Direct Factor Xa Inhibitor Edoxaban Research Articles

Factor Xa Inhibition Reduces Coagulation Activity but Not Inflammation Among People With HIV: A Randomized Clinical Trial.

BackgroundCoagulation activity among persons with HIV is associated with end-organ disease risk, but the pathogenesis is not well characterized. We tested a hypothesis that hypercoagulation contributes to disease risk, in part, via upregulation of inflammation.MethodsTreatment effects of edoxaban (30 mg), a direct factor Xa inhibitor, vs placebo were investigated in a randomized, double-blind crossover trial among participants with HIV and viral suppression and D-dimer levels ≥100 ng/mL. During each 4-month crossover period, blood measures of coagulation, inflammation, and immune activation were assessed. Analyses of change on edoxaban vs change on placebo used linear mixed models.ResultsForty-four participants were randomized, and 40 completed at least 1 visit during each study period. The mean age was 49 years, and the CD4+ count was 739 cells/mm3. Edoxaban treatment led to declines in D-dimer (44%) and thrombin-antithrombin complex (26%) but did not lower inflammatory or immune activation measures. More bruising or bleeding events occurred during edoxaban (n = 28) than during placebo or no drug periods (n = 15).ConclusionsThe direct factor Xa inhibitor edoxaban led to a substantial reduction in coagulation but no effect on inflammation or immune activation. These results do not support that hypercoagulation contributes to ongoing inflammation during chronic antiretroviral therapy–treated HIV disease.

Factor X Inhibition Reduces Coagulation Activity But Not Inflammation Among Persons Living with HIV: A Randomized Clinical Trial

Background: Activation of coagulation among persons with HIV is associated with a broad spectrum of end-organ disease risk, but the underlying pathogenesis is not well characterized. Activated clotting factors, such as factor X, can stimulate leukocytes and amplify immune activation. We tested a hypothesis that hypercoagulation contributes to disease risk, in part, via upregulation of inflammatory pathways, in addition to direct effects from thrombosis. Methods: Treatment effects of oral edoxaban (30mg), a direct factor Xa inhibitor, versus placebo were investigated in a randomized, double-blind, cross-over clinical trial, among participants with HIV receiving ART with plasma HIV RNA <200 copies/mL and D-dimer levels ≥100 ng/mL Blood measures of coagulation, inflammation and immune activation were assessed during each 4-month cross-over treatment period. Soluble biomarkers were measured using ELISA, electrochemiluminescence, and immunoturbidmetric methods. Immunophenotyping was performed among a subset of participants. Analyses report the change on edoxaban versus change on placebo, calculated with linear mixed models. Results: Forty-four participants were randomized among 83 screened; 40 completed at least one on-treatment visit during each study period. Mean age was 49 years and CD4+ count was 739 cells/mm3; 34% with prior AIDS, and 70% were receiving an integrase strand transfer inhibitor. Edoxaban treatment led to declines in D-dimer (44%) and thrombin-antithrombin complex (26%). There was no evidence of a treatment effect on the inflammatory or immune activation measures evaluated. More non-laceration bruising or bleeding events occurred during edoxaban (n=28) than during placebo or no drug periods (n=15). Conclusions: Among persons with HIV receiving ART with viral suppression, the oral direct factor Xa inhibitor edoxaban led to a substantial reduction in coagulation but no effect on inflammation or immune activation. These results support the position that hypercoagulation may be a consequence of, but is not a significant contributor to, systemic inflammation during chronic HIV disease. Trial Registration: NCT02339415 (ClinicalTrials.gov). Funding Statement: This study was funded by the National Heart Lung and Blood Institute (NHLBI/NIH: R01 HL126542). Study drug was provided by Daiichi-Sankyo Pharmaceuticals. The work of IS and HM was supported by the intramural research program of NIAID/NIH. Declaration of Interests: The authors state that they have no conflicts of interest to disclose. Ethics Approval Statement: The trial protocol was approved by the clinical site institutional review board for conduct of human subjects research. All study participants underwent a verbal and written informed consent process prior to enrollment.

Prevention of Stent Thrombosis in Rats by a Direct Oral Factor Xa Inhibitor Edoxaban

Background/Aims: Stent thrombosis is a serious complication after percutaneous coronary intervention and femoropopliteal endovascular intervention. The aim of this study was to determine the antithrombotic effects of a direct factor Xa inhibitor edoxaban alone or in combination with antiplatelet agents in a rat model of stent thrombosis. Methods: Stainless steel stents (4 stents per rat) were placed in an extracorporeal arteriovenous shunt. The shunt was inserted into the carotid artery and the jugular vein in each rat to circulate blood. Stent thrombosis was induced by exposing the stents to arterial blood for 30 min. Protein content of the thrombus was measured. Edoxaban and antiplatelet agents (aspirin, clopidogrel, and ticagrelor) were orally administered before the thrombus induction. Results: Edoxaban (0.3–3 mg/kg), clopidogrel (1–10 mg/kg), aspirin (10–100 mg/kg), and ticagrelor (0.3–3 mg/kg) exerted significant and dose-dependent antithrombotic effects in a rat stent thrombosis model. The effect of edoxaban was comparable to that of antiplatelet agents. The combination of submaximal doses of edoxaban and clopidogrel or aspirin significantly potentiated the antithrombotic effects compared with antiplatelet agents alone. Conclusion: These results suggest that edoxaban alone and in combination with clopidogrel or aspirin are promising antithrombotic therapies for the prevention of stent thrombosis.

Effects of the oral, direct factor Xa inhibitor edoxaban on routine coagulation assays, lupus anticoagulant and anti-Xa assays

Edoxaban is an oral direct factor Xa inhibitor for prophylaxis and treatment of thromboembolic disorders. The effects on common coagulation assays are clinically valuable information and in certain clinical situations a quick assessment of the anticoagulant is wanted. Our aim was to investigate the effect of edoxaban on routine coagulation methods and evaluate anti-Xa assays, commonly used for other direct factor Xa inhibitors, for estimation of the drug concentration. Edoxaban was spiked to plasma samples from healthy subjects in the concentration range 0–742 µg/L and analyzed using different reagents for activated partial thromboplastin time (APTT) and prothrombin time (PT). Assays for antithrombin, activated protein C resistance, lupus anticoagulant (LA) and chromogenic anti-Xa assays were also included. Edoxaban displayed similar effects in vitro to other oral direct Xa inhibitors. The concentration needed to double the coagulation time varied between assays and reagents; 539–758 µg/L for the APTT and between 329 and 2505 µg/L for the PT. Edoxaban gave false high antithrombin activities in assays based on Xa-inhibition. Two integrated assays for LA, both based on activation with dilute Russell’s viper venom, displayed different results. Chromogenic anti-Xa assays displayed linear dose-response curves with edoxaban up to approximately 500 µg/L. In conclusion, therapeutic concentrations of edoxaban variably affect different coagulation assays, and even different reagents within an assay group. In comparison with other oral Xa-inhibitors, the in vitro effects of edoxaban were more similar to rivaroxaban than apixaban. For measurement of edoxaban concentration in plasma, it is possible to use the chromogenic anti-Xa assays.

Edoxaban Versus standard of care and their effects on clinical outcomes in patients having undergone Transcatheter Aortic Valve Implantation in Atrial Fibrillation—Rationale and design of the ENVISAGE-TAVI AF trial

Transcatheter aortic valve implantation, also called transcatheter aortic valve replacement (TAVR), is the treatment of choice for patients with severe aortic stenosis and intermediate to high operative risk. A significant portion of TAVR patients have atrial fibrillation (AF) requiring chronic oral anticoagulation. In moderate- to high-risk AF patients, the direct factor Xa inhibitor edoxaban is noninferior to vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism with less bleeding and cardiovascular deaths. ENVISAGE-TAVI AF (NCT02943785) is a multinational, multicenter, prospective, randomized, open-label, blinded end point evaluation study comparing edoxaban to VKA-based therapy in approximately 1,400 patients with an indication for chronic oral anticoagulation after successful transfemoral TAVR. The coprimary end points are to assess the differential effects of the 2 treatments (a) on net adverse clinical events (the composite of all-cause death, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, and major bleeding events) and (b) on major bleeding. Twelve hours to 5 days after successful TAVR, patients will be randomized to 60 mg daily oral edoxaban or any VKA (international normalized ratio: 2.0-3.0 or 1.6-2.6 [numbers inclusive] in Japan if age ≥ 70 years). Antiplatelet therapy may be administered per physician's discretion. Randomization will be stratified by edoxaban dose reduction (per local label). Treatment duration will be up to 36 months. The study is powered (80%) to detect noninferiority (margin for the hazard ratio: 1.38) for the composite primary end points, followed by superiority testing.

Tranexamic Acid Failed to Reverse the Anticoagulant Effect and Bleeding by an Oral Direct Factor Xa Inhibitor Edoxaban

Background/Aims: Agents to reverse the anticoagulant effect of edoxaban, an oral direct factor Xa inhibitor, would be desirable in emergency situations. The aim of this study is to determine the effect of tranexamic acid, an antifibrinolytic agent, on the anticoagulant activity and bleeding by edoxaban in rats. Methods: A supratherapeutic dose of edoxaban (3 mg/kg) was intravenously administered to rats. Three minutes after dosing, tranexamic acid (100 mg/kg) was given intravenously. Bleeding was induced by making an incision with a blade on the planta 8 min after edoxaban injection and bleeding time was measured. Prothrombin time (PT) and clot lysis were examined. Results: A supratherapeutic dose of edoxaban significantly prolonged PT and bleeding time. Tranexamic acid did not affect PT or bleeding time prolonged by edoxaban, although tranexamic acid significantly inhibited clot lysis in rat plasma. Conclusion: An antifibrinolytic agent tranexamic acid failed to reverse the anticoagulant effect and bleeding by edoxaban in rats.

A direct thrombin inhibitor suppresses protein C activation and factor Va degradation in human plasma: Possible mechanisms of paradoxical enhancement of thrombin generation

We have demonstrated that antithrombin (AT)-independent thrombin inhibitors paradoxically increase thrombin generation (TG) in human plasma in a thrombomodulin (TM)- and protein C (PC)-dependent manner. We determined the effects of AT-independent thrombin inhibitors on the negative-feedback system, activation of PC and production and degradation of factor Va (FVa), as possible mechanisms underlying the paradoxical enhancement of TG. TG in human plasma containing 10nM TM was assayed by means of the calibrated automated thrombography. As an index of PC activation, plasma concentration of activated PC-PC inhibitor complex (aPC-PCI) was measured. The amounts of FVa heavy chain and its degradation product (FVa307–506) were examined by western blotting. AT-independent thrombin inhibitors, melagatran and dabigatran (both at 25–600nM) and 3–30μg/ml active site-blocked thrombin (IIai), increased peak levels of TG. Melagatran, dabigatran and IIai significantly decreased plasma concentration of aPC-PCI complex at 25nM or more, 75nM or more, and 10 and 30μg/ml, respectively. Melagatran (300nM) significantly increased FVa and decreased FVa307–506. In contrast, a direct factor Xa inhibitor edoxaban preferentially inhibited thrombin generation (≥25nM), and higher concentrations were required to inhibit PC activation (≥150nM) and FVa degradation (300nM). The present study suggests that the inhibitions of protein C activation and subsequent degradation of FVa and increase in FVa by antithrombin-independent thrombin inhibitors may contribute to the paradoxical TG enhancement, and edoxaban may inhibit PC activation and FVa degradation as a result of TG suppression.

Direct factor Xa inhibitor edoxaban: from bench to clinical practice

Edoxaban is a direct factor Xa inhibitor and has become the fourth direct oral anticoagulant (DOAC) approved for stroke prevention in atrial fibrillation (AF) and for treatment and secondary prevention of venous thromboembolism (VTE). This review provides an overview of the key characteristics of edoxaban and clinical evaluation program leading to regulatory approval. Approval for AF and VTE treatment was based on large phase III randomized controlled trials that showed that edoxaban reduces the risk of bleeding compared with warfarin and provides similar protection against thromboembolism. Edoxaban is the second once-daily DOAC, is tested in a reduced dose for patients with a moderate renal impairment, body weight of ≤60 kg or concomitant use of p-glycoprotein inhibitors and thereby is a valuable addition to the therapeutic arsenal of modern anticoagulation. For AF regulatory approval in the USA is limited to patients with a creatinine clearance of 15–95 ml/min. Another limitation is the need for initial parenteral anticoagulation with heparin in treatment of acute VTE.

Treatment of venous thrombosis with an oral direct factor Xa inhibitor edoxaban by single and multiple administrations in rats

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.

Pharmacokinetics of the Direct Factor Xa Inhibitor Edoxaban and Digoxin Administered Alone and in Combination

The oral anticoagulant edoxaban, a factor Xa inhibitor, will likely be coadministered with digoxin in some patients with atrial fibrillation. Both drugs are substrates for P-glycoprotein. The objective of this phase 1, parallel study was to assess the effects of coadministration of both drugs on their respective pharmacokinetics (PK) and pharmacodynamics (PD). Forty-eight subjects, aged 18 to 45 years, received either edoxaban 60 mg once daily × 7 days (n = 24) or digoxin 0.25 mg twice daily × 2 days and once daily × 5 days (n = 24) and then concomitantly for 7 days. Serial blood and urine samples were collected for digoxin and edoxaban concentrations on days 7 and 14. Serial coagulation assays were measured for edoxaban on days 7 and 14. Edoxaban PK parameters demonstrated mild increases in area under the curve and peak concentrations of 9.5% and 15.6%, respectively, when coadministered with digoxin. Although digoxin PK parameters demonstrated increased area under the curve and peak concentrations of 8.3% and 28%, respectively, plasma concentrations were within the established therapeutic range. Edoxaban PD were consistent with PK. Both drugs were well tolerated alone or in combination. No clinically significant changes in PK, PD, or renal elimination were observed with concomitant administration of edoxaban and digoxin.

Pharmacokinetics of the Direct Factor Xa Inhibitor Edoxaban and Digoxin Administered Alone and in Combination

The oral anticoagulant edoxaban, a factor Xa inhibitor, will likely be coadministered with digoxin in some patients with atrial fibrillation. Both drugs are substrates for P-glycoprotein. The objective of this phase 1, parallel study was to assess the effects of coadministration of both drugs on their respective pharmacokinetics (PK) and pharmacodynamics (PD). Forty-eight subjects, aged 18 to 45 years, received either edoxaban 60 mg once daily × 7 days (n = 24) or digoxin 0.25 mg twice daily × 2 days and once daily × 5 days (n = 24) and then concomitantly for 7 days. Serial blood and urine samples were collected for digoxin and edoxaban concentrations on days 7 and 14. Serial coagulation assays were measured for edoxaban on days 7 and 14. Edoxaban PK parameters demonstrated mild increases in area under the curve and peak concentrations of 9.5% and 15.6%, respectively, when coadministered with digoxin. Although digoxin PK parameters demonstrated increased area under the curve and peak concentrations of 8.3% and 28%, respectively, plasma concentrations were within the established therapeutic range. Edoxaban PD were consistent with PK. Both drugs were well tolerated alone or in combination. No clinically significant changes in PK, PD, or renal elimination were observed with concomitant administration of edoxaban and digoxin.

Clinical Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Factor Xa Inhibitor Edoxaban in Healthy Volunteers

This is a clinical safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) study of a single ascending dose (SAD) and a multiple ascending dose (MAD) of the oral direct factor Xa inhibitor edoxaban in healthy males. The placebo-controlled, single-blind, randomized, 2-part study consists of a SAD arm with 85 subjects (10, 30, 60, 90, 120, 150 mg) and a MAD arm with 36 subjects (90 mg daily, 60 mg twice daily, 120 mg daily). Effects of food and formulation (tablet vs solution) are assessed in a crossover substudy. In the SAD, doses are well tolerated up to 150 mg. Exposure is proportional to dose. PK profiles are consistent across dose with rapid absorption, biphasic elimination, and terminal elimination half-life of 5.8 to 10.7 hours. In the MAD, mean accumulation after daily dosing is 1.10 to 1.13 and consistent with elimination half-life of 8.75 to 10.4 hours. Intrasubject variability ranges from 12% to 17% for area under the curve. In general, plasma edoxaban concentrations are linearly correlated with coagulation parameters. Edoxaban is safe and well tolerated with no dose-dependent increases in adverse events. It is concluded that single and multiple doses of edoxaban are safe and well tolerated up to 150 mg with predictable PK and PD profiles.