.28) and all-cause mortality (OR 0.90; 95% CI 0.65 to 1.23) was similar between the two treatment groups. Oral factor Xa inhibitors were also associated with reduced bleeding (OR 0.57; 95% CI 0.43 to 0.76). None of the included studies measured post-thrombotic syndrome or health-related quality of life.. NOACs such as DTIs and factor Xa inhibitors may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

Topics: Administration, Oral; Antithrombins; Azetidines; Benzylamines; Dabigatran; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thrombosis

Edoxaban (Lixiana, Savaysa) is an oral, direct factor Xa inhibitor which has recently been approved for use in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) [collectively, venous thromboembolism (VTE)] and for the prevention of recurrent VTE. This article reviews the pharmacological properties of edoxaban as well as its tolerability and therapeutic efficacy in the treatment and prevention of recurrent VTE events. As demonstrated in the pivotal Hokusai-VTE phase III trial, once-daily edoxaban after initial treatment with heparin was non-inferior to standard therapy with heparin/warfarin in preventing recurrent VTE events and was associated with a significantly lower risk of clinically relevant bleeding than the traditional therapy. Edoxaban shares the advantages of other direct oral anticoagulants (DOACs) over traditional therapies, including the lack of requirement for routine coagulation monitoring, a rapid onset and offset of action, and few drug-drug interactions. It offers the convenience of once-daily dosing, can be taken without regard to food and allows for a dose reduction in patients with certain clinical features, such as moderate renal impairment or low body weight. In conclusion, edoxaban represents an effective and potentially safer alternative to traditional vitamin K antagonist therapy for the treatment and prevention of recurrent VTE. Its recent approval expands the range of DOAC agents for recurrent VTE, further facilitating treatment individualization.

Topics: Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyridines; Thiazoles; Venous Thrombosis

Pulmonary embolism is a potentially life-threatening condition in which a clot can travel from the deep veins, most commonly in the leg, up to the lungs. Previously, a pulmonary embolism was treated with the anticoagulants heparin and vitamin K antagonists. Recently, however, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the long-term treatment (minimum duration of three months) of pulmonary embolism.. To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the long-term treatment of pulmonary embolism.. The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). Clinical trials databases were also searched for details of ongoing or unpublished studies. We searched the reference lists of relevant articles retrieved by electronic searches for additional citations.. We included randomised controlled trials in which patients with a pulmonary embolism confirmed by standard imaging techniques were allocated to receive an oral DTI or an oral factor Xa inhibitor for the long-term (minimum duration three months) treatment of pulmonary embolism.. Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third author (PK). We used meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent venous thromboembolism and pulmonary embolism. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI).. We included five randomised controlled trials with a total of 7897 participants. Two studies tested oral DTIs (dabigatran) and three studies tested oral factor Xa inhibitors (one rivaroxaban, one edoxaban and one apixaban).Analysis showed no difference in the effectiveness of oral DTIs and standard anticoagulation in preventing recurrent pulmonary embolism (OR 1.02, 95% CI 0.50 to 2.04; two studies; 1602 participants; high quality evidence), recurrent venous thromboembolism (OR 0.93, 95% CI 0.52 to 1.66; two studies; 1602 participants; high quality evidence), deep vein thrombosis (DVT) (OR 0.79, 95% CI 0.29 to 2.13; two studies; 1602 participants; high quality evidence) and major bleeding (OR 0.50, 95% CI 0.15 to 1.68; two studies; 1527 participants; high quality evidence).For oral factor Xa inhibitors, when we combined the three included studies together in meta-analyses, there was significant heterogeneity for recurrent pulmonary embolism (OR 1.08, 95% CI 0.46 to 2.56; two studies; 4509 participants; I(2) = 58%; moderate quality evidence). The oral factor Xa inhibitors were no more or less effective in the prevention of recurrent venous thromboembolism (OR 0.85, 95% CI 0.63 to 1.15; three studies; 6295 participants; high quality evidence), DVT (OR 0.72, 95% CI 0.39 to 1.32; two studies; 4509 participants; high quality evidence), all-cause mortality (OR 1.16, 95% CI 0.79 to 1.70; one study; 4817 participants; moderate quality evidence) or major bleeding (OR 0.97, 95% CI 0.59 to 1.62; two studies; 4507 participants; high quality evidence). None of the studies measured quality of life.. Moderate to high quality evidence suggests that there are no differences between DOACs and standard anticoagulation for the long-term treatment of pulmonary embolism, for the outcomes recurrent pulmonary embolism, recurrent venous thromboembolism, DVT, all-cause mortality and major bleeding.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Dabigatran; Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thromboembolism; Venous Thrombosis

Dabigatran (a direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct activated factor X inhibitors) are increasingly being used in clinical practice. Compared with vitamin K antagonists, they are more convenient, do not require laboratory monitoring, have limited drug and food interactions, and have fixed dosages suitable for most patients. But the shortcomings of these agents can jeopardize their efficacy and increase the risk of bleeding. Their future role in preventing and treating thromboembolic disease will depend on building clinical experience, but current evidence indicates that they are reasonable alternatives to vitamin K antagonists.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thrombosis

Anticoagulation remains the cornerstone of treatment in patients with deep vein thrombosis (DVT). While parenteral anticoagulants and oral vitamin K antagonists (e.g., warfarin) have been used for many decades, the recent development of novel oral anticoagulants have provided clinicians with an expanding set of therapeutic options for DVT. This review summarizes the pharmacology and clinical trial results of these new oral anticoagulants. Several practical considerations to the use of these oral anticoagulants including issues related to adherence, monitoring, and reversal are also discussed.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Medication Adherence; Morpholines; Patient Selection; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thrombosis

Vitamin K antagonists (VKAs) remain the standard therapy for anticoagulation in prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in atrial fibrillation (AF). Due to numerous limitations of VKAs, target-specific oral anticoagulants have been developed. Edoxaban is a direct activated factor X inhibitor with attractive features among which are once daily dosing, no need for routine monitoring, and minimal drug-drug interactions. In patients undergoing orthopedic surgery, edoxaban was superior to enoxaparin in preventing VTE. Furthermore, a recent large-scale phase III trial in patients with symptomatic VTE demonstrated that edoxaban was noninferior to warfarin in preventing recurrent VTE and reduced bleeding. In the largest trial of anticoagulation in patients with AF to date, edoxaban was noninferior to warfarin in the prevention of stroke or systemic embolism and reduced bleeding and cardiovascular mortality. This review provides an overview of the pharmacology, clinical trial results, and potential indications for edoxaban.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Randomized Controlled Trials as Topic; Thiazoles; Treatment Outcome; Venous Thrombosis; Warfarin

Perioperative pulmonary thromboembolism (PTE) occurred in 2.93 per 10,000 cases and mortality of PTE was 14% in Japan according to the surveillance of Japanese Society of Anesthesiologists from 2009 to 2011. Anesthesiologists have to evaluate perioperative venous thromboembolism (VTE) risk carefully and take adequate measures to prevent PTE. The first step is the assessment of the preoperative probability of VTE and the next step is the assessment of the risk for VTE during and after operation. If a patient has moderate probability of VTE preoperatively, diagnostic procedures are recommended. If the d-dimer is positive, whole-leg ultrasound is recommended. If DVT is positive in proximal vein, further investigation or anticoagulant therapy are considered. Primary preventions of VTE during and after surgeries are as follows. In patients with low or moderate risks for VTE, intermittent pneumatic compression is recommended. In patients with high risks for VTE, pharmacologic prophylaxes are recommended. In recent years newly developed anticoagulants can be available other than low-dose unfractionated heparin. However, the incidence of VTE in Japanese populations is different from western countries. Moreover our own evidence has not fully been accumulated yet. Therefore further investigations for prevention of perioperative VTE in Japan are expected for our own new guidelines.

Topics: Anesthesia, Epidural; Anticoagulants; Biomarkers; Diagnostic Imaging; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Intraoperative Complications; Perioperative Care; Postoperative Complications; Practice Guidelines as Topic; Pulmonary Embolism; Pyridines; Risk Factors; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Warfarin

In the last few years, several phase III clinical trials of new drug treatments for deep vein thrombosis (DVT) have been carried out or are about to finish. These drugs have a predictable and reliable pharmacokinetic and pharmacodynamic response and do not require monitoring and are consequently an attractive alternative for the treatment of a high proportion of patients with DVT. Dabigatran, edoxaban and idrabiotaparinux have been developed as an alternative to warfarin, and apixaban and rivaroxaban as one-drug only treatment for this disease, with a 1- or 3-week intensified phase of initial treatment, respectively. So far, the reported results show non-inferior efficacy and safety to warfarin or to conventional treatment. Therefore, the new anticoagulants will be particularly useful in patients with unstable INRs, warfarin incompatible pharmacologic interactions, and in those without access to regular coagulation monitoring.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Biotin; Clinical Trials, Phase III as Topic; Dabigatran; Drug Administration Schedule; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thrombosis

Topics: Administration, Oral; Animals; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Drug Design; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Intracranial Thrombosis; Postoperative Complications; Pyridines; Secondary Prevention; Thiazoles; Thrombosis; Venous Thrombosis

Topics: Animals; Anticoagulants; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Factor Xa Inhibitors; Humans; Intracranial Thrombosis; Macaca fascicularis; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thrombosis

The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding.. In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point.. From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point.. In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death.. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.

