edoxaban and Acute-Disease

Pulmonary embolism (PE) is characterized by occlusion of blood flow in a pulmonary artery, typically due to a thrombus that travels from a vein in a lower limb. The incidence of PE is approximately 60 to 120 per 100 000 people per year. Approximately 60 000 to 100 000 patients die from PE each year in the US.. PE should be considered in patients presenting with acute chest pain, shortness of breath, or syncope. The diagnosis is determined by chest imaging. In patients with a systolic blood pressure of at least 90 mm Hg, the following 3 steps can be used to evaluate a patient with possible PE: assessment of the clinical probability of PE, D-dimer testing if indicated, and chest imaging if indicated. The clinical probability of PE can be assessed using a structured score or using clinical gestalt. In patients with a probability of PE that is less than 15%, the presence of 8 clinical characteristics (age <50 years, heart rate <100/min, an oxygen saturation level of > 94%, no recent surgery or trauma, no prior venous thromboembolism event, no hemoptysis, no unilateral leg swelling, and no estrogen use) identifies patients at very low risk of PE in whom no further testing is needed. In patients with low or intermediate clinical probability, a D-dimer level of less than 500 ng/mL is associated with a posttest probability of PE less than 1.85%. In these patients, PE can be excluded without chest imaging. A further refinement of D-dimer threshold is possible in patients aged 50 years and older, and in patients with a low likelihood of PE. Patients with a high probability of PE (ie, >40% probability) should undergo chest imaging, and D-dimer testing is not necessary. In patients with PE and a systolic blood pressure of 90 mm Hg or higher, compared with heparin combined with a vitamin K antagonist such as warfarin followed by warfarin alone, direct oral anticoagulants such as apixaban, edoxaban, rivaroxaban, or dabigatran, are noninferior for treating PE and have a 0.6% lower rate of bleeding. In patients with PE and systolic blood pressure lower than 90 mm Hg, systemic thrombolysis is recommended and is associated with an 1.6% absolute reduction of mortality (from 3.9% to 2.3%).. In the US, PE affects approximately 370 000 patients per year and may cause approximately 60 000 to 100 000 deaths per year. First-line therapy consists of direct oral anticoagulants such as apixaban, edoxaban, rivaroxaban, or dabigatran, with thrombolysis reserved for patients with systolic blood pressure lower than 90 mm Hg.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Dabigatran; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Pulmonary Embolism; Risk; Rivaroxaban; United States; Vitamin K; Warfarin

After the CLOT study, LMWHs (low-molecular weight heparins) have gradually replaced warfarin as the treatment of choice for VTE (venous thromboembolism) in cancer patients. Randomized controlled studies comparing DOACs (direct oral anticoagulants) to LMWHs in cancer patients are still limited. However, new emerging data are supporting the use of DOACs in cancer-associated thrombosis. Areas covered: This review will discuss the recent studies that addressed the utilization of such agents in the treatment of VTE in cancer patients. It will also address challenges that can be encountered while using these agents particularly in cancer patients. Expert commentary: Up until the Hokusai VTE Cancer study, data on the use of DOACs in cancer patients have been limited but supportive of their use in such patients. The Hokusai VTE Cancer study shows that edoxaban is non-inferior to dalteparin in prevention of recurrent VTE but at expense of higher major bleeding namely in patients with gastrointestinal cancer. Although further studies involving other DOACs may reinforce the efficacy of DOACs in this population of patients, studies looking at subpopulation of cancer patients may be of more clinical value to clinicians who are trying to balance between treatment of thrombosis and risks of bleeding.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Dalteparin; Gastrointestinal Neoplasms; Humans; Pyridines; Randomized Controlled Trials as Topic; Thiazoles; Venous Thromboembolism

Cancer patients with venous thromboembolism (VTE) are at increased risk for both bleeding and VTE recurrence. Anticoagulation with low-molecular-weight heparin (LMWH) is the standard of care during the initial and long-term treatment phase (i.e. during the first 3 - 6 months of therapy) based on its overall beneficial safety and efficacy profile compared to vitamin K antagonists (VKAs). The direct oral anticoagulants (DOACs) rivaroxaban, apixaban, edoxaban, and dabigatran are approved for the treatment of acute VTE, and the combined six phase-3 trials have included > 1500 patients with active cancer, as defined by variable selection criteria. Subgroup analyses of these patients, either pooled or separately reported, suggest that DOACs could be a safe and efficacious alternative to VKA therapy for the treatment of cancer-associated VTE. However, the populations of cancer patients included in the DOAC and LMWH trials are not comparable with regard to mortality and VTE risk, and no specific data from direct head-to-head comparisons of DOACs with LMWHs are currently available. The use of DOACs for the management of VTE in cancer is thus not recommended by clinical practice guidelines.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Guideline Adherence; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Neoplasms; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thromboembolism

