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.
| S-EPMC5749368 | biostudies-literature
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:To aid trialists, systematic reviewers and others, we evaluated the degree of standardisation of control measure reporting that has occurred in atrial fibrillation (AF) and venous thromboembolism (VTE) studies since 2000; and attempted to determine whether the prior recommendation of reporting ?2 measures per study has been employed.Systematic review.We searched bibliographic databases (2000 to June 2013) to identify AF and VTE studies evaluating dose-adjusted vitamin K antagonists (VKAs) and reporting ?1 control measure. The types of measures reported, proportion of studies reporting ?2 measures and mean (±SD) number of measures per study were determined for all studies and compared between subgroups.Through the use of a standardised data extraction tool, we independently extracted all data, with disagreements resolved by a separate investigator.148 studies were included, 57% of which reported ?2 control measures (mean/study=2.13±1.36). The proportion of time spent in the target international normalised ratio range (TTR) was most commonly reported (79%), and was frequently accompanied by time above/below range (52%). AF studies more frequently reported ?2 control measures compared with VTE studies (63% vs 37%; p=0.004), and reported a greater number of measures per study (mean=2.36 vs 1.53; p<0.001). Observational studies were more likely to provide ?2 measures compared with randomised trials (76% vs 33%; p<0.001) and report a greater number of measures (mean=2.58 vs 1.63; p<0.001). More recent studies (2004-2013) reported ?2 measures more often than older (2000-2003) studies (59% vs 35%; p=0.05) and reported more measures per study (mean=2.23 vs 1.48; p=0.02).While TTR was often utilised, studies reported ?2 measures of VKA control only about half of the time and lacked consistency in the types of measures reported. A trend towards studies reporting greater numbers of VKA control measures over time was observed over our review time horizon, particularly, with AF and observational studies.
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| S-EPMC6449182 | biostudies-literature
Project description:Direct oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ?5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: ?0.61, 95% confidence interval [CI]: ?2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: ?0.59, 95% CI: ?3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin.
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Project description:African Americans (AAs) and obese individuals have increased thrombotic risk. This study evaluated the effectiveness and safety of rivaroxaban versus warfarin in obese, AAs with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Optum® De-Identified Electronic Health Record (EHR) data was used to perform separate propensity-score matched analyses of adult, oral anticoagulant (OAC)-naïve AAs with NVAF or acute VTE, respectively; who had a body mass index≥30kg/m2 and ≥12-months EHR activity with ≥1-encounter before OAC initiation. Cox regression was performed and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). For the NVAF analysis, 1,969 rivaroxaban- and 1,969 warfarin-users were matched. Rivaroxaban was not associated with a difference in stroke/systemic embolism versus warfarin (HR = 0.88, 95%CI = 0.60-1.28), but less major bleeding (HR = 0.68, 95%CI = 0.50-0.94) was observed. Among 683 rivaroxaban-users with VTE, 1:1 matched to warfarin-users, rivaroxaban did not alter recurrent VTE (HR = 1.36, 95%CI = 0.79-2.34) or major bleeding (HR = 0.80, 95%CI = 0.37-1.71) risk versus warfarin at 6-months (similar findings observed at 3- and 12-months). Rivaroxaban appeared to be associated with similar thrombotic, and similar or lower major bleeding risk versus warfarin in these obese, AA cohorts.
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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. SUMMARY:Background 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:Edoxaban is approved for stroke prevention in nonvalvular atrial fibrillation (AF) patients in numerous countries. Outcome data are sparse on edoxaban treatment in AF patients from routine clinical practice, especially in Asian patients. Global ETNA (Edoxaban in rouTine cliNical prActice) is a noninterventional study that integrates data from patients from multiple regional registries into one database. Here, we report the 1-year clinical events from AF patients receiving edoxaban in South Korea and Taiwan. Clinical events assessed included bleeding, strokes, systemic embolic events, transient ischemic attacks (TIAs), and all-cause and cardiovascular death. Overall, 2677 patients (mean (range) age 72 (66-78) years, male 59.7%, mean CHA2DS2-VASc score ± standard deviation 3.1 ± 1.4) were treated with 60 or 30 mg edoxaban and had 1-year follow-up data. The annualized event rates for major bleeding and clinically relevant non-major (CRNM) bleeding were 0.78% and 0.47%, respectively. Annualized event rates for ischemic stroke and hemorrhagic stroke were 0.90% and 0.19%, respectively. Event rates for major and CRNM bleeding and rates of ischemic stroke and TIA were higher in Taiwanese patients than in Korean patients. Event rates were low and similar to those found in other studies of edoxaban in Korean and Taiwanese AF patients, thus supporting the safety and effectiveness of edoxaban in this population.
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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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