Topics: Aged; Anticoagulants; Female; Hemorrhage; Humans; Male; Neoplasms; Thrombosis; Venous Thromboembolism; Venous Thrombosis

Patients with active cancer and venous thromboembolism (VTE) are at high risk of recurrence. Therefore, continued anticoagulant therapy beyond the initial 6 months is suggested in this patient population, but evidence supporting this approach is limited.. The Hokusai VTE Cancer trial compared edoxaban with dalteparin for VTE treatment in patients with active cancer. This post hoc analysis focused on the follow-up period from 6 to 12 months. The primary outcome was the composite of adjudicated first recurrent VTE or major bleeding. Secondary outcomes included recurrent VTE, major bleeding, and clinically relevant bleeding.. Of the 522 and 524 patients randomized to edoxaban or dalteparin, 294 (56%) received edoxaban and 273 (52%) received dalteparin for more than 6 months (median duration of 318 and 211 days, respectively). Between 6 and 12 months, the primary outcome during study treatment occurred in seven patients (2.4%) in the edoxaban group and six patients (2.2%) in the dalteparin group (unadjusted hazard ratio 1.05; 95% confidence interval, 0.36-3.05). Recurrent VTE occurred in two patients (0.7%) in the edoxaban group and in three patients (1.1%) in the dalteparin group, whereas major bleeding occurred in 5 (1.7%) and three patients (1.1%), respectively.. The rates of recurrent VTE or major bleeding are relatively low among patients with active cancer receiving extended anticoagulant therapy beyond 6 months. Extended treatment with oral edoxaban appears as effective and safe as subcutaneous dalteparin.

Topics: Aged; Blood Coagulation; Dalteparin; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Neoplasms; Prospective Studies; Pulmonary Embolism; Pyridines; Recurrence; Risk Factors; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

An analysis of the activated partial thromboplastin time (APTT) in major orthopedic surgery patients receiving edoxaban for the prevention of venous thromboembolism (VTE) was carried out.. The APTT waveform was analyzed in the above patients to monitor edoxaban administration.. Of these 99 patients, 12 exhibited deep vein thrombosis, and 25 had massive bleeding. An increased biphasic pattern of the APTT waveform was observed after the administration of edoxaban, but there were no significant differences between the patients with and without complications. The peak times of acceleration, velocity, and 1/2 fibrin formation were significantly prolonged after the administration of edoxaban, especially in patients with massive bleeding, and were moderately correlated with the anti-Xa activity. While the heights of velocity and acceleration peak 2 were lower in patients receiving warfarin treatment than in those receiving edoxaban, the widths of these parameters were significantly longer. The height of 1/2 fibrin formation and the width of acceleration peaks 1 and 2 and the velocity were significantly increased after the administration of edoxaban.. The peak time of the APTT waveform was significantly prolonged after the administration of edoxaban. The analysis of the APTT waveform may therefore be useful for the prediction of the risk of massive bleeding.

Topics: Aged; Drug Monitoring; Hemorrhage; Humans; Male; Middle Aged; Orthopedic Procedures; Partial Thromboplastin Time; Pyridines; Thiazoles; Venous Thromboembolism; Venous Thrombosis

Sudden death in patients with severe motor and intellectual disabilities (SMID) is sometimes caused in part by pulmonary thromboembolism (PTE), and deep venous thrombosis (DVT) has drawn attention as a possible embolic source. Warfarin, which is a conventional therapeutic agent, is not easy to control appropriately, and daily management can be especially difficult in SMID patients. On the other hand, edoxaban tosilate hydrate, which has been newly approved for insurance coverage for the treatment of DVT, is not listed in the Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (DVT-PTE guidelines). The aim of this study is to evaluate the efficacy and safety of anticoagulation therapy (warfarin vs. edoxaban) in DVT treatment in SMID patients by means of an open-label, randomized controlled trial. The primary endpoint is the incidence of hemorrhagic events during 12 months of follow up.

Topics: Anticoagulants; Factor Xa Inhibitors; Hemorrhage; Humans; Intellectual Disability; Intelligence; Japan; Motor Activity; Motor Disorders; Multicenter Studies as Topic; Persons with Mental Disabilities; Pyridines; Randomized Controlled Trials as Topic; Thiazoles; Time Factors; Treatment Outcome; Venous Thrombosis; Warfarin

This study aimed to determine the appropriate administration duration of edoxaban 15 mg (a factor Xa inhibitor) for the prevention of deep vein thrombosis (DVT) after total knee arthroplasty (TKA).. Our study comprised 202 patients who underwent TKA (excluding bilateral TKA) at our institution between 2014 and 2015. The subjects received edoxaban 15 mg daily for 1 (n = 93) or 2 (n = 109) weeks; group assignment was random. B-mode ultrasonography was performed 7 and 14 days post-TKA for the detection of DVT. We compared the incidence of DVT between the groups and examined for side effects.. The demographic data of the patients in the 1- and 2-week administration groups were similar at baseline. DVT incidence did not differ significantly between the groups at 1 week post-TKA. However, it was significantly lower in the 2-week administration group (n = 0) than in the 1-week administration group (n = 7; p = 0.004) at 2 weeks post-DVT. Neither group exhibited symptomatic DVT. A total of six patients withdrew during the study period because of hepatic dysfunction.. Our results show that the administration of edoxaban 15 mg is more effective in preventing DVT after TKA when administered for 2 weeks than for 1 week.

Topics: Aged; Aged, 80 and over; Arthritis; Arthroplasty, Replacement, Knee; Drug Administration Schedule; Factor Xa Inhibitors; Female; Humans; Incidence; Male; Middle Aged; Postoperative Complications; Prospective Studies; Pyridines; Thiazoles; Venous Thromboembolism; Venous Thrombosis

The purpose of this study was twofold: to investigate whether edoxaban significantly decreases the rate of venous thromboembolism (VTE) following closed-wedge high tibial osteotomy (CWHTO), in terms of phlebographic event, and to determine whether edoxaban is safe or increases the rate of hemorrhagic complications. We hypothesized that edoxaban would decrease the incidence of VTE and would not increase the rate of hemorrhagic complications.. We randomly enrolled 60 patients undergoing CWHTO. The patients were divided into two groups: one group receiving edoxaban (15mg in 5 patients, 30mg in 23 patients) and a non-edoxaban group. All patients underwent computed tomography venography on day 7to diagnose postoperative VTE. Blood samples were obtained on the day before CWHTO and on postoperative days 1, 3, 7 and 14. The incidence of VTE and hemorrhagic events in both groups was compared using unpaired Student t-test or chi-square test.. The incidence of VTE was significantly greater in the non-edoxaban group (31.3% versus 7.1%; P=0.02). The incidence of deep vein thrombosis (DVT) was also significantly greater in the non-edoxaban group (28.1% versus 3.6%; P=0.01). A single patient from the edoxaban group experienced major bleeding. On days 3 and 7, D-dimer levels were significantly lower in the edoxaban group (P=0.03 and 0.003, respectively). On days 3, 7 and 14, activated partial thromboplastin time was significantly greater in the edoxaban group (P=0.02, 0.01 and 0.006, respectively).. Patients undergoing CWHTO are at risk of postoperative VTE. Edoxaban helps prevent asymptomatic phlebographic VTE and DVT following CWHTO; however, the risk of major bleeding must be considered.. II.