Emergency physicians make treatment decisions in patients who present to the emergency department (ED) with acute venous thromboembolism (VTE). They also encounter patients on target-specific oral anticoagulants (TSOACs) who require urgent intervention. New approvals and increasing prescriptions for TSOACs (e.g., apixaban, dabigatran, edoxaban, and rivaroxaban) for the management of several thromboembolic disorders warrant an evaluation of the impact of these agents in the ED setting.. This review discusses the use of TSOACs in the ED for the treatment of acute VTE, and highlights strategies for the management of patients on TSOACs who present to the ED with other complications, such as bleeding complications or requiring emergency surgery.. Apixaban, dabigatran, edoxaban, and rivaroxaban have been approved for the treatment of acute VTE. We discuss the impact of this on ED management of TSOAC-naïve patients and highlight results with TSOACs in high-risk subgroups including the elderly and those with prior VTE or active cancer. This review also discusses management strategies for patients on TSOACs. For emergency physicians, strategies for the management of bleeding, approaches to patient care when emergency surgery is needed, laboratory assays for measuring plasma concentrations of TSOACs, and drug-drug interactions are of special importance.. Familiarity with TSOACs will better position emergency physicians to provide state-of-the art care to their patients with VTE and help them manage potentially complicated circumstances related to the chronic use of these drugs.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Blood Coagulation Tests; Dabigatran; Drug Interactions; Drug Monitoring; Emergency Service, Hospital; Factor Xa Inhibitors; Hemorrhage; Humans; Practice Guidelines as Topic; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

Only vitamin K antagonists could be applied as oral anticoagulants over the past six decades. Coumarols have narrow therapeutic range, and unpredictable anticoagulant effects are resulted by multiple drug interactions. Therefore, regular routine monitoring of the international normalized ratio is necessary. There are two groups of factor-specific anticoagulants: molecules with anti-FIIa (dabigatran) and anti-FXa (rivaroxaban, apixaban and edoxaban) effect. Author summarizes the most important clinical features of the new oral anticoagulants, their indications and the possibilities of laboratory controls. Bleedings are the most important side effects of anticoagulants. This review summarizes the current published evidences for new oral anticoagulants reversal (non-specific and specific) agents, especially in cases with severe acute bleedings or urgent surgery procedures. It reports on how to use inhibitors, the recommended doses and the most important clinical results. The review focuses on idarucizumab - already approved by the U.S. Food and Drug Administration and the European Medicines Agency - which has a key role as the first specific inhibitor of dabigatran.

Topics: Acute Disease; Administration, Oral; Ambulatory Care; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Antithrombins; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Severity of Illness Index; Surgical Procedures, Operative; Thiazoles

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

Direct oral anticoagulants (DOACs) specifically target factor IIa or Xa and represent a major step forward in the treatment of acute- and long-term prevention of venous thrombo-embolism (VTE). They are at least as effective and as safe as conventional therapy (heparins and vitamin-K inhibitors) and have practical advantages, such as fixed dosing and no need for laboratory monitoring. These antithrombotic agents introduce a new paradigm for the day-to-day management of VTE. Direct oral anticoagulants should streamline the management of most patients with VTE and will facilitate care in the outpatient setting. Nevertheless, it remains uncertain how to select specific DOACs for particular profiles of patients, and the optimal management of bleeding complications is evolving.

Topics: Acute Disease; Administration, Oral; Antithrombins; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Long-Term Care; Morpholines; Perioperative Care; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

In the last 4 years, 6 phase 3 trials including a total of 27,023 patients with venous thromboembolism (VTE) compared a direct oral anticoagulant (DOAC) with vitamin K antagonists (VKAs). To aid the clinician in assessing the amount of information, we address frequently raised clinical questions in a review of combined trial results. We included the phase 3 trials that compared dabigatran etexilate, rivaroxaban, apixaban, or edoxaban with VKA therapy in patients with acute symptomatic VTE. Recurrent VTE occurred in 2.0% of DOAC recipients compared with 2.2% in VKA recipients (relative risk [RR] 0.90, 95% confidence interval [CI] 0.77-1.06). Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45-0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor bleeding occurred significantly less in DOAC recipients. The efficacy and safety of DOACs were consistent in patients with pulmonary embolism, deep venous thrombosis, a body weight ≥100 kg, moderate renal insufficiency, an age ≥75 years, and cancer. In conclusion, DOACs and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is consistent in key clinical subgroups. Treatment with a DOAC significantly reduces the risks of major bleeding.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Benzimidazoles; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism; Vitamin K

