Edoxaban: A Comprehensive Review of the Pharmacology and Clinical Data for the Management of Atrial Fibrillation and Venous Thromboembolism.
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SUBMITTER: Stacy ZA
PROVIDER: S-EPMC4906085 | biostudies-other | 2016 Jun
REPOSITORIES: biostudies-other
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Edoxaban: A Comprehensive Review of the Pharmacology and Clinical Data for the Management of Atrial Fibrillation and Venous Thromboembolism.
Stacy Zachary A ZA Call William B WB Hartmann Aaron P AP Peters Golden L GL Richter Sara K SK
Cardiology and therapy 20160302 1
Historically, vitamin K antagonists have been the only class of oral anticoagulants available. Despite our experience with warfarin over the past 60 years, its use is associated with several pharmacokinetic and clinical disadvantages including unpredictable dosing, frequent monitoring, and delayed onset and offset. Edoxaban, an oral direct Xa inhibitor, may provide clinicians with an additional option in patients requiring chronic anticoagulation. This review examines the pharmacology and clinic ...[more]
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Project description:The aim of this study was to investigate whether genetic variants can identify patients with venous thromboembolism (VTE) at an increased risk of bleeding with warfarin.Hokusai-venous thromboembolism (Hokusai VTE), a randomised, multinational, double-blind, non-inferiority trial, evaluated the safety and efficacy of edoxaban versus warfarin in patients with VTE initially treated with heparin. In this subanalysis of Hokusai VTE, patients genotyped for variants in CYP2C9 and VKORC1 genes were divided into three warfarin sensitivity types (normal, sensitive and highly sensitive) based on their genotypes. An exploratory analysis was also conducted comparing normal responders to pooled sensitive responders (ie, sensitive and highly sensitive responders).The analysis included 47.7% (3956/8292) of the patients in Hokusai VTE. Among 1978 patients randomised to warfarin, 63.0% (1247) were normal responders, 34.1% (675) were sensitive responders and 2.8% (56) were highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders had heparin therapy discontinued earlier (p<0.001), had a decreased final weekly warfarin dose (p<0.001), spent more time overanticoagulated (p<0.001) and had an increased bleeding risk with warfarin (sensitive responders HR 1.38 [95% CI 1.11 to 1.71], p=0.0035; highly sensitive responders 1.79 [1.09 to 2.99]; p=0.0252).In this study, CYP2C9 and VKORC1 genotypes identified patients with VTE at increased bleeding risk with warfarin.NCT00986154.
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Project description:Edoxaban, a direct factor Xa inhibitor, was extensively studied in the prevention and treatment of venous thromboembolism and in patients with nonvalvular atrial fibrillation (AF). The aim of this review is to focus specifically on the efficacy and safety profile of edoxaban in patients with AF from preclinical development through the phase III trial that led to regulatory approval.
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Project description:Essentials Atrial fibrillation (AF) may increase risk of venous thromboembolism (VTE), and vice versa. Bidirectionality was assessed prospectively via data from 15 129 black and white individuals. AF was associated with greater risk of developing VTE, and VTE with greater risk of AF. Associations were strongest among blacks and in the first 6 months after initial diagnosis.SummaryBackground Atrial fibrillation (AF) and venous thromboembolism (VTE) frequently co-occur. These conditions have shared risk factors and are accompanied by coagulation abnormalities. Furthermore, mechanistic pathways may directly link the disorders. Objectives To test the hypothesis that individuals with incident AF are at greater risk of developing VTE, and those with VTE are at elevated risk of AF. We also tested whether associations were stronger in the first 6 months after the initial diagnosis, and explored race differences. Patients/Methods A total of 15 129 ARIC study participants (45-64 years, 55% female, 26% Black) were followed from 1987 to 2011 for incident AF and VTE (median follow-up 19.8 years). Multivariable-adjusted Cox regression was used, with AF and VTE modeled as time-dependent exposures. Results Incident AF was associated with greater risk of subsequent incident VTE (hazard ratio [95% CI], 1.71 [1.32-2.22]); the association was stronger in Black people (2.30 [1.48-3.58]) and during the first 6 months after AF diagnosis (5.08 [3.08-8.38]). Similarly, incident VTE was associated with increased risk of incident AF (1.73 [1.34-2.24]), especially in Black people (2.40 [1.55-3.74]) and in the first 6 months after VTE diagnosis (4.50 [2.61-7.77]). Conclusions The occurrence of AF was associated with increased risk of incident VTE, and occurrence of VTE was associated with greater risk of incident AF. Associations were particularly strong among Black people and during the first 6 months after the initial diagnosis, although they remained elevated even after 6 months. These findings highlight patient populations that may be at increased risk of AF and VTE, and perhaps should be targeted with preventive strategies.
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Project description:Background and Purpose: Edoxaban exposure varies across different ethnicities. The purpose of our study was to examine the risk factors associated with high or low edoxaban concentrations in Asian populations. Methods: Participants with atrial fibrillation who were undergoing edoxaban therapy were enrolled. Peak (1-4 h after edoxaban administration) and trough (24 ± 4 h from the last edoxaban dose) blood samples were collected to measure edoxaban concentrations using ultrahigh-performance liquid chromatography with tandem mass spectrometry. The edoxaban concentrations were compared to those observed in clinical trials to define a higher- or lower-than-expected range. Multivariate logistic regression was used to analyze the risk factors associated with high or low edoxaban concentrations. Results: Eighty participants (49 men, 61.3%) were enrolled and provided 78 trough and 76 peak samples. Twenty participants (25.6%) were determined to have low trough concentrations, which was associated with higher creatinine clearance and the use of the 30 mg regimen (odds ratio [OR] and 95% confidence interval [CI], 1.06 [1.01, 1.11], p = 0.01 and 5.77 [1.34, 24.75], p = 0.02, respectively). In contrast, 21 participants (27.6%) had high peak concentrations, which was associated with an off-label overdosing regimen (OR = 4.68 [1.23, 17.70], p = 0.02). Conclusion: Our study identified factors associated with increased or decreased edoxaban exposure. The measurement of edoxaban concentration may be recommended for patients with selected characteristics.
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