Topics: Aged; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; Male; Middle Aged; Osteotomy; Partial Thromboplastin Time; Phlebography; Postoperative Complications; Postoperative Period; Prospective Studies; Pyridines; Thiazoles; Tibia; Tomography, X-Ray Computed; Venous Thromboembolism; Venous Thrombosis

We conducted a randomized clinical trial to compare the effectiveness of the A-V Impulse System foot pump for reducing the incidence of deep-vein thrombosis (DVT) after total knee arthroplasty (TKA) in patients under edoxaban thromboprophylaxis. Patients undergoing primary TKA at our institution between September 2013 and March 2015 were enrolled after obtaining informed consent. The patients were randomized to use the foot pump (n = 58) and not to use the foot pump (n = 62). Both groups were given prophylactic edoxaban. Primary outcomes were any DVT as detected by bilateral ultrasonography up to postoperative day 10 (POD10) and pulmonary embolism (PE) up to POD28. The safety outcomes were bleeding and death of any cause up to POD28. Plasma D-dimer levels were measured before TKA and on POD10 after TKA. Immunoglobulin G (IgG)-class anti-PF4/heparin antibodies were measured using an IgG-specific enzyme-linked immunosorbent assay. The incidences of any DVT up to POD28 were 31.0% and 17.7% in patients with or without the foot pump, respectively. The incidences of major bleeding up to POD28 were 5.1% and 4.8% in patients with or without the foot pump, respectively. Foot pump use did not significantly reduce the incidence of DVTs in patients undergoing TKA under edoxaban thromboprophylaxis. Although seroconversion of anti-PF4/heparin antibodies was confirmed in one-fourth of patients, the seroconversion rates did not differ between patients with (20.7%) or without (25.8%) foot pump use. This study shows that the A-V Impulse system foot pump did not affect the incidence of DVT under edoxaban thromboprophylaxis in patients undergoing TKA. Seroconversion of anti-PF4/heparin antibodies was detected in a significant number of patients who underwent TKA under antithrombotic prophylaxis using edoxaban.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Knee; Body Mass Index; Female; Humans; Incidence; Japan; Male; Physical Therapy Modalities; Postoperative Complications; Pulmonary Embolism; Pyridines; Sex Factors; Thiazoles; Venous Thrombosis

The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14-21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a 'bridge' to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14-21 was similar in patients treated with edoxaban and parenteral anticoagulation as a 'bridge' to warfarin (-50.1% vs -58.9%; 95% confidence interval of treatment difference, -12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens.ClinicalTrials.gov IDENTIFIER NCT01662908: INVESTIGATIONAL NEW DRUG IND APPLICATION EDOXABAN IND # 63266.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Anticoagulants; Blood Coagulation; Drug Therapy, Combination; Factor Xa Inhibitors; Feasibility Studies; Female; Heparin; Humans; International Normalized Ratio; Magnetic Resonance Angiography; Male; Middle Aged; Phlebography; Predictive Value of Tests; Pyridines; Thiazoles; Time Factors; Treatment Outcome; United States; Venous Thrombosis; Warfarin

Edoxaban exposure-response relationships from the phase III study evaluating edoxaban for prevention and treatment of venous thromboembolism (VTE) in patients with acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were assessed by parametric time-to-event analysis. Statistical significant exposure-response relationships were recurrent VTE with hazard ratio (HR) based on average edoxaban concentration at steady state (Cav) (HRCav) = 0.98 (i.e., change in the HR with every 1 ng/mL increase of Cav); the composite of recurrent DVT and nonfatal PE with HRCav = 0.99; and the composite of recurrent DVT, nonfatal PE, and all-cause mortality HRCav = 0.98, and all death using maximal edoxaban concentration (Cmax) with HR (Cmax) = 0.99. No statistical significant exposure-response relationships were found for clinically relevant bleeding or major adverse cardiovascular event. Results support the recommendation of once-daily edoxaban 60 mg, and a reduced 30 mg dose in patients with moderate renal impairment, body weight ≤60 kg, or use of P-glycoprotein inhibitors verapamil or quinidine.

Topics: Aged; Double-Blind Method; Drug Dosage Calculations; Factor Xa Inhibitors; Female; Humans; Male; Pulmonary Embolism; Pyridines; Risk Assessment; Thiazoles; Venous Thrombosis; Warfarin

We evaluated a magnetic resonance venography (MRV) approach with gadofosveset to quantify total thrombus volume changes as the principal criterion for treatment efficacy in a multicenter randomized study comparing edoxaban monotherapy with a heparin/warfarin regimen for acute, symptomatic lower extremities deep vein thrombosis (DVT) treatment. We also used a direct thrombus imaging approach (DTHI, without the use of a contrast agent) to quantify fresh thrombus. We then sought to evaluate the reproducibility of the analysis methodology and applicability of using 3D magnetic resonance venography and direct thrombus imaging for the quantification of DVT in a multicenter trial setting. From 10 randomly selected subjects participating in the edoxaban Thrombus Reduction Imaging Study (eTRIS), total thrombus volume in the entire lower extremity deep venous system was quantified bilaterally. Subjects were imaged using 3D-T1W gradient echo sequences before (direct thrombus imaging, DTHI) and 5 min after injection of 0.03 mmol/kg of gadofosveset trisodium (magnetic resonance venography, MRV). The margins of the DVT on corresponding axial, curved multi-planar reformatted images were manually delineated by two observers to obtain volumetric measurements of the venous thrombi. MRV was used to compute total DVT volume, whereas DTHI was used to compute volume of fresh thrombus. Intra-class correlation (ICC) and Bland Altman analysis were performed to compare inter and intra-observer variability of the analysis. The ICC for inter and intra-observer variability was excellent (0.99 and 0.98, p <0.001, respectively) with no bias on Bland-Altman analysis for MRV images. For DTHI images, the results were slightly lower (ICC = 0.88 and 0.95 respectively, p <0.001), with bias for inter-observer results on Bland-Altman plots. This study showed feasibility of thrombus volume estimation in DVT using MRV with gadofosveset trisodium, with good intra- and inter-observer reproducibility in a multicenter setting.

Topics: Contrast Media; Gadolinium; Humans; Leg; Magnetic Resonance Angiography; Organometallic Compounds; Pelvis; Pyridines; Reproducibility of Results; Thiazoles; Venous Thrombosis

Direct oral anticoagulants have been evaluated for their efficacy and safety in the treatment of venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism. The randomized, double-blind Hokusai-VTE trial demonstrated that 60 mg of edoxaban once daily following initial heparin treatment is non-inferior to heparin overlapped with and followed by warfarin for the treatment of VTE, and is associated with significantly fewer bleeding events.. To assess the efficacy and safety of edoxaban versus warfarin among East Asian patients enrolled in the Hokusai-VTE trial.. The Hokusai-VTE trial enrolled 8292 patients from 439 centers worldwide, including 1109 patients from Japan, China, Korea, and Taiwan. The primary efficacy and safety outcomes were symptomatic recurrent VTE and clinically relevant bleeding, respectively.. In the overall East Asian population, the primary efficacy outcome of symptomatic recurrent VTE occurred in 16 of 563 (2.8%) patients in the edoxaban group versus 24 of 538 (4.5%) patients in the warfarin group (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.34-1.19; P = 0.1601). The primary safety outcome of clinically relevant bleeding occurred in 56 of 563 (9.9%) patients in the edoxaban group versus 93 of 538 (17.3%) patients in the warfarin group (HR 0.56; 95% CI 0.40-0.78; P < 0.001).. Edoxaban is an effective and safer alternative to warfarin in East Asian patients with acute VTE who require anticoagulant therapy, consistent with overall study findings from the Hokusai-VTE trial.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Asia, Eastern; Asian People; Double-Blind Method; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Pulmonary Embolism; Pyridines; Recurrence; Therapeutic Equivalency; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin; Young Adult

This study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism in the Hokusai-VTE phase 3 study. The impact of the protocol-specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CL(cr)) of 30 to 50 ml min(-1) or concomitant P-glycoprotein inhibitor on edoxaban exposure was assessed using simulations.. The sparse data from Hokusai-VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.. A linear two-compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non-renal and renal. The latter increased non-linearly with increasing CL(cr). Compared with healthy volunteers, inter-compartmental clearance and the CL(cr) covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co-administration of P-glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model-based simulations revealed lower exposure in dose-reduced compared with non-dose-reduced patients.. The adopted dose-reduction strategy resulted in reduced exposure compared with non-dose-reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.

Topics: Adolescent; Adult; Aged; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Models, Biological; Pulmonary Embolism; Pyridines; Thiazoles; Venous Thrombosis

Direct oral anticoagulants may be effective and safe for treatment of venous thromboembolism (VTE) in cancer patients, but they have not been compared with low-molecular-weight heparin (LMWH), the current recommended treatment for these patients. The Hokusai VTE-cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. We present the rationale and some design features of the study. One such feature is the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. These two complications occur frequently in cancer patients receiving anticoagulant treatment and have a significant impact. The evaluation beyond six months will fill the current gap in the evidence base for the long-term treatment of these patients. Based on the observation that the risk of recurrent VTE in patients with active cancer is similar to that in those with a history of cancer, the Hokusai VTE-cancer study will enrol patients if whose cancer was diagnosed within the past two years. In addition, patients with incidental VTE are eligible because their risk of recurrent VTE is similar to that in patients with symptomatic disease. The unique design features of the Hokusai VTE-cancer study should lead to enrolment of a broad spectrum of cancer patients with VTE who could benefit from oral anticoagulant treatment.

Topics: Adult; Anticoagulants; Dalteparin; Double-Blind Method; Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Prospective Studies; Pulmonary Embolism; Pyridines; Recurrence; Research Design; Sample Size; Thiazoles; Time Factors; Treatment Outcome; Venous Thrombosis

Edoxaban, an oral direct factor Xa inhibitor, has proven antithrombotic efficacy. In a multicenter, phase II study, 264 total hip arthroplasty (THA) patients randomly received edoxaban 15 or 30 mg once daily or enoxaparin 2000IU (20-mg) twice daily for 11-14 days. Thromboembolic event incidences were 3.8% (3/78), 2.8% (2/72), and 4.1% (3/74) for edoxaban 15-mg, 30-mg, and enoxaparin, respectively (P=1.00). Edoxaban-induced prolongation of prothrombin time, international normalized ratio, and activated partial thromboplastin time were proportional to plasma edoxaban concentration. Major or clinically relevant non-major bleeding incidences were 2.2% (2/89), 1.2% (1/85), and 2.3% (2/87) for edoxaban 15-mg, 30-mg, and enoxaparin, respectively (P=1.00). Once-daily edoxaban showed similar efficacy and safety to enoxaparin for prevention of thromboembolic events in patients undergoing THA.

Topics: Aged; Antithrombins; Arthroplasty, Replacement, Hip; Double-Blind Method; Enoxaparin; Factor Xa Inhibitors; Female; Humans; Japan; Male; Middle Aged; Pyridines; Taiwan; Thiazoles; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

Factor Xa (FXa) is a key serine protease in the coagulation cascade and a promising target for a new antithrombotic agent. Edoxaban is an oral, selective and direct FXa inhibitor. The objective of this study was to compare the antithrombotic and haemorrhagic effects of edoxaban with clinically available anticoagulants, warfarin and enoxaparin, in rat models of thrombosis and haemorrhage.. Rats were treated with single oral administration of edoxaban, repeated oral dosing of warfarin for 4 days and single subcutaneous administration of enoxaparin before thrombosis or haemorrhage induction. Thrombosis was induced by the insertion of a platinum wire into the inferior vena cava for 60 min. Tail template bleeding time was measured after making an incision on the tail.. Edoxaban at 0.3, 1 and 3mg/kg exerted dose-dependent and significant inhibition of venous thrombus formation. The 50% thrombus inhibition dose (ED(50)) was 1.9 mg/kg. At supra-therapeutic doses (10 and 20mg/kg), edoxaban significantly but moderately (less than 2-fold) prolonged bleeding time. Warfarin and enoxaparin also dose-dependently inhibited venous thrombosis and prolonged bleeding time. The ED(50) values of warfarin and enoxaparin were 0.12 mg/kg and 500 IU/kg, and the 2-fold bleeding time prolongation doses (BT2) were 0.16 mg/kg and 1700 IU/kg, respectively. The safety margin (ratio of BT2 to ED(50)) of edoxaban (>10.5) was greater than those of warfarin (1.3) and enoxaparin (3.4).. Edoxaban inhibited venous thrombosis comparably to warfarin and enoxaparin, and the attendant bleeding risk of edoxaban was lower than that of warfarin and enoxaparin in rats.

Topics: Administration, Oral; Animals; Anticoagulants; Enoxaparin; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Hemostatics; Male; Pyridines; Rats; Rats, Wistar; Thiazoles; Treatment Outcome; Venous Thrombosis; Warfarin

Edoxaban is a new oral direct factor Xa inhibitor. The purpose of this study was to evaluate the efficacy and safety of different doses of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement. A total of 903 patients were randomised to oral edoxaban 15, 30, 60 or 90 mg once daily or subcutaneous dalteparin once daily (initial dose 2,500 IU, subsequent doses 5,000 IU). Both drugs were begun 6-8 hours postoperatively and continued for 7-10 days, when bilateral venography was performed. The primary efficacy endpoint was the incidence of total VTE, which included proximal and/or distal deep-vein thrombosis (DVT) by venography or symptomatic, objectively confirmed DVT or pulmonary embolism during the treatment period. The primary safety outcome was the incidence of the composite of major and clinically relevant non-major bleeding. All venograms and bleeding events were reviewed by a central independent adjudication committee blinded as to treatment allocation. Of the 903 patients randomised, 776 were evaluable for the primary efficacy analysis. The incidences of VTE were 28.2%, 21.2%, 15.2%, and 10.6% in patients receiving edoxaban 15, 30, 60 and 90 mg, respectively, compared with 43.8% in the dalteparin group (p<0.005 ). There was a statistically significant (p<0.001) dose-response for efficacy across the edoxaban dose groups for total VTE and for major VTE. The incidence of clinically relevant bleeding was low and similar across the groups. Oral edoxaban once daily is effective for preventing VTE after total hip replacement.

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Canada; Dalteparin; Double-Blind Method; Drug Administration Schedule; Elective Surgical Procedures; Europe; Factor Xa; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Humans; Injections, Subcutaneous; Logistic Models; Male; Middle Aged; Phlebography; Pulmonary Embolism; Pyridines; Risk Assessment; Risk Factors; Thiazoles; Time Factors; Treatment Outcome; United States; Venous Thromboembolism; Venous Thrombosis

We herein report a 99-year-old woman with hypertension and dyslipidemia. From the beginning of August 20XX, significant edema from the left thigh to the toes had been observed, so she had consulted her previous doctor. She had been suspected of having cellulitis and was given antibiotics, but no improvement in her symptoms was noted, so she was transferred to our hospital. The edema of the lower leg was localized to the left lower leg only, and the D-dimer level was as high as 16.6 μg/mL at her visit to the emergency room, so deep vein thrombosis (DVT) was suspected, and the patient received immediate hospitalization. Continuous administration of undifferentiated heparin was started, and lower extremity venous ultrasound was performed. As a result, central-type DVT extending from the left iliac vein to the common iliac vein bifurcation was observed. However, despite administering inferior vena cava (IVC) filter into under the renal vein, and changing heparin to edoxaban 30 mg, no improvement in the lower limb edema was observed. Therefore, catheter-based thrombolysis (CDT) was started on day 11 of illness, and continuous administration of urokinase was started via the catheter. Heparin and edoxaban were not used in combination in order to reduce the risk of bleeding. The edema gradually improved, and after confirming that the thrombus had completely disappeared on lower extremity venous ultrasound, the catheter was removed on day 14 (day 24 of illness) after starting CDT. The IVC filter was also removed, and prescription of edoxaban 30 mg was restarted. Since the patient had used a walking frame at home, she started rehabilitation from the initiation of CDT therapy and was discharged once she was able to use a self-sustaining portable toilet. The basic treatment for DVT is anticoagulant therapy; however, a large amount of thrombosis was observed in the present case, and no marked improvement was observed with conventional anticoagulant therapy. As the patient was particularly elderly, and considering that it was important to improve the edema promptly in order to maintain her activities of daily living, we performed CDT treatment and concluded that it was very effective in this case. However, the CDT procedure for DVT has yet to be standardized, and there are few cases of CDT treatment, especially for such super-elderly patients. In the current aging society, the incidence of DVT diseases is increasing, and in cases such as the present case, anticoagulati

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Anticoagulants; Catheters; Female; Heparin; Humans; Thrombolytic Therapy; Venous Thrombosis

Topics: Disease Progression; Humans; Neoplasms; Thrombosis; Venous Thromboembolism; Venous Thrombosis

Portal vein thrombosis (PVT) is a lethal complication of hepatectomy if not properly treated. An 81-year-old woman diagnosed with postoperative PVT after right hepatectomy and caudate lobectomy for perihilar cholangiocarcinoma. Elevation of serum total bilirubin levels, D-dimer levels, and glossy ascites appeared on postoperative day 5 (POD5), and a contrast-enhanced CT confirmed PVT. Thrombi were found from the umbilical portion of the portal vein to the superior mesenteric vein. There were signs of acute liver failure due to thrombi obstructing the portal vein. Therefore, emergent catheter thrombus aspiration was performed under laparotomy. An aspiration catheter was inserted into the superior mesenteric vein from the ileocolic vein. We performed direct aspiration thrombectomy, followed by anticoagulant administration using urokinase via the catheter. Partial recanalization of the portal vein and superior mesenteric vein was observed. To dissolve residual thrombi, edoxaban administration was started on POD6. Contrast-enhanced CT 16 days after her additional operation showed the thrombi had completely disappeared. The patient was discharged on POD76. She had no recurrence of PVT over the next 6 months. Combination therapy of early intervention using aspiration catheter and systemic anticoagulant medication was useful for severe postoperative PVT accompanied with liver failure.

Topics: Aged, 80 and over; Anticoagulants; Bile Duct Neoplasms; Bilirubin; Female; Hepatectomy; Humans; Klatskin Tumor; Liver Diseases; Mesenteric Veins; Portal Vein; Pyridines; Thiazoles; Thrombectomy; Thrombosis; Urokinase-Type Plasminogen Activator; Venous Thrombosis

We herein report a case involving a 32-year-old Japanese man with recurrent cerebral venous thrombosis due to hereditary protein C deficiency. He was admitted to our hospital with impaired consciousness. Brain magnetic resonance imaging demonstrated high intensities diffusely along the bilateral sulci and magnetic resonance venography revealed left transverse sinus and superior sagittal sinus stenoses. His father had a history of cerebral infarction and venous thrombosis. The protein C activity level examined by chromogenic synthetic substrate assay was markedly reduced. He was diagnosed with protein C deficiency, and a genetic analysis revealed a heterozygous mutation at exon 3 c.199G>A,p.Glu67Lys on the protein C gene. Four months later, at his second admission, he had transient aphasia, and his protein C activity was under 10%. We switched warfarin to the direct oral anticoagulants edoxaban. He remains fully recovered with no adverse events after the administration of edoxaban for a year. Direct oral anticoagulants may be a new tool for treating cerebral venous thrombosis due to hereditary protein C deficiency.