The present article addresses clinical challenges associated with the choice of the anticoagulant agent, the definition of the duration of anticoagulant treatment and the assessment of the risk-to-benefit ratio of prolonged anticoagulation for patients with pulmonary embolism (PE).Anticoagulation is performed with unfractionated heparin (UFH) in hemodynamically unstable patients and with low molecular weight heparins (LWMH) or fondaparinux in normotensive patients. In patients with high or intermediate clinical probability of pulmonary embolism, anticoagulation should be initiated without delay while awaiting the results of diagnostic tests. LMWH and fondaparinux are preferred over UFH in the initial anticoagulation of PE since they are associated with a lower risk of bleeding.All patients with PE require therapeutic anticoagulation for at least three months. The current 2019 guidelines of the European Society of Cardiology (ESC) recommend that all eligible patients should be treated with a non-vitamin K antagonist oral anticoagulant (NOAC) in preference to a vitamin K antagonist (VKA). In patients with active cancer, Apixaban, Edoxaban and Rivaroxaban are effective alternatives to treatment with LMWH.The decision on the duration of anticoagulation should consider both, the individual risk of PE recurrence and the individual risk of bleeding. The risk for recurrent PE after discontinuation of treatment is related to the features of the index PE event. While patients with a strong transient risk factor have a low risk of recurrence and anticoagulation can be discontinued after three months, patients with strong persistent risk factor (such as active cancer) have a high risk of recurrence and thus should receive anticoagulant treatment of indefinite duration. Given the favourable safety profile of NOACs (especially if a reduced dosage of Apixaban or Rivaroxaban is initiated after at least six months of therapeutic anticoagulation), extended oral anticoagulation of indefinite duration should be considered for all patients with intermediate risk of recurrence.

Topics: Acute Disease; Dalteparin; Dose-Response Relationship, Drug; Drug Administration Schedule; Fibrinolytic Agents; Fondaparinux; Guideline Adherence; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Neoplasms; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Recurrence; Risk Assessment; Risk Factors; Rivaroxaban; Thiazoles

It is well known that warfarin inhibits the synthesis of vitamin K-dependent anticoagulants, including thrombin, protein C and S, and factor Xa, leading, paradoxically, to an initial hypercoagulable state. Edoxaban, a direct inhibitor of activated factor X is widely used for the treatment of acute venous thromboembolism (VTE). However, the effect of edoxaban on circulating coagulation factors, in patients with acute VTE, remains unknown.. We enrolled 57 patients with acute VTE with/without pulmonary embolism treated with edoxaban (n=37) or warfarin (n=20) in a clinical setting. Before treatment and 2 weeks after treatment, we evaluated thrombotic burden using ultrasound or computed tomography angiography. We also evaluated thrombin generation, represented by prothrombin fragment F1+2; thrombus degradation, represented by D-dimer; and levels of anticoagulants, including protein C, protein S, and antithrombin III. Both edoxaban and warfarin treatment improved thrombotic burden and decreased prothrombin fragment F1+2, and D-dimer. Edoxaban treatment preserved protein C and protein S levels. In contrast, warfarin decreased protein C and protein S levels. Neither treatment affected antithrombin III.. Edoxaban improves VTE while preserving protein C and protein S levels, thereby indicating that edoxaban improves thrombotic burden while maintaining levels of anticoagulants.

Topics: Acute Disease; Aged; Anticoagulants; Antithrombin III; Female; Humans; Male; Middle Aged; Protein C; Protein S; Pulmonary Embolism; Pyridines; Thiazoles; Treatment Outcome; Venous Thromboembolism; Warfarin

Edoxaban is an oral, selective direct factor Xa inhibitor approved in Japan for venous thromboembolism prevention after orthopedic surgery. Data are lacking regarding reversal strategies for edoxaban; this study assessed whether four-factor prothrombin complex concentrate (Beriplex/Kcentra; CSL Behring GmbH, Marburg, Germany) can effectively reverse its effects on hemostasis using a previously described rabbit model.. The study comprised assessments of thrombin generation in vitro, pharmacokinetic parameters, and edoxaban reversal in vivo. In a blinded in vivo stage, a standardized kidney incision was performed in animals (n = 11 per group) randomized to receive vehicle + saline, edoxaban (1,200 μg/kg) + saline, or edoxaban (1,200 μg/kg) + four-factor prothrombin complex concentrate (50 IU/kg). Animals were monitored for treatment impact on hemostasis and coagulation parameters. Data are median (range). Statistical tests were adjusted for multiple testing.. Edoxaban administration increased blood loss (30 [2 to 44] ml) and time to hemostasis (23 [8.5 to 30.0] min) compared with the control group (3 [1 to 8] ml and 3 [2.0 to 5.0] min, respectively). Biomarkers of coagulation (prothrombin time, activated partial thromboplastin time, whole blood clotting time) and thrombin generation parameters (e.g., peak thrombin, endogenous thrombin potential, lag time) were also affected by edoxaban. Administration of four-factor prothrombin complex concentrate significantly reduced time to hemostasis (to 8 [6.5 to 14.0] min, observed P < 0.0001) and total blood loss (to 9 [4 to 22] ml, observed P = 0.0050) compared with the edoxaban + saline group. Of the biomarkers tested, prothrombin time, whole blood clotting time, and endogenous thrombin potential correlated best with clinical parameters.. In a rabbit model of hemostasis, four-factor prothrombin complex concentrate administration significantly decreased edoxaban-associated hemorrhage.

Topics: Acute Disease; Animals; Blood Coagulation Factors; Blood Coagulation Tests; Chinchilla; Endpoint Determination; Female; Hemorrhage; Hemorrhagic Disorders; Hemostatics; In Vitro Techniques; Pyridines; Rabbits; Thiazoles; Thrombin

Topics: Acute Disease; Anticoagulants; Benzimidazoles; Dabigatran; Drug Approval; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism