[Non-VKA oral anticoagulants: an update for the clinical biologists].

Non-VKA oral anticoagulants (NOACs), thanks to their ease of use and their similar or superior safety/efficacy profiles versus warfarin, have now widely reached the lucrative market of anticoagulation. However, while the marketing authorization holders always claim, in a quite unclear way that no monitoring is required, accumulative evidence and cases of major bleeding have been described in the literature and reported by spontaneous reporting systems at the regulator's level. These compounds are usually given at fixed doses without routine coagulation monitoring.

Pharmacology and laboratory testing of the oral Xa inhibitors.

New oral factor Xa inhibitors are intended to progressively substitute the oral vitamin K antagonists and parenteral indirect inhibitors of factor Xa in the prevention and treatment of venous and arterial thromboembolic episodes. This article focuses on the main clinical studies and on biological measurements of new oral factor Xa inhibitors, and addresses several safety issues. These newer agents do not require any routine laboratory monitoring of blood coagulation; however, biological tests have been developed in order to assess the plasma concentration of these drugs in several clinical settings.

Impact of age on the efficacy and safety of extended-duration thromboprophylaxis in medical patients. Subgroup analysis from the EXCLAIM randomised trial.

The EXCLAIM study enrolled hospitalised acutely ill medical patients with age >40 years and recently-reduced mobility into a trial of extended-duration anticoagulant thromboprophylaxis. This post-hocanalysis evaluated the impact of age on patient outcomes. After completion of open-label therapy with enoxaparin 40 mg once-daily (10 ± 4 days), eligible patients underwent randomisation to receive double-blind therapy of enoxaparin (n=2,975) or placebo (n=2,988) for 28 ± 4 days.

Laboratory assessment of rivaroxaban: a review.

Research into new anticoagulants for preventing and treating thromboembolic disorders has focused on targeting single enzymes in the coagulation cascade, particularly Factor Xa and thrombin, inhibition of which greatly decreases thrombin generation. Based on the results of phase III clinical trials, rivaroxaban, a direct Factor Xa inhibitor, has been approved in many countries for the management of several thromboembolic disorders. Owing to its predictable pharmacokinetic and pharmacodynamic characteristics, fixed-dose regimens are used without the need for routine coagulation monitoring.

Laboratory testing of rivaroxaban in routine clinical practice: when, how, and which assays.

A number of target-specific oral anticoagulants (TSOAs) have been developed in recent years, and some have shown considerable promise in large-scale, randomized clinical trials in the prevention and treatment of thromboembolism. Unlike traditional anticoagulants, such as vitamin K antagonists, these TSOAs exhibit predictable pharmacokinetics and pharmacodynamics. Among these agents, rivaroxaban, a direct Factor Xa inhibitor, has been approved for clinical use in many countries for the management of several thromboembolic disorders.

Monitoring plasma levels of factor Xa inhibitors: how, why and when?

New oral anticoagulants are directed towards a single target, essentially factor Xa (FXa) or factor IIa. They do not require routine coagulation monitoring. However, in special clinical settings (emergency surgery, bleeding, thrombosis, control of the patient's compliance, suspected overdose, potential drug interference, and so on), measurement of plasma levels is needed.

Measurement of dabigatran and rivaroxaban in primary prevention of venous thromboembolism in 106 patients, who have undergone major orthopedic surgery: an observational study.

No routine coagulation laboratory test is recommended during rivaroxaban or dabigatran treatment. However measuring drug concentration and/or anticoagulant activity can be desirable in some special clinical settings, such as bleeding, thrombosis recurrence or emergency surgery. The effects of dabigatran etexilate and rivaroxaban on various coagulation assays have been previously studied in normal plasma spiked with increasing concentrations of the drug.

Venous thromboembolism risk in ischemic stroke patients receiving extended-duration enoxaparin prophylaxis: results from the EXCLAIM study.

Background And Purpose: The optimal duration of venous thromboembolism prophylaxis in acute stroke patients is unknown. This subanalysis of the Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization (EXCLAIM) study investigated extended-duration thromboprophylaxis with enoxaparin, compared with placebo following standard-duration enoxaparin, in ischemic stroke patients.

Methods: Acutely ill medical patients with recently reduced mobility received open-label enoxaparin 40 mg for 10±4 days, and they were then randomized to double-blind enoxaparin 40 mg daily or placebo for further 28±4 days.

Do new oral anticoagulants require laboratory monitoring? The clinician point of view.

Although no laboratory monitoring is needed for new anticoagulants, the measurement of their activity is required in special clinical situations. Standardised tests have been developed for rivaroxaban and dabigatran which allow the measurement of the patient's response to the drug at Cmax (2 to 3 hours after intake) or at trough (before repeated administration). The results can be expressed in mg per ml of plasma and compared to the expected concentrations.

Massive transfusion: an overview of the main characteristics and potential risks associated with substances used for correction of a coagulopathy.

Massive transfusion (MT) is an empiric mode of treatment advocated for uncontrolled bleeding and massive haemorrhage, aiming at optimal resuscitation and aggressive correction of coagulopathy. Conventional guidelines recommend early administration of crystalloids and colloids in conjunction with red cells, where the red cell also plays a critical haemostatic function. Plasma and platelets are only used in patients with microvascular bleeding with PT/APTT values >1.

Evaluation of the prothrombin time for measuring rivaroxaban plasma concentrations using calibrators and controls: results of a multicenter field trial.

This study evaluated the prothrombin time (PT) assay for the measurement of plasma concentrations of rivaroxaban using calibrators and controls. The intra- and interlaboratory precision of the measurement was investigated in a field trial involving 21 laboratories. Each laboratory was provided with rivaroxaban calibrators and control plasma samples containing different concentrations of rivaroxaban, and PT reagents.

Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes.

New antithrombotic drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

This article focuses on new antithrombotic drugs that are in or are entering phase 3 clinical testing. Development of these new agents was prompted by the limitations of existing antiplatelet, anticoagulant, or fibrinolytic drugs. Addressing these unmet needs, this article (1) outlines the rationale for development of new antithrombotic agents; (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs; and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents.

Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls.

Rivaroxaban is an oral, direct factor Xa inhibitor. Routine coagulation monitoring is not required, but a quantitative determination of rivaroxaban concentrations might be useful in some clinical circumstances. This multicentre study assessed the suitability of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations (ng/ml) using rivaroxaban calibrators and controls, and the inter-laboratory precision of the measurement.

In vitro study of the anticoagulant effects of edoxaban and its effect on thrombin generation in comparison to fondaparinux.

Introduction: Edoxaban, an oral direct factor Xa (FXa) inhibitor, is in Phase III development for prevention and treatment of thromboembolic disorders. Fondaparinux is an approved indirect FXa inhibitor. This study compared the effects of edoxaban and fondaparinux on thrombin generation (TG) using the calibrated automated thrombogram (CAT).

Use of low-molecular-weight heparins and new anticoagulants in elderly patients with renal impairment.

Elderly people with renal impairment are at high risk for venous thromboembolism (VTE) and acute coronary syndromes (ACS); however, they are also at increased risk for bleeding complications. Evidence-based data for the management of anticoagulation in elderly patients with severe renal impairment, in particular, are limited. These patients are frequently excluded from randomized clinical trials evaluating anticoagulants, confounding clinical decision making.

The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--compared with other anticoagulants.

Although results of some phase III clinical trials of new oral anticoagulants are now known, it is important to understand the mechanisms of their actions. These new agents exert their anticoagulant effect via direct inhibition of a single Factor within the coagulation cascade (such as Factor Xa or thrombin). Rivaroxaban--the first oral, direct Factor Xa inhibitor--is a small-molecule oxazolidinone derivative that binds directly and reversibly to Factor Xa via the S1 and S4 pockets.

Assays for measuring rivaroxaban: their suitability and limitations.

Several new oral anticoagulants such as rivaroxaban (which targets Factor Xa) and dabigatran etexilate (which targets thrombin) are in advanced stages of clinical development and are already available for clinical use in some countries. Although these agents do not require routine coagulation monitoring, assays to assess the level of anticoagulation may be of assistance in certain circumstances such as in case of overdose, in patients with a hemorrhagic or thromboembolic event during treatment, or to assess compliance. Moreover, the influence of the new oral anticoagulants on routine coagulation tests must be recognized.

Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial.

Background: Extended-duration low-molecular-weight heparin has been shown to prevent venous thromboembolism (VTE) in high-risk surgical patients.

Objective: To evaluate the efficacy and safety of extended-duration enoxaparin thromboprophylaxis in acutely ill medical patients.

Design: Randomized, parallel, placebo-controlled trial.

The significance of endothelial heterogeneity in thrombosis and hemostasis.

The endothelium is recognized today as a functional and dynamic component of the body that plays an important part in health and disease. This article briefly reviews the role of endothelium in thrombosis and hemostasis. There is a paradigm shift from one that regards the endothelium as one single entity to the concept that the endothelium is heterogeneous.

Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor.

Although there is no need for routine coagulation monitoring with rivaroxaban--an oral, direct factor Xa inhibitor--a haemostasis assay might be valuable to measure its pharmacodynamic effects. This study aimed to find assays, among those commercially available, to measure rivaroxaban pharmacodynamics. Several global conventional clotting tests, as well as clotting or chromogenic assays to measure anti-factor Xa activity, were studied.