Topics: Administration, Oral; Adult; Drug Substitution; Factor Xa Inhibitors; Heterozygote; Humans; Intracranial Thrombosis; Male; Mutation; Protein C; Protein C Deficiency; Pyridines; Recurrence; Thiazoles; Treatment Outcome; Venous Thrombosis

Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA.. This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded.. Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6 years (range 2-8) during VKA and 1.9 years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09).. Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Topics: Acenocoumarol; Adult; Anticoagulants; Budd-Chiari Syndrome; Duration of Therapy; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Mesenteric Ischemia; Middle Aged; Portal Vein; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thrombosis; Warfarin

The safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) have been established in randomized controlled trials, but limited data are available on their use in clinical practice across geographical regions.. In the international RE-COVERY DVT/PE observational study (enrollment January 2016 to May 2017), we sought to characterize the patient population and describe the prescribed anticoagulant. Patient characteristics and anticoagulants administered after objective diagnosis of VTE were recorded at the baseline visit and again at hospital discharge or at 14 days after the diagnosis, whichever was later.. A total of 6095 patients were included, 50.2% were male, and the mean age was 61.5 years. The most common comorbidities were hypertension (35%), diabetes mellitus (11%), cancer (11%), prior VTE(11%), and trauma/surgery (7%). Overall, 77% of patients received oral anticoagulants, with 54% on NOACs and 23% on vitamin K antagonists (VKAs); 20% received parenteral anticoagulation only. NOACs comprised about 60% of anticoagulant treatment in Europe and Asia but substantially less in Latin America (29%) and the Middle East (21%). For NOAC therapies, the distribution (as a percentage of the total cohort) was rivaroxaban 25.6%, dabigatran 15.5%, apixaban 11.3%, and edoxaban 1.7%. Treatment with NOACs was less frequent in patients who had cancer, chronic renal disease, heart failure, or stroke.. These findings enhance our understanding of baseline characteristics and the initial management of patients with VTE in routine practice.

Topics: Administration, Oral; Adult; Age Distribution; Aged; Anticoagulants; Asia; Comorbidity; Cross-Sectional Studies; Dabigatran; Diabetes Mellitus; Europe; Factor Xa Inhibitors; Female; Fondaparinux; Heparin; Humans; Hypertension; Latin America; Male; Middle Aged; Middle East; Neoplasms; Postoperative Complications; Practice Patterns, Physicians'; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Wounds and Injuries

Topics: Adult; Ambulatory Care; Bed Rest; COVID-19; Factor Xa Inhibitors; Humans; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Risk Factors; Thiazoles; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first reported in Wuhan, China in December 2019, and is ongoing pandemic. While a majority of patients with SARS-CoV-2 infection shows asymptomatic or mild disease, hospitalized patients can develop critical condition, such as pneumonia, sepsis, and respiratory failure. Some cases deteriorate into sever systemic disease and multiorgan failure. Many patients of severe COVID-19 show hypercoagulable state and complicate with venous thromboembolism and atrial thrombosis. We herein reported a case of COVID-19 who developed cerebral venous thrombosis (CVT) co-incidence with pulmonary thromboembolism (PTE). A 56-year-old Japanese man was presented with fever and malaise and diagnosed with COVID-19. He was treated with ciclesonide and azithromycin, but his respiratory condition deteriorated. Thus, systemic corticosteroids and favipiravir were initiated and these treatments resulted in afebrile state, improving malaise and respiratory failure. However, he suddenly developed severe headache and vomiting with increased concentration of D-dimer. Brain CT and MRI showed typical images of CVT in the left transvers sinus and CT pulmonary angiography showed PE. Administration of unfractionated heparin followed by edoxaban treatment reduced the levels of D-dimer and improved his clinical presentation and thrombosis. Monitoring coagulopathy is important in COVID-19 patients and in case of venous thromboembolism, including cerebral venous system, appropriate anticoagulant therapy should be initiated.

Topics: Betacoronavirus; Coronavirus Infections; COVID-19; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Intracranial Thrombosis; Magnetic Resonance Imaging; Male; Middle Aged; Pandemics; Pneumonia, Viral; Pyridines; SARS-CoV-2; Thiazoles; Tomography, X-Ray Computed; Venous Thrombosis

Antiplatelet agents are typically administered before and after treatment using flow-diverter stents (FDS) to prevent thrombotic complications, but the effects of anticoagulants are unclear. We present a patient with a giant aneurysm treated with an FDS. The thrombus within the aneurysm was dissolved when a direct factor Xa inhibitor was administered to treat lower limb venous thrombosis that occurred secondary to steroid use.. A 60-year-old woman with a 30-mm giant thrombosed aneurysm in the cavernous segment of the right internal carotid artery presenting with headache and right abducens nerve palsy was treated by placing an FDS. Diplopia and increased pain in her right eye appeared on postoperative day 7, and both were alleviated by continuous oral administration of prednisolone. Angiography 3 months postoperatively revealed that the aneurysm thrombosis had progressed, and there were signs of healing. However, at the same time, lower limb venous thrombosis occurred, which was treated by continuous edoxaban. Six months after surgery, her headaches worsened and angiography showed that the aneurysm was again contrast enhanced and that the thrombus within the aneurysm had dissolved. After discontinuing edoxaban 9 months after surgery, the aneurysmal thrombosis had again rapidly progressed.. Administration of a direct factor Xa inhibitor during healing after placing an FDS may cause dissolution of an existing thrombus; therefore factor Xa inhibitors must be used with caution.

Topics: Abducens Nerve Diseases; Carotid Artery Diseases; Carotid Artery, Internal; Factor Xa Inhibitors; Female; Humans; Intracranial Aneurysm; Intracranial Thrombosis; Leg; Middle Aged; Postoperative Complications; Pyridines; Stents; Thiazoles; Venous Thrombosis

Topics: Administration, Oral; Aged; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Factor Xa Inhibitors; Female; Humans; Lower Extremity; Male; Middle Aged; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Thiazoles; Venous Thrombosis

Thromboembolism is a major complication of nephrotic syndrome, with the renal vein being the most frequent site. However, the incidence of portal vein thrombosis (PVT) in patients with nephrotic syndrome is rare. We report a case of a relapsed steroid-dependent minimal change disease with incidental PVT. A 38-year-old man presented with anasarca. Elevated liver enzymes were discovered during routine blood testing within days after commencing treatment. Although drug-induced liver injuries are frequently observed with mild aminotransferase abnormality during therapy with steroid or immune-suppressive agents, imaging revealed a massive thrombus of the portal vein, which was treated by anticoagulant therapy with edoxaban. Treatment with anticoagulant therapy could normalize liver function. Two months after the initiation of treatment with edoxaban, the follow-up CT scan and ultrasound showed the disappearance of PVT. Our case suggests that much attention should be paid to PVT as a cause of liver enzyme elevation when treating patients with nephrotic syndrome.

Topics: Administration, Oral; Adult; Anticoagulants; Chemical and Drug Induced Liver Injury; Factor Xa Inhibitors; Humans; Male; Nephrotic Syndrome; Portal Vein; Pyridines; Thiazoles; Treatment Outcome; Venous Thrombosis

Cerebral venous thrombosis is rare and an uncommon cause of stroke and has diverse etiologies and varied clinical presentations. Here, we report 2 cases of deep cerebral venous thrombosis.. A 64-year-old woman presented with cerebral venous thrombosis due to a hypercoagulable state associated with ovarian tumor. On initial fluid-attenuated inversion recovery and diffusion-weighted imaging, there was a diffuse high-intensity lesion in the bilateral thalamus. Computed tomography angiography showed occlusion of the straight sinus, vein of Galen, and internal cerebral vein. Single-photon emission computed tomography showed decreased cerebral blood flow in the bilateral thalamus. After 3 weeks of factor Xa inhibitor therapy, the patient's consciousness gradually improved and eventually became clear enough to leave the hospital. She had no neurological deficit. Another patient was a 47-year-old man who presented with splitting headache and drowsiness. Magnetic resonance venography confirmed deep thrombosis of the vein of Galen. He completely recovered after 4 weeks of factor Xa inhibitor therapy.. This study reports on 2 rare cases of decreased cerebral blood flow in the bilateral thalamus on single-photon emission computed tomography, which improved following the administration of factor Xa inhibitor.

Topics: Blood Coagulation; Cerebral Angiography; Cerebrovascular Circulation; Computed Tomography Angiography; Diffusion Magnetic Resonance Imaging; Factor Xa Inhibitors; Female; Humans; Intracranial Thrombosis; Male; Middle Aged; Phlebography; Pyridines; Thalamus; Thiazoles; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Venous Thrombosis

Pulmonary arteriovenous fistula (PAVF), a vessel malformation connecting the pulmonary circulation to the systemic circulation while bypassing the pulmonary capillaries, can cause paradoxical cerebral infarction. It is often associated with hereditary hemorrhagic telangiectasia (HHT), a genetic disease characterized by multiple dermal, mucosal, and visceral telangiectasia causing recurrent bleeding. Paradoxical cerebral embolism caused by PAVF without HHT is rare. Here, we report a patient with isolated PAVF who experienced an ischemic stroke caused by a paradoxical embolism from deep venous thrombosis; the patient was successfully treated with recombinant tissue plasminogen activator. She presented with a decrease in arterial oxygen saturation to 91%, and lung disease was suspected. A PAVF was subsequently found in the right S6 region using contrast computed tomography. Interventional radiologists successfully occluded the shunt using 6 microcoils. PAVF should be considered when determining the pathogenesis of cerebral ischemia in patients with hypoxia, which can be the only symptom of PAVF.

Topics: Aged, 80 and over; Arteriovenous Fistula; Cerebral Angiography; Computed Tomography Angiography; Diffusion Magnetic Resonance Imaging; Embolism, Paradoxical; Embolization, Therapeutic; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Humans; Intracranial Embolism; Magnetic Resonance Angiography; Pulmonary Artery; Pulmonary Veins; Pyridines; Recombinant Proteins; Thiazoles; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome; Venous Thrombosis

Deep vein thrombosis (DVT) is one of the main complications following total knee arthroplasty (TKA). In this study, oral administration of 15 mg edoxaban (a factor Xa inhibitor) once daily for 14 days efficiently prevented the incidence of DVT. Our hypothesis was that prothrombin time-international normalized ratio (PT-INR) on the third postoperative day could predict the incidence of DVT following TKA.. In this study, 286 subjects were enrolled and divided into two groups according to the presence or absence of DVT. Several variables [age, body mass index, postoperative D-dimer level, PT-INR, and functional recovery findings (standing)] were analysed to determine the predictors of DVT, and for DVT diagnosis, ultrasonography was performed for seven days after surgery.. The PT-INR levels were significantly higher in the group that did not develop DVT (p = 0.01). Further analysis with logistic regression analysis and receiver operating characteristic curve was performed. The PT-INR on the third postoperative day was an independent factor of the incidence of DVT (odds ratio 0.210; p = 0.035). The cut-off PT-INR was calculated to be 1.425.. PT-INR level is a useful marker in determining whether 15 mg edoxaban administration can prevent DVT after TKA. It is suggested that increment of edoxaban to control PT-INR over the cut-off point might prevent the incidence of DVT.

Topics: Aged; Aged, 80 and over; Arthroplasty, Replacement, Knee; Biomarkers; Early Ambulation; Factor Xa Inhibitors; Female; Humans; International Normalized Ratio; Male; Postoperative Complications; Postoperative Period; Pre-Exposure Prophylaxis; Prospective Studies; Prothrombin Time; Pyridines; ROC Curve; Thiazoles; Ultrasonography, Doppler, Color; Venous Thromboembolism; Venous Thrombosis

An 80-year-old man presented at our hospital with renal failure. He had been treated with edoxaban, an oral direct factor Xa inhibitor, for deep vein thrombosis for 10 months prior to admission. Although the pulses in his bilateral pedal arteries were palpable, cyanosis was present in the bilateral toes. Laboratory data indicated azotemia and eosinophilia. A skin biopsy confirmed a diagnosis of cholesterol crystal embolism (CCE). Because no invasive vascular procedure was performed, we assumed that CCE was related to edoxaban. To the best of our knowledge, this is the first case report suggesting CCE induced by an Xa inhibitor.

Topics: Aged, 80 and over; Anticoagulants; Embolism, Cholesterol; Factor Xa Inhibitors; Humans; Male; Middle Aged; Pyridines; Renal Insufficiency; Thiazoles; Toes; Tretoquinol; Venous Thrombosis

Since 2010, four oral anticoagulants have been approved for marketing in addition to warfarin for treatment of thromboembolic disease. Limited head-to-head data exist comparing these treatments, leaving patients and clinicians with little guidance for selecting a strategy that balances recurrence reduction with bleeding risk. In the dabigatran, apixaban, rivaroxban, edoxaban and warfarin comparative effectiveness research study, we compare all five currently available oral anticoagulant agents for the extended treatment of deep venous thrombosis and pulmonary embolism, as well as no extended treatment, and evaluate whether results differ in specific sub-populations. As our population includes Medicare novel anticoagulant users and large numbers of commercially insured and Medicaid patients, our results will likely be transportable to the majority of US patients experiencing a DVT or pulmonary embolism.. NCT03271450.

Topics: Anticoagulants; Antithrombins; Comparative Effectiveness Research; Dabigatran; Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Research Design; Rivaroxaban; Thiazoles; Venous Thrombosis; Warfarin

We assessed the efficacy and safety of direct oral anticoagulants (DOACs) for the treatment of deep venous thrombosis (DVT) in the chronic phase through comparison with conventional warfarin therapy.A total of 807 consecutive patients who were diagnosed with having DVT in the chronic phase were included (484 patients to warfarin therapy and 323 patients to DOAC therapy). The condition of leg veins was assessed 3 to 6 months after starting the therapies by ultrasound examination. Major bleeding and mortality during the therapies were followed-up.There was no significant difference between the two groups in the thrombosis improvement rate (DOAC group: 91.2% versus warfarin group: 88.9%). There was no significant difference between the two groups in major bleeding (DOAC group: 1.8% versus warfarin group: 1.8%). In patients with active cancer, the DOAC group had a borderline higher thrombosis improvement rate than the warfarin group (92.1% versus 80.0%, P = 0.05). The proportion of major bleeding in the patients with active cancer was slightly higher in the warfarin group than in the DOAC group (4.3% versus 2.8%; P = 0.71). Active cancer was not an independent risk factor for major bleeding and recurrence in the DOAC group (OR 2.68, 95% CI 0.51-14.1; P = 0.24 and OR 0.65, 95% CI 0.20-2.07; P = 0.47).In treatment using oral anticoagulants for DVT in the chronic phase, DOACs exhibited equal efficacy and safety as warfarin did. Particularly DOACs appear to be an attractive therapeutic option for cancer-associated DVT in chronic phase, with relatively low anticipated rates of recurrence and major bleeding.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Chronic Disease; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Humans; Male; Pyrazoles; Pyridines; Pyridones; Recurrence; Thiazoles; Treatment Outcome; Ultrasonography; Venous Thrombosis; Warfarin

Venous compression syndromes are caused by extrinsic venous compression of anatomical structures, such as the adjacent arteries and bones. Chronic venous compression and pulsative vibratory arterial pressure accelerate the development of deep vein thrombosis. Herein, we report the first case of double venous compressions due to a duplicated inferior vena cava-induced right-sided common iliac vein thrombosis. The thrombus was induced by left-sided inferior vena cava entrapment and right-sided common iliac vein compression, resembling nutcracker syndrome and May-Thurner syndrome, respectively. Bypass flow of the right inferior vena cava rendered the right lower extremity asymptomatic. Once daily anticoagulation edoxaban was effective. Congenital venous anomalies and bypass formations should be considered when a common iliac vein thrombus without symptoms in the lower extremities is observed, and a lifelong periodical follow-up is mandatory, even after remission.

Topics: Chest Pain; Constriction, Pathologic; Factor Xa Inhibitors; Female; Humans; Iliac Vein; Middle Aged; Pyridines; Thiazoles; Thrombolytic Therapy; Tomography, X-Ray Computed; Treatment Outcome; Vena Cava, Inferior; Venous Thrombosis

Topics: Atrial Fibrillation; Cost-Benefit Analysis; Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyridines; Stroke; Thiazoles; Treatment Outcome; Venous Thrombosis

Topics: Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Humans; Pyridines; Thiazoles; Venous Thromboembolism; Venous Thrombosis

Topics: Administration, Oral; Anticoagulants; Antithrombins; Dabigatran; Dalteparin; Factor Xa Inhibitors; Hemorrhage; Humans; Multicenter Studies as Topic; Neoplasms; Observational Studies as Topic; Patient Acceptance of Health Care; Prospective Studies; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Antithrombins; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Perioperative Care; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis

Topics: Antithrombins; Dabigatran; Humans; Practice Guidelines as Topic; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Review Literature as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Vitamin K

A 39-year-old man with nephrotic syndrome was admitted due to right dorsal pain. Contrast-enhanced CT led to a diagnosis of renal vein thrombosis and segmental pulmonary thromboembolism. Treatment with heparin and warfarin was started. After 1 month, pulmonary thromboembolism recurred. Warfarin was switched to edoxaban, and steroid therapy was initiated, which led to the remission of nephrotic syndrome and the disappearance of renal vein thrombosis. The efficacy of edoxaban was demonstrated; however, this drug has not been routinely selected for patients with renal disease. Our results suggest that edoxaban is also effective for treating venous thrombosis patients with nephrotic syndrome.

Topics: Adult; Factor Xa Inhibitors; Heparin; Humans; Male; Nephrotic Syndrome; Pulmonary Embolism; Pyridines; Renal Veins; Thiazoles; Treatment Outcome; Venous Thrombosis; Warfarin

Anticoagulant therapy is prescribed to millions of patients worldwide for the prevention and treatment of venous thrombosis. Evidence has indicated that edoxaban is a potential drug of oral anticoagulant in the acute treatment of venous thromboembolism. Hydrogen sulfide and homocysteine plasma concentration are indicators of cardiovascular and neurovascular disease risk factors that have attracted considerable attention for regulation of vascular health and homeostasis. However, the molecular mechanism of edoxaban‑mediated differences of hydrogen sulfide and homocysteine has not been investigated in the progression of venous thrombosis. In the present study, the authors analyzed the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway in the vein endothelial cells and expression levels of hydrogen sulfide and homocysteine. Homocysteine‑hydrogen sulfide metabolism through transsulfuration and that transsulfuration capacity and hydrogen sulfide availability have been investigated both in vitro and in vivo following treatment with edoxaban. Matrix metalloproteinase (MMP) activation and cystathionine β‑synthase (CBS) and cystathionine γ‑lyase (CGL) levels were studied in a cell model and rat model of vein thrombosis prior and post treatment of edoxaban. The therapeutic effects of edoxaban for rats with vein thrombosis were determined by clinical diagnose scores. The results demonstrated that edoxaban increased expression levels of hydrogen sulfide and homocysteine in microvascular endothelial cells. It was observed that the transsulfuration enzymes, CBS and CGL levels were upregulated in murine microvascular endothelial cells. The MMP‑9 expression level and activity and homocysteine‑hydrogen sulfide metabolism were increased in murine microvascular endothelial cells following edoxaban treatment. In addition, CBS and CGL activities were upregulated in murine microvascular endothelial cells and a rat model of venous thrombosis following treatment with edoxaban. Furthermore, it was observed that edoxaban increased PI3K and AKT expression both in vitro and in vivo. In addition, edoxaban significantly improved endothelial injury and inhibited thrombosis factors expression in rat model of venous thrombosis. In conclusion, these findings suggested that edoxaban can improve venous thrombosis by decreasing hydrogen sulfide and homocysteine through the PI3K/AKT signaling pathway.

Topics: Animals; Anticoagulants; Chlorides; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelial Cells; Ferric Compounds; Gene Expression Regulation; Homocysteine; Hydrogen Sulfide; Male; Matrix Metalloproteinase 9; Phosphatidylinositol 3-Kinases; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Pyridines; Rats; Rats, Sprague-Dawley; Signal Transduction; Thiazoles; Venous Thrombosis

In this age of evidence-based medicine, the use of medical thrombosis prophylaxis stockings (AES) as a physical strategy for the prevention of lower limb venous thrombosis has been questioned. The current German S3 guidelines even state that their non-application is, in the vast majority of cases, explicitly covered by the recommendations of this guideline. Low molecular weight heparins (NMH) and direct oral anticoagulants (DOAK) have received approval for thrombosis prophylaxis in elective knee and hip joint replacement, but the use of AES is absent from these approval studies. The results of the additional effects of the AES in the approval studies of Edoxaban were published for the first time. According to these results, the incidence of venous thromboembolism was 6.0% when AES were worn and 13.0% when AES were not worn. Since the approval studies of NMH and the DOAKs did not control for the use of AES, the impact of AES on the overall results remains unclear. Therefore the study results are only valid in the context of the general application of AES. Guidelines commissions should take this into account in their recommendations.. Der Nutzen von medizinischen Thromboseprophylaxestrümpfen (AES) als physikalisches Mittel zur Prävention von venösen Thrombosen der unteren Extremität wird im Zeitalter der evidenzbasierten Medizin infrage gestellt. Die aktuellen S3-Leitlinien schreiben sogar, dass ihre Nichtanwendung in den allermeisten Fällen explizit im Empfehlungskorridor dieser Leitlinie liegt. Die niedermolekularen Heparine (NMH) und die direkten oralen Antikoagulanzien (DOAK) haben über Studien zur Thromboseprophylaxe bei elektivem Knie- und Hüftgelenkersatz ihre Zulassung erhalten, allerdings ist zur Anwendung von AES in diesen Zulassungsstudien nichts bekannt. Nun wurden erstmals die Ergebnisse der zusätzlichen Wirkung der AES in den Zulassungsstudien von Edoxaban publiziert. Danach betrug die Inzidenz von venösen Thromboembolien 6,0%, wenn AES getragen wurden, und 13,0%, wenn keine AES getragen wurden. Da in den Zulassungsstudien von NMH und den DOAKs nicht die Anwendung von AES kontrolliert wurde, kann nicht gesagt werden, wie groß der Effekt der AES auf das Gesamtergebnis ist, und die Studienergebnisse gelten nur vor dem Hintergrund der allgemeinen Anwendung von AES.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Combined Modality Therapy; Drug Approval; Evidence-Based Medicine; Germany; Guideline Adherence; Postoperative Complications; Pyridines; Stockings, Compression; Thiazoles; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Atrial Fibrillation; Chemical and Drug Induced Liver Injury; Factor Xa Inhibitors; Hemorrhage; Humans; International Normalized Ratio; Pulmonary Embolism; Pyridines; Stroke; Thiazoles; Venous Thrombosis; Warfarin

Selective inhibitors of factor Xa (FXa) are widely recognized as useful therapeutic tools for stroke prevention in non-valvular atrial fibrillation or venous thrombosis. Thrombin, which is rapidly generated from pro-thrombin through the activation of factor X to FXa, acts as a potent activator of human platelets. Thus, the reduction of thrombin generation by FXa inhibitor eventually causes a suppressive effect on platelet aggregation. However, little is known whether FXa inhibitors directly affect the function of human platelets. We have previously reported that collagen induces the phosphorylation of heat shock protein 27 (HSP27), a low-molecular weight heat shock protein via Rac-dependent activation of p44/p42 mitogen-activated protein (MAP) kinase in human platelets, eventually resulting in the release of HSP27. In the present study, we investigated the direct effect of FXa inhibitor on the collagen-induced human platelet activation. Rivaroxaban as well as edoxaban significantly reduced the collagen-induced phosphorylation of both HSP27 and p44/p42 MAP kinase without affecting the platelet aggregation. Rivaroxaban significantly inhibited the release of phosphorylated HSP27 from collagen-stimulated platelets but not the secretion of platelet derived growth factor-AB. In patients administrated with rivaroxaban, the collagen-induced levels of phosphorylated HSP27 were markedly diminished after 2 days of administration, which failed to affect the platelet aggregation. These results strongly suggest that FXa inhibitor reduces the collagen-stimulated release of phosphorylated HSP27 from human platelets due to the inhibition of HSP27 phosphorylation via p44/p42 MAP kinase.

Topics: Aged; Blood Platelets; Collagen; Factor Xa Inhibitors; Female; Healthy Volunteers; HSP27 Heat-Shock Proteins; Humans; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Platelet Activation; Platelet Aggregation; Pyridines; Rivaroxaban; Thiazoles; Venous Thrombosis

Topics: Administration, Oral; Dabigatran; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Substitution; Fibrinolytic Agents; General Practice; Heparin, Low-Molecular-Weight; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thrombosis

Topics: Adult; Anticoagulants; Atrial Fibrillation; Drug Approval; Germany; Humans; National Health Programs; Pulmonary Embolism; Pyridines; Stroke; Thiazoles; Thromboembolism; Venous Thrombosis

Patients undergoing total knee arthroplasty (TKA) are at high risk of venous thromboembolism, manifesting as deep vein thrombosis (DVT) or pulmonary embolism. The purpose of this study is to evaluate the efficacy and safety of edoxaban 15 mg once daily (o.d.) for preventing DVT in patients undergoing TKA.. Three hundred patients undergoing primary TKA under general anaesthesia for osteoarthritis were enrolled in this study: 100 treated with enoxaparin 2,000 IU twice daily (b.i.d.), 100 treated with fondaparinux 1.5 mg o.d. and 100 treated with edoxaban 15 mg o.d.. All treatments were scheduled to continue for 14 days.. The incidence of DVT in patients treated with edoxaban 15 mg o.d. was lower than in patients with enoxaparin 2,000 IU b.i.d. and fondaparinux 1.5 mg o.d.. D-dimer levels were significantly lower in patients with edoxaban than in patients with enoxaparin and fondaparinux 1.5 mg o.d. on the first postoperative day; ΔHb levels were lower in patients with edoxaban than in patients with enoxaparin and fondaparinux on postoperative days, However, the difference was not statistically significant. Finally, the incidence of hepatic dysfunction was lower in patients with edoxaban than in patients with enoxaparin and fondaparinux.. Edoxaban 15 mg o.d. was more efficient than enoxaparin 2,000 IU b.i.d. and fondaparinux 1.5 mg o.d.. Furthermore, edoxaban was safe compared with enoxaparin and fondaparinux. Edoxaban, an orally administered direct factor Xa (FXa) inhibitor, may offer a new option for preventing DVT, with a level of evidence III.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Dose-Response Relationship, Drug; Enoxaparin; Female; Fondaparinux; Humans; Incidence; Knee Joint; Male; Osteoarthritis, Knee; Polysaccharides; Pyridines; Retrospective Studies; Thiazoles; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

The successful management of upper gastrointestinal (GI) bleeding requires identification of the source of bleeding and when this is achieved the bleeding can often be treated endoscopically. However, the identification of the bleeding can be challenging due to the location of the bleeding or technical aspects. Therefore it might be necessary to use other measures than endoscopy such as CT angiography. Duodenal diverticula is a rare cause of upper GI bleeding and can be challenging to diagnose as they often require specialised endoscopy procedures such as endoscopy with a side-viewing scope. This case describes the first successful management of this rare condition with an upper GI endoscopy with a colonoscope and afterwards intravascular coiling.

Topics: Aged; Anticoagulants; Colonoscopes; Diverticulum; Duodenal Diseases; Duodenoscopy; Gastrointestinal Hemorrhage; Humans; Male; Pyridines; Severity of Illness Index; Thiazoles; Venous Thrombosis

Edoxaban is an oral and direct activated factor X inhibitor. In this study, the acute treatment effect of edoxaban on venous thrombosis is investigated in rats by single and multiple administrations, and compared to the conventional parenteral anticoagulants, enoxaparin and fondaparinux. Venous thrombus was induced in the inferior vena cava by partial stenosis plus topical application of 10% ferric chloride for 5min. After 1-h thrombus maturation, oral edoxaban and subcutaneous enoxaparin and fondaparinux were given. In the single administration experiment, thrombus weight was measured 1 or 4h after thrombus induction. In the multiple administration experiments, edoxaban was orally administered once daily (QD) and twice daily (BID) for 3 days. In the single administration experiment, oral administration of edoxaban (3.0 and 10mg/kg) 1h after thrombus formation significantly regressed the venous thrombus compared to the thrombus at 1h after thrombus formation. Similarly the significant venous thrombus regression was observed with enoxaparin (10mg/kg) and fondaparinux (0.30-3.0mg/kg). In the multiple administration experiment, both QD and BID administration of edoxaban at daily doses of 5 and 10mg/kg exerted significant treatment effects. QD administration of edoxaban including lower doses (1-10mg/kg) significantly reduced thrombus weight. Edoxaban administered QD and BID was effective in the treatment of venous thrombosis, and the treatment effect of edoxaban was comparable to the conventional parenteral anticoagulants. These data demonstrate the potential of edoxaban as an oral anticoagulant in the acute treatment of venous thromboembolism.

Topics: Administration, Oral; Animals; Anticoagulants; Antithrombin III; Disease Models, Animal; Drug Administration Schedule; Enoxaparin; Factor Xa Inhibitors; Fondaparinux; Male; Peptide Hydrolases; Polysaccharides; Pyridines; Rats; Rats, Wistar; Thiazoles; Venous Thrombosis

Prevention of deep vein thrombosis (DVT) is important in patients undergoing major orthopedic surgery. Although the detection of an elevated D-dimer level is useful for predicting DVT, it is not efficacious in postoperative patients being treated with anti-Xa agents. The soluble platelet glycoprotein VI (sGPVI) level is a marker of activated platelets, but not bleeding. Therefore, sGPVI levels are usually examined as a predictor of DVT in such patients. In the present study, 83 orthopedic patients were treated with 30 mg of edoxaban for prophylaxis of DVT. Fourteen patients developed DVT and 17 patients discontinued the prophylaxis due to decreased hemoglobin levels. Plasma levels of sGPVI in the patients were significantly higher after surgery than before surgery. On day 1, the sGPVI levels increased, while the platelet counts decreased. There were no significant differences in D-dimer, soluble fibrin, or FDP levels in orthopedic patients with and without DVT before surgery and on days 1, 4, and 8. Plasma sGPVI levels were significantly higher in the patients with DVT than in those without DVT on days 1 and 4. Plasma levels of D-dimer were significantly higher in patients with withdrawal than in those without. However, there were no significant differences in sGPVI levels between those with and without withdrawal. As D-dimer levels are known to increase in patients with withdrawal, this parameter is not useful for evaluating the risk of DVT in these patients. In contrast, the sGPVI level is not increased in those with withdrawal and may therefore be useful for evaluating the risk of DVT in postoperative patients treated with an anticoagulant.

Topics: Aged; Biomarkers; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Orthopedic Procedures; Platelet Membrane Glycoproteins; Postoperative Complications; Pyridines; Risk Factors; Thiazoles; Time Factors; Treatment Outcome; Venous Thrombosis

Oral factor Xa (FXa) inhibitors are a novel class of anticoagulants that, unlike heparins, are expected to demonstrate antithrombotic effects independent of plasma antithrombin (AT) concentrations. We utilized heterozygous AT-deficient (AT+/-) mice to determine the impact of AT deficiency on anticoagulant and antithrombotic effects of edoxaban, a direct FXa inhibitor, and compared with heparins (fondaparinux, enoxaparin, and unfractionated heparin [UHF]).. The effects of edoxaban and heparins on in vitro prothrombin time and activated partial thromboplastin time were measured in plasma obtained from wild type (AT+/+) and AT+/- male mice. To assess the antithrombotic effects of these anticoagulants in vivo, venous thrombosis was induced in the inferior vena cava by FeCl3 treatment. Potency ratios of antithrombotic effects in AT+/- compared with AT+/+ mice were analyzed by a parallel line assay.. In vitro studies demonstrated that the clotting-time prolongation effects of edoxaban were not affected by heterozygous AT deficiency whereas those of AT-dependent anticoagulants were attenuated. In AT+/- mice, the antithrombotic effects of AT-dependent anticoagulants were less potent than those in AT+/+ mice. In contrast, edoxaban was equipotent in preventing thrombus formation in both wild-type and AT-deficient mice. The attenuated antithrombotic effects of fondaparinux, enoxaparin, and UFH in AT-deficient mice were restored by AT supplementation. Edoxaban exerts a comparable antithrombotic effect even in mice with low plasma AT antigen and activity to that in wild-type mice.. Edoxaban may potentially be prioritized over AT-dependent anticoagulants in patients with lower plasma AT concentration.

Topics: Animals; Anticoagulants; Antithrombin III; Blood Coagulation Tests; Enoxaparin; Factor Xa Inhibitors; Female; Fondaparinux; Gene Deletion; Hemostasis; Male; Mice; Mice, Inbred C57BL; Polysaccharides; Pyridines; Thiazoles; Venous Thrombosis

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Pulmonary Embolism; Pyridines; Randomized Controlled Trials as Topic; Secondary Prevention; Thiazoles; Venous Thrombosis; Vitamin K; Warfarin

Edoxaban is an oral direct factor Xa inhibitor that is currently undergoing investigation in phase III clinical trials for the prevention of stroke in patients with atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolic events (VTE). Factor Xa is an attractive target for anticoagulant treatment, as it is the primary and rate-limiting source of amplification in the coagulation cascade. Edoxaban is a competitive inhibitor of factor Xa and has >10 000-fold greater selectivity for factor Xa relative to thrombin. In phase I clinical trials, the anticoagulant effects of edoxaban included dose-dependent increases in activated partial thromboplastin time and prothrombin time following single edoxaban doses of 10-150 mg and after multiple ascending doses (60 mg twice daily, 90 mg daily and 120 mg daily). The anticoagulant effects of edoxaban were rapid in onset (time to peak plasma concentration 1-2 hours) and sustained for up to 24 hours. Prolongation of bleeding time in 8% of subjects was >9.5 minutes (none of which appeared to be clinically significant) 2 hours after initial dosing, and was independent of edoxaban dose, formulation or dietary state. In general, plasma edoxaban concentrations were linearly correlated with coagulation parameters. Phase II clinical trials in patients with AF and VTE suggest that the edoxaban 30 mg once-daily and 60 mg once-daily regimens had a similar or better safety profile compared with dose-adjusted warfarin (international normalized ratio 2.0-3.0) in terms of bleeding events, and that edoxaban was not associated with hepatotoxicity. In addition, edoxaban was associated with statistically significant dose-dependent reductions in VTE after orthopaedic surgery compared with placebo or dalteparin sodium. Further clinical investigation of the efficacy and safety of once-daily edoxaban is being conducted in phase III clinical trials in comparison with warfarin in patients with AF in the phase III ENGAGE AF-TIMI 48 trial (NCT00781391), and in comparison with low-molecular weight heparin/warfarin in the prevention of recurrent VTE in patients with symptomatic deep vein thrombosis and/or pulmonary embolism in the HOKUSAI VTE trial (NCT00986154).

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Clinical Trials as Topic; Factor Xa Inhibitors; Humans; Pyridines; Rabbits; Rats; Stroke; Thiazoles; Venous Thrombosis